Carboxylic acid derivatives and drugs containing the same

专利摘要:
The present invention provides a novel carboxylic acid derivative or a salt thereof or a hydrate thereof and a derivative thereof useful as an insulin resistance improving agent as an active ingredient. That is, general formula [Wherein, R 1 represents a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms which may each have one or more substituents; L represents a single bond or a double bond, or an alkylene group having 1 to 6 carbon atoms which may each have one or more substituents; M is a single bond or an alkylene group having 1 to 6 carbon atoms which may each have one or more substituents; T represents a single bond or an alkylene group having 1 to 3 carbon atoms which may each have one or more substituents; W is a carboxy group, a group represented by -CON (R w1 ) R w2 (wherein R w1 and R w2 are the same or different and represent a hydrogen atom, a formyl group, etc.);
公开号:KR20020087383A
申请号:KR1020027004232
申请日:2000-09-29
公开日:2002-11-22
发明作者:마사노부 시노다；에이타 에모리；후미요시 마쓰우라；도시히코 가네코；노리히토 오이；순지 가사이；히데키 요시토미；가즈토 야마자키；사다카즈 미야시타；다로 히바라；다카시 세이키；리차드 클라크
申请人:에자이 가부시키가이샤；
IPC主号:

专利说明:

Carboxylic acid derivatives and pharmaceuticals consisting of the derivatives thereof {CARBOXYLIC ACID DERIVATIVES AND DRUGS CONTAINING THE SAME}
[2] Diabetes mellitus refers to a persistent hyperglycemic state caused by an absolute or relative deficiency of endogenous insulin (a hypoglycemic hormone produced and secreted by the pancreatic Langerhans islet cells). It is a disease that appears.
[3] Diabetes can be attributed to insulin dependent diabetes mellitus (IDDM), non-insulin dependent diabetes mellitus (NIDDM), and other diabetes. (Secondary diabetes mellitus: when diabetes develops as a symptom of another disease).
[4] In particular, with the modernization of life, NIDDM is rapidly increasing due to overeating and lack of exercise, which is a social problem. While IDDM is mainly expressed in children, NIDDM generally accounts for the majority of diabetes in Japan after middle age. Genetic factors such as overeating, lack of exercise, obesity, stress, such as causing the action of insulin (insulin resistance) is said to appear, symptoms appear.
[5] Since diabetes is associated with excessive calorie intake and obesity due to lack of exercise, the treatment is based on diet, exercise therapy, and drug therapy.
[6] However, due to the aging of the recent increase in the number of cases difficult to diet or exercise therapy.
[7] In the drug therapy of NIDDM, sulfonylurea (SU) drugs such as tolbutamide, chlorpropamide, and tolazamide, and biguanide (BG) drugs such as metformin hydrochloride and buformin are used as oral hypoglycemic drugs. However, the characteristics of NIDDM's conditions are insulin deficiency and insulin resistance, and SU drugs that stimulate insulin secretion from pancreatic β cells are sufficient for insulin secretion, but the insulin resistance of NIDDM is high blood sugar due to poor control in the target organs. It could not be said that it is a valid remedy. In addition, BG drugs have a risk of lactic acidosis expression and are therefore used under certain restrictions. In addition, these drugs often caused severe hypoglycemia as a side effect.
[8] In order to improve these drugs, drug development of new mechanisms of action is in progress, and thiazolidine derivatives such as troglitazone, pioglitazone, and rosiglitazone are called insulin resistance improving agents, and insulin secretion from the pancreas is suppressed. It is possible to improve insulin resistance (enhancing insulin action) without lowering blood glucose, thereby lowering blood sugar, which has recently attracted attention.
[9] It has been known that thiazolidine-based drugs express their actions in relation to the differentiation of adipocytes with the internuclear receptor PPARγ (a transcription factor important for adipocyte differentiation). Bio I. Chem. 270 , p12953-12956, 1995). Prior to the differentiation of adipocytes, immature small adipocytes with little secretion of TNFα, FFA and leptin are increased, resulting in improved insulin resistance.
[10] Thiazolidine derivatives such as troglitazone, pioglitazone, and rosiglitazone also act as agonists (agents) of PPARγ, and express an effect of improving insulin resistance.
[11] By the way, in PPAR, several subtypes, such as (alpha) and (beta), are found besides (gamma), and all regulate the expression of the gene related to lipid metabolism. These subtypes have a higher homology between heterologous species of each subtype than homology within the same species, and γ is also locally present in adipose tissue in relation to tissue distribution, whereas α Since it is mainly in the liver, and also in the heart and kidneys, it has been thought that each subtype has an independent function. Recently, PPARγ promotes the expression of genes such as LPL, acyl1-CoA carboxylase, GPDH, and the like, and mainly mediates lipid assimilation, which converts sugar into lipids. Is known to mediate lipid catabolism, which breaks down lipids by regulating the expression of gene groups involved in the uptake and oxidation of fatty acids into cells.
[12] As a thiazolidine derivative which is a dual agonist of PPARγ and α, a compound disclosed in Japanese Patent Application Laid-Open No. 9-48771 is known.
[13] In addition, several compounds are known as insulin resistance improving agents having a carboxylic acid moiety in its structure (Current Pharmaceutical Design, 2, No. 1, p85-102. 1996; Bioorganic & Medicinal Chemistry Letters, 6, No. 17, p2121-2126, 1996), however, some of the drugs of PPARγ agonists have reported liver disorders, so caution should be used when using them. have.
[14] Moreover, the compound which substituted the thiazolidine part with the carboxylic acid derivative is not commercially available, only following literature introduction. Moreover, there is no report that such a compound can be used as a dual agent of PPARγ and α, and little is known about the triple agonist action of γ, α, and β. However, there is also speculation that the toxicity of the PPARγ agonist as described above is unique to the thiazolidine moiety, and in addition, the discovery of a compound expressing the above action with a new structure can completely avoid the toxicity. There is the possibility that it is very useful.
[15] So far, the drug has not yet been effective as regards triglyceride (TG), which is closely related to atherosclerosis.
[16] In addition, PPARβ has been known to induce adipose cell differentiation (J. Biol. Chem., 274, No. 31, p21920-21925), and it has been reported that cholesterol is lowered by this (W09904815). If a compound having an agonist activity against can be found, it can be expected to further improve the activity of the insulin resistance-improvement drug so far or to reduce side effects such as liver toxicity.
[17] In view of the above, the development of an excellent drug is awaited.
[1] The present invention relates to novel carboxylic acid derivatives useful for the prevention and treatment of hyperglycemia and hyperlipidemia, salts or esters thereof or hydrates thereof, and medicaments comprising them.
[18] MEANS TO SOLVE THE PROBLEM The present inventors earnestly researched for the purpose of providing the medicine which is effective in the prevention and treatment of antihyperglycemia which satisfy | fills these various points, and it turns out that the carboxylic acid derivative which has a novel structure has the outstanding antihyperglycemic and antihyperlipidemic effect. Discovered and completed the present invention.
[19] That is, the present invention is a general formula:
[20]
[21] [In formula, R <^1> may have a hydrogen atom, a hydroxyl group, or one or more substituents, respectively. C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 alkylthio group, C1-C6 hydroxyalkyl group, C1-C6 hydroxyalkoxy group, C1-C6 hydroxy Alkylthio group, C1-C6 aminoalkyl group, C1-C6 aminoalkoxy group, C1-C6 aminoalkylthio group, C1-C6 halogenated alkyl group, C1-C6 halogenated alkoxy group, C1-C6 Halogenated alkylthio group having 6 to 6, alkoxyalkyl group having 2 to 12 carbon atoms, alkoxyalkoxy group having 2 to 12 carbon atoms, alkoxyalkylthio group having 2 to 12 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms Oxy group, a cycloalkylthio group having 3 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkenyloxy group having 2 to 6 carbon atoms, an alkenylthio group having 2 to 6 carbon atoms, and carbon atoms An alkynyl group having 2 to 6 carbon atoms, an alkynyloxy group having 2 to 6 carbon atoms, an alkynylthio group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, and an arylthio group having 6 to 12 carbon atoms , An alkylaryl group of 7 to 18 carbon atoms, an alkylaryloxy group of 7 to 18 carbon atoms, an alkylarylthio group of 7 to 18 carbon atoms, an aralkyl group of 7 to 18 carbon atoms, an aralkyloxy group of 7 to 18 carbon atoms, or 7 to 18 carbon atoms 18 aralkylthio groups; L is a single bond or a double bond or an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; M is a single bond or an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; T is a single bond or an alkylene group having 1 to 3 carbon atoms, an alkenylene group having 2 to 3 carbon atoms or an alkynylene group having 2 to 3 carbon atoms, each of which may have one or more substituents; W is a 2,4-dioxothiazolidine-5-yl group, a 2,4-dioxothiazolidine-5-ylidene group, a carboxyl group, or -CON (R ^w1 ) R ^w2 , where R ^w1 , R ^w2 is A hydrogen atom, a formyl group, or an alkyl group of 1 to 6 carbon atoms, an aliphatic acyl group of 2 to 7 carbon atoms, or an aromatic acyl group of 7 to 19 carbon atoms, each of which may be the same or different, and each may have one or more substitutions). In the above definition, T represents a single bond, and W represents a 2,4-dioxothiazolidin-5-yl group or 2,4-dioxothiazolidine-5-ylidene. Except attributable; Is a single bond or a double bond; X is an oxygen atom, an alkenylene group having 2 to 6 carbon atoms which may have one or more substituents, or a hydroxymethylene group, or a general formula -CQ-, where Q represents an oxygen atom or a sulfur atom, -CQNR ^x- Wherein Q is the same group as defined above, R ^x is a hydrogen atom, a formyl group, or an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or having 7 to 7 carbon atoms, each of which may have one or more substitutions. Each represents an aromatic acyl group of 19), -NR ^x CQ-, wherein Q and R ^x each represent the same group as the above definition, -SO ₂ NR ^x- (where R ^x represents the same group as the above definition),- NR ^x SO ₂ - (R ^x represents the same groups as defined above), or -NR CQNR ^{x1 x2} - (wherein Q is the same groups as defined above, R ^x1 or ^x2 is R, a formyl group the same or different and each a hydrogen atom, Or each has one or more substitutions Group represented by an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or an aromatic acyl group having 7 to 19 carbon atoms, respectively), wherein T is a single bond in the above definition. , Except that X is an oxygen atom; Y may have one or more substituents and may have one or more heteroatoms, an aromatic hydrocarbon group having 5 to 12 carbon atoms, or an alicyclic hydrocarbon group having 3 to 7 carbon atoms; Ring Z further represents an aromatic hydrocarbon group having 5 to 6 carbon atoms which may further have a substituent of 0 to 4 and may have one or more heteroatoms; General formula
[22]
[23] (Wherein the symbol in the formula represents the same group as the above definition) and the general formula:
[24]
[25] Carboxylic acid derivatives, salts or esters thereof, or hydrates thereof represented by (wherein the symbols in the formulas represent the same groups as the above definitions), which are bonded to each other over three atoms on ring Z; And the above-mentioned medicine which is a medicine which consists of these, specifically, the medicine based on the action of the dual agent of PPAR (alpha) and (gamma); The above medicament which is a medicament based on the action of triple agents of PPARα, β and γ; The above medicine which is an insulin resistance improving agent; The above medicine, which is an agent for preventing and treating diabetes; It relates to the above-mentioned medicine which is an agent for preventing and treating X syndrome.
[26] The present invention provides a pharmacologically effective amount of a compound represented by the above general formula (I), a salt thereof, or an ester thereof or a hydrate thereof to a patient, so that the action of a dual agent of PPARα and γ or a triple agent of PPARα, β and γ It provides a method for preventing, treating and improving a disease in which the action is effective. The present invention also provides a method for preventing a disease in which a compound represented by the general formula (I), a salt thereof, or an ester thereof or a hydrate thereof is effective as a double agent of PPARα and γ or a triple agent of PPARα, β and γ. What is used for manufacture of a treatment and improvement agent is provided.
[27] Hereinafter, the content of the present invention will be described in detail.
[28] The contents of the present invention are as described above, but preferably, in the general formula (I), W is a carboxylic acid, a salt thereof, or an ester thereof, or a hydrate thereof; In general formula (I), R <^1> is a carboxylic acid derivative, its salt, or its ester, or its hydrate which is a C1-C6 alkyl group and a C1-C6 alkoxy group which may each have one or more substituents; In formula (I), ring Z is a carboxylic acid derivative, a salt thereof, or an ester thereof, or a hydrate thereof, which is a benzene ring which may also have a substituent of 0 to 4; In formula (I), X represents the formula -CQNR ^x -where Q and R ^x represent the same group as the above definition or -NR ^x CQ- where Q and R ^x represent the same group as the above definition Carboxylic acid derivatives, salts or esters thereof, or hydrates thereof, which are groups represented by the above formula, and carboxylic acid derivatives in the general formula (I) wherein Y is an aromatic hydrocarbon group having 5 to 12 carbon atoms, Salts or esters thereof or hydrates thereof; In general formula (I), L or M is a carboxylic acid derivative whose salt is a C1-C6 alkylene group, its salt or its ester, or its hydrate; In general formula (I), R <^1> is a C1-C6 alkyl group and C1-C6 alkoxy group which may respectively have one or more substituents, and ring Z may also have a substituent of 0-4. Carboxylic acid derivatives, salts or esters thereof, or hydrates thereof, which are benzene rings; In formula (I), X represents the formula -CQNR ^x -where Q and R ^x represent the same group as the above definition or -NR ^x CQ- where Q and R ^x represent the same group as the above definition A carboxylic acid derivative, a salt thereof or an ester thereof, or a hydrate thereof, wherein the group is represented by the above formula and Y is an aromatic hydrocarbon group having 5 to 12 carbon atoms, which may have one or more substituents; More preferably, in general formula (I), R <^1> is a C1-C6 alkyl group and a C1-C6 alkoxy group which may each have one or more substituents, Ring Z is also a substituent of 0-4 Is a benzene ring which may have the formula X wherein X is represented ^{by the} formula -CQNR ^x -where Q and R ^x represent the same group as defined above or -NRxCQ- where Q and P represent the same group as defined above Carboxylic acid derivatives, salts thereof or esters thereof, or hydrates thereof, wherein Y is an aromatic hydrocarbon group having 5 to 12 carbon atoms, which may have one or more substituents.
[29] In the present specification, the structural formula of the compound may show a certain isomer for convenience, but the present invention includes all isomers and mixtures of isomers such as all geometric isomers, optical isomers based on sub-carbons, stereoisomers, tautomers, etc. In addition, it is not limited to what was described in a formula for convenience.
[30] Next, the phrase used in this specification is demonstrated in detail.
[31] When R ¹ , W, R ^x , R ^x1 , and R ^x2 represent an alkyl group having 1 to 6 carbon atoms which may have one or more substituents, the alkyl group represents a linear or branched alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group , sec-pentyl group, t-pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, i- Hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2.3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1 -Ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, etc., Preferably, a methyl group, Tyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pen A methyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, i-hexyl group, More preferably, Methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t -Pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, more preferably methyl group, ethyl group, n-propyl group, i -Propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, Most preferably, they are a methyl group, an ethyl group, n-propyl group, and i-propyl group.
[32] Here, "it may have a substituent" specifically, For example, a hydroxyl group; Thiol group; Nitro group; Morpholino group; Thiomorpholino group; Halogen atoms such as fluorine, chlorine, bromine and iodine atoms; Nitrile group; Azide group; Formyl group; Alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group and butyl group; Alkenyl groups such as vinyl, aryl, and propenyl groups; Alkoxy groups, such as a methoxy group, an ethoxy group, a propoxy group, butoxy group, corresponding to an alkynyl group, such as an ethynyl group, butynyl group, and a propalyl group, and a lower alkyl group; Halogenoalkyl groups such as fluoromethyl group, difluoromethyl group, trifluoromethyl group and fluoroethyl group; Hydroxyalkyl groups such as hydroxymethyl group, hydroxyethyl group and hydroxypropyl group; Guanidino groups; Formimidoyl group; Acetoimidoyl group; Carbamoyl groups; Thiocarbamoyl group; Carbamoylalkyl groups such as carbamoylmethyl group and carbamoylethyl group; Alkyl carbamoyl groups, such as a methyl carbamoyl group and a dimethyl carbamoyl group; Carbamide groups; Alkanoyl groups, such as an acetyl group; Amino group; Alkylamino groups such as methylamino group, ethylamino group and isopropylamino group; Dialkylamino groups such as dimethylamino group, methylethylamino group and diethylamino group; Aminoalkyl groups such as aminomethyl group, aminoethyl group and aminopropyl group; Carboxyl groups; Alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group; Alkoxycarbonylalkyl groups such as methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group and propoxycarbonylethyl group; Alkyloxyalkyl groups such as methyloxymethyl group, methyloxyethyl group, ethyloxymethyl group and ethyloxyethyl group; Alkylthioalkyl groups such as methylthiomethyl group, methylthioethyl group, ethylthiomethyl group and ethylthioethyl group; Aminoalkylaminoalkyl groups such as aminomethylaminomethyl group and aminoethylaminomethyl group; Alkylcarbonyloxy groups such as methylcarbonyloxy group, ethylcarbonyloxy group and isopropylcarbonyloxy group; Arylalkoxyalkoxyalkyl groups such as oxymethyl group and pentenyloxyethyloxyethyl group; Hydroxyalkoxyalkyl groups such as hydroxyethyloxymethyl group and hydroxyethyloxyethyl group; Arylalkoxyalkyl groups such as pentenyloxymethyl group, pentenyloxyethyl group and benzyloxypropyl group; Quaternary ammonium groups such as trimethyl ammonium group, methyl ethyl methyl ammonium group and triethyl ammonium group; Cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group; Cycloalkenyl groups such as cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, and cyclohexenyl group; Aryl groups, such as a phenyl group, a pyridinyl group, a thienyl group, a furyl group, and a pyrrolyl group; Alkylthio groups such as methylthio group, ethylthio group, propylthio group and butylthio group; Arylthio groups such as phenylthio group, pyridinylthio group, thienylthio group, furylthio group, and pyrrolylthio group; Aryl lower alkyl groups such as benzyl, trityl, and dimethoxytrityl groups; Substituted sulfonyl groups, such as a sulfonyl group, a mesyl group, and p-toluenesulfonyl group; Allylyl groups, such as a benzoyl group; Halogenoaryl groups such as fluorophenyl group and bromophenyl group; It means what may be substituted by substituents, such as oxyalkoxy groups, such as a methylenedioxy group.
[33] "May have one or more substituents" means that they may have one or a plurality of these groups arbitrarily combined, for example, hydroxyl group, thiol group, nitro group, morpholino group, thiomorpholino group, An alkyl group substituted with a halogen atom, a nitrile group, an azide group, a formyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, a sulfonyl group, or the like; Alkenyl groups; Alkynyl groups; Alkoxy groups are also included in the present invention.
[34] Hereinafter, in the present invention, "may have a substituent" and "may have one or more substituents" are intended to have the above meaning.
[35] When R <^1> represents the C1-C6 alkoxy group which may have one or more substituents, the said alkoxy group represents a C1-C6 linear or branched alkoxy group, Specifically, the oxygen atom couple | bonded with the terminal of the said alkyl group. Examples thereof include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group , i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethyl Propoxy group, n-hexyloxy group, 1-hexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethyl Butoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1 , 1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group, 1-ethyl-2-methylpropoxy group, and the like, and preferably Is a methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group , sec-pentyloxy group, t-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1.1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyl jade It is a time period and i-hexyloxy group, More preferably, it is a methoxy group, an ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group , n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group , 1,2-dimethylpropoxy group, more preferably methoxy group, ethoxy group, n-propoxy group, i-prop Low oxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, Most preferably, they are a methoxy group, an ethoxy group, n-propoxy group, and i-propoxy group.
[36] When R <^1> represents the C1-C6 alkylthio group which may have one or more substituents, the said alkylthio group represents a C1-C6 linear or branched alkylthio group, Specifically, in the terminal of the said alkyl group The thing which a sulfur atom couple | bonded is applicable, for example, methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t- Butylthio group, n-pentylthio group, i-pentylthio group, sec-pentylthio group, t-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1,1 -Dimethylpropylthio group, 1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group, 1-methylpentylthio group, 2-methylpentylthio group, 3-methylpentylthio group, 1, 1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, I, 3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 3,3-dimethyl A methylthio group, 1-ethylbutylthio group, 2-ethylbutylthio group, 1,1,2-trimethylpropylthio group, 1,2,2-trimethylpropylthio group, 1-ethyl-1-methylpropylthio group, 1-ethyl-2-methylpropylthio group etc. are mentioned, Preferably, methylthio group, ethylthio group, n-propylthio group, t-propylthio group, n-butylthio group, i-butyl thi Group, sec-butylthio group, t-butylthio group, n-pentylthio group, i-pentylthio group, sec-pentylthio group, t-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group, More preferably, methylthio group and ethylthio group , n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group, i-pentylthio group, sec -Pentylthio group, t-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutyl O, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, More preferably, methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t-butylthio group, Most preferably, they are methylthio group, ethylthio group, n-propylthio group, and i-propylthio group.
[37] When R <^1> represents the C1-C6 hydroxyalkyl group which may have one or more substituents, the said hydroxyalkyl group is a C1-C6 linear or branched alkyl group in which a replaceable moiety is hydroxy. The group substituted by group is shown. Specifically, a hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, etc. are mentioned.
[38] Similarly, when R ¹ represents a hydroxyalkoxy group having 1 to 6 carbon atoms, which may have one or more substituents, the hydroxyalkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, where a substitutable moiety is The group substituted by the hydroxyl group is shown. Specifically, a hydroxymethoxy group, 2-hydroxyethoxy group, 1-hydroxyethoxy group, etc. are mentioned, for example.
[39] Similarly, when R <^1> represents the C1-C6 hydroxyalkylthio group which may have one or more substituents, the said hydroxyalkylthio group is a C1-C6 linear or branched alkylthio group, Substitutable moiety represents a group substituted with a hydroxy group. Specifically, a hydroxymethylthio group, 2-hydroxyethylthio group, 1-hydroxyethylthio group, etc. are mentioned, for example.
[40] When R ¹ represents an aminoalkyl group having 1 to 6 carbon atoms which may have one or more substituents, the aminoalkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms in which a substitutable moiety is substituted with an amino group. Group. Specifically, an aminomethyl group, 2-aminoethyl group, 1-aminoethyl group, etc. are mentioned.
[41] Similarly, when R <^1> represents the C1-C6 aminoalkoxy group which may have one or more substituents, the said aminoalkoxy group is a C1-C6 linear or branched alkoxy group in which a replaceable site | part is an amino group. It represents a substituted group. Specifically, an aminomethoxy group, 2-aminoethoxy group, 1-aminoethoxy group, etc. are mentioned, for example.
[42] Similarly, when R <^1> represents the C1-C6 aminoalkylthio group which may have one or more substituents, the said aminoalkylthio group is a C1-C6 linear or branched alkylthio group which can be substituted. The site represents a group in which an amino group is substituted. Specifically, an aminomethylthio group, 2-aminoethylthio group, 1-aminoethylthio group, etc. are mentioned, for example.
[43] When R ¹ represents a halogenated alkyl group having 1 to 6 carbon atoms, which may have one or more substituents, the halogenated alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, and the substitutable moiety is represented by at least one halogen atom. It represents a substituted group. Here, the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Specifically, a fluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group etc. are mentioned, for example.
[44] Similarly, when R ¹ represents a halogenated alkoxy group having 1 to 6 carbon atoms which may have one or more substituents, the halogenated alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, and at least one substitutable moiety is present. The group substituted by the halogen atom is shown. Specifically, a fluoromethoxy group, a trifluoromethoxy group, 2-fluoroethoxy group, 1-fluoroethoxy group etc. are mentioned, for example.
[45] Similarly, when R ¹ represents a halogenated alkylthio group having 1 to 6 carbon atoms which may have one or more substituents, the halogenated alkylthio group is a substituted or substituted group in the linear or branched alkylthio group having 1 to 6 carbon atoms. The group represents a group in which one or more halogen atoms are substituted. Specifically, a fluoromethylthio group, trifluoromethylthio group, 2-fluoroethylthio group, 1-fluoroethylthio group, etc. are mentioned, for example.
[46] When R <^1> represents the C2-C12 alkoxyalkyl group which may have one or more substituents, the said alkoxyalkyl group is a C1-C6 linear or branched alkyl group in which a replaceable site | part is substituted with said C1-C1 The group substituted by the linear or branched alkoxy group of 6 is shown. Specifically, a methoxymethyl group, an ethoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 1-ethoxyethyl group, 2-ethoxyethyl group etc. are mentioned, for example.
[47] Similarly, when R <^1> represents the C2-C12 alkoxyalkoxy group which may have one or more substituents, the said alkoxyalkoxy group is a said C1-C6 linear or branched alkoxy group, and a site | part which can be substituted is said carbon number The group substituted by the 1-6 linear or branched alkoxy group is shown. Specifically, a methoxy methoxy group, an ethoxy methoxy group, 1-methoxyethoxy group, 2-methoxyethoxy group, 1-ethoxyethoxy group, 2-ethoxyethoxy group etc. are mentioned, for example. Can be.
[48] Similarly, when R <^1> represents the C2-C12 alkoxyalkylthio group which may have one or more substituents, the said alkoxyalkylthio group is a C1-C6 linear or branched alkylthio group which can be substituted. The site | part represents group substituted by the said C1-C6 linear or branched alkoxy group. Specifically, for example, methoxymethylthio group, ethoxymethylthio group, 1-methoxyethylthio group, 2-methoxyethylthio group, 1-ethoxyethylthio group, 2-ethoxyethylthio group, etc. Can be mentioned.
[49] When R <^1> represents the C3-C7 cycloalkyl group which may have one or more substituents, the said cycloalkyl group means a C3-C7 cyclic alkyl group, Specifically, For example, a cyclopropyl group, Cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group are mentioned.
[50] Similarly, when R <^1> represents the C3-C7 cycloalkyloxy group which may have one or more substituents, the said cycloalkyloxy group is what the oxygen atom couple | bonded with the terminal in the said C3-C7 cyclic alkyl group Substantially, for example, a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group can be mentioned.
[51] Similarly, when R <^1> represents the C3-C7 cycloalkylthio group which may have one or more substituents, the said cycloalkylthio group is the said C3-C7 cycloalkyl group in which the sulfur atom couple | bonded at the terminal is considerable. For example, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, and a cycloheptylthio group are mentioned specifically ,.
[52] When R <^1> represents the C2-C6 alkenyl group which may have one or more substituents, the said alkenyl group represents a C2-C6 linear or branched alkenyl group, and is double in the said C2 or more alkyl group Refers to a compound residue having a bond. Specifically, for example, an ethenyl group, 1-propen-1-yl group, 2-propen-1-yl group, 3-propen-1-yl group, 1-buten-1-yl group, 1-butene-2- Diary, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-methyl-1-propen-1-yl group, 2-methyl -1-propen-1-yl group, 1-methyl-2-propen-1-yl group, 2-methyl-2-propen-1-yl group, 1-methyl-1-buten-1-yl group, 2- Methyl-1-buten-1-yl group, 3-methyl-1-buten-1-yl group, 1-methyl-2-buten-1-yl group, 2-methyl-2-buten-1-yl group, 3-methyl- 2-buten-1-yl group, 1-methyl-3-buten-1-yl group, 2-methyl-3-buten-1-yl group, 3-methyl-3-buten-1-yl group, 1-ethyl-1- Buten-1-yl group, 2-ethyl-1-buten-1-yl group, 3-ethyl-1-buten-1-yl group, 1-ethyl-2-buten-1-yl group, 2-ethyl-2-butene- 1-yl group, 3-ethyl-2-buten-1-yl group, 1-ethyl-3-buten-1-yl group, 2-ethyl-3-buten-1-yl group, 3-ethyl-3-buten-1- Diary, 1,1-dimethyl-1-buten-1-yl group, 1,2-dimethyl-1-buten-1-yl group, 1,3-dimethyl-1-buten-1-yl group, 2.2-dimethyl-1- Buten-1-yl group, 3,3-dimethyl- 1-buten-1-yl group, 1,1-dimethyl-2-buten-1-yl group, 1,2-dimethyl-2-buten-1-yl group, 1,3-dimethyl-2-buten-1-yl group, 2,2-dimethyl-2-buten-1-yl group, 3,3-dimethyl-2-buten-1-yl group, 1,1-dimethyl-3-buten-1-yl group, 1,2-dimethyl-3- Buten-1-yl group, 1,3-dimethyl-3-buten-1-yl group, 2.2-dimethyl-3-buten-1-yl group, 3,3-dimethyl-3-buten-1-yl group, 1-pentene- 1-yl group, 2-penten-1-yl group, 3-benten-1-yl group, 4-penten-1-yl group, 1-penten-2-yl group, 2-penten-2-yl group, 3-pentene-2- Diary, 4-penten-2-yl group, 1-penten-3-yl group, 2-penten-3-yl group, 1-penten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 4-penten-l-yl group, 1-penten- 2-yl group, 2-penten- 2-yl group, 3-penten- 2-yl group, 4-penten- 2-yl group, 1-penten- 3-yl group, 2- Penten-3-yl group, 1-methyl-1-penten-1-yl group, 2-methyl-1-penten-1-yl group, 3-methyl-1-penten-1-yl group, 4-methyl-1-pentene- 1-yl group, 1-methyl-2-penten-1-yl group, 2-methyl-2-penten-1-yl group, 3-methyl-2-penten-1-yl group, 4-methyl-2-penten-1- Diary, 1-methyl-3-penten-1-yl group, 2-methyl-3-pentene-1 -Yl group, 3-methyl-3-penten-1-yl group, 4-methyl-3-penten-1-yl group, 1-methyl-4-penten-1-yl group, 2-methyl-4-penten-1-yl group , 3-methyl-4-penten-1-yl group, 4-methyl-4-penten-1-yl group, 1-methyl-1-penten-2-yl group, 2-methyl-1-penten-2-yl group, 3 -Methyl-1-penten-2-yl group, 4-methyl-1-penten-2-yl group, 1-methyl-2-penten-2-yl group, 2-methyl-2-penten-2-yl group, 3-methyl -2-penten-2-yl group, 4-methyl-2-penten-2-yl group, 1-methyl-3-penten-2-yl group, 2-methyl-3-penten-2-yl group, 3-methyl-3 -Benten-2-yl group, 4-methyl-3-penten-2-yl group, 1-methyl-4-penten-2-yl group, 2-methyl-4-penten-2-yl group, 3-methyl-4-pentene -2-yl group, 4-methyl-4-penten-2-yl group, 1-methyl-1-penten-3-yl group, 2-methyl-1-penten-3-yl group, 3-methyl-1-pentene-3 -Yl group, 4-methyl-1-penten-3-yl group, 1-methyl-2-penten-3-yl group, 2-methyl-2-penten-3-yl group, 3-methyl-2-penten-3-yl group , 4-methyl-2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, 1-hexene-3-yl group, 1-hexene-4-yl group, 1-hexene-5 -Diary, 1-hexene-6-yl, 2-hexen-1-yl, 2-hexen-2-yl, 2-hexene-3-yl, 2-hexen-4-yl, 2-hexene-5-yl, 2-hexene-6-yl, 3-hexen-1-yl, 3-hexen-2-yl, 3- A hexene-3-yl group, etc., Preferably an ethenyl group, 1-propen-1-yl group, 2-propene-yl group, 3-propen-1-yl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-methyl-1-propene-1 -Yl group, 2-methyl-1-propen-1-yl group, 1-methyl-2-propen-1-yl group, 2-methyl-2-propen-1-yl group, 1-methyl-1-butene- 1-yl group, 2-methyl-1-buten-1-yl group, 3-methyl-1-buten-1-yl group, 1-methyl-2-buten-1-yl group, 2-methyl-2-butene-1- Diary, 3-methyl-2-buten-1-yl group, 1-methyl-3-buten-1-yl group, 2-methyl-3-buten-1-yl group, 3-methyl-3-buten-1-yl group, 1-ethyl-1-buten-1-yl group, 2-ethyl-1-buten-1-yl group, 3-ethyl-1-buten-1-yl group, 1-ethyl-2-buten-1-yl group, 2- Ethyl-2-buten-1-yl group, 3-ethyl-2-buten-1-yl group, 1-ethyl-3-buten-1-yl group, 2-ethyl-3-buten-1-yl group, 3-ethyl- 3-buten-1-yl group, 1,1- Methyl-1-buten-1-yl group, 1,2-dimethyl-1-buten-1-yl group, 1,3-dimethyl-1-buten-1-yl group, 2,2-dimethyl-1-butene-1- Diary, 3,3-dimethyl-1-buten-1-yl group, 1,1-dimethyl-2-buten-1-yl group, 1,2-dimethyl-2-buten-1-yl group, 1,3-dimethyl- 2-buten-1-yl group, 2,2-dimethyl-2-buten-1-yl group, 3,3-dimethyl-2-buten-1-yl group, 1,1-dimethyl-3-buten-1-yl group, 1,2-dimethyl-3-buten-1-yl group, 1,3-dimethyl-3-buten-1-yl group, 2,2-dimethyl-3-buten-1-yl group, 3,3-dimethyl-3- Buten-1-yl group, more preferably ethenyl group, 1-propen-1-yl group, 2-propen-1-yl group, 3-propen-1-yl group, 1-buten-1-yl group, 1 -Buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-methyl-1-propene-1- Diary, 2-methyl-1-propen-1-yl group, 1-methyl-2-propen-1-yl group, 2-methyl-2-propen-1-yl group, 1-methyl-1-butene-1 -Yl group, 2-methyl-1-buten-1-yl group, 3-methyl-1-buten-1-yl group, 1-methyl-2-buten-1-yl group, 2-methyl-2-buten-1-yl group , 3-methyl-2-butene-1- Group, 1-methyl-3-buten-1-yl group, 2-methyl-3-buten-1-yl group, 3-methyl-3-buten-1-yl group, most preferably ethenyl group and 1-propene -1-yl group, 2-propene-1-yl group, 3-propene-1-yl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-butene -4-yl group, 2-buten-1-yl group, and 2-buten-2-yl group.
[53] Similarly, when R <^1> represents the C2-C6 alkenyloxy group which may have one or more substituents, the said alkenyloxy group is a C2-C6 linear or branched alkenyl group in the terminal. The thing which the oxygen atom couple | bonded is considerable, Specifically, for example, an ethenyloxy group, 1-propen-1-yloxy group, 2-propen-1-yloxy group, 3-propen-1-yloxy group, 1-butene -1-yloxy group, 1-buten-2-yloxy group, 1-buten-3-yloxy group, 1-buten-4-yloxy group, 2-buten-1-yloxy group, 2-buten-2-yloxy group , 1-methyl-1-propen-1-yloxy group, 2-methyl-1-propen-1-yloxy group, 1-methyl-2-propen-1-yloxy group, 2-methyl-2-prop Phen-1-yloxy group, 1-methyl-1-buten-1-yloxy group, 2-methyl-1-buten-1-yloxy group, 3-methyl-1-buten-1-yloxy group, 1-methyl- 2-buten-1-yloxy group, 2-methyl-2-buten-1-yloxy group, 3-methyl-2-buten-1-yloxy group, 1-methyl-3-buten-1-yloxy group, 2- Butyl-3-buten-1-yloxy group, 3-methyl-3-buten-1-yloxy group, 1-ethyl-1-buten-1-yloxy group, 2-ethyl-1-buten-1-yloxy group, 3-ethyl-1-buten-1-yloxy group, 1-ethyl-2-buten-1-yloxy group, 2-ethyl-2-buten-1-yloxy group, 3-ethyl-2-buten-1-yljade Period, 1-ethyl-3-buten-1-yloxy group, 2-ethyl-3-buten-1-yloxy group, 3-ethyl-3-buten-1-yloxy group, 1,1-dimethyl-1-butene -1-yloxy group, 1,2-dimethyl-1-buten-1-yloxy group, 1,3-dimethyl-1-buten-1-yloxy group, 2,2-dimethyl-1-buten-1-yloxy group , 3,3-dimethyl-1-buten-1-yloxy group, 1,1-dimethyl-2-buten-1-yloxy group, 1,2-dimethyl-2-buten-1-yloxy group, 1,3- Dimethyl-2-buten-1-yloxy group, 2,2-dimethyl-2-buten-1-yloxy group, 3,3-dimethyl-2-buten-1-yloxy group, 1,1-dimethyl-3-butene -1-yloxy group, 1,2-dimethyl-3-buten-1-yloxy group, 1,3-dimethyl-3-buten-1-yloxy group, 2,2-dimethyl-3-buten-1-yloxy group , 3,3-dimethyl-3-buten-1-yloxy group, 1-penten-1-yloxy group, 2-penten-1-yloxy Group, 3-benten-1-yloxy group, 4-penten-1-yloxy group, 1-penten-2-yloxy group, 2-penten-2-yloxy group, 3-penten-2-yloxy group, 4-pentene 2-yloxy group, 1-penten-3-yloxy group, 2-penten-3-yloxy group, 1-penten-1-yloxy group, 2-penten-1-yloxy group, 3-penten-1-yloxy group , 4-penten-1-yloxy group, 1-penten-2-yloxy group, 2-penten-2-yloxy group, 3-penten-2-yloxy group, 4-penten-2-yloxy group, 1-pentene- 3-yloxy group, 2-penten-3-yloxy group, 1-methyl-1-penten-1-yloxy group, 2-methyl-1-penten-1-yloxy group, 3-methyl-1-pentene-1- Iloxy group, 4-methyl-1-penten-1-yloxy group, 1-methyl-2-penten-1-yloxy group, 2-methyl-2-penten-1-yloxy group, 3-methyl-2-pentene- 1-yloxy group, 4-methyl-2-penten-1-yloxy group, 1-methyl-3-penten-1-yloxy group, 2-methyl-3-penten-1-yloxy group, 3-methyl-3- Penten-1-yloxy group, 4-methyl-3-penten-1-yloxy group, 1-methyl-4-penten-1-yloxy group, 2-methyl-4-penten-1-yloxy group, 3-methyl- 4-penten-l-yloxy group, 4-methyl-4-penten-l-yloxy group, 1- Methyl-1-penten-2-yloxy group, 2-methyl-1-penten-2-yloxy group, 3-methyl-1-penten-2-yloxy group, 4-methyl-1-penten-2-yloxy group, 1-methyl-2-penten-2-yloxy group, 2-methyl-2-penten-2-yloxy group, 3-methyl-2-penten-2-yloxy group, 4-methyl-2-penten-2-yl jade Period, 1-methyl-3-penten-2-yloxy group, 2-methyl-3-penten-2-yloxy group, 3-methyl-3-penten-2-yloxy group, 4-methyl-3-pentene-2 -Yloxy group, 1-methyl-4-penten-2-yloxy group, 2-methyl-4-penten-2-yloxy group, 3-methyl-4-benten-2-yloxy group, 4-methyl-4-pentene -2-yloxy group, 1-methyl-1-penten-3-yloxy group, 2-methyl-1-penten-3-yloxy group, 3-methyl-1-penten-3-yloxy group, 4-methyl-1 -Benten-3-yloxy group, 1-methyl-2-penten-3-yloxy group, 2-methyl-2-penten-3-yloxy group, 3-methyl-2-penten-3-yloxy group, 4-methyl -2-penten-3-yloxy group, 1-hexen-1-yloxy group, 1-hexene-2-yloxy group, 1-hexene-3-yloxy group, 1-hexen-4-yloxy group, 1-hexene- 5-yloxy group, 1-hexene-6-yloxy group, 2-hexen-1-yloxy group, 2-hexene-2- Iloxy group, 2-hexene-3-yloxy group, 2-hexen-4-yloxy group, 2-hexene-5-yloxy group, 2-hexene-6-yloxy group, 3-hexen-1-yloxy group, 3- Hexene-2-yloxy group, 3-hexen-3-yloxy group, etc. are mentioned, Preferably an ethenyloxy group, 1-propen-1-yloxy group, 2-propen-1-yloxy group, 3- Proben-1-yloxy group, 1-buten-1-yloxy group, 1-buten-2-yloxy group, 1-buten-3-yloxy group, 1-buten-4-yloxy group, 2-butene-1- Iloxy group, 2-buten-2-yloxy group, 1-methyl-1-propen-1-yloxy group, 2-methyl-1-propen-1-yloxy group, 1-methyl-2-propene-1 -Yloxy group, 2-methyl-2-propen-1-yloxy group, 1-methyl-1-buten-1-yloxy group, 2-methyl-1-buten-1-yloxy group, 3-methyl-1- Buten-1-yloxy group, 1-methyl-2-buten-1-yloxy group, 2-methyl-2-buten-1-yloxy group, 3-methyl-2-buten-1-yloxy group, 1-methyl- 3-buten-1-yloxy group, 2-methyl-3-buten-1-yloxy group, 3-methyl-3-buten-1-yloxy group, 1-ethyl-1-buten-1-yloxy group, 2- Ethyl-1-buten-1-yloxy Group, 3-ethyl-1-buten-1-yloxy group, 1-ethyl-2-buten-1-yloxy group, 2-ethyl-2-buten-1-yloxy group, 3-ethyl-2-butene-1 -Yloxy group, 1-ethyl-3-buten-1-yloxy group, 2-ethyl-3-buten-1-yloxy group, 3-ethyl-3-buten-1-yloxy group, 1,1-dimethyl-1 -Buten-1-yloxy group, 1,2-dimethyl-1-buten-1-yloxy group, 1,3-dimethyl-1-buten-1-yloxy group, 2,2-dimethyl-1-buten-1- Iloxy group, 3,3-dimethyl-1-buten-1-yloxy group, 1,1-dimethyl-2-buten-1-yloxy group, 1,2-dimethyl-2-buten-1-yloxy group, 1, 3-dimethyl-2-buten-1-yloxy group, 2,2-dimethyl-2-buten-1-yloxy group, 3,3-dimethyl-2-buten-1-yloxy group, 1,1-dimethyl-3 -Buten-1-yloxy group, 1,2-dimethyl-3-buten-1-yloxy group, 1,3-dimethyl-3-buten-1-yloxy group, 2,2-dimethyl-3-buten-1- Monooxy group, 3,3-dimethyl-3-buten-1-yloxy group, more preferably ethenyloxy group, 1-propen-1-yloxy group, 2-propen-1-yloxy group, 3-pro Phen-1-yloxy group, 1-buten-1-yloxy group, 1-butene-2- Iloxy group, 1-buten-3-yloxy group, I-buten-4-yloxy group, 2-buten-1-yloxy group, 2-buten-2-yloxy group, 1-methyl-1-propene-1- Iloxy group, 2-methyl-1-propen-1-yloxy group, 1-methyl-2-propen-1-yloxy group, 2-methyl-2-propen-1-yloxy group, 1-methyl-1 -Buten-1-yloxy group, 2-methyl-1-buten-1-yloxy group, 3-methyl-1-buten-1-yloxy group, 1-methyl-2-buten-1-yloxy group, 2-methyl 2-buten-1-yloxy group, 3-methyl-2-buten-1-yloxy group, 1-methyl-3-buten-1-yloxy group, 2-methyl-3-buten-1-yloxy group, 3 -Methyl-3-buten-1-yloxy group, more preferably ethenyloxy group, 1-propen-1-yloxy group, 2-propen-1-yloxy group, 3-propen-1-yloxy group , 1-buten-1-yloxy group, 1-buten-2-yloxy group, 1-buten-3-yloxy group, 1-buten-4-yloxy group, 2-buten-1-yloxy group, 2-butene- It is a 2-yloxy group, Most preferably, it is an ethenyloxy group, the 1-propen-1-yloxy group, the 2-propen-1-yloxy group, and the 3-propen-1-yloxy group.
[54] Similarly, when R <^1> represents the C2-C6 alkenylthio group which may have one or more substituents, the said alkenylthio group is a C2-C6 linear or branched alkenyl group in the terminal. The thing which a sulfur atom couple | bonded is considerable, Specifically, for example, an ethenylthio group, 1-propen-1-ylthio group, 2-propene-1-ylthio group, 3-propene-1-ylthio group, 1-butene -1-ylthio group, 1-buten-2-ylthio group, 1-butene-3-ylthio group, 1-buten-4-ylthio group, 2-buten-1-ylthio group, 2-buten-2-ylthio group , 1-methyl-1-propen-1-ylthio group, 2-methyl-1-propen-1-ylthio group, 1-methyl-2-propen-1-ylthio group, 2-methyl-2-prop Phen-1-ylthio group, 1-methyl-1-buten-1-ylthio group, 2-methyl-1-buten-1-ylthio group, 3-methyl-1-buten-1-ylthio group, 1-methyl- 2-buten-1-ylthio group, 2-methyl-2-buten-1-ylthio group, 3-methyl-2-buten-1-ylthio group, 1-methyl-3-buten-1-ylthio group, 2- Me -3-buten-1-ylthio group, 3-methyl-3-buten-1-ylthio group, 1-ethyl-1-buten-1-ylthio group, 2-ethyl-1-buten-1-ylthio group, 3 -Ethyl-1-buten-1-ylthio group, 1-ethyl-2-buten-1-ylthio group, 2-ethyl-2-buten-1-ylthio group, 3-ethyl-2-buten-1-ylthio group , 1-ethyl-3-buten-1-ylthio group, 2-ethyl-3-buten-1-ylthio group, 3-ethyl-3-buten-1-ylthio group, 1,1-dimethyl-1-butene- 1-ylthio group, 1,2-dimethyl-1-buten-1-ylthio group, 1,3-dimethyl-1-buten-1-ylthio group, 2,2-dimethyl-1-buten-1-ylthio group, 3,3-dimethyl-1-buten-1-ylthio group, 1,1-dimethyl-2-buten-1-ylthio group, 1,2-dimethyl-2-buten-1-ylthio group, 1,3-dimethyl -2-buten-1-ylthio group, 2,2-dimethyl-2-buten-1-ylthio group, 3,3-dimethyl-2-buten-1-ylthio group, 1,1-dimethyl-3-butene- 1-ylthio group, 1,2-dimethyl-3-buten-1-ylthio group, 1,3-dimethyl-3-buten-1-ylthio group, 2.2-dimethyl-3-buten-1-ylthio group, 3, 3-dimethyl-3-buten-1-ylthio group, 1-penten-1-ylthio group, 2-penten-1-ylthio , 3-penten-1-ylthio group, 4-penten-1-ylthio group, 1-penten-2-ylthio group, 2-penten-2-ylthio group, 3-penten-2-ylthio group, 4-pentene- 2-ylthio group, 1-penten-3-ylthio group, 2-penten-3-ylthio group, 1-penten-1-ylthio group, 2-penten-1-ylthio group, 3-penten-1-ylthio group, 4-penten-1-ylthio group, 1-penten-2-ylthio group, 2-penten-2-ylthio group, 3-penten-2-ylthio group, 4-penten-2-ylthio group, 1-benten-3 -Ylthio group, 2-penten-3-ylthio group, 1-methyl-1-penten-1-ylthio group, 2-methyl-1-penten-1-ylthio group, 3-methyl-1-penten-1-yl tea Ogi, 4-methyl-1-penten-1-ylthio group, 1-methyl-2-penten-1-ylthio group, 2-methyl-2-penten-1-ylthio group, 3-methyl-2-pentene-1 -Ylthio group, 4-methyl-2-penten-1-ylthio group, 1-methyl-3-penten-1-ylthio group, 2-methyl-3-benten-1-ylthio group, 3-methyl-3-pentene -1-ylthio group, 4-methyl-3-penten-1-ylthio group, 1-methyl-4-penten-1-ylthio group, 2-methyl-4-penten-1-ylthio group, 3-methyl-4 -Penten-1-ylthio group, 4-methyl-4-penten-1-ylthio group, 1- Methyl-1-penten-2-ylthio group, 2-methyl-1-penten-2-ylthio group, 3-methyl-1-penten-2-ylthio group, 4-methyl-1-penten-2-ylthio group, 1-methyl-2-penten-2-ylthio group, 2-methyl-2-penten-2-ylthio group, 3-methyl-2-penten-2-ylthio group, 4-methyl-2-penten-2-yl tea Ogi, 1-methyl-3-penten-2-ylthio group, 2-methyl-3-penten-2-ylthio group, 3-methyl-3-penten-2-ylthio group, 4-methyl-3-pentene-2 -Ylthio group, 1-methyl-4-penten-2-ylthio group, 2-methyl-4-penten-2-ylthio group, 3-methyl-4-penten-2-ylthio group, 4-methyl-4-pentene -2-ylthio group, 1-methyl-1-penten-3-ylthio group, 2-methyl-penten-3-ylthio group, 3-methyl-1-penten-3-ylthio group, 4-methyl-1-pentene -3-ylthio group, 1-methyl-2-penten-3-ylthio group, 2-methyl-2-penten-3-ylthio group, 3-methyl-2-penten-3-ylthio group, 4-methyl-2 -Penten-3-ylthio group, 1-hexene-1-ylthio group, 1-hexene-2-ylthio group, 1-hexene-3-ylthio group, 1-hexene-4-ylthio group, 1-hexene-5- Ilthio group, 1-hexene-6-ylthio group, 2-hexene-1-ylthio group, 2-hexen-2-yl Ogi, 2-hexene-3-ylthio group, 2-hexene-4-ylthio group, 2-hexene-5-ylthio group, 2-hexene-6-ylthio group, 3-hexene-1-ylthio group, 3-hexene 2-ylthio group, 3-hexene-3-ylthio group, etc. are mentioned, Preferably an ethenylthio group, 1-propen-1-ylthio group, 2-propen-1-ylthio group, 3-pro Phen-1-ylthio group, 1-buten-1-ylthio group, 1-buten-2-ylthio group, 1-buten-3-ylthio group, 1-buten-4-ylthio group, 2-buten-1-ylthio Ogi, 2-buten-2-ylthio group, 1-methyl-1-propen-1-ylthio group, 2-methyl-1-propen-1-ylthio group, 1-methyl-2-propene-1- Ylthio group, 2-methyl-2-propen-1-ylthio group, 1-methyl-1-buten-1-ylthio group, 2-methyl-1-buten-1-ylthio group, 3-methyl-1-butene -1-ylthio group, 1-methyl-2-buten-1-ylthio group, 2-methyl-2-buten-1-ylthio group, 3-methyl-2-buten-1-ylthio group, 1-methyl-3 -Buten-1-ylthio group, 2-methyl-3-buten-1-ylthio group, 3-methyl-3-buten-1-ylthio group, 1-ethyl-1-buten-1-ylthio group, 2-ethyl -1-butene-1-ylthio group , 3-ethyl-1-buten-1-ylthio group, 1-ethyl-2-buten-1-ylthio group, 2-ethyl-2-buten-1-ylthio group, 3-ethyl-2-butene-1- Ylthio group, 1-ethyl-3-buten-1-ylthio group, 2-ethyl-3-buten-1-ylthio group, 3-ethyl-3-buten-1-ylthio group, 1,1-dimethyl-1- Buten-1-ylthio group, 1,2-dimethyl-1-buten-1-ylthio group, 1,3-dimethyl-1-buten-1-ylthio group, 2,2-dimethyl-1-buten-1-yl tea Ogi, 3,3-dimethyl-1-buten-1-ylthio group, 1,1-dimethyl-2-buten-1-ylthio group, 1,2-dimethyl-2-buten-1-ylthio group, 1,3 -Dimethyl-2-buten-1-ylthio group, 2,2-dimethyl-2-buten-1-ylthio group, 3,3-dimethyl-2-buten-1-ylthio group, 1,1-dimethyl-3- Buten-1-ylthio group, 1,2-dimethyl-3-buten-1-ylthio group, 1,3-dimethyl-3-buten-1-ylthio group, 2,2-dimethyl-3-buten-1-yl tea Ogi, 3,3-dimethyl-3-buten-1-ylthio group, 1-penten-1-ylthio group, 2-penten-1-ylthio group, 3-penten-1-ylthio group, 4-pentene-1- Ilthio group, 1-penten-2-ylthio group, 2-penten-2-ylthio group, 3-penten-2-ylthio group, 4 -Penten-2-ylthio group, 1-penten-3-ylthio group, 2-penten-3-ylthio group, 1-penten-1-ylthio group, 2-penten-1-ylthio group, 3-pentene-1- Ilthio group, 4-penten-l-ylthio group, 1-penten- 2-ylthio group, 2-penten- 2-ylthio group, 3-penten- 2-ylthio group, 4-penten- 2-ylthio group, 1- Benten-3-ylthio group, 2-penten-3-ylthio group, 1-methyl-1-penten-1-ylthio group, 2-methyl-1-penten-1-ylthio group, 3-methyl-1-pentene- 1-ylthio group, 4-methyl-1-penten-1-ylthio group, 1-methyl-2-penten-1-ylthio group, 2-methyl-2-penten-1-ylthio group, 3-methyl-2- Penten-1-ylthio group, 4-methyl-2-penten-1-ylthio group, 1-methyl-3-penten-1-ylthio group, 2-methyl-3-benten-1-ylthio group, 3-methyl- 3-penten-1-ylthio group, 4-methyl-3-penten-1-ylthio group, 1-methyl-4-penten-1-ylthio group, 2-methyl-4-penten-1-ylthio group, 3- Methyl-4-penten-1-ylthio group, 4-methyl-4-penten-1-ylthio group, 1-methyl-1-penten-2-ylthio group, 2-methyl-1-penten-2-ylthio group, 3-methyl-1-penten-2-ylthio group, 4-methyl-1-penten-2-ylthio , 1-methyl-2-penten-2-ylthio group, 2-methyl-2-penten-2-ylthio group, 3-methyl-2-penten-2-ylthio group, 4-methyl-2-pentene-2- Ylthio group, 1-methyl-3-penten-2-ylthio group, 2-methyl-3-penten-2-ylthio group, 3-methyl-3-penten-2-ylthio group, 4-methyl-3-pentene- 2-ylthio group, 1-methyl-4-penten-2-ylthio group, 2-methyl-4-penten-2-ylthio group, 3-methyl-4-penten-2-ylthio group, 4-methyl-4- Penten-2-ylthio group, 1-methyl-1-penten-3-ylthio group, 2-methyl-1-penten-3-ylthio group, 3-methyl-1-penten-3-ylthio group, 4-methyl- 1-penten-3-ylthio group, 1-methyl-2-penten-3-ylthio group, 2-methyl-2-penten-3-ylthio group, 3-methyl-2-penten-3-ylthio group, 4- Methyl-2-penten-3-ylthio group, 1-hexene-1-ylthio group, 1-hexene-2-ylthio group, 1-hexene-3-ylthio group, 1-hexene-4-ylthio group, 1-hexene -5-ylthio group, 1-hexene-6-ylthio group, 2-hexene-1-ylthio group, 2-hexene-2-ylthio group, 2-hexene-3-ylthio group, 2-hexene-4-ylthio group , 2-hexene-5-ylthio group, 2-hexene-6-ylthio group, 3-hexene-1-yl tea Ogi, 3-hexene-2-ylthio group, 3-hexene-3-ylthio group, etc. are mentioned, Preferably, an ethenylthio group, 1-propen-1-ylthio group, 2-propene-1-yl tea are mentioned. Ogi, 3-propen-1-ylthio group, 1-buten-1-ylthio group, 1-buten-2-ylthio group, 1-butene-3-ylthio group, 1-buten-4-ylthio group, 2- Buten-1-ylthio group, 2-buten-2-ylthio group, 1-methyl-1-propen-1-ylthio group, 2-methyl-1-propen-1-ylthio group, 1-methyl-2- Propen-1-ylthio group, 2-methyl-2-propen-1-ylthio group, 1-methyl-1-buten-1-ylthio group, 2-methyl-1-buten-1-ylthio group, 3- Methyl-1-buten-1-ylthio group, 1-methyl-2-buten-1-ylthio group, 2-methyl-2-buten-1-ylthio group, 3-methyl-2-buten-1-ylthio group, 1-methyl-3-buten-1-ylthio group, 2-methyl-3-buten-1-ylthio group, 3-methyl-3-buten-1-ylthio group, 1-ethyl-1-buten-1-yl tea Ogi, 2-ethyl-1-buten-1-ylthio group, 3-ethyl-1-buten-1-ylthio group, 1-ethyl-2-buten-1-ylthio group, 2-ethyl-2-butene-1 -Ylthio group, 3-ethyl-2-buten-1-yl Thiogi, 1-ethyl-3-buten-1-ylthio group, 2-ethyl-3-buten-1-ylthio group, 3-ethyl-3-buten-1-ylthio group, 1,1-dimethyl-1- Buten-1-ylthio group, 1,2-dimethyl-1-buten-1-ylthio group, 1,3-dimethyl-1-buten-1-ylthio group, 2,2-dimethyl-1-buten-1-yl tea Ogi, 3,3-dimethyl-1-buten-1-ylthio group, 1,1-dimethyl-2-buten-1-ylthio group, 1,2-dimethyl-2-buten-1-ylthio group, 1,3 -Dimethyl-2-buten-1-ylthio group, 2,2-dimethyl-2-buten-1-ylthio group, 3,3-dimethyl-2-buten-1-ylthio group, 1,1-dimethyl-3- Buten-1-ylthio group, 1,2-dimethyl-3-buten-1-ylthio group, 1,3-dimethyl-3-buten-1-ylthio group, 2,2-dimethyl-3-buten-1-yl tea Thio, 3,3-dimethyl-3-buten-1-ylthio group, more preferably ethenylthio group, 1-propen-1-ylthio group, 2-propen-1-ylthio group, 3-propene -1-ylthio group, 1-buten-1-ylthio group, 1-butene-2-ylthio group, 1-butene-3-ylthio group, 1-buten-4-ylthio group, 2-buten-1-ylthio group , 2-butene2-ylthio group, 1-methyl-1-prop Phen-1-ylthio group, 2-methyl-1-propen-1-ylthio group, 1-methyl-2-propen-1-ylthio group, 2-methyl-2-propen-1-ylthio group, 1 -Methyl-1-buten-1-ylthio group, 2-methyl-1-buten-1-ylthio group, 3-methyl-1-buten-1-ylthio group, 1-methyl-2-buten-1-ylthio group , 2-methyl-2-buten-1-ylthio group, 3-methyl-2-buten-1-ylthio group, 1-methyl-3-buten-1-ylthio group, 2-methyl-3-butene-1- Ilthio group, 3-methyl-3-buten-1-ylthio group, more preferably ethenylthio group, 1-propen-1-ylthio group, 2-propen-1-ylthio group, 3-propene- 1-ylthio group, 1-buten-1-ylthio group, 1-buten-2-ylthio group, 1-buten-3-ylthio group, 1-buten-4-ylthio group, 2-buten-1-ylthio group, 2-buten-2-ylthio group, Most preferably, it is an ethenylthio group, the 1-propen-1-ylthio group, the 2-propen-1-ylthio group, and the 3-propene-1-ylthio group.
[55] When R <^1> represents the C2-C6 alkynyl group which may have one or more substituents, the said alkynyl group represents a C2-C6 linear or branched alkynyl group, and is triplet in the said C2 or more alkyl group Refers to a compound residue having a bond. Specifically, for example, an ethynyl group, 1-propyn-1-yl group, 2-propyn-1-yl group, 3-propyn-1-yl group, 1-butyn-1-yl group, 1-butyn-2- Diary, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 2-butyn-2-yl, I-methyl-1-propyn-1-yl, 2-methyl -1-propyn-1-yl group, 1-methyl-2-propyn-1-yl group, 2-methyl-2-propyn-1-yl group, 1-methyl-1-butyn-1-yl group, 2- Methyl-1-butyn-1-yl group, 3-methyl-1-butyn-1-yl group, 1-methyl-2-butyn-1-yl group, 2-methyl-2-butyn-1-yl group, 3-methyl- 2-butyn-1-yl group, 1-methyl-yl group, 2-methyl-yl group, 3-methyl-yl group, 1-ethyl-1-butyn-1-yl group, 2-ethyl-1-butyn-1 -Yl group, 3-ethyl-1-butyn-1-yl group, 1-ethyl-2-butyn-1-yl group, 2-ethyl-2-butyn-1-yl group, 3-ethyl-2-butyn-1-yl group , 1-ethyl-3-butyn-1-yl group, 2-ethyl-3-butyn-1-yl group, 3-ethyl-3-butyn-1-yl group, 1,1-dimethyl-1-butyn-1-yl group , 1,2-dimethyl-1-butyn-1-yl group, 1,3-dimethyl-1-butyn-1-yl group, 2,2-dimethyl-1-butyn-1-yl group, 3,3-dimethyl-1 -Butyn-1-yl, 1,1-dime Methyl-2-butyn-1-yl, 1,2-dimethyl-2-butyn-1-yl, 1,3-dimethyl-2-butyn-1-yl, 2,2-dimethyl-2-butyn-1- Diary, 3,3-dimethyl-2-butyn-1-yl group, 1,1-dimethyl-3-butyn-1-yl group, 1,2-dimethyl-3-butyn-1-yl group, 1,3-dimethyl- 3-butyn-1-yl group, 2,2-dimethyl-3-butyn-1-yl group, 3.3-dimethyl-3-butyn-1-yl group, 1-pentin-1-yl group, 2-pentin-1-yl group, 3-pentin-1-yl group, 4-pentin-1-yl group, 1-pentin-2-yl group, 2-pentin-2-yl group, 3-pentin-2-yl group, 4-pentin-2-yl group, 1- Pentin-3-yl group, 2-pentin-3-yl group, 1-pentin-1-yl group, 2-pentin-1-yl group, 3-pentin-1-yl group, 4-pentin-1-yl group, 1-pentin- 2-yl group, 2-pentin-2-yl group, 3-pentin-2-yl group, 4-pentin-2-yl group, 1-pentin-3-yl group, 2-pentin-3-yl group, 1-methyl-1- Pentin-1-yl group, 2-methyl-1-pentin-1-yl group, 3-methyl-1-pentin-1-yl group, 4-methyl-1-pentin-1-yl group, 1-methyl-2-pentin- 1-yl group, 2-methyl-2-pentin-1-yl group, 3-methyl-2-pentin-1-yl group, 4-methyl-2-pentin-1-yl group, 1-methyl-3-pentin-1- Diary, 2-methyl-3-pentin-1-yl, 3-methyl-3-pentin-1- Diary, 4-methyl-3-pentin-1-yl group, 1-methyl-4-pentin-1-yl group, 2-methyl-4-pentin-1-yl group, 3-methyl-4-pentin-1-yl group, 4-methyl-1-pentin-1-yl group, 1-methyl-1-pentin-2-yl group, 2-methyl-1-pentin-2-yl group, 3-methyl-1-pentin-2-yl group, 4- Methyl-1-pentyn-2-yl group, 1-methyl-2-pentyn-2-yl group, 2-methyl-2-pentin-2-yl group, 3-methyl-2-pentin-2-yl group, 4-methyl- 2-pentin-2-yl group, 1-methyl-3-pentin-2-yl group, 2-methyl-3-pentin-2-yl group, 3-methyl-3-pentin-2-yl group, 4-methyl-3- Pentin-2-yl group, 1-methyl-4-pentin-2-yl group, 2-methyl-4-pentin-2-yl group, 3-methyl-4-pentin-2-yl group, 4-methyl-4-pentin- -2-yl group, 1-methyl-1-pentin-3-yl group, 2-methyl-1-pentin-3-yl group, 3-methyl-1-pentin-3-yl group, 4-methyl-1-pentin-3 -Group, 1-methyl-2-pentin-3-yl group, 2-methyl-2-pentin-3-yl group, 3-methyl-2-pentin-3-yl group, 4-methyl-2-pentin-3-yl group , 1-hexyn-1-yl group, 1-hexyn-2-yl group, 1-hexyn-3-yl group, 1-hexyn-4-yl group, I-hexyn-5-yl group, 1-hexyn-6-yl group, 2 -Hexyn-1-yl group, 2-hexyn-2-yl group, 2-hexyn-3-yl group, 2-hexine- 4-yl group, 2-hexyn-5-yl group, 2-hexyn-6-yl group, 3-hexyn-1-yl group, 3-hexyn-2-yl group, 3-hexyn-3-yl group, etc. are mentioned, It is preferable. Preferably, an ethynyl group, 1-propyn-1-yl group, 2-propyn-1-yl group, 3-propyn-1-yl group, 1-butyn-1-yl group, 1-butyn-2-yl group, 1- Butyn-3-yl group, 1-butyn-4-yl group, 2-butyn-1-yl group, 2-butyn-2-yl group, 1-methyl-1-propyn-1-yl group, 2-methyl-1-prop Pin-1-yl group, 1-methyl-2-propyn-1-yl group, 2-methyl-2-propyn-1-yl group, 1-methyl-1-butyn-1-yl group, 2-methyl-1- Butyn-1-yl group, 3-methyl-1-butyn-1-yl group, 1-methyl-2-butyn-1-yl group, 2-methyl-2-butyn-1-yl group, 3-methyl-2-butyn- 1-yl group, 1-methyl-3-butyn-1-yl group, 2-methyl-3-butyn-1-yl group, 3-methyl-3-butyn-1-yl group, 1-ethyl-1-butyn-1- Diary, 2-ethyl-1-butyn-1-yl group, 3-ethyl-1-butyn-1-yl group, 1-ethyl-2-butyn-1-yl group, 2-ethyl-2-butyn-1-yl group, 3-ethyl-2-butyn-1-yl group, 1-ethyl-3-butyn-1-yl group, 2-ethyl-3-butyn-1-yl group, 3-ethyl-3-butyn-1-yl group, 1, 1-dimethyl-1-butyn-1-yl group, 1,2-dimethyl-1-butyn-1-yl group, 1,3-dimethyl-1-butyn-1-yl group, 2,2-dimethyl-1-butyn-1-yl group, 3,3-dimethyl-1- Butyn-1-yl group, 1,1-dimethyl-2-butyn-1-yl group, 1,2-dimethyl-2-butyn-1-yl group, 1,3-dimethyl-2-butyn-1-yl group, 2, 2-dimethyl-2-butyn-1-yl group, 3,3-dimethyl-2-butyn-1-yl group, 1,1-dimethyl-3-butyn-1-yl group, 1,2-dimethyl-3-butyne- 1-yl group, 1,3-dimethyl-3-butyn-1-yl group, 2,2-dimethyl-3-butyn-1-yl group, 3,3-dimethyl-3-butyn-1-yl group, More preferably Is an ethynyl group, 1-propyn-1-yl group, 2-propyn-1-yl group, 3-propyn-1-yl group, 1-butyn-1-yl group, 1-butyn-2-yl group, 1-butyne -3-yl group, 1-butyn-4-yl group, 2-butyn-1-yl group, 2-butyn-2-yl group, 1-methyl-1-propyn-1-yl group, 2-methyl-1-propyne -1-yl group, 1-methyl-2-propyn-1-yl group, 2-methyl-2-propyn-1-yl group, 1-methyl-1-butyn-1-yl group, 2-methyl-1-butyne -1-yl group, 3-methyl-1-butyn-1-yl group, 1-methyl-2-butyn-1-yl group, 2-methyl-2-butyn-1-yl group, 3-methyl-2-butyn-1 Diary, 1-methyl-3-butyn-1- Diary, 2-methyl-3-butyn-1-yl group, 3-methyl-3-butyn-1-yl group, More preferably, an ethynyl group, 1-propyn-1-yl group, 2-propyn-1- Diary, 3-propyn-1-yl, 1-butyn-1-yl, I-butyn-2-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl , 2-butyn-2-yl group, and most preferably an ethynyl group, a 1-propyn-1-yl group, a 2-propyn-1-yl group, and a 3-propyn-1-yl group.
[56] Similarly, when R <^1> represents the C2-C6 alkynyloxy group which may have one or more substituents, the said alkynyloxy group is a C2-C6 linear or branched alkynyl group in the terminal. The thing which the oxygen atom couple | bonded is considerable, Specifically, for example, an ethynyloxy group, 1-propyn-1-yloxy group, 2-propyn-1-yloxy group, 3-propyn-1-yloxy group, 1-butyne -1-yloxy group, 1-butyn-2-yloxy group, 1-butyn-3-yloxy group, 1-butyn-4-yloxy group, 2-butyn-1-yloxy group, 2-buten-2-yloxy group , 1-methyl-1-propyn-1-yloxy group, 2-methyl-1-propyn-1-yloxy group, 1-methyl-2-propyn-1-yloxy group, 2-methyl-2-prop Pin-1-yloxy group, 1-methyl-1-butyn-1-yloxy group, 2-methyl-1-butyn-1-yloxy group, 3-methyl-1-butyn-1-yloxy group, 1-methyl- 2-butyn-1-yloxy group, 2-methyl-2-butyn-1-yloxy group, 3-methyl-2-butyn-1-yloxy group, 1-methyl-3-butyn-1-yloxy group, 2- Methyl-3-butyn-1-yloxy, 3-methyl-3-butyn-1-yloxy, 1-ethyl-1-butyn-1-yloxy, 2-ethyl-1-butyn-1-yloxy, 3-ethyl-1-butyn-1-yloxy group, 1-ethyl-2-butyn-1-yloxy group, 2-ethyl-2-butyn-1-yloxy group, 3-ethyl-2-butyn-1-yljade Period, 1-ethyl-3-butyn-1-yloxy group, 2-ethyl-3-butyn-1-yloxy group, 3-ethyl-3-butyn-1-yloxy group, 1,1-dimethyl-1-butyne -1-yloxy group, 1,2-dimethyl-1-butyn-1-yloxy group, 1,3-dimethyl-1-butyn-1-yloxy group, 2,2-dimethyl-1-butyn-1-yloxy group , 3,3-dimethyl-1-butyn-1-yloxy group, 1,1-dimethyl-2-butyn-1-yloxy group, 1,2-di, methyl-2-butyn-1-yloxy group, 1, 3-dimethyl-2-butyn-1-yloxy group, 2,2-dimethyl-2-butyn-1-yloxy group, 3,3-dimethyl-2-butyn-1-yloxy group, 1,1-dimethyl-3 -Butyn-1-yloxy group, 1,2-dimethyl-3-butyn-1-yloxy group, 1,3-dimethyl-3-butyn-1-yloxy group, 2,2-dimethyl-3-butyn-1- Iloxy group, 3,3-dimethyl-3-butyn-1-yloxy group, 1-pentyn-1-yloxy group, 2-pentyn-1-yl jade Period, 3-pentyn-1-yloxy group, 4-pentin-1-yloxy group, 1-pentin-2-yloxy group, 2-pentin-2-yloxy group, 3-pentin-2-yloxy group, 4-pentin -2-yloxy group, 1-penten-3-yloxy group, 2-pentin-3-yloxy group, 1-pentin-1-yloxy group, 2-pentin-1-yloxy group, 3-pentin-1-yloxy group , 4-pentin-1-yloxy group, 1-pentin-2-yloxy group, 2-pentin-2-yloxy group, 3-pentin-2-yloxy group, 4-pentin-2-yloxy group, 1-pentin- 3-yloxy group, 2-pentyn-3-yloxy group, 1-methyl-1-pentin-1-yloxy group, 2-methyl-1-pentin-1-yloxy group, 3-methyl-1-pentin-1- Iloxy group, 4-methyl-1-pentin-1-yloxy group, 1-methyl-2-pentin-1-yloxy group, 2-methyl-2-pentin-1-yloxy group, 3-methyl-2-pentin- 1-yloxy group, 4-methyl-2-pentin-1-yloxy group, 1-methyl-3-pentin-1-yloxy group, 2-methyl-3-pentin-1-yloxy group, 3-methyl-3- Pentin-1-yloxy group, 4-methyl-3-pentin-1-yloxy group, 1-methyl-4-pentin-1-yloxy group, 2-methyl-4-pentin-1-yloxy group, 3-methyl- 4-pentyn-1-yloxy group, 4-methyl-4-pentyn-1-yloxy group, 1-methyl-1-pentin-2-yloxy group, 2-methyl-1-pentin-2-yloxy group, 3-methyl-1-pentin-2-yloxy group, 4-methyl-1-pentin-2-yljade Period, 1-methyl-2-pentyn-2-yloxy group, 2-methyl-2-pentin-2-yloxy group, 3-methyl-2-pentin-2-yloxy group, 4-methyl-2-pentin-2 -Yloxy group, 1-methyl-3-pentin-2-yloxy group, 2-methyl-3-pentin-2-yloxy group, 3-methyl-3-pentin-2-yloxy group, 4-methyl-3-pentin -2-yloxy group, 1-methyl-4-pentyn-2-yloxy group, 2-methyl-4-penten-2-yloxy group, 3-methyl-4-pentyn-2-yloxy group, 4-methyl-4 -Pentin-2-yloxy group, 1-methyl-1-pentin-3-yloxy group, 2-methyl-1-pentin-3-yloxy group, 3-methyl-1-pentin-3-yloxy group, 4-methyl -1-pentin-3-yloxy group, 1-methyl-2-pentin-3-yloxy group, 2-methylnopentin-3-yloxy group, 3-methyl-2-pentin-3-yloxy group, 4-methyl -2-pentin-3-yloxy group, 1-hexyn-1-yloxy group, 1-hexyn-2-yloxy group, 1-hexyn-3-yloxy group, 1-hexyn-4-yloxy group, 1-hexin- 5-yloxy group, 1-hexyn-6-yloxy group, 2-hexyn-1-yloxy group, 2-hexine 2-yloxy group, 2-hexyn-3-yloxy group, 2-hexyn-4-yloxy group, 2-hexyn-5-yloxy group, 2-hexyn-6-yloxy group, 3-hexyn-1-yloxy group , 3-hexyn-2-yloxy group, 3-hexyn-3-yloxy group, etc. are mentioned, Preferably an ethynyloxy group, 1-propyn-1-yloxy group, 2-propyn-1-yloxy group , 3-propyn-1-yloxy group, 1-butyn-1-yloxy group, 1-butyn-2-yloxy group, 1-butyn-3-yloxy group, 1-butyn-4-yloxy group, 2-butyne -1-yloxy group, 2-butyn-2-yloxy group, 1-methyl-1-propyn-1-yloxy group, 2-methyl-1-propyn-1-yloxy group, 1-methyl-2-prop Pin-1-yloxy group, 2-methyl-2-propyn-1-yloxy group, 1-methyl-1-butyn-1-yloxy group, 2-methyl-1-butyn-1-yloxy group, 3-methyl -1-butyn-1-yloxy group, 1-methyl-2-butyn-1-yloxy group, 2-methyl-2-butyn-1-yloxy group, 3-methyl-2-butyn-1-yloxy group, 1 -Methyl-3-butyn-1-yloxy group, 2-methyl-3-butyn-1-yloxy group, 3-methyl-3-butyn-1-yloxy group, 1-ethyl-1-butyn-1-yloxy group , 2-ethyl-1-butyn-1-yl jade Period, 3-ethyl-1-butyn-1-yloxy group, 1-ethyl-2-butyn-1-yloxy group, 2-ethyl-2-butyn-1-yloxy group, 3-ethyl-2-butyne-1 -Yloxy group, 1-ethyl-3-butyn-1-yloxy group, 2-ethyl-3-butyn-1-yloxy group, 3-ethyl-3-butyn-1-yloxy group, 1,1-dimethyl-1 -Butyn-1-yloxy group, 1,2-dimethyl-1-butyn-1-yloxy group, 1,3-dimethyl-1-butyn-1-yloxy group, 2,2-dimethyl-1-butyn-1- Iloxy group, 3,3-dimethyl-1-butyn-1-yloxy group, 1,1-dimethyl-2-butyn-1-yloxy group, 1,2-dimethyl-2-butyn-1-yloxy group, 1, 3-dimethyl-2-butyn-1-yloxy group, 2,2-dimethyl-2-butyn-1-yloxy group, 3,3-dimethyl-2-butyn-1-yloxy group, 1,1-dimethyl-3 -Butyn-1-yloxy group, 1,2-dimethyl-3-butyn-1-yloxy group, 1,3-dimethyl-3-butyn-1-yloxy group, 2,2-dimethyl-3-butyn-1- Iloxy group, 3,3-dimethyl-3-butyn-1-yloxy group, More preferably, an ethynyloxy group, 1-propyn-1-yloxy group, 2-propyn-1-yloxy group, 3-prop Pin-1-yloxy, 1-butyn-1-yloxy, 1-butyne -2-yloxy group, 1-butyn-3-yloxy group, 1-butyn-4-yloxy group, 2-butyn-1-yloxy group, 2-butyn-2-yloxy group, 1-methyl-1-propyne -1-yloxy group, 2-methyl-1-propyn-1-yloxy group, 1-methyl-2-propyn-1-yloxy group, 2-methyl-2-propyn-1-yloxy group, 1- Methyl-1-butyn-1-yloxy group, 2-methyl-1-butyn-1-yloxy group, 3-methyl-1-butyn-1-yloxy group, 1-methyl-2-buten-1-yloxy group, 2-methyl-2-butyn-1-yloxy group, 3-methyl-2-butyn-1-yloxy group, 1-methyl-3-butyn-1-yloxy group, 2-methyl-3-butyn-1-yljade It is a time period, 3-methyl-3- butyn-1-yloxy group, More preferably, an ethynyloxy group, 1-propyn-1-yloxy group, 2-propyn-1-yloxy group, 3-propyn-1 -Yloxy group, 1-butyn-1-yloxy group, 1-butyn-2-yloxy group, 1-butyn-3-yloxy group, 1-butyn-4-yloxy group, 2-butyn-1-yloxy group, 2 -Butyn-2-yloxy group, most preferably an ethynyloxy group, a 1-propyn-1-yloxy group, a 2-propyn-1-yloxy group, and a 3-propyn-1-yloxy group.
[57] Similarly, when R <^1> represents the C2-C6 alkynylthio group which may have one or more substituents, the said alkynylthio group is a C2-C6 linear or branched alkynyl group in the terminal. The thing which a sulfur atom couple | bonded is considerable, Specifically, for example, an ethynylthio group, 1-propyn-1-ylthio group, 2-propyn-1-ylthio group, 3-propyn-1-ylthio group, 1-butyne -1-ylthio group, 1-butyn-2-ylthio group, 1-butyn-3-ylthio group, 1-butyn-4-ylthio group, 2-butyn-1-ylthio group, 2-butyn-2-ylthio group , 1-methyl-1-propyn-1-ylthio group, 2-methyl-1-propyn-1-ylthio group, 1-methyl-2-propyn-1-ylthio group, 2-methyl-2-prop Pin-1-ylthio group, 1-methyl-1-butyn-1-ylthio group, 2-methyl-1-butyn-1-ylthio group, 3-methyl-1-butyn-1-ylthio group, 1-methyl- 2-butyn-1-ylthio group, 2-methyl-2-butyn-1-ylthio group, 3-methyl-2-butyn-1-ylthio group, 1-methyl-3-butyn-1-ylthio group, 2- Me -3-butyn-1-ylthio group, 3-methyl-3-butyn-1-ylthio group, 1-ethyl-1-butyn-1-ylthio group, 2-ethyl-1-butyn-1-ylthio group, 3 -Ethyl-1-butyn-1-ylthio group, 1-ethyl-2-butyn-1-ylthio group, 2-ethyl-2-butyn-1-ylthio group, 3-ethyl-2-butyn-1-ylthio group , 1-ethyl-3-butyn-1-ylthio group, 2-ethyl-3-butyn-1-ylthio group, 3-ethyl-3-butyn-1-ylthio group, 1,1-dimethyl-1-butyne- 1-ylthio group, 1,2-dimethyl-1-butyn-1-ylthio group, 1,3-dimethyl-1-butyn-1-ylthio group, 2,2-dimethyl-1-butyn-1-ylthio group, 3,3-dimethyl-1-butyn-1-ylthio group, 1,1-dimethyl-2-butyn-1-ylthio group, 1,2-dimethyl-2-butyn-1-ylthio group, 1,3-dimethyl -2-butyn-1-ylthio group, 2,2-dimethyl-2-butyn-1-ylthio group, 3,3-dimethyl-2-butyn-1-ylthio group, 1,1-dimethyl-3-butyne- 1-ylthio group, 1,2-dimethyl-3-butyn-1-ylthio group, 1,3-dimethyl-3-butyn-1-ylthio group, 2,2-dimethyl-3-butyn-1-ylthio group, 3,3-dimethyl-3-butyn-1-ylthio group, 1-pentin-1-ylthio group, 2-pentin-1-ylthio , 3-pentin-1-ylthio group, 4-pentin-1-ylthio group, 1-pentin-2-ylthio group, 2-pentin-2-ylthio group, 3-pentin-2-ylthio group, 4-pentin- 2-ylthio group, 1-pentin-3-ylthio group, 2-pentin-3-ylthio group, 1-pentin-1-ylthio group, 2-pentin-1-ylthio group, 3-pentin-1-ylthio group, 4-pentin-1-ylthio group, 1-pentin-2-ylthio group, 2-pentin-2-ylthio group, 3-pentin-2-ylthio group, 4-pentin-2-ylthio group, 1-pentin-3 -Ylthio group, 2-pentin-3-ylthio group, 1-methyl-1-pentin-1-ylthio group, 2-methyl-1-pentin-1-ylthio group, 3-methyl-1-pentin-1-yl tea Ogi, 4-methyl-1-pentin-1-ylthio group, 1-methyl-2-pentin-1-ylthio group, 2-methyl-2-pentin-1-ylthio group, 3-methyl-2-pentin-1 -Ylthio group, 4-methyl-2-pentin-1-ylthio group, 1-methyl-3-pentin-1-ylthio group, 2-methyl-3-pentin-1-ylthio group, 3-methyl-3-pentin -1-ylthio group, 4-methyl-3-pentin-1-ylthio group, 1-methyl-4-pentin-1-ylthio group, 2-methyl-4-pentin-1-ylthio group, 3-methyl-4 -Pentin-1-ylthio group, 4-methyl-4-pentyn-1-ylthio group, 1- Methyl-1-pentyn-2-ylthio group, 2-methyl-1-pentin-2-ylthio group, 3-methyl-1-pentin-2-ylthio group, 4-methyl-1-pentin-2-ylthio group, 1-methyl-2-pentyn-2-ylthio group, 2-methyl-2-pentin-2-ylthio group, 3-methyl-2-pentin-2-ylthio group, 4-methyl-2-pentin-2-yl tea Ogi, 1-methyl-3-pentin-2-ylthio group, 2-methyl-3-pentin-2-ylthio group, 3-methyl-3-pentin-2-ylthio group, 4-methyl-3-pentin-2 -Ylthio group, 1-methyl-4-pentin-2-ylthio group, 2-methyl-4-pentin-2-ylthio group, 3-methyl-4-pentin-2-ylthio group, 4-methyl-4-pentine -2-ylthio group, 1-methyl-1-pentin-3-ylthio group, 2-methyl-1-pentin-3-ylthio group, 3-methyl-1-pentin-3-ylthio group, 4-methyl-1 -Pentin-3-ylthio group, 1-methyl-2-pentin-3-ylthio group, 2-methyl-2-pentin-3-ylthio group, 3-methyl-2-pentin-3-ylthio group, 4-methyl -2-pentin-3-ylthio group, 1-hexyn-1-ylthio group, 1-hexyn-2-ylthio group, 1-hexyn-3-ylthio group, 1-hexyn-4-ylthio group, 1-hexine- 5-ylthio group, 1-hexyn-6-ylthio group, 2-hexyn-1-ylthio group, 2-hexyn-2- Thiogi, 2-hexyn-3-ylthio group, 2-hexyn-4-ylthio group, 2-hexyn-5-ylthio group, 2-hexyn-6-ylthio group, 3-hexyn-1-ylthio group, 3- Hexyn-2-ylthio group, 3-hexyn-3-ylthio group, etc. are mentioned, Preferably an ethynylthio group, 1-propyn-1-ylthio group, 2-propyn-1-ylthio group, 3- Propyn-1-ylthio group, 1-butyn-1-ylthio group, 1-butyn-2-ylthio group, 1-butyn-3-ylthio group, 1-butyn-4-ylthio group, 2-butyn-1- Ylthio group, 2-butyn-2-ylthio group, 1-methyl-1-propyn-1-ylthio group, 2-methyl-1-propyn-1-ylthio group, 1-methyl-2-propyne-1 -Ylthio group, 2-methyl-2-propyn-1-ylthio group, 1-methyl-1-butyn-1-ylthio group, 2-methyl-1-butyn-1-ylthio group, 3-methyl-1- Butyn-1-ylthio group, 1-methyl-2-butyn-1-ylthio group, 2-methyl-2-butyn-1-ylthio group, 3-methyl-2-butyn-1-ylthio group, 1-methyl- 3-butyn-1-ylthio group, 2-methyl-3-butyn-1-ylthio group, 3-methyl-3-butyn-1-ylthio group, 1-ethyl-1-butyn-1-ylthio group, 2- Ethyl-1-butyn-1-ylthio , 3-ethyl-1-butyn-1-ylthio group, 1-ethyl-2-butyn-1-ylthio group, 2-ethyl-2-butyn-1-ylthio group, 3-ethyl-2-butyn-1- Ylthio group, 1-ethyl-3-butyn-1-ylthio group, 2-ethyl-3-butyn-1-ylthio group, 3-ethyl-3-butyn-1-ylthio group, 1, I-dimethyl-1- Butyn-1-ylthio group, 1,2-dimethyl-1-butyn-1-ylthio group, 1,3-dimethyl-1-butyn-1-ylthio group, 2,2-dimethyl-1-butyn-1-yl tea Ogi, 3,3-dimethyl-1-butyn-1-ylthio group, 1,1-dimethyl-2-butyn-1-ylthio group, 1,2-dimethyl-2-butyn-1-ylthio group, 1,3 -Dimethyl-2-butyn-1-ylthio group, 2,2-dimethyl-2-butyn-1-ylthio group, 3.3-dimethyl-2-butyn-1-ylthio group, 1,1-dimethyl-3-butyne- 1-ylthio group, 1,2-dimethyl-3-butyn-1-ylthio group, 1,3-dimethyl-3-butyn-1-ylthio group, 2,2-dimethyl-3-butyn-1-ylthio group, 3,3-dimethyl-3-butyn-1-ylthio group, More preferably, an ethynylthio group, 1-propyn-1-ylthio group, 2-propyn-1-ylthio group, 3-propyn-1 -Ylthio group, 1-butyn-1-ylthio group, 1-butyn-2- Thiogi, 1-butyn-3-ylthio group, 1-butyn-4-ylthio group, 2-butyn-1-ylthio group, 2-butyn-2-ylthio group, 1-methyl-1-propyn-1- Ylthio group, 2-methyl-1-propyn-1-ylthio group, 1-methyl-2-propyn-1-ylthio group, 2-methyl-2-propyn-1-ylthio group, 1-methyl-1 -Butyn-1-ylthio group, 2-methyl-1-butyn-1-ylthio group, 3-methyl-1-butyn-1-ylthio group, 1-methyl-2-butyn-1-ylthio group, 2-methyl -2-butyn-1-ylthio group, 3-methyl-2-butyn-1-ylthio group, 1-methyl-3-butyn-1-ylthio group, 2-methyl-3-butyn-1-ylthio group, 3 -Methyl-3-butyn-1-ylthio group, more preferably an ethynylthio group, a 1-propyn-1-ylthio group, a 2-propyn-1-ylthio group, a 3-propyn-1-ylthio group , 1-butyn-1-ylthio group, 1-butyn-2-ylthio group, 1-butyn-3-ylthio group, 1-butyn-4-ylthio group, 2-butyn-1-ylthio group, 2-butyne- 2-ylthio group, Most preferably, it is an ethynylthio group, the 1-propyn-1-ylthio group, the 2-propyn-1-ylthio group, and the 3-propyn-1-ylthio group.
[58] When R ¹ represents an aryl group having 6 to 12 carbon atoms which may have one or more substituents, the aryl group refers to an aromatic ring group, and specifically, for example, a phenyl group, 1-naphthyl group, 2-naphthyl group, as- Indasenyl group, s-indacenyl group, acenaphthylenyl group, etc. are mentioned. Preferably they are a phenyl group, 1-naphthyl group, and 2-naphthyl group, More preferably, they are a phenyl group.
[59] Similarly, when R <^1> represents the C6-C12 aryloxy group which may have one or more substituents, in the said C6-C12 aryl group, the thing which the oxygen atom couple | bonded at the terminal is considerable, and is specific As a phenyloxy group, a 1-naphthyloxy group, 2-naphthyloxy group, an as-indacenyloxy group, the s-indacenyloxy group, an acenaphthylenyloxy group etc. are mentioned as an example. Preferably they are a phenyloxy group, 1-naphthyloxy group, and 2-naphthyloxy group, More preferably, they are a phenyloxy group.
[60] Similarly, when R <^1> represents the C6-C12 arylthio group which may have one or more substituents, the said arylthio group is the said C6-C12 aryl group in which the sulfur atom couple | bonded at the terminal is considerable, and is specific Examples thereof include a phenylthio group, 1-naphthylthio group, 2-naphthylthio group, as-indasenylthio group, s-indasenylthio group, acenaphthylenylthio group, and the like. Preferably they are a phenylthio group, 1-naphthylthio group, and 2-naphthylthio group, More preferably, they are a phenylthio group.
[61] When R ¹ represents an alkylaryl group having 7 to 18 carbon atoms which may have one or more substituents, the alkylaryl group is an aryl group having 6 to 12 carbon atoms, wherein a substitutable moiety is substituted with an alkyl group having 1 to 6 carbon atoms. A group is mentioned, Specifically, a tolyl group, xylyl group, cumenyl group, mesityl group, cymenyl group, styryl group, etc. are mentioned, for example. Preferably they are tolyl group, xylyl group, cumenyl group, mesityl group, cymenyl group, and styryl group, More preferably, they are tolyl group, xylyl group, cumenyl group, and mesityl group, More preferably, tolyl group and xylyl Group, cumenyl group.
[62] Similarly, when R ¹ represents an alkylaryloxy group having 7 to 18 carbon atoms which may have one or more substituents, the alkylaryloxy group is an alkylaryl group having 7 to 18 carbon atoms, in which an oxygen atom is bonded to the terminal thereof. Specifically, for example, o-tolyloxy group, m-tolyloxy group, p-tolyloxy group, 2,3-xylyl-1-oxy group, 2,4-xylyl-1-oxy group, 2,5-xylyl-1-oxy group, o-cumenyloxy group, m-cumenyloxy group, p-cumenyloxy group, mesityloxy group, 2,3-cymenyl-1-oxy group, 2,4- Cymenyl-1-oxy group, 2, 5- simenyl-1-oxy group, o-styryloxy group, m-styryloxy group, p- styryloxy group, etc. are mentioned. Preferably o-tolyloxy group, m-tolyloxy group, p-tolyloxy group, 2,3-xylyl-1-oxy group, 2,4-xylyl-1-oxy group, 2,5- size Silyl-1-oxy group, o-cumenyloxy group, m-cumenyloxy group, p-cumenyloxy group, mesityloxy group, 2.3-cymenyl-1-oxy group, 2,4-cymenyl-1-oxy group , 2.5-cymenyl-1-oxy group, o-styryloxy group, m-styryloxy group, p-styryloxy group, More preferably, o-tolyloxy group, m-tolyloxy group, p-tolyl jade Period, 2,3-xylyl-1-oxy group, 2,4-xylyl-1-oxy group, 2,5-xylyl-1-oxy group, o-cumenyloxy group, m-cumenyloxy group, p-cumenyloxy group, mesityloxy group, o-styryloxy group, m-styryloxy group, p-styryloxy group, More preferably, o-tolyloxy group, m-tolyloxy group, p-tolyloxy group , 2,3-xylyl-1-oxy group, 2,4-xylyl-1-oxy group, 2,5-xylyl-1-oxy group, mesityloxy group, and most preferably o-tolyl jade It is a period, m-tolyloxy group, and p-tolyloxy group.
[63] Similarly, when R <^1> represents the C7-C18 alkylarylthio group which may have one or more substituents, the said alkylarylthio group is the thing of the C7-C18 alkylaryl group in which the sulfur atom couple | bonded at the terminal is considerable. Specifically, for example, o-tolylthio group, m-tolylthio group, p-tolylthio group, 2,3-xylyl-1-thio group, 2,4-xylyl-1-thio group, 2,5-xylyl-1-thio group, o-cumenylthio group, m-cumenylthio group, p-cumenylthio group, mesitylthio group, 2,3-cymenyl-1-thio group, 2,4- Cymenyl-1-thio group, 2,5-cymenyl-1-thio group, o-styrylthio group, m-styrylthio group, p-styrylthio group, etc. are mentioned. Preferably o-tolylthio group, m-tolylthio group, p-tolylthio group, 2,3-xylyl-1-thio group, 2,4-xylyl-1-thio group, 2.5-xylyl- 1-thio group, o-cumenylthio group, m-cumenylthio group, p-cumenylthio group, mesitylthio group, 2,3-cymenyl-1-thio group, 2,4-cymenyl-1-thio group , 2,5-cymenyl-1-thio group, o-styrylthio group, m-styrylthio group, p-styrylthio group, More preferably, o-tolylthio group, m-tolylthio group, p- Tolylthio group, 2,3-xylyl-1-thio group, 2,4-xylyl-1-thio group, 2,5-xylyl-1-thio group, o-cumenylthio group, m-cumenylti O-, p-cumenylthio group, mesitylthio group, o-styrylthio group, m-styrylthio group, p-styrylthio group, More preferably, o-tolylthio group, m-tolylthio group, p-tol Arylthio group, 2,3-xylyl-1-thio group, 2,4-xylyl-1-thio group, 2,5-xylyl-1-thio group, mesitylthio group, and most preferably o- Tolylthio group, m-tolylthio group, and p-tolylthio group.
[64] When R ¹ represents an aralkyl group having 7 to 18 carbon atoms that may have one or more substituents, the aralkyl group is an alkyl group having 1 to 6 carbon atoms, and a substitutable moiety is substituted with an aryl group having 6 to l 2 carbon atoms. Group, and specifically, for example, a benzyl group, a phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthylmethyl group, 2-naphthyl Methyl group, 1-naphthyl ethyl group, 2-naphthyl ethyl group, 1-naphthyl propyl group, 2-naphthyl propyl group, etc. are mentioned. Preferably benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-naphthylethyl group , 2-naphthylethyl group, 1-naphthylpropyl group, 2-naphthylpropyl group, more preferably benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, more preferably benzyl group, phenethyl group, 3-phenylpropyl group, 4-phenylbutyl group, most preferably benzyl group, phene Til group.
[65] Similarly, in the case where R ¹ represents an aralkyloxy group having 7 to 18 carbon atoms which may have one or more substituents, the aralkyloxy group is an aralkyl group having 7 to 18 carbon atoms, in which an oxygen atom is bonded to the terminal. Specifically, for example, benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1-naphthylmethyl jade A time period, 2-naphthyl methyloxy group, 1-naphthyl ethyloxy group, 2-naphthyl ethyloxy group, 1-naphthyl propyloxy group, 2-naphthyl propyloxy group, etc. are mentioned. Preferably benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1-naphthylmethyloxy group, 2-naph Methylmethyloxy group, 1-naphthylethyloxy group, 2-naphthylethyloxy group, 1-naphthylpropyloxy group, 2-naphthylpropyloxy group, More preferably, benzyloxy group, phenethyloxy group, 3-phenylpropyloxy group, 4-phenylbutyloxy group, 5-phenylpentyloxy group, 6-phenylhexyloxy group, 1-naphthylmethyloxy group, 2-naphthylmethyloxy group, More preferably, benzyl It is an oxy group, a phenethyloxy group, 3-phenylpropyloxy group, and 4-phenylbutyloxy group, Most preferably, they are a benzyloxy group and a phenethyloxy group.
[66] Similarly, in the case where R ¹ represents an aralkylthio group having 7 to 18 carbon atoms which may have one or more substituents, the aralkylthio group is an aralkyl group having 7 to 18 carbon atoms, in which a sulfur atom is bonded to the terminal. Specifically, for example, benzylthio group, phenethylthio group, 3-phenylpropylthio group, 4-phenylbutylthio group, 5-phenylpentylthio group, 6-phenylhexylthio group, 1-naphthylmethyl tea A group, 2-naphthyl methylthio group, 1-naphthyl ethylthio group, 2-naphthyl ethylthio group, 1-naphthyl propylthio group, 2-naphthyl propylthio group, etc. are mentioned. Preferably, benzylthio group, phenethylthio group, 3-phenylpropylthio group, 4-phenylbutylthio group, 5-phenylpentylthio group, 6-phenylhexylthio group, 1-naphthylmethylthio group, 2-naph A methylmethylthio group, 1-naphthylethylthio group, 2-naphthylethylthio group, 1-naphthylpropylthio group, 2-naphthylpropylthio group, more preferably benzylthio group, phenethylthio group, 3-phenylpropylthio group, 4-phenylbutylthio group, 5-phenylpentylthio group, 6-phenylhexylthio group, 1-naphthylmethylthio group, 2-naphthylmethylthio group, More preferably, benzyl Thio group, a phenethylthio group, 3-phenylpropylthio group, and 4-phenylbutylthio group, Most preferably, they are a benzylthio group and a phenethylthio group.
[67] When L represents a single bond, the following general formulas in which the groups X and Y are bonded in a single bond
[68]
[69] The symbol in the formula is the same as that defined above, and represents a carboxylic acid derivative, a salt thereof, or an ester thereof or a hydrate thereof.
[70] Similarly, in the case where L represents a double bond, the following general formula wherein X and Y are bonded by a single bond
[71]
[72] The symbol in the formula is the same as that defined above, and represents a carboxylic acid derivative, a salt thereof, or an ester thereof or a hydrate thereof.
[73] When M represents a single bond, the following general formula
[74]
[75] The symbol in the formula is the same as that defined above, and represents a carboxylic acid derivative, a salt thereof, or an ester thereof or a hydrate thereof.
[76] When T represents a single bond, the following general formula
[77]
[78] The symbol in the formula is the same as that defined above, and represents a carboxylic acid derivative, a salt thereof, or an ester thereof or a hydrate thereof.
[79] When L and M represent an alkylene group having 1 to 6 carbon atoms which may have one or more substituents, the alkylene group means a divalent group derived by further removing one hydrogen atom from the alkyl group having 1 to 6 carbon atoms. Specifically, for example, methylene group, ethylene group, methyl ethylene group, propylene group, ethyl ethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, trimethylene group, 1-methyltri Methylene group, 1-ethyltrimethylene group, 2-methyltrimethylene group, 1,1-dimethyltrimethylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like. Preferably, methylene group, ethylene group, methyl ethylene group, propylene group, ethyl ethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, trimethylene group, 1-methyltrimethylene group, 1-ethyl Trimethylene group, 2-methyltrimethylene group, 1,1-dimethyltrimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, more preferably methylene group, ethylene group, methylethylene group, propylene group, Ethyl ethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, trimethylene group, 1-methyltrimethylene group, 1-ethyltrimethylene group, 2-methyltrimethylene group, 1,1-dimethyl It is a trimethylene group, More preferably, it is a methylene group, an ethylene group, a methyl ethylene group, a propylene group, an ethyl ethylene group, a 1, 1- dimethyl ethylene group, a 1, 2- dimethyl ethylene group, a trimethylene group, It is further more preferable Preferably it is a methylene group, ethylene group, methyl ethylene group, a propylene group, Most preferably, methylene Is an ethylene group.
[80] Similarly, when T represents an alkylene group having 1 to 3 carbon atoms which may have one or more substituents, the alkylene group means a divalent group derived by further removing one hydrogen atom from the alkyl group having 1 to 3 carbon atoms. Specific examples thereof include an alkylene group having 1 to 3 carbon atoms shown above. Preferably they are a methylene group, an ethylene group, and a propylene group, More preferably, they are a methylene group and an ethylene group, Most preferably, it is a methylene group.
[81] When L, M, and X represent an alkenylene group having 2 to 6 carbon atoms which may have one or more substituents, the alkenylene group is derived by further removing one hydrogen atom from the alkenyl group having 2 to 6 carbon atoms. A divalent group is mentioned, and a vinylene group, a propenylene group, butenylene group, a pentenylene group, a hexenylene group etc. are mentioned specifically ,. Preferably they are a vinylene group, a propenylene group, butenylene group, and a pentenylene group, More preferably, they are a vinylene group, a propenylene group, butenylene group, More preferably, they are a vinylene group and a propenylene group, Most preferably, Is a vinylene group.
[82] Similarly, when T represents an alkenylene group having 2 to 3 carbon atoms which may have one or more substituents, the alkenylene group is a divalent group derived by further removing one hydrogen atom from the alkenyl group having 2 to 3 carbon atoms. The alkenylene group of 2 to 3 carbon atoms shown above is mentioned specifically ,. Preferably they are a vinylene group and a propenylene group, More preferably, it is a vinylene group.
[83] When L and M represent an alkynylene group having 2 to 6 carbon atoms which may have one or more substituents, the alkynylene group is a divalent group derived by further removing one hydrogen atom from the alkynyl group having 2 to 6 carbon atoms. Specifically, for example, an ethynylene group, propynylene group, butynylene group, hexynylene group, hexynylene group and the like can be mentioned. Preferably they are an ethynylene group, a propynylene group, butynylene group, and a hexynylene group, More preferably, they are an ethynylene group, a propynylene group, butynylene group, More preferably, they are an ethynylene group, a propynylene group, Most preferably, it is an ethynylene group.
[84] Similarly, when T represents an alkynylene group having 2 to 3 carbon atoms which may have one or more substituents, the alkynylene group is a divalent group derived by further removing one hydrogen atom from the alkynyl group having 2 to 3 carbon atoms. The alkynylene group of 2 to 3 carbon atoms shown above is mentioned specifically ,. Preferably it is an ethynylene group and a propynylene group, More preferably, it is an ethynylene group.
[85] When R ^w1 , R ^w2 , R ^x , R ^x1, and R ^x2 represent an aliphatic acyl group having 2 to 7 carbon atoms which may have one or more substituents, the aliphatic acyl group is an alkyl group having 1 to 6 carbon atoms and the carbon atoms having 2 to 6 carbon atoms. In the alkenyl group of 6 or the alkynyl group of the said C2-C6, what the carbonyl group couple | bonded at the terminal is corresponded, specifically, for example, an acetyl group, a propionyl group, butyryl group, isobutyryl group, valeryl group, iso And groups such as valeryl group, pivaloyl group, hexanoyl group, octanoyl group, acryloyl group, methacryloyl group and crotonyl group. Preferably they are acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group, acryloyl group, methacryloyl group, and crotonyl group, More preferably Preferably it is acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, octanoyl group, More preferably, acetyl group, propionyl group, butyryl group, isobuty It is a aryl group, Most preferably, they are an acetyl group and a propionyl group.
[86] When R ^w1 , R ^w2 , R ^x , R ^x1 and R ^x2 represent an aromatic acyl group having 7 to 19 carbon atoms which may have one or more substituents, the aromatic acyl group is the terminal of the aryl group having 5 to 12 carbon atoms. Equivalently, a group derived by further removing one hydrogen atom from a carbonyl group or the aliphatic acyl group having 2 to 7 carbon atoms to which the derived group is bound is used. Specifically, for example, a benzoyl group, an o-toluyl group, and an m-toluyl group , p-toluoyl group, cinnamoyl group, 1-naphthoyl group, 2-naphthoyl group and the like. Preferably it is a benzoyl group, o-toluoyl group, m-toluoyl group, p-toluoyl group, cinnamoyl group, 1-naphthoyl group, 2-naphthoyl group, More preferably, benzoyl group and o- Toluoyl group, m-toluoyl group, p-toluoyl group, cinnamoyl group, More preferably, they are benzoyl group and cinnamoyl group, Most preferably, they are benzoyl group.
[87] Represents a single bond or a double bond. Therefore, the following general formula (I)
[88]
[89] [The symbol in the formula is the same as the above definition] The compound of the present invention is represented by the following general formulas:
[90]
[91]
[92] The symbol in the formula is the same as the above definition, and includes carboxylic acid derivatives, salts thereof or esters thereof or hydrates thereof.
[93] Q represents an oxygen atom or a sulfur atom. Thus, the general formula -CQ- means a carbonyl group or a thiocarbonyl group.
[94] When Y represents an aromatic hydrocarbon group having 5 to 12 carbon atoms, which may have one or more substituents and may have one or more heteroatoms, the aromatic hydrocarbon group is an aryl group having 6 to 12 carbon atoms or 6 to 12 carbon atoms. In the aryl group, the substitutable moiety refers to a group substituted with the aliphatic hydrocarbon group having 1 to 6 carbon atoms, provided that the aromatic hydrocarbon group does not have more than 12 carbon atoms, and the aliphatic hydrocarbon group is monovalent and higher Airway), specifically, for example, a phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-k Silyl, mesityl, cymenyl, o-cumenyl, m-cumenyl, p-cumenyl, benzyl, phenethyl, α-methylbenzyl, benzhydryl, trityl, benzylidene, styryl , Cinnamil group, cinnamildene group, 3-phenylpropyl , 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthyl group, 2-naphthyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1-naphthylethyl group, 2-naph A methyl ethyl group, an as-indacenyl group, an s-indacenyl group, an acenaphthylenyl group, etc. are mentioned. Preferably, a phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, mesityl group, simenyl group, o-cumenyl group, m-cumenyl group, p-cumenyl group, benzyl group, phenethyl group, α-methylbenzyl group, benzhydryl group, trityl group, benzylidene group, styryl group, cinnamil group, cinnamildene group, 3 -Phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthyl group, 2-naphthyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, I-naphthylethyl group , 2-naphthylethyl group, as-indasenyl group, s-indasenyl group, acenaphthylenyl group, More preferably, they are a phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3- Xylyl, 2,4-xylyl, 2,5-xylyl, mesityl, cymenyl, o-cumenyl, m-cumenyl, p-cumenyl, benzyl, phenethyl, α-methyl Benzyl group, benzhydryl group, trityl group, benzylidene group, styryl group, cinnamil group, cinnamildene group, 3-phenylpropyl group, 4-phenylbutyl , 5-phenylpentyl group, 6-phenylhexyl group, 1-naphthyl group, 2-naphthyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, More preferably, it is a phenyl group, o-tolyl group, m-tol Aryl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, mesityl group, cymenyl group, o-cumenyl group, m-cumenyl group, p-cume It is a nil group, a benzyl group, a phenethyl group, the (alpha)-methyl benzyl group, the benzhydryl group, a trityl group, a benzylidene group, a styryl group, a cinnamic group, a cinnamilide group, More preferably, it is a phenyl group, o-tolyl group, m -Tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2,5-xylyl group, mesityl group, cymenyl group, o-cumenyl group, m-cumenyl group, p -Cumenyl group, benzyl group, phenethyl group, most preferably phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 2,3-xylyl group, 2,4-xylyl group, 2, 5-xylyl group and benzyl group.
[95] Here, the hetero atom may specifically include an oxygen atom, a sulfur atom, a nitrogen atom, phosphorus, arsenic, antimony, silicon, germanium, tin, lead, boron, mercury, and the like, preferably an oxygen atom, a sulfur atom, or nitrogen. Atom, phosphorus, More preferably, they are an oxygen atom, a sulfur atom, and a nitrogen atom, More preferably, they are a sulfur atom and a nitrogen atom.
[96] Hereinafter, in the present specification, the hetero atom in “which may have one or more heteroatoms” means the above definition.
[97] Therefore, specifically showing the case where Y represents an aromatic hydrocarbon group having 5 to 12 carbon atoms having at least one heteroatom, for example, pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole , Imidazole, triazole, pyrazole, furazane, thiadiazole, oxadiazole, pyridazine, pyrimidine, pyrazine, indole, isoindole, indazole, chromen, quinoline, isoquinoline, cinnoline, quinazoline , Quinoxaline, nattylidine, phthalazine, purine, pteridine, thienofuran, imidazothiazole, benzofuran, benzothiophene, benzoxazole, benzthiazole, benzthiadiazole, benzimidazole , Imidazopyridine, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine, and the like, and preferably pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, and already Dazole, Triazole, Pyrazole, Furazane, Thiadiazole, Jade Saradiazole, pyridazine, pyrimidine, pyrazine, indole, isoindole, indazole, chromen, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, nattilidine, phthalazine, purine, pteridine, Thienofuran, imidazothiazole, benzofuran, benzothiophene, benzoxazole, benzthiazole, benzthiadiazole, benzimidazole, imidazopyridine, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine More preferably pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane, thiadiazole, oxadiazole, pyridazine , Pyrimidine, pyrazine, indole, isoindole, indazole, benzoxazole, benzthiazole, benzthiadiazole, more preferably thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole , Imidazole, triazole, pyrazole, furazane, thiadiazole, oxadiazole, indole, iso Indole, indazole, even more preferably thiophene, furan, pyrrole, oxazole, thiazole, imidazole, indole, and most preferably oxazole and indole.
[98] When Y represents an alicyclic hydrocarbon group having 3 to 7 carbon atoms which may have one or more substituents and may have one or more heteroatoms, the alicyclic hydrocarbon group means a cyclic aliphatic hydrocarbon group having 3 to 7 carbon atoms. Specifically, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group and the like Can be mentioned. Preferably, they are cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and cycloheptenyl group, More preferably, cyclo It is a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group, More preferably, they are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, Most preferably, a cyclopropyl group and a cyclo Butyl group and cyclopentyl group
[99] When ring Z represents a C5-6 aromatic hydrocarbon group which may further have a substituent of 0-4 and may have one or more heteroatoms, C5 in the said C5-12 aromatic hydrocarbon group The aromatic hydrocarbon groups of the 6 to 6 correspond, specifically, a phenyl group is mentioned, for example. Herein, an aromatic hydrocarbon group having 5 to 6 carbon atoms in which ring Z has at least one heteroatom, specifically, for example, pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, Dazole, triazole, pyrazole, furazane, thiadiazole, oxadiazole, pyridazine, pyrimidine, pyrazine, etc. are mentioned. Preferably pyridine, thiophene, furan, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, pyrazole, furazane, thiadiazole, oxadiazole, pyridazine, pyrimidine And pyrazine, more preferably pyridine, pyridazine, pyrimidine and pyrazine.
[100] Here, general formula
[101]
[102] The group represented by (wherein the symbol in the formula represents the same group as the above definition), the general formula
[103]
[104] The group represented by (wherein, the symbol in the formula represents the same group as the above definition) is to be bonded to each other on the ring Z with three atoms therebetween. Specifically, for example, when ring Z is a benzene ring, the general formula
[105]
[106] (Wherein, the symbol in the formula represents the same group as the above definition). Therefore, in the case where ring Z is a benzene ring, the groups are bonded to each other at the m position. Moreover, when ring Z is a furan ring, for example, it is a general formula
[107]
[108] Like the compound represented by (wherein, the symbol in the formula represents the same group as the above definition), it means to bond with three atoms in between each group. However, in the case of this furan ring, the position of the oxygen atom is not limited to the position of the said compound.
[109] In the present invention, the type of salt is not particularly limited, but specifically, addition of inorganic acids such as hydrofluoric acid salt, hydrochloride salt, sulfate salt, nitrate salt, perchlorate salt, phosphate salt, carbonate salt, bicarbonate salt, hydrobromide salt and hydroiodide salt salt; Addition salts of organic carboxylic acids such as acetates, maleates, fumarates, oxalates, lactates, tartarates and trifluoro acetates; Addition salts of organic sulfonic acids such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, hydroxymethane sulfonate, hydroxyethane sulfonate, benzene sulfonate, toluene sulfonate and taurine salts; Trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanol Addition salts of amines such as amine salts, tris (hydroxymethylamino) methane salts and phenethylbenzylamine salts; Addition salts of alkali metals such as sodium salts and potassium salts; Addition salts of alkaline earth metals such as magnesium salts and calcium salts; And addition salts of amino acids such as arginine salts, lysine salts, serine salts, glycine salts, asparagine salts and glutamate salts. Preferably a pharmacologically acceptable salt.
[110] Pharmacologically acceptable salts include, but are not particularly limited to, addition salts of inorganic acids such as hydrochloride, sulfate, carbonate, bicarbonate, hydrobromide and hydroiodide; Addition salts of organic carboxylic acids such as acetates, maleates, lactates, tartarates and trifluoroacetates; Addition salts of organic sulfonic acids such as methane sulfonate, hydroxymethane sulfonate, hydroxyethane sulfonate, benzene sulfonate, toluene sulfonate and taurine salts; Trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanol Addition salts of amines such as amine salts, tris (hydroxymethylamino) methane salts and phenethylbenzylamine salts; Addition salts of alkali metals such as sodium salts and potassium salts; And addition salts of amino acids such as arginine salts, lysine salts, serine salts, glycine salts, asparagine salts and glutamate salts.
[111] In the present invention, ester means an ester of a carboxy group of W in General Formula (I). This is not particularly limited as long as it is commonly used in terms of organic synthesis, and includes an ester group which is physiologically acceptable and hydrolyzed under physiological conditions, and specifically includes, for example, an alkyl group having 1 to 6 carbon atoms and an aryl having 6 to 12 carbon atoms. Aralkyl groups having 7 to 20 carbon atoms, such as groups and benzyl groups, heteroarylalkyl groups having 7 to 20 carbon atoms, 4-methoxybenzyl groups, alkanoyloxyalkyl groups, such as acetoxymethyl groups, propionyloxymethyl groups or pivaloxymethyl groups , Alkoxycarbonyloxyalkyl group, for example, methoxycarbonyloxymethyl group, ethoxycarbonyloxymethyl group or 2-methoxycarbonyloxyethyl group, (5-methyl-2-oxo-1,3-dioxo-4 -Yl) -methyl group etc. are mentioned.
[112] In the present invention, when the carboxylic acid derivative having the general formula (I) or a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof forms a solvate, these are all included in the present invention. do.
[113] Formula (I)
[114] (I)
[115] Although the compound of this invention represented by (the symbol in a formula represents the same group as the said definition) can be synthesize | combined by a conventional method, For example, it can synthesize | combine by the following method.
[116] A. General formula in which T is a single bond in General formula (I).
[117]
[118] The symbol of a formula shows the same group as the said definition, The manufacturing method of the compound of this invention.
[119] Specifically in the present invention, the following general formula
[120]
[121] The compound represented by (the symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following general manufacturing method A (1) or A (2), for example.
[122] General Recipe A (1)
[123]
[124] [Wherein, each symbol is the same group as defined above, Pc is a protecting group of a carboxy group, m ¹ is a single bond or an alkylene group of 1 to 5 carbon atoms, each of which may have one or more substituents, An alkenylene group or an alkynylene group having 2 to 5 carbon atoms, R ⁰ is an alkyl group having 1 to 6 carbon atoms, R ¹¹ is a hydrogen atom, a hydroxyl group protected with a protecting group, or each having 1 to 6 carbon atoms which may have one or more substituents C1-C6 hydroxyalkyl group in which the alkyl group, hydroxyl group is protected by a protecting group, C1-C6 aminoalkyl group in which an amino group was protected by the protecting group, C1-C6 halogenated alkyl group, C2-C12 alkoxyalkyl group, C3 A cycloalkyl group of 7 to 7, an alkenyl group of 2 to 6 carbon atoms, an alkynyl group of 2 to 6 carbon atoms, an aryl group of 6 to 12 carbon atoms, an alkylatom of 7 to 18 carbon atoms Group, each represents an aralkyl group having 7 to 18; The group represented by the general formula PcOCQ-, wherein the symbol in the formula represents the same group as the above definition, and the group represented by the general formula -M ^l CHO (where the symbol in the formula represents the same group as the above definition), have three groups on ring Z. It is assumed that the atoms are bonded to each other with the atoms in between.
[125] The compound of the general formula (1-i) can be produced by reacting the compound of the general formula (1-ii) with the compound of the general formula (1-i).
[126] The reaction is carried out using a compound of the general formula (1-ii) and a compound of the general formula (1-i) in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide, and the like, sodium hydride, potassium hydride and t-part. It can be performed in the presence of oxypotassium and the like. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[127] The compound of the formula (1-V) can be produced by reducing the compound of the formula (1-V) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran.
[128] Compounds of formula (1-v) may be prepared by acting on compounds of formula (1-v) to compounds of formula (1-v).
[129] The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[130] The compound of the general formula (1-vi) can be produced by hydrolyzing the compound of the general formula (1-v) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[131] General recipe A (2)
[132]
[133]
[134] [Wherein each symbol is the same group as defined above, Pn and Pn 'are each different and are a protecting group of an amino group, R ¹² is a hydrogen atom, a hydroxyl group protected with a protecting group, or each of which may have one or more substituents; An alkyl group of 6 to 6, a hydroxyalkyl group of 1 to 6 carbon atoms in which the hydroxyl group is protected by a protecting group, an aminoalkyl group of 1 to 6 carbon atoms in which the amino group is protected by a protecting group, a halogenated alkyl group of 1 to 6 carbon atoms, an alkoxyalkyl group of 2 to 12 carbon atoms, A cycloalkyl group having 3 to 7 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms, respectively. Represent; The group represented by the general formula PcOCQ-, wherein the symbol in the formula represents the same group as the above definition, and the group represented by the general formula -m ^l CHO (where the symbol in the formula represents the same group as the above definition), have three groups on ring Z. It is assumed that the atoms are bonded to each other with the atoms in between.
[135] The compound of the general formula (2-VII) can be produced by reacting the compound of the general formula (2-ii) with the compound of the general formula (2-i).
[136] The reaction is carried out using an organic solvent such as tetrahydrofuran, N, N-dimethylformamide, a compound of the general formula (2-ii) and a compound of the general formula (2-i) with sodium hydride, potassium hydride and t-butoxy It can be performed in the presence of potassium or the like. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[137] The compound of the general formula (2-VII) can be produced by reducing the compound of the general formula (2-VII) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran. As reaction temperature, it can carry out under ice cooling to room temperature.
[138] The compound of formula (2-v) may be prepared by reacting a compound of formula (2-V) with di-t-butyldicarbonate.
[139] The reaction can be carried out by reacting a compound of the general formula (2-VII) with di-t-butyldicarbonate in an organic solvent such as ethanol or methanol in the presence of an organic base such as triethylamine. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[140] The compound of formula (2-vi) can be prepared by acting on the compound of formula (2-v) with the compound of formula (1-V).
[141] The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[142] The compound of the general formula (2-VII) can be prepared by reacting the compound of the general formula (2-vi) with hydrochloric acid or the like in an organic solvent such as methanol, tetrahydrofuran, acetone, ethyl acetate and the like. As reaction temperature, it can carry out at ice-cooling to room temperature.
[143] The compound of the general formula (2-v ') can be produced by the reaction of the compound of the general formula (2-v') with isoamyl nitrite.
[144] The reaction can be carried out by adding isoamyl nitrite to a compound of the general formula (2-VIII) in the presence of an organic acid such as acetic acid in an organic solvent such as chloroform. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[145] The compound of formula (2-ix) can be prepared by heating and refluxing the compound of formula (2-v ') and the compound of formula (2-xi) in the presence of rhodium acetate.
[146] The compound of the general formula (2-x) can be produced by hydrolyzing the compound of the general formula (2-ix) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[147] In the present invention, the following general formula
[148]
[149] The compound represented by (the symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following general manufacturing method A (3), for example.
[150] General Recipe A (3)
[151]
[152] [Wherein, each symbol represents the same group as defined above, R ¹³ represents a hydrogen atom, a hydroxyl group protected by a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, and carbon number protected by a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms; The group represented by the formula O ₂ N- and the group represented by the general formula -m ^l CHO (where the symbol in the formula represents the same group as the above definition) are to be bonded to each other with three atoms on the ring Z.]
[153] The compound of the general formula (3-ii) can be produced by reacting the compound of the general formula (1-ii) with the compound of the general formula (3-i).
[154] The reaction is carried out using an organic solvent such as tetrahydrofuran, N, N-dimethylformamide, a compound of the general formula (1-ii) and a compound of the general formula (3-i) with sodium hydride, potassium hydride and t-butoxy It can be performed in the presence of potassium or the like. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[155] The compound of the general formula (3-X) can be produced by reducing the compound of the general formula (3-ii) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran.
[156] The compound of formula (3-VII) may be prepared by acting on the compound of formula (3-VII) with the compound of formula (3-vi).
[157] The reaction can be carried out by treatment with a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, carbonyldiimidazole and the like in an organic solvent such as tetrahydrofuran or the like. . If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[158] The compound of the general formula (3-v) can be produced by hydrolyzing the compound of the general formula (3-v) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[159] In the present invention, the following general formula
[160]
[161] The compound represented by (the symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following general manufacturing method A (4), for example.
[162] General Recipe A (4)
[163]
[164] [Wherein, each symbol represents the same group as defined above, R ¹⁴ represents a hydrogen atom, a hydroxyl group protected by a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, and carbon number protected by a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms; The group represented by the general formula PcOCQ-, wherein the symbol in the formula represents the same group as the above definition, and the group represented by the general formula -M ^l CHO (where the symbol in the formula represents the same group as the above definition), have three groups on ring Z. It is assumed that the atoms are bonded to each other with the atoms in between.
[165] The compound of the general formula (4-ii) can be produced by reacting the compound of the general formula (1-ii) with the compound of the general formula (4-i).
[166] The reaction is carried out using an organic solvent such as tetrahydrofuran, N, N-dimethylformamide, or a compound of the general formula (1-ii) and a compound of the general formula (4-i) with sodium hydride, potassium hydride and t-butoxy. It can be performed in the presence of potassium or the like. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[167] The compound of the general formula (4-VII) can be produced by treating the compound of the general formula (4-ii) with an organic acid such as trifluoroacetic acid in an organic solvent, for example, tetrahydrofuran, dichloromethane or the like.
[168] The compound of the general formula (4-VII) can be prepared by acting on the compound of the general formula (4-VII) with the compound of the general formula (1-VII).
[169] The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[170] The compound of the general formula (4-v) can be prepared by hydrolyzing the compound of the general formula (4-v) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent.
[171] The reaction temperature can be carried out at room temperature to under reflux.
[172] In the present invention, the following general formula
[173]
[174] (The symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following general manufacturing method A (5), for example.
[175] General Recipe A (5)
[176]
[177] [Wherein, each symbol represents the same group as defined above, R ¹⁵ represents a hydrogen atom, a hydroxyl group protected by a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, and carbon number protected by a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms; The group represented by the general formula P ^x2 HN-, where the symbol in the formula represents the same group as the above definition, and the group represented by the general formula -MCH (R ¹⁵ ) W (where the symbol in the formula represents the same group as the above definition) It is assumed that they are bonded to each other on the ring Z with three atoms therebetween.
[178] The compound of the general formula (5-ii) can be synthesized by reacting the compound of the general formula (3-X) and the compound of the general formula (5-i) in a solvent such as tetrahydrofuran. As reaction temperature, it can carry out at 50 degreeC from room temperature.
[179] The compound of the general formula (5-i) can be synthesized by reacting diphenylphosphoryl azide (DPPA) with the compound of the general formula (5-VII).
[180] The reaction can be carried out in the presence of an organic base such as triethylamine in an organic solvent such as toluene, tetrahydrofuran or the like. As reaction temperature, it can carry out by heating and reflux from room temperature.
[181] Next, the general synthesis method of the compound of the present invention will be described more specifically. The compounds of the present invention can be produced by the following general synthesis methods and by ordinary organic synthesis methods.
[182] Recipe A (1)
[183]
[184] [Symbols in the formula have the same meaning as the above definition, and R ^la is a hydrogen atom, a hydroxyl group protected with a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, carbon number protected with a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms.
[185] The compound of the general formula (1c) can be produced by reacting the compound of the general formula (lb) with the compound of the general formula (1a).
[186] The reaction is carried out by the presence of sodium hydride, potassium hydride and t-butoxy potassium in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide, or a compound of formula (lb) and a compound of formula (1a). Can be performed under the following conditions. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[187] The compound of the general formula (1d) can be produced by reducing the compound of the general formula (1c) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran.
[188] The compound of formula (1e) may be prepared by acting on the compound of formula (1d) with a compound of formula (lg).
[189] The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[190] The compound of the general formula (1f) can be produced by hydrolyzing the compound of the general formula (1e) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out by heating and reflux from room temperature.
[191] Recipe A (2)
[192]
[193]
[194] [Symbols in the formula have the same meaning as defined above, and R ^1b is a hydrogen atom, a hydroxyl group protected with a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, carbon number protected with a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms.
[195] The compound of the general formula (2c) can be produced by reacting the compound of the general formula (2b) with the compound of the general formula (2a).
[196] The reaction is carried out by the presence of sodium hydride, potassium hydride, t-butoxy potassium, etc. Can be performed under the following conditions. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[197] The compound of the formula (2d) can be produced by reducing the compound of the formula (2c) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran. As reaction temperature, it can carry out under ice cooling to room temperature.
[198] The compound of formula (2e) may be prepared by reacting the compound of formula (2d) with di-t-butyldicarbonate.
[199] The reaction can be carried out by reacting the compound of formula (2d) with di-t-butyldicarbonate in an organic solvent such as ethanol or methanol in the presence of an organic base such as triethylamine. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[200] The compound of formula (2f) may be prepared by acting on the compound of formula (2e) with the compound of formula (lg).
[201] The reaction is carried out in an organic solvent such as dimethyl sulfoxide, NlN-dimethylformamide, or the like as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, or the like. This can be done by processing. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[202] The compound of the formula (2 g) can be prepared by reacting the compound of the formula (2f) with hydrochloric acid or the like in an organic solvent such as methanol, tetrahydrofuran, acetone, ethyl acetate and the like. As reaction temperature, it can carry out at ice-cooling to room temperature.
[203] The compound of the formula (2h) can be produced by the reaction of the compound of the formula (2g) with isoamyl nitrite.
[204] The reaction can be carried out by adding isoamyl nitrite to the compound of the formula (2 g) in the presence of an organic acid such as acetic acid in an organic solvent such as chloroform. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[205] The compound of formula (2i) can be prepared by heating and refluxing the compound of formula (2h) and the compound of formula (2k) in the presence of rhodium acetate.
[206] The compound of the formula (2j) can be prepared by hydrolyzing the compound of the formula (2i) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out by heating and reflux from room temperature.
[207] Recipe A (3)
[208]
[209] [Symbols in the formula have the same meaning as defined above, and R ^1c is a hydrogen atom, a hydroxyl group protected with a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, carbon number protected with a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms.
[210] The compound of the general formula (3b) can be produced by reacting the compound of the general formula (1b) with the compound of the general formula (3a).
[211] The reaction is carried out in the presence of sodium hydride, potassium hydride, t-butoxy potassium and the like in a compound of the general formula (1b) such as tetrahydrofuran, N, N-dimethylformamide and the compound of the general formula (3a). Can be performed under the following conditions. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[212] The compound of the general formula (3c) can be produced by reducing the compound of the general formula (3b) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate or tetrahydrofuran.
[213] The compound of general formula (3d) can be prepared by acting on the compound of general formula (3c) with the compound of general formula (3f).
[214] The reaction can be carried out by treatment with a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, carbonyldiimidazole and the like in an organic solvent such as tetrahydrofuran or the like. . If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[215] The compound of the general formula (3e) can be produced by hydrolyzing the compound of the general formula (3d) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out by heating and reflux from room temperature.
[216] Recipe A (4)
[217]
[218] [Symbols in the formula have the same meaning as defined above, and R ^1d is a hydrogen atom, a hydroxyl group protected with a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, and carbon number protected with a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms.
[219] The compound of the general formula (4b) can be produced by reacting the compound of the general formula (1b) with the compound of the general formula (4a).
[220] The reaction is carried out in the presence of sodium hydride, potassium hydride, t-butoxy potassium and the like in a compound of the general formula (1b) such as tetrahydrofuran, N, N-dimethylformamide and the compound of the general formula (4a). Can be performed under the following conditions. As reaction temperature, it can carry out at ice-cooling-50 degreeC.
[221] The compound of the general formula (4c) can be produced by treating the compound of the general formula (4b) with an organic acid such as trifluoroacetic acid in an organic solvent, for example, tetrahydrofuran, dichloromethane or the like.
[222] The compound of the general formula (4d) can be prepared by acting on the compound of the general formula (4c) with the compound of the general formula (1 g).
[223] The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[224] The compound of the general formula (4e) can be produced by hydrolyzing the compound of the general formula (4d) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out by heating and reflux from room temperature.
[225] Recipe A (5)
[226]
[227] [Wherein each symbol is the same group as defined above, R ^1e is a hydrogen atom, a hydroxyl group protected by a protecting group, or an alkyl group having 1 to 6 carbon atoms, each of which may have one or more substituents, and carbon number protected by a protecting group 1 to 6 hydroxyalkyl groups, amino groups having 1 to 6 carbon atoms in which the amino group is protected with a protecting group, halogenated alkyl groups having 1 to 6 carbon atoms, alkoxyalkyl groups having 2 to 12 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, and 2 to 6 carbon atoms An alkenyl group, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkylaryl group having 7 to 18 carbon atoms, and an aralkyl group having 7 to 18 carbon atoms.
[228] The compound of the general formula (5b) can be synthesized by reacting the compound of the general formula (3c) with the compound of the general formula (5a) in a solvent such as tetrahydrofuran. As reaction temperature, it can carry out at 50 degreeC from room temperature.
[229] The compound of formula (5a) can be synthesized by reacting diphenylphosphoryl azide (DPPA) with the compound of formula (5c).
[230] The reaction can be carried out in the presence of an organic base such as triethylamine in an organic solvent such as toluene, tetrahydrofuran or the like. As reaction temperature, it can carry out by heating and reflux from room temperature.
[231] B. In general formula (I), T is not a single bond,
[232]
[233] The symbol of a formula shows the same group as the said definition, The manufacturing method of the compound of this invention.
[234] Hereinafter, the general synthesis method of the compound of the present invention will be described.
[235] Specifically in the present invention, the following general formula
[236]
[237] The compound represented by (the symbol in a formula represents the same group as the said definition, respectively) can be synthesize | combined with the following manufacturing methods B (1), B (6) or B (7), for example.
[238] Specifically in the present invention, the following general formula
[239]
[240] The compound represented by (the symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following manufacturing method B (3), for example.
[241] Specifically in the present invention, the following general formula
[242]
[243] The compound represented by (the symbol in a formula represents each group same as the said definition) can be synthesize | combined with the following manufacturing method B (4) or B (5), for example.
[244] Recipe B (1)
[245]
[246] [In the formula, each symbol represents the same group as the above definition, and R ² represents a group corresponding to the YL-group or Y = 1-group shown above, respectively.]
[247] The compound of the general formula (1b) is made into an acid anhydride by reacting a compound of the general formula (1a) with methyl chloroformate, ethyl chloroformate, etc. in an organic solvent such as tetrahydrofuran, and then sodium borohydride, potassium borohydride, or the like. It can manufacture by reducing to.
[248] The compound of formula (1c) may be prepared by reacting a compound of formula (1b) with diphenylphosphoryl azide in an organic solvent such as diazabicyclo [5.4.0] undecene in an organic solvent such as toluene. Can be.
[249] The compound of the general formula (1d) can be produced by acting triphenylphosphine on the compound of the general formula (1c) in an organic solvent such as tetrahydrofuran.
[250] The compound of the general formula (1e) can be prepared by acting on the compound of the general formula (1d) with the compound of the general formula (1 g). The reaction is carried out in an organic solvent such as dimethyl sulfoxide, NN-dimethylformamide, or the like, for example, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, or the like. This can be done by processing. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[251] The compound of the general formula (1f) can be produced by hydrolyzing the compound of the general formula (1e) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[252] Recipe B (2)
[253]
[254] [Wherein, R ³ represents a protecting group of a hydroxyl group, and R ⁴ and R ⁵ each represent a substituent in Y.]
[255] The compound of the general formula (2b) reacts a strong base such as normal butyl lithium, sec-butyl lithium, lithium diisopropyl amide in a solvent such as anhydrous diethyl ether or tetrahydrofuran to the general formula (2a), and alkoxy group After rethiolating the ortho position of, it can be prepared by reacting a formylating agent such as N, N-dimethylformamide. As reaction temperature, it can carry out at -78 degreeC-50 degreeC.
[256] The compound of the general formula (2c) acts an acid such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, methanesulfonic acid in a solvent such as acetone or tetrahydrofuran when R ¹ of the compound of the general formula (2b) is a methoxymethyl group or the like. You can get it.
[257] The compound of the general formula (2d) is a compound of the general formula (2c) such as sodium hydride and potassium tert-butoxide in a solvent such as N, N-dimethylformamide, tetrahydrofuran or N-methylpyrrolidone. After reacting a base, it can obtain by making halogenated alkyl, such as methyl iodide, etc. react. Reaction temperature can be performed in the range of -78 degreeC-100 degreeC.
[258] The compound of the general formula (2e) can be obtained by acting the compound of the general formula (2d) with an oxidizing agent such as sodium chlorite in a mixed solvent of dimethyl sulfoxide and an aqueous sodium dihydrogen phosphate solution.
[259] Recipe B (3)
[260]
[261]
[262] [In the formula, each symbol represents the same group as the above definition, the R ⁶ O- group represents a substituent on the ring Z, and R ⁷ represents a protecting group of the carboxy group, respectively.]
[263] The compound of the general formula (3b) reacts an appropriate aniline derivative with a compound of the general formula (3a) by reacting an acid halogenating agent such as thionyl chloride or oxalyl dichloride in a solvent such as dichloromethane, carbon tetrachloride or chloroform. Can be prepared. The reaction can be performed at -20 ° C to 100 ° C.
[264] The compound of the general formula (3c) is a compound of the general formula (3b) and hexamethylenetetramine in a solvent such as trifluoroacetic acid in the range of 50 ℃ to 100 ℃, or dichloromethyl methyl ether in dichloromethane And titanium tetrachloride may be prepared by acting at -20 ° C to 50 ° C.
[265] The compound of the general formula (3d) can be prepared by acting on the compound of the general formula (3c) with a suitable phosphoran or phosphonate among N, N-dimethylformamide, N-methylpyrrolidone and tetrahydrofuran. .
[266] The compound of the general formula (3e) can be produced by carrying out the hydrogenation reaction of the compound of the general formula (3d) in the presence of a catalyst such as palladium carbon in a solvent such as ethanol, ethyl acetate, methanol or tetrahydrofuran.
[267] The compound of the general formula (3f) can be produced by hydrolyzing the compound of the general formula (3e) with an inorganic base such as sodium hydroxide or potassium hydroxide in a solvent such as ethanol, methanol or tetrahydrofuran.
[268] Recipe B (4)
[269]
[270]
[271] [In the formula, each symbol represents the same group as the above definition.]
[272] The compound of the general formula (4c) can be produced by reacting the compound of the general formula (4b) with the compound of the general formula (4a). The reaction is carried out by diethylazodicarboxylate and diisopropylazodicaride in an organic solvent, such as tetrahydrofuran, in the presence of triphenylphosphine, a compound of formula (4a) and a compound of formula (4b). It can carry out by processing with a carboxylate.
[273] The compound of the general formula (4d) can be prepared by acting the compound of the general formula (4c) and hexamethylenetetramine in a solvent such as trifluoroacetic acid in a range of 50 ° C to 100 ° C.
[274] The compound of the general formula (4f) is reacted with a compound of the general formula (4e) in an organic solvent such as tetrahydrofuran in the presence of sodium hydride and potassium hydride, and then reacted with ethanol or ethyl acetate. It can manufacture by reducing in presence of a catalyst, such as palladium carbon, in a solvent.
[275] The compound of the general formula (4 g) can be produced by hydrolyzing the compound of the general formula (4f) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[276] Recipe B (5)
[277]
[278]
[279] [Wherein, each symbol represents the same group as defined above and R ⁸ represents a group corresponding to the YL-group or Y = L-group shown above, respectively.]
[280] The compound of the general formula (5b) is made into an acid anhydride by reacting a compound of the general formula (5a) with methyl chloroformate, ethyl chloroformate and the like in an organic solvent such as tetrahydrofuran, and then sodium borohydride, potassium borohydride and the like. It can manufacture by reducing to.
[281] The compound of the general formula (5d) can be prepared by reacting the compound of the general formula (5c) in the presence of sodium hydride, potassium hydride and the like in an organic solvent such as tetrahydrofuran.
[282] The compound of formula (5e) is reacted with N, N-dimethylformamide, N-formylmorpholine, etc. in an organic solvent such as tetrahydrofuran in the presence of n-butyllithium, etc. It can manufacture.
[283] The compound of the general formula (5f) is reacted with a compound of the general formula (4e) in the presence of sodium hydride, potassium hydride, etc. in an organic solvent such as tetrahydrofuran, and then ethanol, ethyl acetate, or the like. It can manufacture by reducing in presence of catalysts, such as palladium carbon, in the solvent of.
[284] The compound of the general formula (5 g) can be produced by hydrolyzing the compound of the general formula (5f) with an inorganic base such as sodium hydroxide, potassium hydroxide or the like in an ethanol solvent. As reaction temperature, it can carry out at room temperature to heating reflux.
[285] Recipe B (6)
[286]
[287] [In the formula, each symbol represents the same group as the above definition, and R ² represents a group corresponding to the YL-group or Y = L- group shown above, respectively.]
[288] Compounds of formula (6b) can be prepared by acting 2-methoxybenzyl alcohol on compounds of formula (6a). The reaction can be carried out in an organic solvent such as dimethyl sulfoxide, N, N-dimethylformamide, or the like, as a condensing agent such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate. It can carry out by processing by such. If necessary, an organic base such as triethylamine may be added. As reaction temperature, it can carry out at ice-cooling to room temperature.
[289] The compound of the formula (6c) is a compound of the formula (6b) and hexamethylenetetramine in a solvent such as trifluoroacetic acid in the range of 50 ℃ to 100 ℃, or dichloromethyl methyl ether in dichloromethane And titanium tetrachloride may be prepared by acting at -20 ° C to 50 ° C.
[290] The compound of the general formula (6d) can be prepared by acting 2.4-thiazolidinedione on the compound of the general formula (6c). The reaction can be carried out by refluxing in the presence of a secondary amine (piperidine, pyrrolidine, etc.) and an organic acid (acetic acid, benzoic acid, etc.) as a catalyst in an organic solvent such as benzene, toluene and the like.
[291] Recipe B (7)
[292]
[293] [In the formula, each symbol represents the same group as the above definition, and R ² represents a group corresponding to the YL-group or Y = L- group shown above, respectively.]
[294] The compound of the general formula (7b) is a compound of the general formula (7a) in a solvent such as ethanol, ethyl acetate, N, N- dimethylformamide, at room temperature to heating, in the presence of a catalyst such as palladium carbon, from normal pressure to 20kg / ㎠ It can manufacture by performing hydrogenation reaction under reduced pressure.
[295] Recipe C (1)
[296]
[297] The compound of formula (1b) may be prepared by reacting a compound of formula (1b) with diphenylphosphoryl azide in an organic solvent such as diazabicyclo [5.4.0] undecene in an organic solvent such as toluene. Can be. As reaction temperature, -20 degreeC-50 degreeC are preferable.
[298] The compound of the general formula (1c) can be produced by catalytic hydrogenation of the compound of the general formula (1b) in the presence of 10% palladium carbon and tertiary butyl dicarbonate in an organic solvent such as ethyl acetate.
[299] The compound of the general formula (1d) can be prepared by reacting the compound of the general formula (1c) with N-bromosuccimid in an organic solvent such as N, N-dimethylformamide or acetonitrile. As reaction temperature, -20 degreeC-50 degreeC are preferable.
[300] The compound of the formula (1e) is a compound of the formula (1c) and carbon monoxide in an organic solvent such as N, N-dimethylformamide in the presence of a metal catalyst such as dichlorobistriphenylphosphinepalladium and a reducing agent such as sodium formate. It can be prepared by reacting with. As reaction temperature, 80 degreeC-150 degreeC is preferable.
[301] The compound of the general formula (1f) is reacted with N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, or the appropriate phosphorane and phosphonate to the compound of the general formula (1e), followed by ethanol, In solvents, such as ethyl acetate, methanol, and tetrahydrofuran, it can manufacture by performing hydrogenation reaction in presence of catalysts, such as palladium carbon. As reaction temperature, 0 to 50 degreeC is preferable.
[302] Recipe C (2)
[303]
[304] [Wherein, R represents a group corresponding to the Y-L- group or Y = L- group shown above.]
[305] The compound of formula (2b) is reacted with (triphenylphosphoranylidene) acetaldehyde in a solvent such as toluene in a solvent such as toluene, preferably N, N-dimethyl to the compound of formula (2a). In a solvent such as formamide, N-methylpyrrolidone or tetrahydrofuran, a suitable phosphonate is reacted in the presence of a base such as sodium hydride, followed by palladium in a solvent such as methanol or ethanol ethyl tetrahydrofuran. It can manufacture by performing hydrogenation reaction in presence of catalysts, such as carbon.
[306] The compound of the general formula (2c) deprotects tert-butoxycarbonyl group, which is a protecting group of the amino group of the compound of the formula (2b), under acidic conditions, condenses RC0OH to the resulting amino group, and then hydrolyzes the ester group with a base. It can manufacture by doing. The deprotection reaction is carried out using an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as dichloromethane, 1,4-dioxane, methanol, or ethanol. The condensation reaction can be carried out using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate or the like as a condensation agent in an organic solvent such as dimethyl sulfoxide or N, N-dimethylformamide. . Moreover, if necessary, bases, such as a triethylamine, can also be added. The hydrolysis reaction can be performed using a base such as sodium hydroxide or potassium hydroxide in a solvent such as methanol or ethanol.
[307] Recipe C (3)
[308]
[309] [Wherein, R represents a group corresponding to the Y-L- group or Y = L- group shown above.]
[310] The compound of formula (3b) can be produced by acting the compound of formula (3a) in an organic peroxide such as m-chloroperbenzoic acid in a solvent such as dichloromethane. The present compound can also be prepared by reacting acetic acid, water and the like with hydrogen peroxide in a solvent.
[311] The compound of formula (3c) can be produced by acting the compound of formula (3b) in a solvent such as dichloromethane with dimethylcarbamyl chloride and trimethylsilylcyanide.
[312] The compound of formula (3d) can be produced by subjecting the compound of formula (3c) to a hydrogenation reaction in the presence of a catalyst such as palladium carbon in a solvent such as methanol or ethanol ethyl tetrahydrofuran. At this time, when an acid represented by hydrochloric acid or the like is added, the reaction is accelerated.
[313] The compound of general formula (3e) can be manufactured by condensing RCOOH with the amino group of the compound of formula (3d), and then hydrolyzing the ester group with a base. The condensation reaction can be performed using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate or the like as a condensation agent in an organic solvent such as dimethyl sulfoxide or N, N-dimethylformamide. If necessary, bases such as triethylamine may be added. The hydrolysis reaction can be performed using a base such as sodium hydroxide or potassium hydroxide in a solvent such as methanol or ethanol.
[314] Recipe C (4)
[315]
[316] The compound of general formula (4a) is obtained by reducing the corresponding benzoic acid and benzaldehyde derivative using sodium borohydride, diborane, or the like. As reaction temperature, -20 degreeC-50 degreeC are preferable.
[317] The compound of the general formula (4b) is obtained by reacting an alkylating agent such as trialkylsilyl halide with a compound of the general formula (4b) in a solvent such as tetrahydrofuran. As reaction temperature, 0 to 50 degreeC is preferable.
[318] The compound of the general formula (4c) is reacted with a strong base such as butyllithium to the compound of the general formula (4b) in a solvent such as tetrahydrofuran and lithiated to form a formylating agent such as 4-formylmorpholine. It can be prepared by the reaction. As reaction temperature, -78 degreeC is suitable.
[319] The compound of the general formula (4d) is reacted with a compound of the general formula (4c) with N, N-dimethylformamide, N-methylpyrrolidone or tetrahydrofuran with a suitable phosphoran and phosphonate, and then tetrahydro It is obtained by reacting tetrabutylammonium fluoride in a solvent such as furan. As reaction temperature, 0 to 50 degreeC is preferable.
[320] The compound of formula (4e) is reacted with the compound of formula (4d) and diphenylphosphoryl azide in an organic solvent such as diazabicyclo [5.4.0] undecene in an organic solvent such as toluene, It can manufacture by catalytic hydrogenation reduction in presence of 10% palladium carbon and 3 butyl dicarbonate in organic solvents, such as ethyl acetate. As reaction temperature, -20 degreeC-50 degreeC are preferable.
[321] Recipe C (5)
[322]
[323] The compound of the general formula (5b) is obtained by reacting a compound of the general formula (5a) with a dehydrating agent such as trimethyl orthoformate and an acid catalyst such as tosyl acid in a solvent such as methanol at a temperature of 0 ° C to 80 ° C. Lose.
[324] The compound of the general formula (5c) is a diazabi in an organic solvent such as toluene and the alcohol obtained by reacting a compound of the general formula (5b) with a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran or diethyl ether. It is obtained by reacting with diphenylphosphoryl azide in the presence of an organic base such as cyclo [5.4.0] undecene and then acting with an acid such as hydrochloric acid.
[325] The compound of the general formula (5d) is reacted with N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, or the appropriate phosphoran and phosphonate to the compound of the general formula (5c), followed by ethanol, In solvents, such as ethyl acetate, methanol, and tetrahydrofuran, it can manufacture by performing hydrogenation reaction in presence of catalysts, such as palladium carbon. As reaction temperature, 0 to 50 degreeC is preferable.
[326] The compound of the general formula (5e) is a compound of the general formula (5d) in iodomethane, ethane, propane, trifluoromethanesulfonyl chloride in organic solvents such as N, N-dimethylformamide, acetonitrile and pyridine. It is obtained by reacting an alkylating agent such as 0 ° C. to 50 ° C.
[327] The compound of the general formula (5f) is a compound of the general formula (5e) (R2 = trifluoromethanesulfone derivative) in an organic solvent such as toluene, a metal catalyst such as tetrakistriphenylphosphinepalladium and inorganic such as potassium carbonate. In the presence of a base, allylboric acid derivatives are obtained by reacting at 80 ° C to 150 ° C.
[328] Recipe C (6)
[329]
[330] The compound of formula (6b) may be prepared by reacting the compound of formula (6a) with N-iodosuccimide in an organic solvent such as N, N-dimethylformamide, acetonitrile, or the like. . As reaction temperature, -0 degreeC-50 degreeC are preferable.
[331] The compound of the general formula (6c) is represented by the general formula (6b) in the presence of an organic base such as metal catalyst such as dichlorobistriphenylphosphinepalladium, copper iodide, triethylamine, and the like in an organic solvent such as N, N-dimethylformamide. It can be prepared by reacting a compound of acetylene with acetylene. As reaction temperature, 80 degreeC-150 degreeC is preferable.
[332] The compound of the formula (6d) is obtained by heating the compound of the formula (6c) in the presence of an inorganic base such as potassium carbonate in an organic solvent such as N, N-dimethylformamide. As reaction temperature, 80 degreeC-150 degreeC is preferable.
[333] Recipe C (7)
[334]
[335]
[336] The compound of the general formula (7c) is reacted with hexamethyldisilazane sodium, lithium diisopropylamide and the like of the compound of the general formula (7b) in anhydrous solvents such as tetrahydrofuran in the range of -78 ° C to 0 ° C. It can then be prepared by reacting with a compound of the general formula (7a) (PG means a protecting group which is broken by acid).
[337] The compound of formula (7d) can be prepared by reacting trifluoroacetic acid and triethylsilane with the compound of formula (7c) in the range of 0 ° C to room temperature.
[338] The compound of the general formula (7e) is general in the presence of a base such as pyridine and triethylamine in anhydrous solvents such as N, N-dimethylformamide, dichloromethane or diethyl ether in the range from -78 ° C to room temperature. It can be prepared by reacting the compound of formula (7d) with a suitable acid chloride, activated ester, and the like.
[339] The compound of the general formula (7f) can be produced by hydrolyzing the compound of the general formula (7e) with an inorganic base such as sodium hydroxide or lithium hydroxide in a solvent such as ethanol, methanol, or tetrahydrofuran.
[340] The intermediate 7e can also be produced by the following route.
[341]
[342]
[343] The compound of the general formula (7h) is reacted with hexamethyldisilazane sodium, lithium diisopropylamide and the like of the compound of the general formula (7b) in anhydrous solvents such as tetrahydrofuran in the range of -78 ° C to 0 ° C. It can then be prepared by reacting with a compound of the general formula (7 g).
[344] The compound of formula (7e) may be prepared by reacting trifluoroacetic acid and triethylsilane with the compound of formula (7h) in the range of 0 ° C to room temperature.
[345]
[346] The compound of the formula (7j) is dibutyl in the compound of the formula (7i) (X means a subsidiary auxiliary group such as oxazolidinone) in anhydrous solvents such as toluene and dichloromethane in the range of -78 ° C to room temperature. After reacting a dialkyl borane compound such as boron triflate and the like, the compound is reacted with a compound of the general formula (7a) (PG means a protecting group which is broken by an acid) in the range of -78 ° C to room temperature. Stereo selective production can be made.
[347] The compound of general formula (7k) can be prepared by reacting trifluoroacetic acid and triethylsilane with the compound of general formula (7j) in the range of 0 ° C to room temperature. .
[348] The compound of the general formula (7l) is general in the presence of a base such as pyridine or triethylamine in anhydrous solvents such as N, N-dimethylformamide, dichloromethane, or diethyl ether in the range from -78 ° C to room temperature. It can be prepared by reacting the compound of formula (7k) with a suitable acid chloride, active ester, and the like.
[349] The compound of the general formula (7m) is a compound of the general formula (7l) in a solvent such as ethanol, methanol or tetrahydrofuran or a mixed solvent of water and one of these solvents in the range of -30 ° C to room temperature. It may be prepared by reacting with an inorganic base such as lithium hydroxide / hydrogen peroxide or sodium hydroxide or by sequentially reacting sodium methoxide with sodium hydroxide.
[350] The intermediate 7l can also be produced by the following route.
[351]
[352] The compound of the formula (7m) is dibutyl in a compound of the formula (7i) (X means a subsidiary auxiliary such as oxazolidinone) in anhydrous solvents such as toluene and dichloromethane in the range of -78 ° C to room temperature. After reacting a dialkyl boron compound such as boron triflate and then reacting with a compound of the general formula (7 g) in the range of -78 ° C to room temperature, diastereo can be selectively prepared.
[353] The compound of formula (7l) can be prepared by reacting trifluoroacetic acid and triethylsilane with a compound of formula (7m) in the range of 0 ° C to room temperature.
[354] Recipe C (8)
[355]
[356]
[357] Compounds of formula (1b) can be prepared by acting orthoesters in the presence of Lewis acid on compounds of formula (1a). The reaction can be carried out in an organic solvent such as methanol, ethanol, toluene or the like. P-toluenesulfonic acid, hydrochloric acid, etc. can be used as a Lewis acid, methyl ortho formate, ethyl ortho formate, etc. can be used as an ortho ester. As reaction temperature, it can carry out at room temperature-100 degreeC.
[358] The compound of formula (8c) can be prepared by reacting a compound such as n-butyllithium with a compound of formula (8b) and reacting N, N-dimethylformamide, N-formylmorpholine, or the like. have. The reaction can be carried out in an organic solvent such as diethyl ether, tetrahydrofuran or the like, and can be carried out at -80 ° C to 0 ° C as the reaction temperature.
[359] The compound of the general formula (8d) can be prepared by reacting a compound of the general formula (8c) with a solvent such as methanol or ethanol dehydrogen borohydride. As reaction temperature, it can carry out at 0 degreeC-room temperature.
[360] Compounds of formula (8e) can be synthesized by reacting diphenylphosphoryl azide with compounds of formula (8d) in the presence of 1.8-diazabicyclo [5.4.0] -7-undecene. The reaction can be carried out in toluene and can be carried out at 0 ° C to room temperature as the reaction temperature.
[361] Compounds of formula (8f) can be prepared by acting triphenylphosphine on the compounds of formula (8e). The reaction can be carried out in an organic solvent such as tetrahydrofuran, water or the like, and can be carried out at 0 ° C to 50 ° C as the reaction temperature.
[362] Compounds of formula (8g) can be prepared by acting a third butyldicarbonate on the compound of formula (8f). The reaction can be carried out in an organic solvent such as tetrahydrofuran, dichloromethane or the like, and can be carried out at 0 ° C to room temperature as the reaction temperature.
[363] The compound of the formula (8h) can be produced by treating the compound of the formula (8g) with an acid such as hydrochloric acid. Reaction can be performed in an organic solvent, for example, tetrahydrofuran, acetone, etc., and can be performed at 0 degreeC-room temperature as reaction temperature.
[364] Recipe C (9)
[365]
[366] The compound of the general formula (9b) can be produced by acting on phosphorus tribromide, thionyl bromide or the like in a solvent such as dichloromethane to the compound of the general formula (9a).
[367] The compound of the formula (9c) is etherified by reacting the compound of the formula (9b) with an alcohol in a solvent such as tetrahydrofuran in the presence of a base such as sodium hydride, followed by sodium hydroxide or hydroxide in ethanol or methanol. It can manufacture by hydrolyzing with inorganic bases, such as potassium.
[368] Recipe C (10)
[369]
[370] The compound of the general formula (10b) is contained in organic solvents such as benzene and toluene in the presence of organic acids (acetic acid, benzoic acid, etc.) and secondary amines (piperidine, pyrrolidine, etc.) in the compound of the general formula (9b). After 4-thiazolidinedione was reacted under heating and refluxing, in a solvent such as ethanol, ethyl acetate, N, N-dimethylformamide, and at room temperature to heating, under the presence of a catalyst such as palladium carbon, under normal pressure to 20 kg / cm &lt; 2 &gt; It can manufacture by performing a hydrogenation reaction.
[371] The compound of the general formula (10c) can be produced by condensing carboxylic acid with the resulting amino group after deprotecting the tert-butoxycarbonyl group, which is a protecting group of the amino group of the compound of the general formula (10b), under acidic conditions. The deprotection reaction is carried out using an acid such as hydrochloric acid or trifluoroacetic acid in a solvent such as dichloromethane, 1,4-dioxane, methanol, or ethanol. The condensation reaction can be carried out using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate or the like as a condensation agent in an organic solvent such as dimethyl sulfoxide or N.N-dimethylformamide. If necessary, bases such as triethylamine may be added.
[372] Recipe C (11)
[373]
[374] The compound of the general formula (11b) is generally used at room temperature or under reflux under a catalyst such as 1,1-bis (diphenylphosphino) ferrocene dichloropalladium and an inorganic base such as potassium acetate in a solvent such as dimethyl sulfoxide. It can be prepared by reacting the formula (11a) and bis (pinacholate) diboron.
[375] The compound of the general formula (11c) is generally used at room temperature or under reflux under a catalyst such as 1,1-bis (diphenylphosphino) ferrocene dichloropalladium and an inorganic base such as potassium carbonate in a solvent such as dimethoxyethane. After reacting Formula (11b) and allyl bromide, it can be produced by hydrolysis with an inorganic base such as sodium hydroxide or potassium hydroxide in ethanol or methanol.
[376] In the above synthesis method, the hydroxyl group protected with a protecting group means a hydroxyl group protected with a protecting group of a hydroxyl group, and any specific group is particularly limited as long as it is a hydroxyl group protected with a group commonly known as a protecting group of an organic synthetic hydroxyl group. Although it does not, for example, As a protecting group of a hydroxyl group, Lower alkyl silyl groups, such as a trimethylsilyl group and t-butyl dimethyl silyl group; Lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; For example, tetrahydropyranyl group; Aralkyl groups, such as a benzyl group, p-methoxybenzyl group, 2, 4- dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, and trityl group; For example, acyl groups, such as a formyl group and an acetyl group; Lower alkoxycarbonyl groups such as t-butoxycarbonyl group, 2-iodine ethoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; For example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyl Alkenyloxycarbonyl groups such as an oxycarbonyl group and a cinnamiloxycarbonyl group; For example, an aralkyloxycarbonyl group, such as a benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc. are mentioned.
[377] Desorption of these protecting groups can be performed by normal methods, such as hydrolysis and a reduction, corresponding to the kind of protecting group used.
[378] The protecting group of the amino group in the amino group protected by the protecting group may be any group as long as it is, for example, a group generally known as a protecting group of an amino group in organic synthesis, and is not particularly limited. For example, formyl group and acetyl Substituted or unsubstituted lower alkanoyl groups, such as group, a chloroacetyl group, a dichloroacetyl group, a propionyl group, a phenylacetyl group, a phenoxyacetyl group, a thienylacetyl group; Substituted or unsubstituted lower alkoxycarbonyl groups, such as a benzyloxycarbonyl group, t-butoxycarbonyl group, and p-nitrobenzyloxycarbonyl group; Substituted lower alkyl groups such as methyl group, t-butyl group, 2,2,2-trichloroethyl group, trityl group, p-methoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group and pivaloyloxymethyl group; Substituted silyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; Substituted silyl alkoxy alkyl groups, such as a trimethyl silyl methoxymethyl group, a trimethyl silyl ethoxy methyl group, t-butyl dimethyl silyl methoxymethyl group, and a t-butyl dimethyl silyl ethoxy methyl group; Benzylidene group, sillylidene group, p-nitrobenzylidene group, m-chlorobenzylidene group, 3,5-di (t-butyl) -4-hydroxybenzylidene group, 3,5-di (t-butyl Substituted or unsubstituted benzylidene groups, such as the benzylidene group, etc. are mentioned.
[379] Removal of these protecting groups can be carried out by conventional methods such as hydrolysis and reduction, depending on the type of protecting group used.
[380] The protecting group of the carboxyl group is not particularly limited as long as it is a carboxyl group that is usually protected with a group known as a protecting group of an organic synthetic carboxyl group. Examples of the protecting group for the carboxyl group include methyl, ethyl and iso groups. Linear or branched lower alkyl groups having 1 to 4 carbon atoms such as propyl group and t-butyl group, for example, halogeno lower alkyl groups such as 2-iodine iodide group and 2,2,2-trichloroethyl group, for example Lower aliphatic acyloxymethyl groups such as methoxymethyl group, ethoxymethyl group, isobutoxymethyl group, butyryloxymethyl group, pivaloyloxymethyl group, for example, 1-methoxycarbonyloxyethyl group, 1- to 1-lower alkoxycarbonyloxyethyl groups such as oxycarbonyloxyethyl groups, for example arals such as benzyl, p-methoxybenzyl groups, o-nitrobenzyl groups, p-nitrobenzyl groups A kill group, a benzhydryl group, a phthalidyl group, etc. are mentioned.
[381] Removal of these protecting groups can be carried out by conventional methods such as hydrolysis and reduction, depending on the type of protecting group used.
[382] As described above, the solvent that can be used in the present invention does not inhibit the reaction, and any solvent is not particularly limited as long as it is normally used in organic synthesis. For example, methanol, ethanol, propanol, butanol Lower alcohols such as these, polyalcohols such as ethylene glycol and glycerin, ketones such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane and 2-methoxy Ethers such as ethanol and 1,2-dimethoxyethane, nitriles such as acetonitrile and propionitrile, esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate, dichloromethane, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene, tetrachloroethylene, benzene, toluene, xylene, mono Aromatics such as rorobenzene, nitrobenzene, indene, pyridine, quinoline, collidine and phenol, hydrocarbons such as pentane, cyclohexane, hexane, heptane, octane, isooctane, petroleum benzine and petroleum ether, ethanolamine and diethanolamine Amines such as triethanolamine, pyrrolidine, piperidine, piperazine, morpholine, aniline, dimethylaniline, benzylamine, toluidine, formamide, N-methylpyrrolidone, N, N-dimethylimidazolone, Amides such as N, N-dimethylacetamide, N, N-dimethylformamide, phosphate amides such as hexamethyl phosphate triamide and hexamethyl phosphite triamide, water, and other commonly used solvents; 2 or more types of mixed solvent are mentioned, The mixing ratio is not specifically limited.
[383] As described above, the base that can be used in the present invention is not particularly limited as long as it does not inhibit the reaction and is commonly known as an organic synthetic base, and specifically, for example, sodium carbonate and hydrogen carbonate Sodium, potassium carbonate, sodium hydride, potassium hydride, t-butoxypotassium, pyridine, dimethylaminopyridine, trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpi Lolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5,4,0] undeca-7-ene (DBU), pyridine, 4-dimethylaminopyridine, blood Sodium or potassium alcohols such as choline, lutidine, quinoline, isoquinoline, sodium hydroxide, potassium hydroxide, lithium hydroxide, butyllithium, sodium methylate, potassium methylate, sodium ethylate, and the like.
[384] As described above, the reducing agent that can be used in the present invention does not inhibit the reaction, and is not particularly limited as long as it is usually used for organic synthesis. Specifically, for example, NaBH ₄ , LiBH ₄ , Zn (BH ₄ ) ₂ , Me ₄ NBH (OAc) ₃ , NaBH ₃ CN, Selectride, Super Hydride (LiBHEt ₃ ), LiAlH ₄ , DIBAL, LiAlH (t-BuO) ₃ , Red- In addition to al, binap, etc., catalytic hydrogenation catalysts, such as platinum, palladium, rhodium, ruthenium, and nickel, etc. are mentioned.
[385] After the completion of the above reaction, it can be purified by recrystallization from column chromatography using a silica gel, an adsorptive resin, or the like or a suitable solvent according to a conventional treatment method as desired.
[386] The medicament according to the present invention improves insulin resistance by the agonist action of PPAR as described above, but the present invention is not limited to an insulin resistance improver, and the agonist action of PPAR (α, β, γ) [for example, PPARα And the action of the dual agent of γ, or may be based on the action of the triple agent of PPARα, β, and γ].
[387] For example, in addition to insulin resistance, PPARs are associated with blood lipids or with inflammatory diseases [Current Opinionin Lipido1. 10: 245-257, 1999: Jiang, C. et al., PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines, Nature 391: 82-86 (1998); Jackson, S.M. Et al., Peroxisome proliferator-actedated receptor actinators target human endothelial cells to inhibit 1eukocyte-endothelial cell interaction., Arterioscler. Thromb. Vasc. Biol. 19; 2094-2104 (1999); Su, C.G. Et al., A novel therapy for colitis utilizing PPAR-gamma ligands to inhit the epithelial inflammatory response., J Clin Invest 1999 Aug: 104 (4): 383-9; Ricote, M. et al., The peroxisome proliferator-actedated receptor-gamma is a negatⅳe regulator of macro phage activation, Nature 1998 Jan l; 39l (6662): 79-82] Can also be used.
[388] The dosage of the medicament according to the present invention varies depending on the severity of symptoms, age, sex, weight, dosage form, type of disease, and the like, but is usually 100 µg to 10 g per adult, divided once to several times.
[389] The dosage form of the medicament according to the present invention is not particularly limited and can be administered orally or parenterally by a commonly used method.
[390] In these formulations, excipients, binders, lubricants, colorants, colloids, and the like commonly used, and stabilizers, emulsifiers, absorption accelerators, surfactants, and the like can be used, if necessary. Generally, ingredients used as raw materials for pharmaceutical preparations are blended. Formulated by conventional methods.
[391] These components include, for example, animal and vegetable oils (soybean oil, tallow, synthetic glycerides, etc.), hydrocarbons (fluid paraffins, squalanes, solid paraffins, etc.), ester oils (octylate acid octydodecyl, myristic acid isopropyl, etc.). ), Higher alcohols (cetostearyl alcohol, phenyl alcohol, etc.), silicone resins, silicone oils, surfactants (polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene Hardened castor oil, polyoxyethylene polyoxypropylene block copolymer, etc.), water-soluble polymer (hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone, methyl cellulose, etc.), alcohol (ethanol, isopropanol ), Polyhydric alcohols (glycerine, propylene glycol, dipropylene glycol, sorbitol, etc.), sugars (glucose, sucrose, etc.), Inorganic powder (anhydrous silicic acid, magnesium aluminum silicate, aluminum silicate, etc.), purified water, and the like. For pH preparation, inorganic acids (hydrochloric acid, phosphoric acid, etc.), alkali metal salts of inorganic acids (sodium phosphate, etc.), inorganic bases (sodium hydroxide, etc.), organic acids (low fatty acids, citric acid, lactic acid, etc.), alkali metal salts of organic acids (sodium citrate, lactic acid) Sodium, etc.), an organic base (arginine, ethanolamine, etc.) etc. can be used. Moreover, preservative, antioxidant, etc. can be added as needed.
[392] Next, the pharmacological experiment example is shown to show the usefulness of this application.
[393] Experimental Example 1: Measurement of blood glucose lowering rate, blood triglyceride lowering rate, blood free fatty acid lowering rate
[394] For male db / db mice (Charles River, Yokohama, Japan), 1 mg / kg / day for drug suspended in 0.5% methyl cellulose solution (30 mg / kg / day; Example 36g) and 37e). It was administered orally once a day using Sonde. Blood collection was done from the tail vein after 1 hour of fasting, before dosing, and on days 4 and 9. The oral glucose loading test on the 10th day was performed by fasting overnight from the day before, and then loading 2 g / kg of glucose the next morning. Plasma glucose, triglyceride (TG), and free fatty acid (NEFA) are glucose C-II Test Wako (trademark; Wakojunyaku, Tokyo), Detamina-L TG II (trademark; Kyowa Medex, Tokyo), NEFA C It was measured using a commercial kit from Test Wako (trademark; Wakojunyaku, Tokyo). The obtained blood sugar lowering rate, blood triglyceride lowering rate, and blood free fatty acid lowering rate are shown in Table 1, respectively.
[395] TABLE 1
[396] In vivo db / db mice on day 9
[397] Blood sugar drop rate (%) Blood triglyceride reduction rate (%) Blood free fatty acid reduction rate (%) Example 2d) 44.6 71.6 46.7 Example 3d) 27.5 63.8 47 Example 5d) 53.6 58.8 65.5 Example 9b) 46.1 80.4 62.9 Example 36g) * 51.5 55.2 54.0 Example 37e) * 48.1 68.3 70.2
[398] Experimental Example 2: Measurement of Transcriptional Activity
[399] The chimeric expression vector of GAL4-PPAR LBD is a 167-468 (PPARα), 138-440 (NUC-1), 174-475 (PPARY) amino acid of human PPAR in the 1-147 amino acid region of GAL4, a yeast transcription factor. Ligand Binding Domains (LBDs) were connected to each other. The reporter gene was constructed by using PLAP (Placental Alkaline Phosphatase) and linking it downstream of the TK promoter containing 5 copies of GAL4DNA binding elements. CV-1 (ATCC CC1-70) was used for host cells. That is, CV-1 cells were expanded to 5x10E5 in a 35 mm dish, incubated for 24 hours in 10% FCS / DMEM, and then FuGENE 6 transfection reagent was used to express GAL4-PPAR LBD expression vector and GAL4 DBD-. TK-PLAP expression vectors were co-transfected. After 24 hours of transfection, the cells were redeployed on 96-weI1 plates again to be 1 × 10 E4 / wel 1, and the culture was further continued for 24 hours. After 24 hours, in order to inactivate the intrinsic alkaline phosphatase, the compound was added to the DMEM containing 10% FCS treated at 65 ° C, and the compound was added at an arbitrary concentration. Transcriptional activity was measured by PLAP activity secreted 24 hours after compound addition, and EC50 was computed. PLAP activity was measured after 10 hours of culture supernatant, 50 µl of assay buffer and 50 µm of chemiluminescent substrate, and 1 hour of culture at room temperature. The transcriptional activities for PPARα, PPARβ and PPARγ are shown in Table 2, respectively.
[400] TABLE 2
[401] Transcription EC50 unit is μM
[402] PPARα PPARβ PPARγ Example 2d) 0.08 2.513 0.382 Example 3d) 0.087 5.072 0.217 Example 5d) 0.394 0.789 0.254 Example 9b) 0.701 ＞ 30 0.746 Example 18d) 0.162 8.054 ＞ 10 Example 36g) 0.012 0.037 0.047 Example 37e) 0.028 0.432 0.016
[403] As described above, the compound of the present invention has excellent blood sugar and blood lipid improving action, and is very useful as an antidiabetic agent, antihyperlipidemic agent and insulin resistance improving agent.
[404] Although the present invention will be described in detail and specifically by the following examples, the present invention is not limited to these examples.
[405] Example 1
[406] Preparation Example 1a)
[407]
[408] 1.5 g of ethyl 2- (diethylphosphoryl) -2-ethyl acetate was dissolved in 30 ml of tetrahydrofuran, and 0.26 g of 60% sodium hydride was added under ice cooling. The reaction solution was stirred for 30 minutes under ice-cooling, then 1.5 g of benzyl 5-formyl-2-methoxybenzoate was added and stirred at room temperature for 20 hours. An aqueous ammonium chloride solution was added to the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and benzyl 5- (3-ethoxy-2-ethoxy-3-oxo-1-propenyl) -2 from hexane-ethyl acetate (4: 1) eluted fraction. 1.6 g methoxybenzoate was obtained as an EZ mixture.
[409] ¹ H-NMR (Z-isomer, CDCl ₃ ) δ: 1.25 (t, J = 6.8 Hz, 3H) 1.36 (t, J = 7.2 Hz, 3H) 3.96 (s, 3H) 3.98 (q, J = 6.8 Hz , 2H) 4.27 (q, J = 7.2 Hz, 2H) 6.92 (s, 1H) 6.98 (d, J = 8.0 Hz, 1H) 7.30-7.43 (m, 5H) 7.90 (dd, J = 2.4, 8.0 Hz, 1H) 8.32 (d, J = 2.4Hz, 1H)
[410] Preparation Example 1b)
[411]
[412] 1.6 g of benzyl 5- (3-ethoxy-2-ethoxy-3-oxo-1-propenyl) -2-methoxybenzoate was dissolved in 30 ml of ethanol, 0.35 g of 10% palladium carbon was added, and hydrogen atmosphere It stirred under 16 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography, and the 5- (3-ethoxy-2-ethoxy-3-oxopropyl was extracted from the hexane-ethyl acetate (2: 1) elution fraction. 1.2 g of) -2-methoxybenzoic acid was obtained.
[413] 1 H-NMR (CDCl 3) δ: 1.16 (t, J = 6.8 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.8 , 14.0Hz, 1H) 3.34 (dq, J = 6.8, 9.2Hz, 1H) 3.61 (dq, J = 6.8, 9.2Hz, 1H) 3.98 (dd, J = 4.8, 8.0Hz, 1H) 4.05 (s, 3H ) 4.18 (q, J = 7.2Hz, 2H) 6.97 (d, J = 8.0Hz, 1H) 7.47 (dd, J = 2.4, 8.0Hz, 1H) 8.06 (d, J = 2.4Hz, 1H)
[414] Example 1c)
[415]
[416] 0.58 g of 5- (3-ethoxy-2-ethoxy-3-oxopropyl) -2-methoxybenzoic acid and 0.34 g of 4- (trifluoromethyl) benzylamine are dissolved in 7 ml of N, N-dimethylformamide. Then, 0.30 ml of diethyl cyanophosphonic acid and 0.27 ml of triethylamine were added under ice cooling. The reaction mixture was stirred at room temperature for 16 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and ethyl 2-ethoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl) from the hexane-ethyl acetate (3: 1) eluting fraction. ] 0.6) g of amino) carbonyl) phenyl) propanoate was obtained.
[417] ¹ H-NMR (CDCl ₃ ) δ: 1.16 (t, J = 6.8 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.8, 14.0Hz, 1H) 3.34 (dq, J = 6.8, 9.2Hz, 1H) 3.61 (dq, J = 6.8, 9.2Hz, 1H) 3.93 (s, 3H) 4.01 (dd, J = 4.8, 8.0Hz , 1H) 4.18 (q, J = 7.2 Hz, 2H) 4.73 (d, J = 6.0 Hz, 2H) 6.91 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.4, 8.0 Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.12 (d, J = 2.4Hz, 1H) 8.29 (m, 1H)
[418] Example 1d)
[419]
[420] 0.25 g of ethyl 2-ethoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoate was dissolved in 7 ml of methanol, and 1N sodium hydroxide. 3 ml were added and it stirred at room temperature for 14 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 2-ethoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carboxe Carbonyl) phenyl) propanoic acid 0.189 was obtained
[421] ¹ H-NMR (DMSO-d ₆ ) δ: 1.02 (t, J = 7.2 Hz, 3H) 2.82 (dd, J = 8.0, 14.4 Hz, 1H) 2.91 (dd, J = 5.2, 14.4 Hz, 1H) 3.30 (dq, J = 7.2, 9.6Hz, 1H) 3.50 (dq, J = 7.2, 9.6Hz, 1H) 3.86 (s, 3H) 3.94 (dd, J = 5.2, 8.0Hz, 1H) 4.55 (d, J = 6.0Hz, 2H) 7.05 (d, J = 8.0Hz, 1H) 7.32 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.61 (d, J = 2.4Hz, 1H ) 7.68 (d, J = 2.4Hz, 2H) 8.78 (t, J = 6.0Hz, 1H)
[422] Example 2
[423] Preparation Example 2b)
[424]
[425] 5- (3-Ethoxy-2-isopropoxy-3-oxopropyl) -2-methoxybenzoic acid was obtained in the same manner as in Production Example 1b).
[426] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.26 (t, J = 7.2 Hz, 3H) 2.93 (dd, J = 8.0 , 14.0Hz, 1H) 3.02 (dd, J = 4.8, 14.0Hz, 1H) 3.52 (sept, J = 6.0Hz, 1H) 4.03 (dd, J = 4.8, 8.0Hz, 1H) 4.06 (s, 3H) 4.15 -4.22 (m, 2H) 6.98 (d, J = 8.0 Hz, 1H) 7.47 (dd, J = 2.4, 8.0 Hz, 1H) 8.08 (d, J = 2.4 Hz, 1H)
[427] Example 2c)
[428]
[429] In the same manner as in Example 1c), ethyl 2-isopropoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoate was obtained. .
[430] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.92 (dd, J = 8.0 , 14.0Hz, 1H) 3.01 (dd, J = 4.8, 14.0Hz, 1H) 3.51 (sept, J = 6.0Hz, 1H) 3.93 (s, 3H) 4.05 (dd, J = 4.8, 8.0Hz, 1H) 4.14 -4.21 (m, 2H) 4.73 (d, J = 6.0 Hz, 2H) 6.90 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.4, 8.0 Hz, 1H) 7.47 (d, J = 8.0 Hz , 2H) 7.59 (d, J = 8.0 Hz, 2H) 8.13 (d, J = 2.4 Hz, 1H) 8.30 (m, 1H)
[431] Example 2d)
[432]
[433] In the same manner as in Example 1d), 2-isopropoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoic acid was obtained.
[434] ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (t, J = 6.0 Hz, 3H) 1.03 (t, J = 6.0 Hz, 3H) 2.76 (dd, J = 8.0, 14.0 Hz, 1H) 2.88 (dd , J = 4.8, 14.0Hz, 1H) 3.48 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 3.99 (dd, J = 4.8, 8.0Hz, 1H) 4.55 (d, J = 6.0Hz, 2H ) 7.04 (d, J = 8.0 Hz, 1H) 7.32 (dd, J = 2.4, 8.0 Hz, 1H) 7.52 (d, J = 8.0 Hz, 2H) 7.62 (d, J = 2.4 Hz, 1H) 7.68 (d , J = 8.0Hz, 2H) 8.77 (t, J = 6.0Hz, 1H)
[435] Example 3
[436] Preparation Example 3b)
[437]
[438] 5- (3-Ethoxy-2-tert-butoxy-3-oxopropyl) -2-methoxybenzoic acid was obtained in the same manner as in Production Example 1b).
[439] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (s, 9H) 1.25 (t, J = 7.2 Hz, 3H) 2.85 (dd, J = 8.0,14.0 Hz, 1H) 2.95 (dd, J = 4.8, 14.0 Hz , 1H) 4.06 (s, 3H) 4.10 (dd, J = 4.8, 8.0 Hz, 1H) 4.18 (q, J = 7.2 Hz, 2H) 6.98 (d, J = 8.0 Hz, 1H) 7.47 (dd, J = 2.4, 8.0 Hz, 1H) 8.07 (d, J = 2.4 Hz, 1H)
[440] Example 3c)
[441]
[442] Ethyl 2-tert-butoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoate was prepared in the same manner as in Example 1c). Got it.
[443] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (s, 9H) 1.25 (t, J = 7.2 Hz, 3H) 2.85 (dd, J = 8.0, 14.0 Hz, 1H) 2.95 (dd, J = 4.8, 14.0 Hz , 1H) 3.93 (s, 3H) 4.10 (dd, J = 4.8, 8.0 Hz, 1H) 4.18 (q, J = 7.2 Hz, 2H) 4.73 (d, J = 6.0 Hz, 2H) 6.90 (d, J = 8.0Hz, 1H) 7.37 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.13 (d, J = 2.4Hz, 1H ) 8.29 (m, 1H)
[444] Example 3d)
[445]
[446] 2-tert-butoxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoic acid was obtained in the same manner as in Example 1d).
[447] ¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (s, 9H) 2.70 (dd, J = 8.8, 13.2 Hz, 1H) 2.83 (dd, J = 4.4, 13.2 Hz, 1H) 3.86 (s, 3H) 4.01 (dd, J = 4.4, 8.8 Hz, 1H) 4.56 (d, J = 6.0 Hz, 2H) 7.04 (d, J = 8.0 Hz, 1H) 7.31 (dd, J = 2.0, 8.0 Hz, 1H) 7.52 ( d, J = 8.0Hz, 2H) 7.63 (d, J = 2.0Hz, 1H) 7.68 (d, J = 8.0Hz, 2H) 8.77 (t, J = 6.0Hz, 1H)
[448] Example 4
[449] Preparation Example 4b)
[450]
[451] 5- (3-Ethoxy-2-hydroxy-3-oxopropyl) -2-methoxybenzoic acid was obtained in the same manner as in Production Example 1b).
[452] ¹ H-NMR (CDCl ₃ ) δ: 1.31 (t, J = 7.2 Hz, 3H) 2.95 (dd, J = 8.0, 14.0 Hz, 1H) 3.12 (dd, J = 4.8, 14.0 Hz, 1H) 4.06 (s , 3H) 4.23 (q, J = 7.2 Hz, 2H) 4.40 (dd, J = 4.8, 8.0 Hz, 1H) 6.98 (d, J = 8.0 Hz, 1H) 7.47 (dd, J = 2.4, 8.0 Hz, 1H ) 8.01 (d, J = 2.4Hz, 1H)
[453] Example 4c)
[454]
[455] In the same manner as in Example 1c), ethyl 2-hydroxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoate was obtained.
[456] ¹ H-NMR (CDCl ₃ ) δ: 1.31 (t, J = 7.2 Hz, 3H) 2.95 (dd, J = 8.0, 14.0 Hz, 1H) 3.15 (dd, J = 4.8, 14.0 Hz, 1H) 3.92 (s , 3H) 4.23 (q, J = 7.2 Hz, 2H) 4.40-4.43 (m, 1H) 4.73 (d, J = 6.0 Hz, 2H) 6.92 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.08 (d, J = 2.4Hz, 1H) 8.28 (m, 1H)
[457] Example 4d)
[458]
[459] In the same manner as in Example 1d), 2-hydroxy-3- (4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) propanoic acid was obtained.
[460] ¹ H-NMR (DMSO-d ₆ ) δ: 2.75 (dd, J = 8.0, 14.0 Hz, 1H) 2.90 (dd, J = 4.8, 14.0 Hz, 1H) 3.86 (s, 3H) 4.08 (dd, J = 4.8, 8.0Hz, 1H) 4.55 (d, J = 6.0Hz, 2H) 7.05 (d, J = 8.0Hz, 1H) 7.32 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz , 2H) 7.62 (d, J = 2.4Hz, 1H) 7.68 (d, J = 8.0Hz, 2H) 8.77 (t, J = 6.0Hz, 1H)
[461] Example 5
[462] Preparation Example 5b)
[463]
[464] 5- [2- (ethoxycarbonyl) butyl] -2-methoxybenzoic acid was obtained in the same manner as in Production Example 1b).
[465] ¹ H-NMR (CDCl ₃ ) δ: 0.92 (t, J = 7.6 Hz, 3H) 1.17 (t, J = 6.8 Hz, 3H) 1.51-1.70 (m, 2H) 2.54-2.60 (m, 1H) 2.75 ( dd, J = 6.4, 13.6Hz, 1H) 2.91 (dd, J = 8.4, 13.6Hz, 1H) 4.02-4.10 (m, 2H) 4.05 (s, 3H) 6.96 (d, J = 8.0Hz, 1H) 7.37 (dd, J = 2.4, 8.0Hz, 1H) 8.00 (d, J = 2.4Hz, 1H)
[466] Example 5c)
[467]
[468] In the same manner as in Example 1c), ethyl 2- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) benzyl] butanoate was obtained.
[469] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.6 Hz, 3H) 1.18 (t, J = 6.8 Hz, 3H) 1.51-1.70 (m, 2H) 2.54-2.61 (m, 1H) 2.75 ( dd, J = 6.4, 13.6 Hz, 1H) 2.92 (dd, J = 8.4, 13.6 Hz, 1H) 3.92 (s, 3H) 4.04-4.15 (m, 2H) 4.73 (d, J = 6.0 Hz, 2H) 6.89 (d, J = 8.0Hz, 1H) 7.26 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.05 (d, J = 2.4 Hz, 1H) 8.30 (m, 1H)
[470] Example 5d)
[471]
[472] 2- [4-methoxy-3- [4- (trifluoromethyl) benzyl] amino) carbonyl) benzyl] butanoic acid was obtained in the same manner as in Example 1d).
[473] ¹ H-NMR (DMSO-d ₆ ) δ: 0.84 (t, J = 7.2 Hz, 3H) 1.43-1.49 (m, 2H) 2.38-2.43 (m, 1H) 2.64 (dd, J = 6.0, 13.6 Hz, 1H) 2.75 (dd, J = 8.8, 13.6 Hz, 1H) 3.85 (s, 3H) 4.54 (d, J = 6.4 Hz, 2H) 7.04 (d, J = 8.0 Hz, 1H) 7.27 (dd, J = 2.4 , 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.55 (d, J = 2.4Hz, 1H) 7.68 (d, J = 8.0Hz, 2H) 8.78 (t, J = 6.4Hz, 1H)
[474] Example 6
[475] Preparation Example 6b)
[476]
[477] 5- (2- (ethoxycarbonyl) ethyl) -2-methoxybenzoic acid was obtained in the same manner as in Production Example 1b).
[478] ¹ H-NMR (CDCl ₃ ) δ: 1.14 (t, J = 6.8 Hz, 3H) 2.56 (t, J = 7.2 Hz, 2H) 2.88 (t, J = 7.2 Hz, 2H) 3.98 (s, 3H) 4.06 (q, J = 6.8Hz, 2H) 6.92 (d, J = 8.0Hz, 1H) 7.37 (dd, J = 2.4, 8.0Hz, 1H) 7.98 (d, J = 2.4Hz, 1H)
[479] Example 6c)
[480]
[481] In the same manner as in Example 1c), ethyl 3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoate was obtained.
[482] ¹ H-NMR (CDCl ₃ ) δ: 1.12 (t, J = 6.8 Hz, 3H) 2.60 (t, J = 7.2 Hz, 2H) 2.95 (t, J = 7.2 Hz, 2H) 3.92 (s, 3H) 4.11 (q, J = 6.8Hz, 2H) 4.73 (d, J = 6.0Hz, 2H) 6.90 (d, J = 8.0Hz, 1H) 7.26 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.07 (d, J = 2.4Hz, 1H) 8.30 (m, 1H)
[483] Example 6d)
[484]
[485] 3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoic acid was obtained in the same manner as in Example 1d).
[486] ¹ H-NMR (DMSO-d ₆ ) δ: 2.48 (t, J = 7.2 Hz, 2H) 2.76 (t, J = 7.2 Hz, 2H) 3.85 (s, 3H) 4.54 (d, J = 6.4 Hz, 2H ) 7.04 (d, J = 8.0 Hz, 1H) 7.31 (dd, J = 2.4, 8.0 Hz, 1H) 7.51 (d, J = 8.0 Hz, 2H) 7.57 (d, J = 2.4 Hz, 1H) 7.68 (d , J = 8.0Hz, 2H) 8.78 (t, J = 6.4Hz, 1H)
[487] Example 7
[488] Example 7c)
[489]
[490] Ethyl 2-ethoxy-3- [4-methoxy-3-(([(1-methyl-1H-2-indolyl) methyl] amino) carbonyl) phenyl] propano in the same manner as in Example 1c) Obtained eight.
[491] ¹ H-NMR (CDCl ₃ ) δ: 1.16 (t, J = 6.8 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.8, 14.0 Hz, 1H) 3.34 (dq, J = 6.8, 9.2 Hz, 1H) 3.61 (dq, J = 6.8, 9.2 Hz, 1H) 3.74 (s, 3H) 3.84 (s, 3H) 4.01 (dd, J = 4.8, 8.0Hz, 1H) 4.18 (q, J = 7.2Hz, 2H) 4.87 (d, J = 6.0Hz, 2H) 6.87 (d, J = 8.0Hz, 1H) 6.90 (s, 1H) 7.11 ( dd, J = 0.8, 8.0Hz, 1H) 7.20 (dd, J = 0.8, 8.0Hz, 1H) 7.30 (d, J = 8.0Hz, 1H) 7.37 (dd, J = 2.4, 8.0Hz, 1H) 7.59 ( d, J = 8.0Hz, 1H) 8.10 (m, 1H) 8.12 (d, J = 2.4Hz, 1H)
[492] Example 7d)
[493]
[494] 2-ethoxy-3- [4-methoxy-3-(([(1-methyl-1H-2-indolyl) methyl] amino) carbonyl) phenyl] propanoic acid was prepared in the same manner as in Example 1d). Got it.
[495] ¹ H-NMR (DMSO-d ₆ ) δ: 1.03 (t, J = 6.8 Hz, 3H) 2.83 (dd, J = 7.2, 14.0 Hz, 1H) 2.91 (dd, J = 4.8, 14.0 Hz, 1H) 3.30 (dq, J = 6.8, 9.6Hz, 1H) 3.50 (dq, J = 6.8, 9.6Hz, 1H) 3.74 (s, 3H) 3.84 (s, 3H) 3.94 (dd, J = 4.8, 7.2Hz, 1H) 4.67 (d, J = 5.6 Hz, 2H) 6.35 (s, 1H) 6.97 (dd, J = 0.8, 8.0 Hz, 1H) 7.04 (d, J = 8.0 Hz, 1H) 7.09 (dd, J = 0.8, 8.0 Hz, 1H) 7.31 (dd, J = 2.0, 8.0Hz, 1H) 7.39 (d, J = 8.0Hz, 1H) 7.46 (d, J = 8.0Hz, 1H) 7.61 (d, J = 2.0Hz, 1H) 8.57 (t, J = 5.6 Hz, 1H)
[496] Example 8
[497] Example 8c)
[498]
[499] In the same manner as in Example 1c), ethyl 3- [3-(([cyclohexylmethyl] amino) carbonyl) -4-methoxyphenyl] -2-ethoxypropanoate was obtained.
[500] ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.07 (m, 2H) 1.16 (t, J = 6.8 Hz, 3H) 1.16-1.25 (m, 3H) 1.25 (t, J = 7.2 Hz, 3H) 1.50- 1.80 (m, 6H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.8, 14.0 Hz, 1H) 3.30 (t, J = 6.4 Hz, 2H) 3.34 (dq, J = 6.8 , 9.2Hz, 1H) 3.61 (dq, J = 6.8, 9.2Hz, 1H) 3.94 (s, 3H) 4.01 (dd, J = 4.8, 8.0Hz, 1H) 4.18 (q, J = 7.2Hz, 2H) 6.87 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.4, 8.0 Hz, 1H) 7.90 (m, 1H) 8.08 (d, J = 2.4 Hz, 1H)
[501] Example 8d)
[502]
[503] 3- (3-[((cyclohexylmethyl) amino) carbonyl] -4-methoxyphenyl) -2-ethoxypropanoic acid was obtained in the same manner as in Example 1d).
[504] ¹ H-NMR (DMSO-d ₆ ) δ: 0.89-0.95 (m, 2H) 1.03 (t, J = 7.2 Hz, 3H) 1.14-1.20 (m, 3H) 1.45-1.70 (m, 6H) 2.81 (dd , J = 8.0, 14.0Hz, 1H) 2.90 (dd, J = 5.2, 14.0Hz, 1H) 3.10 (dd, J = 6.4, 6.4Hz, 2H) 3.30 (dq, J = 7.2, 9.6Hz, 1H) 3.50 (dq, J = 7.2, 9.6Hz, 1H) 3.83 (s, 3H) 3.93 (dd, J = 5.2, 8.0Hz, 1H) 7.02 (d, J = 8.0Hz, 1H) 7.28 (dd, J = 2.4, 8.0Hz, 1H) 7.57 (d, J = 2.4Hz, 1H) 8.07 (t, J = 6.4Hz, 1H)
[505] Example 9
[506] Example 9a)
[507]
[508] 0.25 g of methyl 2-amino-3-methoxy (([4- (trifluoromethyl) benzyl] amino) carbonylphenyl) propanoate and 0.12 ml of acetic acid are dissolved in 8 ml of chloroform and isoamyl nitrite at room temperature 0.10 ml was added. The reaction solution was heated to reflux for 30 minutes, cooled to room temperature and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 8 ml of 1-propanol, and 13 mg of rhodium acetate was added at room temperature. The reaction solution was heated to reflux for 5 hours, the solvent was distilled off under reduced pressure, the residue was treated by silica gel column chromatography, and the methyl 3- [4-methoxy-3- ( 0.18 g of [[4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] -2-propoxypropanoate was obtained.
[509] ¹ H-NMR (CDCl ₃ ) δ: 0.84 (t, J = 7.2 Hz, 3H) 1.55 (tq, J = 6.8, 7.2 Hz, 2H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd , J = 4.8, 14.0Hz, 1H) 3.21 (dt, J = 6.8, 8.8Hz, 1H) 3.53 (dt, J = 6.8, 8.8Hz, 1H) 3.73 (s, 3H) 3.93 (s, 3H) 4.02 ( dd, J = 4.8, 8.0 Hz, 1H) 4.73 (d, J = 6.0 Hz, 2H) 6.91 (d, J = 8.0 Hz, 1H) 7.36 (dd, J = 2.4, 8.0 Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.10 (d, J = 2.4Hz, 1H) 8.29 (m, 1H)
[510] Example 9b)
[511]
[512] 0.1 g of methyl 3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] -2-propoxypropanoate is dissolved in 2 ml of methanol and 1N 2 ml of sodium hydroxide was added, and it stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 3-4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl) -2 0.15 g of propoxypropanoic acid was obtained.
[513] ¹ H-NMR (DMSO-d ₆ ) δ: 0.76 (t, J = 7.2 Hz, 3H) 1.41 (tq, J = 6.4, 7.2 Hz, 2H) 2.82 (dd, J = 8.0, 14.4 Hz, 1H) 2.91 (dd, J = 4.8, 14.4Hz, 1H) 3.17 (dt, J = 6.4, 9.2Hz, 1H) 3.43 (dt, J = 6.4, 9.2Hz, 1H) 3.86 (s, 3H) 3.92 (dd, J = 4.8, 8.0Hz, 1H) 4.55 (d, J = 6.0Hz, 2H) 7.05 (d, J = 8.0Hz, 1H) 7.32 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz , 2H) 7.61 (d, J = 2.4Hz, 1H) 7.68 (d, J = 8.0Hz, 2H) 8.78 (t, J = 6.0Hz, 1H)
[514] Example 10
[515] Example 10a)
[516]
[517] In the same manner as in Example 9a), methyl-2-butoxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoate was obtained. .
[518] ¹ H-NMR (CDCl ₃ ) δ: 0.84 (t, J = 7.2 Hz, 3H) 1.25-1.32 (m, 2H) 1.46-1.55 (m, 2H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.8, 14.0 Hz, 1H) 3.25 (dt, J = 6.8, 8.8 Hz, 1H) 3.55 (dt, J = 6.8, 8.8 Hz, 1H) 3.73 (s, 3H) 3.93 (s, 3H ) 4.01 (dd, J = 4.8, 8.0Hz, 1H) 4.73 (d, J = 6.0Hz, 2H) 6.91 (d, J = 8.0Hz, 1H) 7.35 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.10 (d, J = 2.4Hz, 1H) 8.29 (m, 1H)
[519] Example 10b)
[520]
[521] 2-butoxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoic acid was obtained in the same manner as in Example 9b).
[522] ¹ H-NMR (DMSO-d ₆ ) δ: 0.77 (t, J = 7.2 Hz, 3H) 1.15-1.25 (m, 2H) 1.32-1.41 (m, 2H) 2.82 (dd, J = 8.4, 14.0 Hz, 1H) 2.91 (dd, J = 4.8, 14.0 Hz, 1H) 3.20 (dt, J = 6.4, 9.2 Hz, 1H) 3.46 (dt, J = 6.4, 9.2 Hz, 1H) 3.86 (s, 3H) 3.90 (dd , J = 4.8, 8.4Hz, 1H) 4.55 (d, J = 6.0Hz, 2H) 7.05 (d, J = 8.0Hz, 1H) 7.32 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.61 (d, J = 2.4Hz, 1H) 7.68 (d, J = 8.0Hz, 2H) 8.77 (t, J = 6.0Hz, 1H)
[523] Example 11
[524] Example 1la)
[525]
[526] Methyl-2-cyclohexyloxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoate in the same manner as in Example 9a) Got.
[527] ¹ H-NMR (CDCl ₃ ) δ: 0.80 (dd, J = 6.4, 16.0 Hz, 1H) 1.08-1.90 (m, 9H) 2.96 (dd, J = 8.0, 14.0 Hz, 1H) 3.02 (dd, J = 4.8, 14.0 Hz, 1H) 3.14-3.21 (m, 1H) 3.73 (s, 3H) 3.93 (s, 3H) 4.10 (dd, J = 4.8, 8.0 Hz, 1H) 4.73 (d, J = 6.0 Hz, 2H ) 6.91 (d, J = 8.0 Hz, 1H) 7.36 (dd, J = 2.4, 8.0 Hz, 1H) 7.47 (d, J = 8.0 Hz, 2H) 7.59 (d, J = 8.0 Hz, 2H) 8.10 (d , J = 2.4Hz, 1H) 8.29 (m, 1H)
[528] Example 11b)
[529]
[530] 2-cyclohexyloxy-3- [4-methoxy-3- [4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoic acid was obtained in the same manner as in Example 9b).
[531] ¹ H-NMR (DMSO-d ₆ ) δ: 0.75 (dd, J = 6.4, 16.0 Hz, 1H) 1.00-1.71 (m, 9H) 2.78 (dd, J = 8.0, 14.0 Hz, 1H) 2.89 (dd, J = 4.8, 14.0Hz, 1H) 3.18-3.23 (m, 1H) 3.86 (s, 3H) 4.03 (dd, J = 4.8, 8.0Hz, 1H) 4.55 (d, J = 6.0Hz, 2H) 7.05 (d , J = 8.0Hz, 1H) 7.33 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.63 (d, J = 2.4Hz, 1H) 7.67 (d, J = 8.0 Hz, 2H) 8.77 (t, J = 6.0 Hz, 1H)
[532] Example 12
[533] Example 12a)
[534]
[535] Methyl 3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] -2- (2,2,2-tri in the same manner as in Example 9a) Fluoroethoxy) propanoate was obtained.
[536] ¹ H-NMR (CDCl ₃ ) δ: 3.04 (dd, J = 8.0, 14.0 Hz, 1H) 3.15 (dd, J = 4.8, 14.0 Hz, 1H) 3.67 (dd, J = 8.8, 12.0 Hz, 1H) 3.73 (s, 3H) 3.93 (s, 3H) 4.03 (d, J = 8.8, 12.0 Hz, 1H) 4.20 (dd, J = 4.8, 8.0 Hz, 1H) 4.73 (d, J = 6.0 Hz, 2H) 6.91 ( d, J = 8.0Hz, 1H) 7.36 (dd, J = 2.4, 8.0Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 1H) 8.10 (d, J = 8.0 Hz, 2H) 8.29 (m, 1H)
[537] Example 12b)
[538]
[539] 3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] -2- (2,2,2-trifluoro in the same manner as in Example 9b) Roethoxy) propanoic acid was obtained.
[540] ¹ H-NMR (DMSO-d ₆ ) δ: 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.01 (dd, J = 4.8, 14.0 Hz, 1H) 3.87 (s, 3H) 4.03 (dd, J = 8.8, 12.0 Hz, 1H) 4.11 (d, J = 8.8, 12.0 Hz, 1H) 4.26 (dd, J = 4.8, 8.0 Hz, 1H) 4.55 (d, J = 6.4 Hz, 2H) 7.06 (d, J = 8.0Hz, 1H) 7.31 (dd, J = 2.4, 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.61 (d, J = 2.4Hz, 1H) 7.68 (d, J = 8.0Hz, 2H ) 8.78 (t, J = 6.4Hz, 1H)
[541] Example 13
[542] Example 13a)
[543]
[544] In the same manner as in Example 9a), methyl-2-isobutoxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoate was obtained. .
[545] ¹ H-NMR (CDCl ₃ ) δ: 0.82 (d, J = 6.4 Hz, 6H) 1.80 (tq, J = 6.4, 6.4 Hz, 1H) 2.98 (dd, J = 8.0, 14.0 Hz, 1H) 2.99 (dd , J = 6.4, 8.8Hz, 1H) 3.04 (dd, J = 4.8, 14.0Hz, 1H) 3.36 (dd, J = 6.4, 8.8Hz, 1H) 3.72 (s, 3H) 3.93 (s, 3H) 4.00 ( dd, J = 4.8, 8.0 Hz, 1H) 4.73 (d, J = 6.0 Hz, 2H) 6.91 (d, J = 8.0 Hz, 1H) 7.36 (dd, J = 2.4, 8.0 Hz, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.59 (d, J = 8.0Hz, 2H) 8.10 (d, J = 2.4Hz, 1H) 8.29 (m, 1H)
[546] Example 13b)
[547]
[548] In the same manner as in Example 9b), 2-isobutoxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] amino) carbonyl) phenyl] propanoic acid was obtained.
[549] ¹ H-NMR (DMSO-d ₆ ) δ: 0.74 (d, J = 6.4 Hz, 6H) 1.67 (tq, J = 6.4, 6.4 Hz, 1H) 2.82 (dd, J = 8.0, 14.4 Hz, 1H) 2.92 (dd, J = 4.8, 14.4Hz, 1H) 2.96 (dd, J = 6.4, 8.8Hz, 1H) 3.26 (dd, J = 6.4, 8.8Hz, 1H) 3.86 (s, 3H) 3.90 (dd, J = 4.8, 8.0 Hz, 1H) 4.55 (d, J = 6.0 Hz, 2H) 7.04 (d, J = 8.0 Hz, 1H) 7.32 (dd, J = 2.4, 8.0 Hz, 1H) 7.51 (d, J = 8.0 Hz , 2H) 7.62 (d, J = 2.4Hz, 1H) 7.67 (d, J = 8.0Hz, 2H) 8.76 (t, J = 6.0Hz, 1H)
[550] Example 14
[551] Preparation Example 14a)
[552]
[553] 1.5 g of ethyl 2- (diethylphosphoryl-2-isopropylacetate) was dissolved in 10 ml of tetrahydrofuran, and 0.22 g of 60% sodium hydride was added under ice cooling. 0.88 g of oxy-3-nitrobenzaldehyde was added and the mixture was stirred at room temperature for 2 hours, an aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue was treated by silica gel column chromatography, and ethyl-2-isopropoxy-3- (4-methoxy-3-nitrophenyl) -2-prop from the hexane-ethyl acetate (9: 1) elution fraction. 0.85 g of panoate was obtained as an EZ mixture.
[554] ¹ H-NMR (CDCl ₃ ) δ: 1.17 + 1.37 (t, J = 6.0Hz, 3H) 1.27 + 1.31 (d, J = 6.0Hz, 6H) 3.94 + 3.98 (s, 3H) 4.17 + 4.28 (q, J = 6.0Hz, 2H) 6.10 + 6.88 (s, 1H) 7.00 + 7.06 (d, J = 8.0Hz, 1H) 7.40 + 7.91 (dd, J = 8.0, 2.0Hz, 1H) 7.75 + 8.37 (d, J = 2.0 Hz, 1H)
[555] Preparation Example 14b)
[556]
[557] 0.85 g of ethyl-2-isopropoxy-3- (4-methoxy-3-nitrophenyl) -2-propanoate was dissolved in 15 ml of ethanol, 0.3 g of 10% palladium carbon was added, and the mixture was kept under hydrogen atmosphere for 4 hours. Stirred. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the residue was then subjected to silica gel column chromatography, and the ethyl-3- (3-amino-4-methoxyphenyl) -2 was extracted from the hexane-ethyl acetate (6: 1) elution fraction. 0.72 g of isopropoxypropanoate was obtained.
[558] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.0 Hz, 3H) 2.83 (m, 2H) 3.50 (dq, J-6.4, 6.4 Hz, 1H) 3.81 (s, 3H) 4.00 (dd, J = 8.4, 4.8 Hz, 1H) 4.17 (q, J = 6.0 Hz, 2H) 6.60 (dd, J = 8.0, 2.0 Hz, 1H) 6.67 (d, J = 2.0 Hz, 1H) 6.70 (d, J = 8.0 Hz, 1H)
[559] Example 14c)
[560]
[561] 0.3 g of ethyl 3- (3-amino-4-methoxyphenyl) -2-isopropoxypropanoate and 0.218 g of (α, α, α-trifluoro-p-tolyl) acetic acid were added to 7 ml of tetrahydrofuran. It melt | dissolved, 0.22 g of carbonyl diimidazole, and 0.23 ml of triethylamine were added, and it stirred at 50 degreeC for 2 hours. The reaction mixture was ice cooled, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and ethyl-2-isopropoxy-3-4-methoxy-3- (4-trifluoromethylphenylacetylamino) phenyl was extracted from the hexane-ethyl acetate (6: 1) elution fraction. ] 0.34 g of propanoate was obtained.
[562] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.10 (d, J = 6.0 Hz, 3H) 1.22 (t, J = 7.2 Hz, 3H) 2.83 (dd, J = 14.0 , 6.0 Hz, 1H) 2.93 (dd, J = 14.0, 4.4 Hz, 1H) 3.48 (dq, J = 6.0, 6.0 Hz, 1H) 3.73 (s, 3H) 3.78 (s, 2H) 4.02 (dd, J = 7.6, 4.4 Hz, 1H) 4.15 (q, J = 8.0 Hz, 2H) 6.72 (d, J = 8.0 Hz, 1H) 6.91 (dd, J = 8.0, 2.0 Hz, 1H) 7.46 (d, J = 8.0 Hz , 2H) 7.64 (d, J = 8.0 Hz, 2H) 7.73 (s, 1H) 8.24 (d, J = 2.0 Hz, 1H)
[563] Example 14d)
[564]
[565] 0.34 g of ethyl-2-isopropoxy-3- (4-methoxy-3- (4-trifluoromethylphenylacetylamino) phenyl) propanoate was dissolved in 5 ml of ethanol, 0.28 ml of 5N sodium hydroxide was added, It stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 2-isopropoxy-3- (4-methoxy-3-([2- (4-trifluoromethyl) phenyl] acetyl 0.28 g of)) amino) phenylpropanoic acid was obtained.
[566] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.89 (dd, J = 14.0, 6.0 Hz, 1H) 3.06 (dd, J = 14.0, 4.4 Hz, 1H) 3.58 (dq, J = 6.0, 6.0 Hz, 1H) 3.75 (s, 3H) 3.80 (s, 2H) 4.13 (dd, J = 7.6, 4.4 Hz, 1H) 6.74 (d, J = 8.0 Hz, 1H) 6.90 (dd, J = 8.0, 2.0 Hz, 1H) 7.48 (d, J = 8.0 Hz, 2H) 7.65 (d, J = 8.0 Hz, 2H) 7.73 (s, 1H) 8.26 ( d, J = 2.0 Hz, 1H)
[567] Example 15
[568] Example 15c)
[569]
[570] By the same method as in Example 14c), ethyl-2-isopropoxy-3- (4-methoxy-3-([2- (5-methyl-2-phenyl-1,3-oxazolyl-4- Il) acetyl] amino) phenyl) propanoate was obtained.
[571] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.13 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 2.40 (s, 3H) 2.87 (dd, J = 14.0, 8.8 Hz, 1H) 2.95 (dd, J = 14.0, 8.8 Hz, 1H) 3.50 (dq, J = 6.4, 6.4 Hz, 1H) 3.63 (s, 2H) 3.75 (s, 3H) 4.04 (dd, J = 8.4, 4.8 Hz, 1H) 4.17 (q, J = 7.2 Hz, 2H) 6.73 (d, J = 8.0 Hz, 1H) 6.90 (dd, J = 8.0, 2.0 Hz, 1H) 7.47 ( m, 3H) 8.08 (m, 2H) 8.33 (d, J = 2.0 Hz, 1H) 9.42 (s, 1H)
[572] Example 15d)
[573]
[574] 2-isopropoxy-3- (4-methoxy-3-([2- (5-methyl-2-phenyl-1,3-oxazol-4-yl)) by the same method as in Example 14d). Acetyl] amino) phenyl) propanoic acid was obtained.
[575] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.40 (s, 3H) 2.89 (dd, J = 14.0, 8.8 Hz, 1H ) 3.09 (dd, J = 14.0, 8.8 Hz, 1H) 3.58 (dq, J = 6.4, 6.4 Hz, 1H) 3.63 (s, 2H) 3.75 (s, 3H) 4.14 (dd, J = 8.4, 4.8 Hz, 1H) 6.75 (d, J = 8.0 Hz, 1H) 6.88 (dd, J = 8.0, 2.0 Hz, 1H) 7.46 (m, 3H) 8.08 (m, 2H) 8.33 (d, J = 2.0 Hz, 1H) 9.46 (s, 1H)
[576] Example 16
[577] Preparation Example 16a)
[578]
[579] 1.6 g of ethyl 2- (diethylphosphoryl) -2-isopropyl acetate was dissolved in 30 ml of tetrahydrofuran, and 0.24 g of 60% sodium hydride was added under ice cooling. The reaction solution was stirred for 30 minutes under ice cooling, and then 1.2 g of tert-butyl 5-formyl-2-methoxybenzoate was added, followed by stirring at room temperature for 3 hours. An aqueous ammonium chloride solution was added to the reaction, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and tert-butyl 5- (3-ethoxy-2-isopropoxy-3-oxo-1-propenyl) -2 from hexane-ethyl acetate (3: 1) eluted fraction. 1.5 g methoxybenzoate was obtained as an EZ mixture.
[580] ¹ H-NMR (Z-isomer, CDCl ₃ ) δ: 1.28 (d, J = 6.4 Hz, 6H) 1.36 (t, J = 7.2 Hz, 3H) 1.59 (s, 9H) 3.91 (s, 3H) 4.29 ( q, J = 7.2Hz, 2H) 4.41 (sept, J = 6.4Hz, 1H) 6.92 (d, J = 8.0Hz, 1H) 6.96 (s, 1H) 7.85 (dd, J = 2.4, 8.0Hz, 1H) 8.26 (d, J = 2.4 Hz, 1H)
[581] Preparation Example l6b)
[582]
[583] 0.3 g of tert-butyl 5- (3-ethoxy-2-isopropoxy-3-oxo-1-propenyl) -2-methoxybenzoate was dissolved in 2.5 ml of dichloromethane, and trifluoroacetic acid under ice-cooling 1.2 ml was added and it stirred for 2 hours as it was under ice cooling. 30 ml of toluene was added to the reaction mixture, and the operation of distilling off the solvent under reduced pressure was repeated twice, and then the residue was treated by silica gel column chromatography, and 5-[(Z)- 65 mg of 3-ethoxy-2-isopropoxy-3-oxo-1-propenyl] -2-methoxybenzoic acid were obtained.
[584] ¹ H-NMR (CDCl ₃ ) δ: 1.30 (d, J = 6.4 Hz, 6H) 1.36 (t, J = 7.2 Hz, 3H) 4.09 (s, 3H) 4.29 (q, J = 7.2 Hz, 2H) 4.47 (sept, J = 6.4Hz, 1H) 6.96 (s, 1H) 7.05 (d, J = 8.0Hz, 1H) 8.18 (dd, J = 2.4, 8.0Hz, 1H) 8.57 (d, J = 2.4Hz, 1H )
[585] Example 16c)
[586]
[587] 65 mg of 5-[(E) -3-ethoxy-2-isopropoxy-3-oxo-1-propenyl] -2-methoxybenzoic acid and 37 mg of 4- (trifluoromethyl) benzylamine It was dissolved in 1 ml of dimethylformamide, and 33 µl of cyanophosphonic acid diethyl and 30 µl of triethylamine were added under ice cooling. The reaction mixture was stirred at room temperature for 16 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and the ethyl (Z) -2-isopropoxy-3- [4-methoxy-3-(([4- (tri 77 mg of fluoromethyl) benzyl] amino) carbonylphenyl] -2-propenoate was obtained.
[588] ¹ H-NMR (CDCl ₃ ) δ: 1.30 (d, J = 6.4 Hz, 6H) 1.36 (t, J = 7.2 Hz, 3H) 3.97 (s, 3H) 4.29 (q, J = 7.2 Hz, 2H) 4.47 (sept, J = 6.4Hz, 1H) 4.75 (d, J = 6.0Hz, 2H) 6.99 (d, J = 8.0Hz, 1H) 7.01 (s, 1H) 7.47 (d, J = 8.0Hz, 2H) 7.60 (d, J = 8.0Hz, 2H) 8.12 (dd, J = 2.4, 8.0Hz, 1H) 8.18 (m, 1H) 8.57 (d, J = 2.4Hz, 1H)
[589] Example 16d)
[590]
[591] 77 mg of ethyl (Z) -2-isopropoxy-3- [4-methoxy-3-([[4- (trifluoromethyl) benzyl] amino] carbonyl) phenyl] -2-propenoate is methanol It dissolved in 2 ml, added 1 ml of 1N sodium hydroxide, and stirred for 22 hours at room temperature. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulphate and the solvent was distilled off under reduced pressure to give (Z) -2-isopropoxy-3- [4-methoxy-3-(([4- (trifluoromethyl 44 mg of) benzyl] amino) carbonyl) phenyl] -2-propenoic acid was obtained.
[592] ¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (d, J = 6.4 Hz, 6H) 3.90 (s, 3H) 4.46 (sept, J = 6.4 Hz, 1H) 4.56 (d, J = 6.4 Hz, 2H ) 6.90 (s, 1H) 7.15 (d, J = 8.8 Hz, 1H) 7.53 (d, J = 8.0 Hz, 2H) 7.68 (d, J = 8.0 Hz, 2H) 7.87 (dd, J = 2.4, 8.8 Hz , 1H) 8.30 (d, J = 2.4Hz, 1H) 8.82 (m, 1H)
[593] Example 17
[594] Preparation Example 17a)
[595]
[596] In the same manner as in Production Example 14a), ethyl 2-ethyl-3- (4-methoxy-3-nitrophenyl) -2-propenoate was obtained as an E-Z mixture.
[597] ¹ H-NMR (CDCl ₃ ) δ: 1.15 + 1.35 (m, 6H) 2.45 + 2.53 (q, J = 6.0Hz, 2H) 3.95 + 3.98 (s, 3H) 4.18 + 4.27 (d, J = 6.0Hz, 2H) 6.52 + 7.53 (d, 1H) 7.01 + 7.11 (d, J = 8.0Hz, 1H) 7.44 + 7.55 (dd, J = 8.0, 2.0Hz, 1H) 7.79 + 7.89 (d, J = 2.0Hz, 1H )
[598] Preparation Example 17b)
[599]
[600] Ethyl 2- (3-amino-4-methoxybenzyl) butanoate was obtained in the same manner as in Production Example 14b).
[601] ¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.0 Hz, 3H) 1.17 (t, J = 6.0 Hz, 3H) 1.56 (m, 2H) 2.52 (m, 1H) 2.59 (dd, J = 13.5,7.0 Hz, 1H) 2.80 (dd, J = 13.5, 8.0 Hz, 1H) 3.81 (s, 3H) 4.08 (q, J = 6.0 Hz, 2H) 6.50 (dd, J = 8.0, 2.0 Hz, 1H) 6.54 (d, J = 2.0 Hz, 1H) 6.68 (d, J = 8.0 Hz, 1H)
[602] Example 17c)
[603]
[604] Ethyl 2- (4-methoxy-3-([2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) acetyl] amino) benzyl) buta in the same manner as in Example 14c) Obtained No Eight.
[605] ¹ H-NMR (CDCl ₃ ) δ: 0.89 (t, J = 6.0 Hz, 3H) 1.18 (t, J = 6.0 Hz, 3H) 1.58 (m, 2H) 2.56 (m, 1H) 2.68 (dd, J = 13.5, 7.0 Hz, 1H) 2.88 (dd, J = 13.5, 8.0 Hz, 1H) 3.63 (s, 2H) 3.74 (s, 3H) 4.08 (q, J = 6.0 Hz, 2H) 6.71 (d, J = 8.0 Hz, 2H) 6.79 (dd, J = 8.0, 2.0 Hz, 2H) 7.46 (m, 3H) 8.07 (m, 2H) 8.25 (d, J = 2.0 Hz, 1H) 9.40 (bs, 1H)
[606] Example 17d)
[607]
[608] 2- (4-methoxy-3-([2- (5-methyl-2-phenyl-1,3-oxazol-4-yl) acetyl] amino) benzyl) butanoic acid in the same manner as in Example 14d) Got.
[609] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 6.0 Hz, 3H) 1.60 (m, 2H) 2.61 (m, 1H) 2.72 (dd, J = 13.5, 7.0 Hz, 1H) 2.90 (dd, J = 13.5, 8.0 Hz, 1H) 3.62 (s, 2H) 3.74 (s, 3H) 6.73 (d, J = 8.0 Hz, 2H) 6.83 (dd, J = 8.0, 2.0 Hz, 2H) 7.46 (m, 3H ) 8.06 (m, 2H) 8.26 (d, J = 2.0 Hz, 1H) 9.40 (bs, 1H)
[610] Example 18
[611] Example 18c)
[612]
[613] In the same manner as in Example 17c), ethyl 2- (4-methoxy-3-([2- (3-fluoro-4-trifluoromethylphenyl) acetyl] amino) benzyl) butanoate was obtained.
[614] ¹ H-NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.0 Hz, 3H) 1.17 (t, J = 6.0 Hz, 3H) 1.58 (m, 2H) 2.54 (m, 1H) 2.67 (dd, J = 13.5, 7.0 Hz, 1H) 2.86 (dd, J = 13.5, 8.0 Hz, 1H) 3.77 (s, 2H) 3.79 (s, 3H) 4.08 (q, J = 6.0 Hz, 2H) 6.73 (d, J = 8.0 Hz, 1H) 6.83 (dd, J = 8.0, 2.0 Hz, 1H) 7.24 (m, 2H) 7.61 (t, J = 7.5 Hz, 1H) 7.77 (bs, 1H) 8.17 (d, J = 2.0 Hz, 1H )
[615] Example 18d)
[616]
[617] 2- (4-methoxy-3-([2- (3-fluoro-trifluoromethylphenyl) acetyl] amino) benzyl) butanoic acid was obtained in the same manner as in Example 17d).
[618] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 6.0 Hz, 3H) 1.59 (m, 2H) 2.59 (m, 1H) 2.70 (dd, J = 13.5, 7.0 Hz, 1H) 2.89 (dd, J = 13.5, 8.0 Hz, 1H) 3.70+ 3.77 (s, 2H) 3.79+ 3.81 (s, 3H) 6.74 (d, J = 8.0 Hz, 1H) 6.86 (dd, J = 8.0, 2.0 Hz, 1H) 7.17 (d, J = 8.0 Hz, 1H) 7.22 (d, J = 10.5 Hz, 1H) 7.60 (t, J = 7.5 Hz, 1H) 7.78 (bs, 1H) 8.17 (d, J = 2.0 Hz, 1H)
[619] Example 19
[620] Preparation Example 19a)
[621]
[622] 0.50 g of 5- [2- (ethoxycarbonyl) butyl] -2-methoxybenzoic acid was dissolved in 8 ml of tetrahydrofuran, and 0.20 ml of ethyl chloroformate and 0.29 ml of triethylamine were added under ice cooling. The reaction solution was stirred for 10 minutes under ice cooling, and then the insolubles were filtered out. The mother liquor was ice-cooled again, 10 ml of water and 136 mg of sodium borohydride were added, followed by stirring at room temperature for 2 hours. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 0.47 g of ethyl 2- [3- (hydroxymethyl) -4-methoxybenzyl] butanoate from an hexane-ethyl acetate (3: 1) elution fraction.
[623] ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 7.2 Hz, 3H) 1.17 (t, J = 6.8 Hz, 3H) 1.50-1.64 (m, 2H) 2.51-2.57 (m, 1H) 2.68 ( dd, J = 6.8, 14.0 Hz, 1H) 2.87 (dd, J = 8.0, 14.0 Hz, 1H) 3.84 (s, 3H) 4.04-4.10 (m, 2H) 4.65 (s, 2H) 6.78 (d, J = 9.2 Hz, 1H) 7.05 (d, J = 9.2 Hz, 1H) 7.07 (s, 1H)
[624] Preparation Example 19b)
[625]
[626] 0.47 g of ethyl 2- [3- (hydroxymethyl) -4-methoxybenzyl] butanoate was dissolved in 6 ml of toluene, 0.54 ml of diphenylphosphoryl azide and diazabicyclo [5.4.0] undecene 0.37 mI was added and stirred at room temperature for 16 hours. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and 1- (5- [2- (ethoxycarbonyl) butyl] -2-methoxybenzyl) -1,2- from hexane-ethyl acetate (5: 1) elution fraction. 0.47 g of triazadiene-2-ium was obtained.
[627] ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 7.2 Hz, 3H) 1.17 (t, J = 6.8 Hz, 3H) 1.50-1.64 (m, 2H) 2.51-2.57 (m, 1H) 2.68 ( dd, J = 6.8, 14.0 Hz, 1H) 2.87 (dd, J = 8.0, 14.0 Hz, 1H) 3.82 (s, 3H) 4.02-4.12 (m, 2H) 4.30 (s, 2H) 6.81 (d, J = 8.0 Hz, 1H) 7.03 (s, 1H) 7.11 (d, J = 8.0 Hz, 1H)
[628] Preparation Example 19c)
[629]
[630] 0.47 g of 1- (5- [2- (ethoxycarbonyl) butyl] -2-methoxybenzyl) -1,2-triazadien-2-ium was dissolved in 6 ml of tetrahydrofuran, 0.4 ml of water and 0.55 g of triphenylphosphines were added, and it stirred at room temperature for 20 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and ethyl 2- [3- (aminomethyl) -4-methoxy was extracted from ethyl acetate-methanol-triethylamine (10: 1: 0.1). Benzyl] butanoate 0.40 g was obtained.
[631] ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 7.2 Hz, 3H) 1.17 (t, J = 6.8 Hz, 3H) 1.50-1.64 (m, 2H) 2.49-2.56 (m, 1H) 2.67 ( dd, J = 6.8, 14.0 Hz, 1H) 2.86 (dd, J = 8.0, 14.0 Hz, 1H) 3.77 (s, 2H) 3.81 (s, 3H) 4.04-4.10 (m, 2H) 6.76 (d, J = 8.8 Hz, 1H) 7.00 (d, J = 8.8 Hz, 1H) 7.01 (s, 1H)
[632] Example 19d)
[633]
[634] 0.40 g of ethyl 2- [3- (aminomethyl) -4-methoxybenzyl] butanoate and 0.29 g of 4- (trifluoromethyl) benzoic acid are dissolved in 5 ml of N, N-dimethylformamide, and cooled on ice. 0.24 ml of diethyl nophosphonic acid and 0.21 ml of triethylamine were added. The reaction mixture was stirred at room temperature for 16 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and ethyl 2- [4-methoxy-3-(([4- (trifluoromethyl) benzoyl] amino) methyl) from the hexane-ethyl acetate (3: 1) eluting fraction. 0.59 g of benzyl] butanoate was obtained.
[635] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.2 Hz, 3H) 1.16 (t, J = 6.8 Hz, 3H) 1.50-1.67 (m, 2H) 2.49-2.56 (m, 1H) 2.68 ( dd, J = 6.4, 14.0Hz, 1H) 2.86 (dd, J = 8.6, 14.0Hz, 1H) 3.86 (s, 3H) 4.01-4.10 (m, 2H) 4.61 (d, J = 6.0Hz, 2H) 6.67 -6.72 (m, 1H) 6.81 (d, J = 8.0 Hz, 1H) 7.08 (dd, J = 2.4, 8.0 Hz, 1H) 7.13 (d, J = 2.4 Hz, 1H) 7.68 (d, J = 8.0 Hz , 2H) 7.86 (d, J = 8.0 Hz, 2H)
[636] Example 19e)
[637]
[638] 0.59 g of ethyl 2- [4-methoxy-3-(([4- (trifluoromethyl) benzoyl] amino) methyl) benzyl] butanoate was dissolved in 5 ml of ethanol, 2 ml of 1N sodium hydroxide was added, 70 It stirred at 4 degreeC. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 2- [4-methoxy-3-(([4- (trifluoromethyl) benzoyl] amino) methyl) benzyl] butanoic acid 0.50 g was obtained
[639] ¹ H-NMR (DMSO-d ₆ ) δ: 0.80 (t, J = 7.2 Hz, 3H) 1.39-1.46 (m, 2H) 2.33-2.40 (m, 1H) 2.55 (dd, J = 6.4, 14.0 Hz, 1H) 2.72 (dd, J = 8.0, 14.0 Hz, 1H) 3.77 (s, 3H) 4.42 (d, J = 5.6 Hz, 2H) 6.88 (d, J = 8.0 Hz, 1H) 7.01 (s, 1H) 7.03 (d, J = 8.0Hz, 1H) 7.85 (d, J = 8.0Hz, 2H) 8.07 (d, J = 8.0Hz, 2H) 9.03 (t, J = 5.6Hz, 1H)
[640] Example 20
[641] Preparation Example 20a)
[642]
[643] Ethyl 3- [3- (hydroxymethyl) -4-methoxyphenyl] -2-isopropoxypropanoate was obtained in the same manner as in Production Example 19a).
[644] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 2.88 (dd, J = 8.4 , 14.0Hz, 1H) 2.95 (dd, J = 5.2, 14.0Hz, 1H) 3.50 (sept, J = 6.0Hz, 1H) 3.85 (s, 3H) 4.00 (dd, J = 5.2, 8.4Hz, 1H) 4.11 -4.21 (m, 2H) 4.65 (d, J = 6.4 Hz, 2H) 6.79 (d, J = 8.8 Hz, 1H) 7.14 (d, J = 8.8 Hz, 1H) 7.15 (s, 1H)
[645] Preparation Example 20b)
[646]
[647] In the same manner as in Production Example 19b), 1- [5- (3-ethoxyisopropoxyoxopropyl) -2-methoxybenzyl] -1,2-triazadien-2-ium was obtained.
[648] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.88 (dd, J = 8.8 , 13.6Hz, 1H) 2.95 (dd, J = 4.8, 13.6Hz, 1H) 3.50 (sept, J = 6.0Hz, 1H) 3.84 (s, 3H) 4.00 (dd, J = 4.8, 8.8Hz, 1H) 4.15 -4.21 (m, 2H) 4.32 (s, 2H) 6.83 (d, J = 8.0 Hz, 1H) 7.14 (d, J = 2.0 Hz, 1H) 7.20 (dd, J = 2.0, 8.0 Hz, 1H)
[649] Preparation Example 20c)
[650]
[651] 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate was obtained in the same manner as in Production Example 19c).
[652] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.88 (dd, J = 8.8 , 13.6Hz, 1H) 2.95 (dd, J = 4.8, 13.6Hz, 1H) 3.50 (sept, J = 6.0Hz, 1H) 3.84 (s, 3H) 4.00 (dd, J = 4.8, 8.8Hz, 1H) 4.15 -4.21 (m, 2H) 4.32 (s, 2H) 6.83 (d, J = 8.0 Hz, 1H) 7.14 (d, J = 2.0 Hz, 1H) 7.20 (dd, J = 2.0, 8.0 Hz, 1H)
[653] Preparation Example 20d)
[654]
[655] In the same manner as in Production Example 19d), 2-isopropoxy-3- [4-methoxy-3-(([4-trifluoromethyl) benzoyl] amino) methyl) phenyl] propanoate was obtained.
[656] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 2.88 (dd, J = 8.4 , 14.0Hz, 1H) 2.95 (dd, J = 4.8, 14.0Hz, 1H) 3.51 (sept, J = 6.0Hz, 1H) 3.87 (s, 3H) 4.01 (dd, J = 4.8, 8.4Hz, 1H) 4.12 -4.20 (m, 2H) 4.62 (d, J = 6.0 Hz, 2H) 6.65-6.70 (m, 1H) 6.82 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.68 (d, J = 8.4 Hz, 2H) 7.86 (d, J = 8.4 Hz, 2H)
[657] Example 20e)
[658]
[659] In the same manner as in Example 19e), 2-isopropoxy-3- [4-methoxy-3-(([4- (trifluoromethyl) benzoyl] amino) methyl) phenyl] propanoic acid was obtained.
[660] ¹ H-NMR (DMSO-d ₆ ) δ: 0.78 (d, J = 6.0Hz, 3H) 0.93 (d, J = 6.0Hz, 3H) 2.68 (dd, J = 8.0, 14.0Hz, 1H) 2.81 (dd , J = 4.0, 14.0Hz, 1H) 3.41 (sept, J = 6.0Hz, 1H) 3.78 (s, 3H) 3.92 (dd, J = 4.8, 8.4Hz, 1H) 4.43 (d, J = 6.0Hz, 2H ) 6.88 (d, J = 8.0Hz, 1H) 7.07 (s, 1H) 7.08 (d, J = 8.0Hz, 1H) 7.85 (d, J = 8.0Hz, 2H) 8.09 (d, J = 8.0Hz, 2H ) 9.06 (t, J = 6.0 Hz, 1H)
[661] Example 21
[662] Preparation Example 21a)
[663]
[664] 7.0 g of 1- (methoxymethyl) -3- (trifluoromethyl) benzene was dissolved in 300 ml of anhydrous diethyl ether, and 19 ml of normal butyllithium (2.5 M hexane solution) was added dropwise at -78 deg. The reaction mixture was stirred at room temperature for 3 hours, cooled to -78 ° C again, and 10 ml of N, N-dimethylformamide was added. The reaction solution was returned to room temperature, poured into water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the residue was treated by silica gel column chromatography, and 5.0 g of 1- (methoxymethyl) -3- (trifluoromethyl) benzaldehyde was added dropwise from the hexane-ethyl acetate (9: 1) elution fraction. Obtained as an orange oil.
[665] ¹ H-NMR (CDCl ₃ ) δ: 3.54 (s, 3H) 5.35 (s, 2H) 7.34 (d, J = 8 Hz, 1H) 7.49 (s, 1H) 7.94 (d, J = 8 Hz, 1H) 10.52 (s, 1 H)
[666] Preparation Example 21b)
[667]
[668] 5.0 g of 1- (methoxymethyl) -3- (trifluoromethyl) benzaldehyde was dissolved in 25 ml of acetone, and 22 ml of 6N hydrochloric acid was added. It was made to react at room temperature for 3 hours, water was added, and it extracted with ethyl acetate. After washing with saturated brine, it was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and 4.5 g of 2-hydroxy-4- (trifluoromethyl) benzaldehyde was obtained as a pale reddish oily substance.
[669] ¹ H-NMR (CDCl ₃ ) δ: 7.2-7.3 (m, 2H) 7.70 (d, J = 8 Hz, 1H) 10.0 (s, 1H) 11.1 (s, 1H)
[670] Preparation Example 21c)
[671]
[672] 4.5 g of 2-hydroxy-4- (trifluoromethyl) benzaldehyde was dissolved in 20 ml of N, N-dimethylformamide, 1.0 g of sodium hydride (60% oil) was added, and the mixture was stirred at room temperature for 30 minutes. 1.8 ml of methyl iodide was dripped at this, and it was made to react for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate and washing with saturated brine. It dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 2-methoxy-4- (trifluoromethyl) benzaldehyde 3.09 as a colorless oil from the hexane-ethyl acetate (9: 1) elution fraction.
[673] ¹ H-NMR (CDCl ₃ ) δ: 4.00 (s, 3H) 7.22 (s, 1H) 7.29 (d, J = 8Hz, 1H) 7.93 (d, J = 8Hz, 1H) 10.50 (s, 1H)
[674] Preparation Example 21d)
[675]
[676] 3.0 g of 2-methoxy-4- (trifluoromethyl) benzaldehyde was dissolved in 50 ml of dimethyl sulfoxide and 1.6 g of sodium dihydrogen phosphate solution (20 ml), and 8.0 g aqueous solution of sodium chlorite (30 ml) was added dropwise. After stirring at room temperature for 3 days, water was added and the mixture was extracted with ethyl acetate. After washing with saturated brine and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and 0.8 g of 2-methoxy-4- (trifluoromethyl) benzoic acid was obtained as a colorless solid from the hexane-ethyl acetate (3: 7) elution fraction.
[677] ¹ H-NMR (CDCl ₃ ) δ: 4.14 (s, 3H) 7.29 (s, 1H) 7.41 (d, J = 8Hz, 1H) 8.30 (d, J = 8Hz, 1H)
[678] Example 21e)
[679]
[680] Example 4 d) 0.24 g of 2-methoxy-4- (trifluoromethyl) benzoic acid and 0.3 g of ethyl 2- [3- (aminomethyl) -4-methoxybenzyl] butanoate were followed by Example 19d). 19e) and 0.3 g of 2- [4-methoxy-3-(([2-methoxy-4- (trifluoromethyl) benzoyl) amino) methyl) benzyl] butanoic acid as pale yellow oil. Got it.
[681] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 7 Hz, 3H) 1.5-1.7 (m, 2H) 2.5-2.6 (m, 1H) 2.69 (dd, J = 7.14 Hz, 1H) 2.89 (dd, J = 8,14 Hz, 1H) 3.87 (s, 3H) 3.98 (s, 3H) 4.62 (d, J = 6 Hz, 2H) 6.80 (d, J = 8 Hz, 1H) 7.08 (dd, J = 2,8 Hz, 1H) 7.16 (s, 2H) 7.28-7.34 (m, 1H) 8.26-8.40 (m, 1H) 8.36 (t, J = 6 Hz, 1H)
[682] Example 22
[683] Preparation Example 22a)
[684]
[685] 5.0 g of 2-methoxyphenyl acetic acid was dissolved in 20 ml of dichloromethane, 4.6 g of oxalyl dichloride was added, and the mixture was stirred at room temperature for 3 hours. The solvent and excess oxalyl dichloride were removed under reduced pressure, the residue was dissolved in 20 ml of dichloromethane, 14 g of 4-trifluoromethylaniline was added under ice cooling, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with 1N hydrochloric acid and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The precipitated solid was filtered and washed with diethyl ether to obtain 8.0 g of N- [4- (trifluoromethyl) phenyl] -2- (2-methoxyphenyl) acetamide as a colorless solid.
[686] ¹ H-NMR (CDCl ₃ ) δ: 3.73 (s, 2H) 4.95 (s, 3H) 6.98 (d, J = 8 Hz, 1H) 7.00 (d, J = 8 Hz, 1H) 7.28-7.35 (m, 2H) 7.50-7.60 (m, 4H) 7.91 (s, 1H)
[687] Preparation Example 22b)
[688]
[689] 1.0 g of N- [4- (trifluoromethyl) phenyl] -2- (2-methoxyphenyl) acetamide was dissolved in 10 ml of trifluoroacetic acid, 0.46 g of hexamethylenetetramine was added, and 3 hours at 85 ° C. Reacted. The reaction liquid was returned at room temperature, water and ethyl acetate were added, and sodium hydrogencarbonate was added until pH = 8. After extraction with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was treated by silica gel column chromatography, and N- [4- (trifluoromethyl) phenyl] -2- (5-formyl) was extracted from the hexane-ethyl acetate (1: 1) elution fraction. 0.7 g of 2-methoxyphenyl) acetamide was obtained as a colorless oil.
[690] ¹ H-NMR (CDCl ₃ ) δ: 3.78 (s, 2H) 4.00 (s, 3H) 7.07 (d, J = 8 Hz, 1H) 7.54 (d, J = 9 Hz, 2H) 7.57 (d, J = 9 Hz, 2H) 7.85 (d, J = 2 Hz, 1H) 7.83-7.90 (m, 1H) 9.91 (s, 1H)
[691] Example 22c)
[692]
[693] 0.7 g of N- [4- (trifluoromethyl) phenyl] -2- (5-formyl-2-methoxyphenyl) acetamide and 1.6 g of ethyl 2-phosphonobutanoate were treated as in Production Example 1a, Colorless oily 0.8 g of ethyl 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl) phenyl) -2-propenoate Obtained as.
[694] ¹ H-NMR (CDCl ₃ ) δ: 1.18 (t, J = 7 Hz, 3H) 1.34 (t, J = 7 Hz, 3H) 2.55 (q, J = 7 Hz, 2H) 3.74 (s, 2H) 3.97 (s, 3H) 4.26 (q, J = 7 Hz, 2H) 6.99 (d, J = 9 Hz, 1H) 7.34 (d, J = 9 Hz, 1H) 7.38 (dd, J = 2,8 Hz, 1H ) 7.48-7.62 (m, 5H) 7.82 (s, 1H)
[695] Example 22d)
[696]
[697] 0.3 g of ethyl 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl) phenyl) -2-propenoate Preparation Example 1b) The mixture was treated as above to obtain 0.39 of ethyl 2- (4-methoxy-3- (2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl) benzyl) butanoate as a colorless oil.
[698] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7 Hz, 3H) 1.14 (t, J = 7 Hz, 3H) 1.5-1.8 (m, 2H) 2.48-2.60 (m, 1H) 2.71 ( dd, J = 6,14 Hz, 1H) 2.87 (dd, J = 4,14 Hz, 1H) 3.68 (s, 2H) 3.91 (s, 3H) 3.95-4.10 (m, 2H) 6.86 (d, J = 9 Hz, 1H) 7.09 (s, 1H) 7.06-7.12 (m, 1H) 7.51 (d, J = 9 Hz, 2H) 7.56 (d, J = 9 Hz, 2H) 7.94 (s, 1H)
[699] Example 22e)
[700]
[701] 0.3 g of ethyl 2- (4-methoxy-3- (2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl) benzyl) butanoate was treated as in Example 19e), and 2- 0.11 g of (4-methoxy-3-12-oxo-2- [4- (trifluoromethyl) phenyl] ethyl) benzyl) butanoic acid was obtained as a colorless solid.
[702] ¹ H-NMR (DMSO-d ₆ )
[703] δ: 0.84 (t, J = 8 Hz, 3H) 1.46 (sept, J = 8 Hz, 2H) 2.35-2.60 (m, 1H) 2.57 (dd, J = 6,14 Hz, 1H) 2.74 (dd, J = 8,14 Hz, 1H) 3.61 (s, 2H) 3.71 (s, 3H) 6.86 (d, J = 8 Hz, 1H) 7.02 (s, 1H) 7.03 (d, J = 8 Hz, 1H) 7.64 ( d, J = 9 Hz, 2H) 7.79 (d, J = 9 Hz, 2H) 10.4 (s, 1H) 12.1 (s, 1H)
[704] Example 23
[705] Example 23a)
[706]
[707] Example 19d) of 0.15 g of ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 0.24 g of 2-methoxy-4- (trifluoromethyl) benzoic acid Subsequently, it was treated in the same manner as in Example 1d) and 2-isopropoxy-3- [4-methoxy-3-(([2-methoxy-4- (trifluoromethyl) benzoyl] amino) methyl 0.15 g of) phenyl) propanoic acid was obtained as a pale yellow oil.
[708] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6 Hz, 3H) 1.14 (d, J = 6 Hz, 3H) 2.90 (dd, J = 8,14 Hz, 1H) 3.03 (dd, J = 4,14 Hz, 1H) 3.56 (sept, J = 6 Hz, 1H) 3.88 (s, 3H) 4.00 (s, 3H) 4.08 (dd, J = 4,8 Hz, 1H) 4.63 (d, J = 6 Hz, 2H) 6.81 (d, J = 8 Hz, 1H) 7.14 (dd, J = 2,8 Hz, 1H) 7.17 (s, 1H) 7.22 (d, J = 2 Hz, 1H) 7.32 (d, J = 8 Hz, 1H) 8.30 (d, J = 8 Hz, 1H) 8.35 (t, J = 8 Hz, 1H)
[709] Example 24
[710] Example 24a)
[711]
[712] 0.15 g of ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate is dissolved in 5 ml of N, N-dimethylformamide, 0.2 ml of pyridine and 2-fluoro- 0.24 g of 4- (trifluoromethyl) benzoic acid chloride was added and reacted at room temperature for 12 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was treated by silica gel column chromatography, and ethyl 2-isopropoxy-3- [4-methoxy-3-(([ 0.29 of 2-fluoro-4- (trifluoromethyl) benzoyl] amino) methyl) phenyl] propanoate was obtained as a pale yellow oil. This was also treated as in Example 1d) and 2-isopropoxy-3- [4-methoxy-3-(([2-fluoro-4- (trifluoromethyl) benzoyl] amino) methyl) phenyl ] 0.15 g of propanoic acid was obtained as a pale yellow solid.
[713] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6 Hz, 3H) 1.15 (d, J = 6 Hz, 3H) 2.91 (dd, J = 8,14 Hz, 1H) 3.04 (dd, J = 4,14 Hz, 1H) 3.56 (sept, J = 6 Hz, 1H) 3.87 (s, 3H) 4.09 (dd, J = 4,8 Hz, 1H) 4.64 (d, J = 6 Hz, 2H) 6.82 (d, J = 8 Hz, 1H) 7.16 (dd, J = 2,8 Hz, 1H) 7.22 (d, J = 2 Hz, 1H) 7.37 (d, J = 12 Hz, 1H) 7.51 (d, J = 8 Hz, 1H) 7.34-7.5 (m, 1H) 8.22 (t, J = 8 Hz, 1H)
[714] Example 25
[715] Preparation Example 25a)
[716]
[717] 1.1 g of 4-hydroxybenzotrifluoride and 1.0 g of 2-methoxyphenethyl alcohol were dissolved in 200 ml of tetrahydrofuran, 2.6 g of triphenylphosphine and 2.0 g of diisopropylazodicarboxylate were added, followed by room temperature. Stirred for 24 hours. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography and purified from 1-methoxy-2- (2- [4- (trifluoromethyl) phenoxy from the hexane-ethyl acetate (10: 1) elution fraction. ] 1.6 g of ethyl) benzene were obtained.
[718] ¹ H-NMR (CDCl ₃ ) δ: 3.14 (t, J = 7.2 Hz, 2H) 3.85 (s, 3H) 4.20 (t, J = 7.2 Hz, 2H) 6.85-6.92 (m, 2H) 6.96 (d, J = 8.0Hz, 2H) 7.20-7.27 (m, 2H) 7.51 (d, J = 8.0Hz, 2H)
[719] Preparation Example 25b)
[720]
[721] 1.6 g of 1-methoxy-2- [2- [4- (trifluoromethyl) phenoxy] ethyl) benzene was treated as in Example 22b) and 4-methoxy-3- (2- [4- 0.20 g of (trifluoromethyl) phenoxy] ethyl) benzaldehyde was obtained.
[722] ¹ H-NMR (CDCl ₃ ) δ: 3.18 (t, J = 7.2 Hz, 2H) 3.93 (s, 3H) 4.20 (t, J = 7.2 Hz, 2H) 6.95 (d, J = 8.0 Hz, 2H) 6.99 (d, J = 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H) 7.78 (s, 1H) 7.80 (d, J = 8.0Hz, 1H) 9.89 (s, 1H)
[723] Example 25c)
[724]
[725] 0.20 g of 4-methoxy-3- [2- [4- (trifluoromethyl) phenoxy] ethyl] benzaldehyde was followed by Preparation Example 1a), followed by Preparation Example 1b), followed by ethyl 2- (4 0.22 g of -methoxy-3- [2- [4- (trifluoromethyl) phenoxy] ethyl) benzyl) butanoate was obtained.
[726] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 6.8 Hz, 3H) 1.16 (t, J = 7.2 Hz, 3H) 1.52-1.67 (m, 2H) 2.48-2.56 (m, 1H) 2.67 ( dd, J = 6.8, 13.6Hz, 1H) 2.86 (dd, J = 8.4, 13.6Hz, 1H) 3.07 (t, J = 7.2Hz, 2H) 3.81 (s, 3H) 4.04-4.10 (m, 2H) 4.16 (t, J = 7.2Hz, 2H) 6.77 (d, J = 8.0Hz, 1H) 6.96 (d, J = 8.0Hz, 2H) 7.00 (s, 1H) 7.01 (d, J = 8.0Hz, 1H) 7.52 (d, J = 8.0Hz, 2H)
[727] Example 25d)
[728]
[729] 0.22 g of ethyl 2- (4-methoxy-3- (2- [4- (trifluoromethyl) phenoxy] ethyl) benzylbutanoate were treated as in Example 19e) and 2- (4-meth 0.20 g of oxy-3- (2- [4- (trifluoromethyl) phenoxy] ethyl) benzyl) butanoic acid were obtained.
[730] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 7.2 Hz, 3H) 1.53-1.67 (m, 2H) 2.52-2.60 (m, 1H) 2.69 (dd, J = 6.8, 14.0 Hz, 1H) 2.90 (dd, J = 8.0, 14.0 Hz, 1H) 3.07 (t, J = 7.2 Hz, 2H) 3.81 (s, 3H) 4.16 (t, J = 7.2 Hz, 2H) 6.78 (d, J = 8.0 Hz, 1H) 6.96 (d, J = 8.0 Hz, 2H) 7.02 (s, 1H) 7.03 (d, J = 8.0 Hz, 1H) 7.52 (d, J = 8.0 Hz, 2H)
[731] Example 26
[732] Preparation Example 26a)
[733]
[734] 3.0 g of 5-bromo-2-methoxybenzoic acid was treated in the same manner as in Preparation Example 9a) to obtain 1.7 g of 5-bromo-2-methoxyphenylmethanol.
[735] ¹ H-NMR (CDCl ₃ ) δ: 2.20 (m, 1H) 3.82 (s, 3H) 4.64 (d, J = 6.0 Hz, 2H) 6.77 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.0, 8.0Hz, 1H) 7.52 (d, J = 2.0Hz, 1H)
[736] Preparation Example 26b)
[737]
[738] 0.8 g of 5-bromo-2-methoxyphenylmethanol is dissolved in 30 ml of tetrahydrofuran, 2.6 g of 4- (trifluoromethyl) benzylbromide and 0.22 g of sodium hydride (60% oil phase) are added, and 16 at room temperature. It stirred for hours. Water was added to the reaction solution, followed by extraction with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and 4-bromo-1-methoxy-2-(([4- (trifluoromethyl) benzyl] oxy) methyl from the hexane-ethyl acetate (9: 1) elution fraction. ) 1.4g of benzene was obtained.
[739] ¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 3H) 4.57 (s, 2H) 4.64 (s, 2H) 6.77 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.0, 8.0 Hz, 1H) 7.50 (d, J = 8.0 Hz, 2H) 7.52 (d, J = 2.0 Hz, 1H) 7.61 (d, J = 8.0 Hz, 2H)
[740] Preparation Example 26c)
[741]
[742] 1.4 g of 4-bromo-1-methoxy-2-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzene was dissolved in 15 ml of tetrahydrofuran, cooled to -78 deg. 3.0 ml of butyllithium (1.5 M pentane solution) were added. After stirring the reaction liquid at -78 ° C for 30 minutes, 0.45 ml of N-formylmorpholine was added and stirred at -78 ° C for 1 hour. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and 0.42 g of 4-methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzaldehyde was extracted from the hexane-ethyl acetate (3: 1) elution fraction. Got it.
[743] ¹ H-NMR (CDCl ₃ ) δ: 3.92 (s, 3H) 4.63 (s, 2H) 4.70 (s, 2H) 6.99 (d, J = 8.0 Hz, 1H) 7.51 (d, J = 8.0 Hz, 2H) 7.62 (d, J = 8.0 Hz, 2H) 7.84 (dd, J = 2.0, 8.0 Hz, 1H) 7.98 (d, J = 2.0 Hz, 1H) 9.90 (s, 1H)
[744] Example 26d)
[745]
[746] 0.42 g of 4-methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzaldehyde was followed by Preparation Example 1a), followed by Preparation Example 1b), followed by ethyl 2- [4. 0.33 g of -methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzyl] butanoate was obtained.
[747] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.6 Hz, 3H) 1.16 (t, J = 7.2 Hz, 3H) 1.52-1.68 (m, 2H) 2.50-2.57 (m, 1H) 2.70 ( dd, J = 6.8, 14.0Hz, 1H) 2.88 (dd, J = 8.4, 14.0Hz, 1H) 3.80 (s, 3H) 4.01-4.10 (m, 2H) 4.57 (s, 2H) 4.64 (s, 2H) 6.78 (d, J = 8.0 Hz, 1H) 7.06 (dd, J = 2.0, 8.0 Hz, 1H) 7.19 (d, J = 2.0 Hz, 1H) 7.50 (d, J = 8.0 Hz, 2H) 7.61 (d, J = 8.0Hz, 2H)
[748] Example 26e)
[749]
[750] 0.33 g of ethyl 2- [4-methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzyl] butanoate were treated as in Example 19e) and 2- [4- 0.30 g of methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzyl] butanoic acid were obtained.
[751] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 7.2 Hz, 3H) 1.54-1.68 (m, 2H) 2.55-2.62 (m, 1H) 2.71 (dd, J = 6.8, 13.6 Hz, 1H) 2.92 (dd, J = 8.0, 13.6 Hz, 1H) 3.79 (s, 3H) 4.57 (s, 2H) 4.63 (s, 2H) 6.78 (d, J = 8.0 Hz, 1H) 7.08 (dd, J = 2.0, 8.0Hz, 1H) 7.21 (d, J = 2.0Hz, 1H) 7.49 (d, J = 8.0Hz, 2H) 7.61 (d, J = 8.0Hz, 2H)
[752] Example 27
[753] Preparation Example 27a)
[754]
[755] 5.7 g of 4- (trifluoromethyl) benzoic acid and 4.0 g of 2-methoxybenzylamine were dissolved in 100 ml of N, N-dimethylformamide, and 4.8 ml of diethyl cyanophosphonic acid and 4.2 ml of triethylamine were added under ice cooling. . The reaction mixture was stirred at room temperature for 16 hours, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 8.7 g of N1- (2-methoxybenzyl) -4- (trifluoromethyl) benzamide from the hexane-ethyl acetate (2: 1) elution fraction.
[756] ¹ H-NMR (CDCl ₃ ) δ: 3.89 (s, 3H) 4.65 (d, J = 5.6 Hz, 2H) 6.70 (br, 1H) 6.92 (d, J = 8.4 Hz, 1H) 6.95 (t, J = 7.6 Hz, 1H) 7.28-7.36 (m, 2H) 7.68 (d, J = 8.4 Hz, 2H) 7.86 (d, J = 8.4 Hz, 2H)
[757] Preparation Example 27b)
[758]
[759] 8.7 g of N1- (2-methoxybenzyl) -4- (trifluoromethyl) benzamide was dissolved in 20 ml of trifluoroacetic acid, 3.9 g of hexamethylenetetramine was added, and reacted at 85 ° C for 3 hours. The reaction liquid was returned at room temperature, water and ethyl acetate were added, and sodium hydrogencarbonate was added until pH = 8. After extraction with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was treated by silica gel column chromatography and extracted with N1- (5-formyl-2-methoxybenzyl) -4- (trifluoro) from the hexane-ethyl acetate (2: 1) elution fraction. 4.2 g of methyl) benzamide was obtained.
[760] ¹ H-NMR (CDCl ₃ ) δ: 3.99 (s, 3H) 4.72 (d, J = 5.6 Hz, 2H) 6.70 (br, 1H) 7.02 (d, J = 8.4 Hz, 1H) 7.68 (d, J = 8.4 Hz, 2H) 7.83-7.90 (m, 4H) 9.89 (s, 1H)
[761] Example 27c)
[762]
[763] 1.5 g of N1- (5-formyl-2-methoxybenzyl) -4- (trifluoromethyl) benzamide was dissolved in 15 ml of toluene, 0.52 g of 2,4-thiazolidinedione, 36 mg of pyrrolidine and 30 mg of acetic acid was added, the Dean Stark apparatus was attached, and it heated and refluxed for 2 hours. After cooling to room temperature, the precipitated crystals were filtered, washed with ethyl acetate and dried, and then dried, N1-5-[(2,4-dioxo-1,3-thiazolan-5-ylidene) methyl] 1.4 g of 2-methoxybenzyl) -4- (trifluoromethyl) benzamide was obtained.
[764] ¹ H-NMR (DMSO-d ₆ ) δ: 3.90 (s, 3H) 4.47 (d, J = 5.6 Hz, 2H) 6.70 (br, 1H) 7.17 (d, J = 8.8 Hz, 1H) 7.40 (s, 1H) 7.54 (d, J = 8.8Hz, 1H) 7.70 (s, 1H) 7.87 (d, J = 8.0Hz, 2H) 8.13 (d, J = 8.0Hz, 2H) 9.23 (t, J = 5.6Hz, 1H)
[765] Example 28
[766] Preparation Example 28a)
[767]
[768] 1.5 g of 2-fluoro-4- (trifluoromethyl) benzoic acid and 0.90 g of 2-methoxybenzylamine were treated as in Production Example 27a), and N1- (2-methoxybenzyl) -2-fluoro- 2.0 g of 4- (trifluoromethyl) benzamide was obtained.
[769] ¹ H-NMR (CDCl ₃ ) δ: 3.90 (s, 3H) 4.67 (d, J = 4.8 Hz, 2H) 6.90-6.96 (m, 2H) 7.25-7.39 (m, 4H) 7.52 (d, J = 8.0 Hz, 1H) 8.24 (t, J = 8.0Hz, 1H)
[770] Preparation Example 28b)
[771]
[772] 2.0 g of N1- (2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide was treated as in Production Example 27b), and N1- (5-formyl-2-methoxybenzyl 1.1 g of) -2-fluoro-4- (trifluoromethyl) benzamide was obtained.
[773] ¹ H-NMR (CDCl ₃ ) δ: 4.00 (s, 3H) 4.72 (d, J = 5.6 Hz, 2H) 7.03 (d, J = 8.0 Hz, 1H) 7.32 (br, 1H) 7.40 (d, J = 12.0Hz, 1H) 7.53 (d, J = 8.0Hz, 1H) 7.84-7.88 (m, 2H) 8.25 (t, J = 8.0Hz, 1H) 9.89 (s, 1H)
[774] Example 28c)
[775]
[776] 1.1 g of N1- (5-formyl-2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide was treated as in Example 27C) and N1- (5-[(2 0.70 g of, 4-dioxo-1,3-thiazolan-5-ylidene) methyl] -2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide was obtained.
[777] ¹ H-NMR (DMSO-d ₆ ) δ: 3.89 (s, 3H) 4.45 (d, J = 5.6 Hz, 2H) 7.18 (d, J = 8.8 Hz, 1H) 7.44 (d, J = 2.0 Hz, 1H ) 7.55 (dd, J = 2.0, 8.8Hz, 1H) 7.68 (d, J = 8.0Hz, 1H) 7.71 (s, 1H) 7.83-7.90 (m, 2H) 9.02 (t, J = 5.6Hz, 1H)
[778] Example 29
[779]
[780] 0.55 g of N1- (5-[(2,4-dioxo-1,3-thiazolan-5-ylidene) methyl] 2-methoxybenzyl) -4- (trifluoromethyl) benzamide was added N, It was suspended in 20 ml of N-dimethylformamide, 0.60 g of 10% palladium carbon was added, and the mixture was stirred at 50 degrees and 15 kg / cm 2 under hydrogen pressure for 16 hours. After the reaction, the catalyst was filtered off, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was treated by silica gel column chromatography, and the N1-5-[(2,4-dioxo-1,3-thiazolan-5 was separated from the hexane-ethyl acetate (1: 1) elution fraction. 1.2 g of -yl) methyl) -2-methoxybenzyl) -4- (trifluoromethyl) benzamide was obtained.
[781] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 9.2, 17.5 Hz, 1H) 3.28 (dd, J = 4.0, 17.5 Hz, 1H) 3.79 (s, 3H) 4.42 (d, J = 5.6 Hz, 2H) 4.79 (dd, J = 4.0, 9.2 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.08 (d, J = 2.0 Hz, 1H) 7.10 (dd, J = 2.0, 8.4 Hz , 1H) 7.84 (d, J = 8.0Hz, 2H) 8.08 (d, J = 8.0Hz, 2H) 9.05 (t, J = 5.6Hz, 1H)
[782] Example 30
[783]
[784] N1- (5-[(2,4-dioxo-1,3-thiazolan-5-ylidene) methyl] -2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benz 0.70 g of the amide was treated as in Production Example 29, and N1- (5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl) -2- 0.47 g of fluoro-4- (trifluoromethyl) benzamide was obtained.
[785] ¹ H-NMR (DMSO-d ₆ ) δ: 3.01 (dd, J = 9.6,18.0 Hz, 1H) 3.31 (dd, J = 4.0,18.0 Hz, 1H) 3.79 (s, 3H) 4.40 (d, J = 5.6 Hz, 2H) 4.81 (dd, J = 4.0, 9.6 Hz, 1H) 6.94 (d, J = 9.2 Hz, 1H) 7.12 (m, 2H) 7.66 (d, J = 7.2 Hz, 1H) 7.80-7.84 ( m, 2H) 8.88 (t, J = 5.6 Hz, 1H)
[786] Example 31
[787] Preparation Example 31a)
[788]
[789] 13.0 g of 2-methoxybenzylamine were dissolved in 80 ml of tetrahydrofuran, and a tetrahydrofuran (20 ml) solution of 16 g of third butyldicarbonate was added. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed sequentially with 1N hydrochloric acid and saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 19.0 g of third butyl N- (2-methoxybenzyl) carbamate.
[790] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H) 3.84 (s, 3H) 4.27-4.33 (m, 2H) 5.01 (br, 1H) 6.84 (d, J = 8.8 Hz, 1H) 6.94 (t , J = 8.8Hz, 1H) 7.23-7.29 (m, 2H)
[791] MS m / e (ESI) 440 (MH ⁺ )
[792] Preparation Example 31b)
[793]
[794] 6.04 g of third butyl N- (2-methoxybenzyl) carbamate was dissolved in 50 ml of acetonitrile, and 4.6 g of N-bromosuccinimide was added. After stirring for 3 hours at room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed sequentially with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with a mixture of methyl tertiary butylmethylethyl and hexane to give 6.97 g of tertiary butyl N- (5-bromo-2-methoxybenzyl) carbamate.
[795] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H) 3.62 (s, 3H) 4.26 (d, J = 6.4 Hz, 2H) 4.97 (br, 1H) 6.72 (d, J = 8.8 Hz, 1H) 7.34 (dd, J = 2.8, 11.2 Hz) 7.35 (s, 1H)
[796] Preparation Example 31c)
[797]
[798] Tertiary butyl N- (5-bromo-2-methoxybenzyl) carbamate 1.015 g, dichlorobis (triphenylphosphine) palladium (II) 45 mg, sodium formate 330 mg, and 17 mg of triphenylphosphine as anhydrous N, It dissolved in N-dimethylformamide and stirred at 110 degreeC for 2 hours in carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 640 mg of third butyl N- (5-formyl-2-methoxybenzyl) carbamate from the hexane-ethyl acetate (3: 1) elution fraction.
[799] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H) 3.94 (s, 3H) 4.36 (d, J = 6.0 Hz, 2H) 5.00 (br, 1H) 6.98 (d, J = 8.4 Hz, 1H) 7.80-7.83 (m, 2H) 9.88 (s, 1H)
[800] Preparation Example 31d)
[801]
[802] 80 ml of hexamethyldisilazane sodium (1M tetrahydrofuran solution) was diluted with 40 ml of tetrahydrofuran under nitrogen atmosphere, cooled to -78 ° C, and then tetrahydrofuran (10 ml) of 11.68 g of ethyl 2-isopropoxyacetic acid (10 ml). Solution was added. After stirring for 30 minutes, 10.73 g of tetrahydrofuran (10 mI) solution of tert-butyl N- (5-formyl-2-methoxybenzyl) carbamate was added, followed by stirring for 1 hour, followed by saturated aqueous ammonium chloride solution. 100 ml was added. The reaction solution was poured into 400 ml of water and 500 ml of ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; hexane-ethyl acetate) and ethyl 3- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxyphenyl 12.8 g of) -3-hydroxy-2-isopropoxypropanoate (a mixture of erythro and treosome) was obtained as a colorless oil.
[803] ¹ H-NMR (CDCl ₃ ) δ:
[804] 0.99 (d, J = 6.1 Hz, 3H) 1.15 (d, J = 6.1 Hz, 3H) 1.19 (t, J = 7.6 Hz, 3H) 1.44 (s, 9H) 2.91 (d, J = 5.2 Hz, 1H) 3.43 (sept, J = 6.1 Hz, 1H) 3.83 (s, 3H) 4.03 (d, J = 6.3 Hz, 1H) 4.12 (q, J = 7.6 Hz, 2H) 4.29 (d, J = 6.6 Hz, 2H) 4.86 (dd, J = 5.2,6.3 Hz, 1H) 4.99 (t, J = 6.6 Hz, 1H) 6.81 (d, J = 8.7 Hz, 1H) 7.23-7.29 (m, 2H)
[805] δ: 1.11 (t, J = 6.9 Hz, 3H) 1.17 (d, J = 6.1, Hz, 3H) 1.19 (d, J = 6.1 Hz, 3H) 1.44 (s, 9H) 3.00 (d, J = 4.4 Hz , 1H) 3.63 (sept, J = 6.1 Hz, 1H) 3.83 (s, 3H) 3.95 (d, J = 5.9 Hz, 1H) 4.08 (q, J = 6.9 Hz, 2H) 4.29 (d, J = 6.6 Hz , 2H) 4.80 (dd, J = 4.4,5.9 Hz, 1H) 4.99 (t, J = 6.6 Hz, 1H) 6.81 (d, J = 8.7 Hz, 1H) 7.23-7.29 (m, 2H)
[806] Preparation Example 31e)
[807]
[808] 24.7 g of ethyl 3- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxyphenyl) -3-hydroxy-2-isopropoxypropanoate (mixture of erythro and treosomes) Was dissolved in 400 ml of trifluoroacetic acid, 96 ml of triethylsilane was added, and the mixture was stirred for 38 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of 3N hydrochloric acid and 200 ml of hexane. The aqueous layer was washed with 100 ml of hexane, made alkaline with 5N sodium hydroxide solution and extracted four times with 200 ml of dichloromethane. Combined organic layers. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, the same ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2- as the compound obtained in Preparation Example 2c) in tlc and 1H-mnr 13.0 g of isopropoxypropanoate was obtained as a pale yellow oil.
[809] Example 31f)
[810]
[811] To a solution of 18.67 g of ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 7.7 g of triethylamine in diethyl ether (300 ml) under water cooling 2,4-dichloro Tetrahydrofuran (15 ml) solution of 15.9 g of benzoyl chloride was added dropwise. After stirring for 30 minutes under ice-cooling and 30 minutes at room temperature, the reaction solution was poured into 500 ml of water, and extracted from 300 ml of ethyl acetate. The organic layer was washed with 200 ml of saturated aqueous sodium hydrogen sulphate solution, 200 ml of saturated sodium bicarbonate, and 200 ml of saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure ″, the residue was purified by silica gel column chromatography (elution solvent; hexane-ethyl acetate), and the same ethyl 3- (3- (2 as in compound 31g in tlc and 1H-nmr) was obtained. 28.2 g of, 4-dichlorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoate were obtained as a colorless solid.
[812] Example 31g)
[813]
[814] Ethyl 3- (3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 2,4-dichlorobenzoic acid were treated as in Example 19d, and ethyl 3- (3- ( [(2,4-dichlorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoate was obtained.
[815] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 6.8 Hz, 3H) 2.87 (dd, J = 8.4 , 13.6Hz, 1H) 2.94 (dd, J = 4.8, 13.6Hz, 1H) 3.50 (sept, J = 6.0Hz, 1H) 3.84 (s, 3H) 4.01 (dd, J = 4.8, 8.4Hz, 1H) 4.05 -4.20 (m, 2H) 4.61 (d, J = 5.6 Hz, 2H) 6.74-6.84 (m, 1H) 6.79 (d, J = 8.4 Hz, 1H) 7.16 (dd, J = 2.0, 8.4 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.29 (dd, J = 2.0, 8.4 Hz, 1H) 7.39 (d, J = 2.0 Hz, 1H) 7.64 (d, J = 8.0 Hz, 1H)
[816] Example 31h)
[817]
[818] It treated like Example 1d) and obtained 3- (3-([(2,4-dichlorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoic acid.
[819] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.91 (dd, J = 7.2,14 Hz, 1H) 3.04 (dd, J = 4.0, 14Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 3.84 (s, 3H) 4.09 (dd, J = 4.4, 7.6Hz, 1H) 4.60 (d, J = 6.0Hz, 2H) 6.81 (d , J = 8.4Hz, 1H) 6.83 (m, 1H) 7.16 (dd, J = 2.4, 8.4Hz, 1H) 7.23 (d, J = 2.0Hz, 1H) 7.29 (dd, J = 2.0, 8.4Hz, 1H ) 7.39 (d, J = 2.0 Hz, 1H) 7.64 (d, J = 8.4Hz, 1H)
[820] Example 31i)
[821]
[822] 1.0 g of 3- (3-([(2,4-dichlorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoic acid was dissolved in 5 ml of ethanol, and 2.3 ml of 1N aqueous sodium hydroxide solution was added thereto. The solvent was distilled off under reduced pressure to obtain 3- (3-([(2,4-dichlorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoate sodium.
[823] ¹ H-NMR (DMSO-d ₆ ) δ: 0.79 (d, J = 6.0 Hz, 3H) 0.97 (d, J = 6.0 Hz, 3H) 2.51 (dd, J = 9.2, 13.6 Hz, 1H) 2.79 (dd , J = 4.0, 13.6Hz, 1H) 3.48 (sept, J = 6.0Hz, 1H) 3.63 (dd, J = 3.6, 8.8Hz, 1H) 3.75 (s, 3H) 4.35 (d, J = 6.0Hz, 2H ) 6.82 (d, J = 8.4 Hz, 1H) 7.07 (d, J = 7.6 Hz, 1H) 7.15 (s, 1H) 7.48 (s, 2H) 7.67 (s, 1H) 8.87 (t, J = 6.0 Hz, 1H)
[824] Example 32
[825] Example 32a)
[826]
[827] Ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 4-chloro-2-fluorobenzoic acid were treated as in Example 19d), and ethyl 3- ( 3-([(4-chloro-2-fluorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoate was obtained.
[828] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.13 (d, J = 6.0 Hz, 3H) 1.22 (t, J = 7.2 Hz, 3H) 2.86 (dd, J = 8.0 , 14Hz, 1H) 2.93 (dd, J = 4.8, 14Hz, 1H) 3.49 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.00 (dd, J = 5.2, 8.0Hz, 1H) 4.05-4.25 (m, 2H) 4.62 (d, J = 5.6 Hz, 2H) 6.80 (d, J = 8.4 Hz, 1H) 7.10-7.20 (m, 2H) 7.20 (d, J = 2.0 Hz, 1H) 7.23 (dd, J = 2.0, 8.4Hz, 1H) 7.2-7.35 (m, 1H) 8.06 (t, J = 8.4Hz, 1H)
[829] Example 32b)
[830]
[831] 3- (3-([(4-chloro-2-fluorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 1d).
[832] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.6, 14 Hz, 1H) 3.04 (dd, J = 4.0, 14Hz, 1H) 3.55 (sept, J = 6.0Hz, 1H) 3.87 (s, 3H) 4.09 (dd, J = 4.0, 7.6Hz, 1H) 4.62 (d, J = 5.6Hz, 2H) 6.82 (d , J = 8.0Hz, 1H) 7.08-7.18 (m, 2H) 7.16-7.28 (m, 2H) 7.24-7.38 (m, 1H) 8.05 (t, J = 8.4Hz, 1H)
[833] Example 32b)
[834]
[835] Sodium 3- (3-([(4-chloro-2-fluorobenzoyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypropanoate was obtained in the same manner as in Example 31c).
[836] ¹ H-NMR (DMSO-d ₆ ) δ: 0.77 (d, J = 6.4 Hz, 3H) 0.95 (d, J = 6.0 Hz, 3H) 2.53 (dd, J = 9.2, 14 Hz, 1H) 2.79 (dd, J = 3.2, 14Hz, 1H) 3.46 (sept, J = 6.0Hz, 1H) 3.64 (dd, J = 3.6, 9.2Hz, 1H) 3.76 (s, 3H) 4.38 (t, J = 5.2Hz, 2H) 6.82 (d, J = 8.4 Hz, 1H) 7.07 (d, J = 8.8 Hz, 1H) 7.10 (s, 1H) 7.36 (d, J = 8 Hz, 1H) 7.53 (d, J = 10 Hz, 1H) 7.67 ( t, J = 8 Hz, 1H) 8.76 (m, 1H)
[837] Example 33
[838] Example 33a)
[839]
[840] Ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 2-methoxy-6-methylnicotinic acid were treated in the same manner as in Example 19d) to obtain ethyl 2 -Isopropoxy-3- [4-methoxy-3-(([(2-methoxy-6-methyl-3-pyridyl) carbonyl] amino) methyl) phenyl] propanoate was obtained.
[841] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.12 (d, J = 6.0 Hz, 3H) 1.21 (t, J = 7.2 Hz, 3H) 2.47 (s, 3H) 2.86 (dd, J = 8.4, 14Hz, 1H) 2.93 (dd, J = 5.2, 14Hz, 1H) 3.49 (sept, J = 6.0Hz, 1H) 3.89 (s, 3H) 4.00 (dd, J = 4.8, 8.0Hz , 1H) 4.04 (s, 3H) 4.1-4.2 (m, 2H) 4.62 (d, J = 6.0 Hz, 2H) 6.80 (d, J = 8.4 Hz, 1H) 6.86 (d, J = 7.6 Hz, 1H) 7.14 (dd, J = 2.0, 8.0Hz, 1H) 7.20 (d, J = 2.0Hz, 1H) 8.39 (d, J = 7.6Hz, 1H) 8.42 (m, 1H)
[842] Example 33b)
[843]
[844] 2-isopropoxy-3- [4-methoxy-3-(([(2-methoxy-6-methyl-3-pyridyl) carbonyl] amino) methyl) by the same method as in Example 1d) Phenyl] propanoic acid was obtained.
[845] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.4 Hz, 3H) 2.47 (s, 3H) 2.90 (dd, J = 7.2, 14 Hz, 1H) 3.04 (dd, J = 4.4, 14 Hz, 1H) 3.56 (sept, J = 6.4 Hz, 1H) 3.89 (s, 3H) 4.06 (s, 3H) 4.0-4.15 (m, 1H) 4.61 (d, J = 4.0 Hz, 2H) 6.81 (d, J = 8.4 Hz, 1H) 6.86 (d, J = 7.6 Hz, 1H) 7.12 (dd, J = 2.0, 8.4 Hz, 1H) 7.20 (d, J = 2.4 Hz, 1H) 8.37 (d, J = 7.6Hz, 1H) 8.48 (m, 1H)
[846] Example 34
[847]
[848] Example 1d), followed by Example 20d) with ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 4-chloro-2-methoxybenzoic acid It treated similarly and obtained 3- (3-([(4-chloro-2-methoxybenzoyl) amino) methyl] -4-methoxyphenyl) -2-isopropoxypropanoic acid.
[849] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.6, 14 Hz, 1H) 3.03 (dd, J = 4.4, 14 Hz, 1H) 3.56 (sept, J = 6.0 Hz, 1H) 3.88 (s, 3H) 3.94 (s, 3H) 4.05-4.15 (m, 1H) 4.61 (dd, J = 2.0, 6.0 Hz, 2H) 6.81 (d, J = 8.4 Hz, 1H) 6.95 (d, J = 2.0 Hz, 1H) 7.05 (dd, J = 2.0, 8.4 Hz, 1H) 7.13 (dd, J = 2.0, 8.4 Hz, 1H) 7.20 ( d, J = 2.0Hz, 1H) 8.14 (d, J = 8.4Hz, 1H) 8.28 (t, J = 5.6Hz, 1H)
[850] Example 35
[851] Example 35d)
[852]
[853] Ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate and 2,6-dimethoxynicotinic acid following Example 20d) were treated as in Example 1d) 3- [3-(([(2,6-dimethoxy-3-pyridyl) carbonyl] amino) methyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid was obtained.
[854] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.4 Hz, 3H) 1.13 (d, J = 6.4 Hz, 3H) 2.89 (dd, J = 7.6, 14 Hz, 1H) 3.03 (dd, J = 4.4, 14 Hz, 1H) 3.55 (sept, J = 6.0 Hz, 1H) 3.88 (s, 3H) 3.95 (s, 3H) 4.07 (s, 3H) 3.8-4.2 (m, 1H) 4.60 (dd, J = 1.6 , 6.0 Hz, 2H) 6.41 (d, J = 8.4 Hz, 1H) 6.80 (d, J = 8.4 Hz, 1H) 7.13 (dd, J = 2.0, 8.4 Hz, 1H) 7.21 (d, J = 2.0 Hz, 1H) 8.32 (m, 1H) 8.41 (d, J = 8.4 Hz, 1H)
[855] Example 36
[856] Preparation Example 36a)
[857]
[858] A tetrahydrofuran (4L) solution of 98 g of 2-isopropoxyacetic acid and 360 ml of triethylamine was cooled to -25 ° C, 92 ml of 2,2-dimethylpropanoyl chloride was added dropwise, and the reaction solution was then-for 5 hours. It stirred at 20 degreeC. 50 g of anhydrous lithium chloride and 120 g of (4S) -4-benzyl-1,3-oxazolon-2-one were added sequentially, and after stirring at room temperature overnight, the reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in 2 L of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; hexane-acetic acid) and ethyl (4S) -4-benzyl-3- (2-isopropoxyacetyl) -1,3-oxa 106.6 g of jolon-2-one was obtained as a colorless oil.
[859] ¹ H-NMR (CDCl ₃ ) δ: 1.17 (d, J = 6.0 Hz, 6H) 2.81 (dd, J = 9.5,13.4 Hz, 1H) 3.35 (dd, J = 3.2,13.4 Hz, 1H) 3.74 (sept , J = 6.0 Hz, 1H)) 4.24 (dd, J = 3.5,9.3 Hz) 4.29 (t, J = 9.3 Hz, 1H) 4.65 (d, J = 19.5 Hz, 1H) 4.69 (m, 1H) 4.70 ( d, J = 19.5 Hz, 1H) 7.22 (d, J = 7.2 Hz, 2H) 7.30-7.45 (m, 3H)
[860] Preparation Example 36b)
[861]
[862] 12.4 g of (4S) -4-benzyl-3- (2-isopropoxyacetyl) -1,3-oxazolon-2-one toluene (4L) solution was divided into equal parts and cooled to -75 ° C 28.0 g of triethylamine was added to the solution. 232 ml of dibutyl boron triplate (1M dichloromethane solution) was dripped at the speed which internal temperature does not exceed -70 degreeC. After stirring for 50 minutes after dropping, the internal temperature was raised to 0 ° C, further stirred for 50 minutes, and cooled to -75 ° C. To this reaction solution was added a dichloromethane (1.4 L) solution of tert-butyl N- (5-formyl-2-methoxybenzyl) carbamate which had been cooled to about -70 DEG C in advance using a cannula,- After stirring at 75 ° C for 30 minutes, the internal temperature was raised to 0 ° C by 10 ° C every 10 minutes after about 1 hour. After stirring for 75 minutes at 0 ° C, a mixed solution of 1.21 L of methanol, 0.605 L of pH7 buffer (dibasic sodium hydrogen phosphate-citric acid), and 0.262 L of hydrogen peroxide (30% aqueous solution) were added. The two reaction liquids were combined, poured into 9 L of water, and extracted from 1 L of dichloromethane. The organic layer was washed with 4 L of saturated brine, and the aqueous layers were combined and extracted with 4 L of ethyl acetate. All organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane-ethyl acetate), tert-butyl N- (5- (lR, 2S) -3-[(4S) -4-benzyl-2-oxo-1, 111.0 g of 3-oxazolan-3-yl] -1-hydroxy-2-isopropoxy-3-oxopropyl-2-methoxybenzyl) carbamate was obtained as a colorless solid.
[863] ¹ H-NMR (CDCl ₃ ) δ: 1.17 (d, J = 6.2 Hz, 3H) 1.21 (d, J = 6.2 Hz, 3H) 1.43 (s, 9H) 2.75 (dd, J = 9.6, 13.2 Hz, 1H ) 3.02-3.15 (br.s, 1H) 3.24 (dd, J = 3.6, 13.2 Hz, 1H) 3.64-3.73 (m, 2H) 3.83 (s, 3H) 4.02 (d, J = 8.2 Hz, 1H) 4.23 (dd, J = 6.2,15.6 Hz, 1H) 4.31 (dd, J = 6.4,15.6 Hz, 1H) 4.46 (m, 1H) 4.78 (d, J = 5.6 Hz, 1H) 4.99 (m, 1H) 5.42 ( d, J = 5.6 Hz, 1H) 6.83 (d, J = 8.3 Hz, 1H) 7.19 (d, J = 7.2 Hz, 2H) 7.26-7.39 (m, 5H)
[864] Preparation 36c)
[865]
[866] Tert-butyl N- (5- (lR, 2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolan-3-yl] -1-hydro as in Preparation Example 31e) After 8.90 g of oxy-2-isopropoxy-3-oxopropyl-2-methoxybenzyl) carbamate was reduced, 50 ml of 4N ethyl acetate solution was added to the crude product. After distilling off the solvent under reduced pressure, the residue was suspended with diisopropylethylhexane, the solid was filtered and washed with the solvent, and (4S) -3- (2S) -3- [3- (aminomethyl)- 7.89 g of 4-methoxyphenyl] -2-isopropoxypropanoyl-4-benzyl-1,3-oxazolin-2-one hydrochloride were obtained as a colorless solid.
[867] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.3 Hz, 3H) 1.14 (d, J = 6.3 Hz, 3H) 2.77-2.85 (m, 2H) 2.94 (dd, J = 3.5, 11.9 Hz , 1H) 3.28 (dd, J = 1.7 pcs, 12.8 Hz, 1H) 3.50 (sept, J = 6.3 Hz, 1H) 3.82 (s, 3H) 4.10-4.19 (m, 4H) 4.64 (m, 1H) 5.28 ( dd, J = 3.5,7.9 Hz, 1H) 6.81 (d, J = 8.4 Hz, 1H) 7.20 (d, J = 7.0 Hz, 2H) 7.25-7.34 (m, 5H) 8.25 (br.s, 3H)
[868] Preparation Example 36d)
[869]
[870] (4S) -3- (2S) -3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoyl-4-benzyl-1,3- as in Production Example 31f) After amidating 7.66 g of oxazolan-2-one hydrochloride, the crude product was dissolved in 20 ml of ethyl acetate under reflux and cooled at room temperature. 60 ml of diisopropylethyl and 120 ml of hexane were added sequentially, and the precipitate was collected by filtration and N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolane-3 -Yl] -2-isopropoxy-3-oxopropyl-2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide was obtained as a colorless solid.
[871] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.2 Hz, 3H) 1.16 (d, J = 6.2 Hz, 3H) 2.75 (dd, J = 10.1, 12.6 Hz, 1H) 2.88 (dd, J = 7.9,13.9 Hz, 1H) 2.93 (dd, J = 4.7, 13.9 Hz, 1H) 3.32 (dd, J = 3.5,12.6 Hz, 1H) 3.52 (sept, J = 6.2 Hz, 1H) 3.86 (s, 3H) 3.98 (t, J = 8.5 Hz, 1H) 4.11 (dd, J = 2.6,8.5 Hz, 1H) 4.56 (m, 1H) 4.65 (d, J = 5.9 Hz, 2H) 5.34 (dd, J = 4.7 Dog, 7.9 Hz, 1H) 6.8 (d, J = 8.7 Hz, 1H) 7.20-7.38 (m, 8H) 7.56 (d, J = 8.7 Hz, 1H), 8.34 (t, J = 8.7 Hz, 1H)
[872] Example 36e)
[873]
[874] 1.39 g of (4S) -4-benzyl-3- (2-isopropoxyacetyl) -1,3-oxazol-2-one and N1- (5-formyl-2-methoxy as in Preparation Example 36b) Benzyl) -2-fluoro-4- (trifluoromethyl) benzamide from 0.89 g N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxa Zolan-3-yl] -1-hydroxy-2-isopropoxy-3-oxopropyl-2-methoxybenzyl] -2-fluoro-4- (trifluoromethyl) benzamide 1.36 g colorless solid Obtained as.
[875] ¹ H-NMR (CDCl ₃ ) δ: 1.15 (d, J = 6.0 Hz, 3H) 1.20 (d, J = 3 Hz, 3H) 2.67 (dd, J = 9.6,13.4 Hz, 1H) 3.05-3.14 (br s, 1H) 3.25 (dd, J = 3.8,13.4 Hz, 1H) 3.61 (t, J = 8.6 Hz, 1H) 3.67 (sept, J = 6.0 Hz, 1H) 3.86 (s, 3H) 3.93 (dd, J = 1.7, 8.6 Hz, 1H) 4.44 (m, 1H) 4.60 (dd, J = 5.2,14.1 Hz, 1H) 4.66 (dd, J = 5.2,14.1 Hz) 4.79 (d, J = 5.8 Hz, 1H ) 5.42 (d, J = 5.8 Hz, 1H) 6.88 (d, J = 8.7 Hz, 1H) 7.19 (d, J = 7.1 Hz, 2H) 7.27-7.33 (m, 4H) 7.36 (dd, J = 0.8, 11.1 Hz, 1H) 7.39 (dd, J = 2.0, 8.0 Hz, 1H) 7.44 (d, J = 7.7 Hz, 1H) 8.03 (t, J = 7.7 Hz, 1H)
[876] Example 36f)
[877]
[878] N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolin-3-yl] -1-hydroxy-2-iso as in Preparation Example 31e) N1-same as the compound obtained in tlc and 1H-nmr in Preparation Example 36d) from 1.36 g of propoxy-3-oxopropyl-2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide (5- (2S) -3-[(4S) -4-benzylnooxo-1,3-oxazolan-3-yl] -2-isopropoxy-3-oxopropyl-2-methoxybenzyl)- 1.30 g of 2-fluoro-4- (trifluoromethyl) benzamide were obtained as a colorless solid.
[879] Example 36g)
[880]
[881] N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolin-3-yl] -2-isopropoxy-3- as in Production Example 37c) (2S) -3- [same as the compound obtained in Example 6a in tlc and IH-nmr from 6.46 g of oxopropyl-2-methoxybenzyl) -2-fluoro-4- (trifluoromethyl) benzamide 4.81 g of 3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid were obtained as a colorless oil. Purity by HPLC analysis; 97.7%, optical purity; 96.8% e.e. (OD column; flow rate 0.5 ml / min; 2-propanol: hexane: trifluoroacetic acid = 700: 300: 1).
[882] Example 37
[883] Preparation Example 37a)
[884]
[885] N-N-dimethylformamide (400 ml) solution of 50 mL of 2-methoxybenzylamine and 123 mL of pyridine was added dropwise 45 ml of 2,4-dichlorobenzoyl chloride at 5-10 ° C for 1.5 hours, followed by stirring at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, saturated aqueous ammonium chloride solution and 1N aqueous sodium hydroxide solution. The organic layer was washed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid (x2), saturated aqueous ammonium chloride solution (x2), and saturated brine, and then dried over anhydrous sodium sulfate and concentrated. The residue was suspended with diisopropylethyl (30OmL) and diethylether (50OmL), the solid was filtered, washed with diethylether and N1- (2-methoxybenzyl) -2,4-dichlorobenzamide 81.1 g was obtained as a pale yellow solid.
[886] ¹ H-NMR (CDCl ₃ ) δ: 3.87 (s, 3H) 4.64 (d, J = 6.0 Hz, 2H) 6.82 (br, 1H) 6.89 (d, J = 8.4 Hz, 1H) 6.92-6.98 (m, 1H) 7.26-7.32 (m, 2H) 7.35 (dd, J = 2.4, 7.6 Hz, 1H) 7.40 (d, J = 2.4 Hz, 1H) 7.65 (d, J = 8.4 Hz, 1H)
[887] Preparation Example 37b)
[888]
[889] 9.04 g of hexamethylenetetramine was added to a trifluoroacetic acid (20OmL) solution of 10.0 g of N1- (2-methoxybenzyl) -2,4-dichlorobenzamide, and stirred at 50 ° C for 23 hours. The reaction solution was allowed to cool to room temperature and then concentrated. The residue was diluted with ice water and adjusted to pH = 11-12 with 1N aqueous sodium hydroxide solution. This was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution (× 3), 1N hydrochloric acid (× 2), and saturated brine, dried over anhydrous sodium sulfate, and filtered through 10 g of silica gel. After the filtrate was concentrated, the residue was suspended with ethyl acetate. The solid was filtered and washed with ethyl acetate to obtain 7.15 g of N1- (5-formyl-2-methoxybenzyl) -2,4-dichlorobenzamide as a colorless solid.
[890] ¹ H-NMR (CDCl ₃ ) δ: 3.97 (s, 3H) 4.68 (d, J = 6.0 Hz, 2H) 6.81 (br, 1H) 7.01 (d, J = 8.4 Hz, 1H) 7.31 (dd, J = 2.0, 8.4 Hz, 1H) 7.41 (d, J = 2.0 Hz, 1H) 7.68 (d, J = 8.4 Hz, 1H) 7.85 (dd, J = 2.0, 8.4 Hz, 1H) 7.90 (d, J = 2.0 Hz , 1H) 9.88 (s, 1H)
[891] Example 37c)
[892]
[893] 125.0 g of (4S) -4-benzyl-3- (2-isopropoxyacetyl) -1,3-oxazol-2-one and N1- (5-formyl-2-methoxy as in Preparation Example 36b) N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazol-3-yl] -1 from 101.9 g of benzyl) -2,4-dichlorobenzamide 167.0 g of -hydroxy-2-isopropoxy-3-oxopropyl-2-methoxybenzyl) -2,4-dichlorobenzamide were obtained as a colorless solid.
[894] ¹ H-NMR (CDCl ₃ ) δ: 1.15 (d, J = 6.2 Hz, 3H) 1.20 (d, J = 6.2 Hz, 3H) 2.71 (dd, J = 9.5,14.1 Hz, 1H) 3.06-3.15 (br s, 1H) 3.25 (dd, J = 3.2,14.1 Hz, 1H) 3.68 (sept, J = 6.2 Hz, 1H) 3.69 (dd, J = 7.8, 8.5 Hz, 1H) 3.84 (s, 3H) 3.97 ( dd, J = 2.1,8.5 Hz, 1H) 4.44 (m, 1H) 4.58 (dd, J = 5.3,13.9 Hz, H) 4.63 (dd, J = 5.3,13.9 Hz, 1H) 4.79 (d, J = 5.6 Hz, 1H) 5.40 (d, J = 5.6 Hz, 1H) 6.73 (t, J = 5.3 Hz, 1H) 6.85 (d, J = 8.2 Hz, 1H) 7.16 (d, J = 7.0 Hz, 2H) 7.25- 7.34 (m, 5H) 7.37 (dd, J = 1.9,8.2 Hz, 1H) 7.40 (d, J = 1.9 Hz, 1H) 7.58 (d, J = 8.2 Hz, 1H)
[895] Preparation Example 37d)
[896]
[897] N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolin-3-yl] -1-hydroxy-2-iso as in Preparation Example 31e) Crude product was obtained from 167 g of propoxy-3-oxopropyl-2-methoxybenzyl) -2,4-dichlorobenzamide, which was dissolved in 550 ml of ethyl acetate under reflux, cooled at room temperature, and then 550 ml of diisopropylethyl. And 80Oml of hexane were added sequentially, and the precipitate was filtered off, and N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazol-3-yl] -2 119.7 g of isopropoxy-3-oxopropyl-2-methoxybenzyl) -2,4-dichlorobenzamide were obtained as a colorless solid.
[898] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.2 Hz, 3H) 1.17 (d, J = 6.2 Hz, 1H) 2.96 (dd, J = 9.1, 13.3 Hz, 1H) 2.89 (dd, J = 7.8, 13.2 Hz, 1H) 2.94 (dd, J = 5.3, 13.2 Hz, 1H) 3.30 (dd, J = 3.1, 13.3 Hz, 1H) 3.53 (sept, J = 6.2 Hz, 1H) 3.84 (s, 3H ) 4.02 (t, J = 8.4 Hz, 1H) 4.11 (dd, J = 1.6,8.4 Hz, 1H) 4.57 (m, 1H) 4.59 (dd, J = 6.2,14.3 Hz, 1H) 4.63 (dd, J = 6.2,14.3 Hz, 1H) 5.34 (dd, J = 5.3,7.8 Hz, 1H) 6.75 (t, J = 6.2 Hz, 1H) 6.80 (d, J = 8.2 Hz, 1H) 7.19 (d, J = 8.3 Hz , 2H) 7.22-7.33 (m, 6H) 7.40 (d, J = 2.8 Hz, 1H) 7.63 (d, J = 10.3 Hz, 1H)
[899] Preparation Example 37e)
[900]
[901] N1- (5- (2S) -3-[(4S) -4-benzyl-2-oxo-1,3-oxazolan-3-yl] -2-isopropoxy-3-oxopropyl-2-meth To a solution of oxybenzyl) -2,4-dichlorobenzamide 124.9 g of tetrahydrofuran (1.6 L) was added 400 ml of water, cooled to -10 ° C, and then l84 ml of 30% hydrogen peroxide solution and 20.3 g of lithium hydroxide (150 ml) ) Solution was added sequentially, and it stirred at 4 degreeC for 24 hours. After cooling to -10 占 폚, 1.5 L of 2M aqueous sodium sulfite solution was added, the pH was adjusted to 2-3 with 5N hydrochloric acid, and extracted from 1.5 L of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1N sodium hydroxide, and the aqueous layer was extracted four times from 1 L of a 4: 1 mixed solvent of diethyl ether dichloromethane. The organic layers were combined and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to recover 33.7 g of (4S) -4-benzyl-3- (2-isopropoxyacetyl) -1,3-oxazolon-2-one. The aqueous layer was adjusted to pH 2-3 with 5N hydrochloric acid, and extracted with 1.5 L and 0.5 L of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the same compound as in (2S) -3- [3-([2,4-dichlorobenzoyl) obtained in Preparation Example 31b in tlc and 1H-nmr. ] 8methyl g of] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid was obtained. Purity by HPLC analysis; 98.6% (OD column; flow rate 0.5 ml / min; 2-propanol: hexane: trifluoroacetic acid = 700: 300: 1). Purity by HPLC analysis by purification of this compound by silica gel column chromatography (elution solvent hexane-ethyl acetate) and then recrystallization in 41Oml of ethyl acetate and 410ml of heptane; 99.8%, optical purity; 61.6 g of a colorless solid 99.7% e.e. were obtained.
[902] Example 38
[903] Preparation Example 38a)
[904]
[905] Toluene (50 ml) suspension of 2.75 g of tert-butyl N- (5-formyl-2-methoxybenzyl) carbamate and 4.73 g of (triphenylphosphoranilidene) acetaldehyde was stirred at 80 ° C for 16 hours. After allowing the reaction solution to cool to room temperature, the insolubles were filtered off through silica gel, and the filtrate was concentrated. Using 2.47 g of the obtained residue, in the same manner as in Production Example 1a) and Production Example 1b), ethyl 5- (3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl) -2 630 mg of isopropoxypentanoate was obtained as a colorless oil.
[906] ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, J = 6.0 Hz, 3H) 1.19 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 1.50 -1.80 (m, 4H) 2.55 (t, J = 7.2 Hz, 2H) 3.57 (sept, J = 6.0 Hz, 1H) 3.81 (s, 3H) 3.88 (dd, J = 4.8, 7.6 Hz, 1H) 4.19 ( q, J = 7.2 Hz, 2H) 4.27 (d, J = 5.6Hz, 2H) 5.01 (br, 1H) 6.76 (d, J = 8.0Hz, 1H) 7.00-7.08 (m, 2H)
[907] Example 38b)
[908]
[909] To 50 mg of ethyl 5- (3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypentanoate was added 2 ml of 4N HC1 / dioxane, 3.5 at room temperature. It stirred for hours. After concentrating the reaction solution, the residue was dissolved in 2 ml of N, N-dimethylformamide, 12 mg of 2,4-dichlorobenzoic acid, 9 µl of cyanophosphonic acid diethyl, and 17 µl of triethylamine were added to 1 ml of them. It stirred at room temperature for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. After the organic layer was concentrated, the residue was dissolved in 0.4 ml of methanol, 0. l ml of 5N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated and neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the residue was purified by HPLC using water-acetonitrile-trifluoroacetic acid as an eluting solvent in a column of reversed phase, and 5- (3 ([(2,4-dichlorobenzoyl) amino] methyl)- 5.02 mg of 4-methoxyphenyl] -2-isopropoxypentanoic acid was obtained.
[910] MS m / e (ESI) 468 (MH ⁺ )
[911] Example 39
[912]
[913] 2-isopropoxy-5- [4-methoxy-3-(([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] amino] methyl) phenyl] pentanoic acid Silver was obtained in the same manner as in Example 38 using ethyl 5- (3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl) -2-isopropoxypentanoate.
[914] MS m / e (ESI) 497 (MH ⁺ )
[915] Example 40
[916] Preparation Example 40a)
[917]
[918] 4.88 g of ethyl 2-isopropoxy-3- (4-pyridyl) propanoate was obtained as a colorless oil by using 4.0 g of 4-pyridinecarboxyaldehyde and in the same manner as in Preparation Example 1a) and Preparation Example 1b).
[919] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.26 (t, J = 7.2 Hz, 3H) 2.92 (dd, J = 8.8 , 13.6Hz, 1H) 3.00 (dd, J = 4.4, 13.6Hz, 1H) 3.52 (sept, J = 6.0Hz, 1H) 4.06 (dd, J = 4.4, 8.8Hz, 1H) 4.15-4.24 (m, 2H ) 7.19 (dd, J = 1.6, 4.4 Hz, 2H) 8.51 (dd, J = 1.6, 4.4 Hz, 2H)
[920] Preparation Example 40b)
[921]
[922] 6.0 g of m-chloroperbenzoic acid was added to the dichloromethane (50 mL) solution of 4.88 g of ethyl 2-isopropoxy-3- (4-pyridyl) propanoate, and it stirred at room temperature for 1.5 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and then concentrated to give 6.40 g of a crude product of 4- (3-ethoxy-2-isopropoxy-3-oxopropyl) -1-pyridinium oleate as a yellow oil.
[923] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 2.93 (dd, J = 8.8 , 14.0Hz, 1H) 3.00 (dd, J = 4.0, 14.0Hz, 1H) 3.55 (sept, J = 6.0Hz, 1H) 4.03 (dd, J = 4.0, 8.8Hz, 1H) 4.16-4.25 (m, 2H ) 7.20-7.25 (m, 2H) 8.16-8.21 (m, 2H)
[924] Preparation Example 40c)
[925]
[926] 6.40 g of a crude product of 4- (3-ethoxy-2-isopropoxy-3-oxopropyl) -1-pyridinium oleate and dimethylcarbamyl chloride in a solution of dichloromethane (60 ml) in 3.3 ml of trimethylsilylcyanide 2.3 ml was dripped over 40 minutes, and it stirred for 11.5 hours. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography to obtain 3.87 g of ethyl 3- (2-cyano-4-pyridyl) -2-isopropoxypropanoate as a pale yellow oil.
[927] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.28 (t, J = 7.2 Hz, 3H) 2.99 (dd, J = 8.8 , 14.0Hz, 1H) 3.06 (dd, J = 4.0, 14.0Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 4.06 (dd, J = 4.0, 8.8Hz, 1H) 4.17-4.26 (m, 2H ) 7.43 (dd, J = 1.6, 5.0 Hz, 1H) 7.63 (dd, J = 0.8, 1.6 Hz, 1H) 8.61 (dd, J = 0.8, 5.0 Hz, 2H)
[928] Preparation Example 40d)
[929]
[930] 1.0 g of ethyl 3- (2-cyano-4-pyridyl) -2-isopropoxypropanoate was dissolved in 70 mL of ethanol, 1.9 mL of concentrated hydrochloric acid and 0.9 g of 10% palladium carbon were added, under a hydrogen atmosphere, It stirred at room temperature for 2 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure, followed by azeotroping with ethyl acetate and toluene to prepare 1.21 g of ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Obtained as product.
[931] ¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (d, J = 6.0 Hz, 3H) 1.07 (d, J = 6.0 Hz, 3H) 1.19 (t, J = 7.2 Hz, 3H) 2.96 (dd, J = 8.8, 14.0 Hz, 1H) 3.08 (dd, J = 4.4, 8.8 Hz, 1H) 3.55 (sept, J = 6.0 Hz, 1H) 4.13 (q, J = 7.2 Hz, 2H) 4.25 (br, 2H) 4.31 (dd, J = 4.4, 8.8Hz, 1H) 7.52 (d, J = 5.2Hz, 1H) 7.97 (s, 1H) 8.63 (d, J = 5.2Hz, 1H) 8.66-8.83 (m, 3H)
[932] Example 40e)
[933]
[934] 3- (2-([(2,4-dichlorobenzoyl) amino] methyl) -4-pyridyl) -2-isopropoxypropanoic acid trifluoro acetate was ethyl 3- [2- (aminomethyl) -4 -Pyridyl] -2-isopropoxypropanoate hydrochloride was obtained in the same manner as in Example 19d) and Example 19e).
[935] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 3.27 (d, J = 5.6 Hz, 2H) 3.69 (sept, J = 6.0 Hz, 1H) 4.30 (t, J = 5.6 Hz, 1H) 4.80-4.91 (m, 2H) 7.27 (dd, J = 2.0, 7.8 Hz, 1H) 7.39 (d, J = 2.0 Hz, 1H) 7.48 (d , J = 7.8Hz, 1H) 7.68 (dd, J = 1.6, 6.0Hz, 1H) 7.93 (d, J = 1.6Hz, 1H) 8.56 (d, J = 6.0Hz, 1H) 8.60 (t, J = 6.0 Hz, 1H)
[936] MS m / e (ESI) 440 (MH ⁺ )
[937] Example 41
[938]
[939] 2-isopropoxy-3- [2-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] amino) methyl) -4-pyridyl] propanoic acid trifluoro Rho acetate was obtained in the same manner as in Example 19d) and Example 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride.
[940] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.19 (d, J = 6.0 Hz, 3H) 2.72 (s, 3H) 3.28 (d, J = 6.0 Hz, 2H) 3.71 (sept, J = 6.0 Hz, 1H) 4.31 (t, J = 5.6 Hz, 1H) 4.84 (dd, J = 2.8,5.6 Hz, 2H) 7.41-7.49 (m, 3H) 7.68 (dd, J = 2.0, 6.0 Hz, 1H) 7.88-7.93 (m, 2H) 7.94 (d, J = 1.2 Hz, 1H) 8.57 (d, J = 6.0 Hz, 1H) 8.74 (t, J = 6.0 Hz, 1H)
[941] Example 42
[942]
[943] 3- (2-([(2-chloro-4-isopropoxybenzoyl) amino] methyl) -4-pyridyl) -2-isopropoxypropanoic acid trifluoroacetic acid ethyl 3- [2- (amino Using methyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride in the same manner as in Example 19d) and Example 19e).
[944] MS m / e (ESI) 435 (MH ⁺ )
[945] Example 43
[946]
[947] 3- (2-([(2-chloro-4-propoxybenzoyl) amino] methyl) -4-pyridyl) -2-isopropoxypropanoic acid trifluoro acetate was ethyl 3- [2- (aminomethyl ) -4-pyridyl] -2-isopropoxypropanoate hydrochloride was obtained in the same manner as in Example 19d) and Example 19e).
[948] MS m / e (ESI) 435 (MH ⁺ )
[949] Example 44
[950]
[951] 3- [2-(([2-chloro-4- (cyclopentyloxy) benzoyl] amino) methyl) -4-pyridyl] -2-isopropoxypropanoic acid trifluoro acetate was ethyl 3- [2- Using (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride in the same manner as in Example 19d) and Example 19e).
[952] MS m / e (ESI) 461 (MH ⁺ )
[953] Example 45
[954]
[955] Ethyl 3- [2-(([2-fluoro-4- (trifluoromethyl) benzoyl] amino) methyl) -4-pyridyl] -2-isopropoxypropanoic acid trifluoro acetate is ethyl 3- Using the same method as Example 19d) and Example 19e) using [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride.
[956] MS m / e (ESI) 429 (MH ⁺ )
[957] Example 46
[958]
[959] 2-isopropoxy-3- (2-[(([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl Propanoic acid trifluoro acetate was prepared in the same manner as in Example 19d) and 19e, using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Got as.
[960] MS m / e (ESI) 454 (MH ⁺ )
[961] Example 47
[962]
[963] 3- (2-[(([2- (3-chloro-4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl Example 19d) and the practice of (2) -2-isopropoxypropanoic acid trifluoro acetate using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride In the same manner as in Example 19e).
[964] MS m / e (ESI) 492 (MH ⁺ )
[965] Example 48
[966]
[967] 3- (2-[(([2- (4-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonyl] amino) methyl] -4-pyridyl) -2-iso Propoxypropanoic acid trifluoro acetate was the same as Example 19d) and Example 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Got in the way.
[968] MS m / e (ESI) 474 (MH ⁺ )
[969] Example 49
[970]
[971] 3- (2-[(([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl) -2-iso Propoxypropanoic acid trifluoro acetate was the same as Example 19d) and Example 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Got in the way.
[972] MS m / e (ESI) 474 (MH ⁺ )
[973] Example 50
[974]
[975] 3- (2-[(([2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl) -2 Isopropoxypropanoic acid trifluoroacetate was prepared using Example 3-d- (2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride, Example 19d) and Example 19e). Obtained in the same way as
[976] MS m / e (ESI) 508 (MH ⁺ )
[977] Example 51
[978]
[979] 2-isopropoxy-3- (2-[(([2- (4-methoxyphenyl) -5-methyl-1,3-thiazol-4-yl] carbonyl) amino) methyl] -4- Pyridyl] propanoic acid trifluoro acetate was prepared using Example 3-d and 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Obtained in the same way.
[980] MS m / e (ESI) 470 (MH ⁺ )
[981] Example 52
[982]
[983] 2-isopropoxy-3-12-[(([5-methyl-2- (2-methylphenyl) -1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl) Propanoic acid trifluoro acetate was prepared in the same manner as Example 19d) and Example 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. Got it.
[984] MS m / e (ESI) 454 (MH ⁺ )
[985] Example 53
[986]
[987] 2-isopropoxy-3-12-[(5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] carbonyl) amino) methyl] -4-pyridyl) propane Acid trifluoro acetate was obtained by the same method as Example 19d) and Example 19e) using ethyl 3- [2- (aminomethyl) -4-pyridyl] -2-isopropoxypropanoate hydrochloride. .
[988] MS m / e (ESI) 446 (MH ⁺ )
[989] Example 54
[990]
[991] Using cinnamic acid, 2-isopropoxy-3- [4-methoxy-3-([(E) -3-phenyl-2-propenyl]] in the same manner as in Example 19d) and Example 19e) Aminomethyl) phenyl] propionic acid was obtained.
[992] MS m / e (ESI) 398 (MH ⁺ )
[993] Example 55
[994]
[995] 2-isopropoxy-3- [4-methoxy-3-([(E) -2-methyl-3-phenyl-2-propenyl] aminomethyl) phenyl] propionic acid was prepared in the same manner as in Example 54. Got it.
[996] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.09 (d, J = 1.2 Hz, 3H) 2.92 (dd, J = 7.2 , 13.6Hz, 1H) 3.07 (dd, J = 4.4, 14.0Hz, 1H) 3.60 (sept, J = 6.0Hz, 1H) 3.87 (s, 3H) 4.12 (dd, J = 4.4, 7.2Hz, 1H) 4.54 (d, J = 5.6Hz, 2H) 6.46 (br, 1H) 6.82 (d, J = 8.4Hz, 1H) 7.15 (dd, J = 2.0, 8.4Hz, 1H) 7.22 (d, J = 2.4Hz, 1H ) 7.26-7.39 (m, 6H)
[997] MS m / e (ESI) 412 (MH ⁺ )
[998] Example 56
[999]
[1000] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (2-chlorophenyl-2-propenyl] aminomethyl) phenyl] propionic acid was prepared in the same manner as in Example 54. Got it.
[1001] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 7.2, 13.6 Hz, 1H) 3.05 (dd, J = 4.4, 14.0Hz, 1H) 3.57 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.11 (t, J = 4.4Hz, 1H) 4.54 (d, J = 5.6Hz, 2H) 6.22 (br , 1H) 6.40 (d, J = 16.0 Hz, 1H) 6.81 (d, J = 8.4 Hz, 1H) 7.14 (d, J = 8.0 Hz, 1H) 7.21-7.27 (m, 2H) 7.40 (d, J = 2.0, 7.6Hz, 1H) 7.56 (d, J = 7.6Hz, 1H) 7.97 (d, J = 16.0Hz, 1H)
[1002] MS m / e (ESI) 432 (MH ⁺ )
[1003] Example 57
[1004]
[1005] 2-Isopropoxy-3- [4-methoxy-3-([(E) -3- (3-chlorophenyl-2-propenyl] aminomethyl) phenyl] propionic acid was prepared in the same manner as in Example 54. Got it.
[1006] MS m / e (ESI) 432 (MH ⁺ )
[1007] Example 58
[1008]
[1009] 2-Isopropoxy-3- [4-methoxy-3-([(E) -3- (4-chlorophenyl-2-propenyl] aminomethyl) phenyl] propionic acid was prepared in the same manner as in Example 54. Got it.
[1010] MS m / e (ESI) 432 (MH ⁺ )
[1011] Example 59
[1012]
[1013] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (3,4-dichlorophenyl-2-propenyl] aminomethyl) phenyl] in the same manner as in Example 54] Propionic acid was obtained.
[1014] MS m / e) ESD 466 (MH ⁺ )
[1015] Example 60
[1016] Preparation Example 6Oa)
[1017]
[1018] 600 mg of diethylphosphonoacetic acid and 969 mg of 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropionate ethyl ester were dissolved in 10 ml of N, N-dimethylformamide, and cyanophosphonic acid di 470 µl of ethyl and 1.07 ml of triethylamine were added sequentially. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 1.387 g of 3- [3-([2- (diethoxyphosphoryl) acetyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropionic acid ethyl ester was obtained.
[1019] ¹ H-NMR (CDCl ₃ )
[1020] δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23-1.30 (m, 9H) 2.84 (d, J = 20.4 Hz, 2H) 2.85-2.94 (m, 2H ) 3.48 (sept, J = 6.0 Hz, 1H) 3.84 (s, 3H) 4.00 (dd, J = 4.8, 8.4 Hz, 1H) 4.03-4.21 (m, 6H) 4.43 (d, J = 6.0 Hz, 2H) 6.77 (d, J = 8.0 Hz, 1H) 7.12-7.15 (m, 2H)
[1021] Example 60b)
[1022]
[1023] 15 mg of 3- [3-([2- (diethoxyphosphoryl) acetyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropionic acid ethyl ester was dissolved in 0.4mI of tetrahydrofuran, 3 mg was added and it stirred at room temperature for 0.5 hour. A solution of 10 mg of 4- (trifluoromethyl) benzaldehyde in N, N-dimethylformamide (0.1 ml) was added. After stirring at room temperature for 1 hour, 0.5 ml of methanol and 0.1 ml of 5N-sodium hydroxide were added, and after stirring overnight at room temperature, 1N hydrochloric acid was added, extraction was performed with ethyl acetate, and the solvent was concentrated under reduced pressure. The residue was purified by HPLC and 2-isopropoxy-3-4-methoxy-3- (E) -3- [4- (trifluoromethyl) phenyl] -2-propenoylamino) methyl] phenyl 9.26 mg of propionic acid was obtained.
[1024] MS m / e (ESI) 466 (MH ⁺ )
[1025] Example 61
[1026]
[1027] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (2,3-dichlorophenyl-2-propenyl] aminomethyl) phenyl] in the same manner as in Example 60] Propionic acid was obtained.
[1028] MS m / e (ESI) 466 (MH ⁺ )
[1029] Example 62
[1030]
[1031] 2-isopropoxy-3-4-methoxy-3-[((E) -3- [2-fluoro-3- (trifluoromethyl) phenyl] -2-prop in the same manner as in Example 60 Phenoylamino) methyl] phenylpropionic acid was obtained.
[1032] MS m / e (ESI) 484 (MH ⁺ )
[1033] Example 63
[1034]
[1035] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (2,4-dichlorophenyl-2-propenyl] aminomethyl) phenyl] in the same manner as in Example 60] Propionic acid was obtained.
[1036] MS m / e (ESI) 466 (MH ⁺ )
[1037] Example 64
[1038]
[1039] 2-Isopropoxy-3- [4-methoxy-3-([E) -3-) 4-bromo-2-fluorophenyl-2-propenoyl] aminomethyl in the same manner as in Example 60 ) Phenyl] propionic acid was obtained.
[1040] MS m / e (ESI) 494 (MH ⁺ )
[1041] Example 65
[1042]
[1043] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (2,5-dichlorophenyl-2-propenyl] aminomethyl) phenyl] in the same manner as in Example 60] Propionic acid was obtained.
[1044] MS m / e (ESI) 466 (MH ⁺ )
[1045] Example 66
[1046]
[1047] 2-isopropoxy-3- [4-methoxy-3-([(E) -3- (1-naphthyl) -2-propenyl] aminomethyl) phenyl] propionic acid in the same manner as in Example 60 Got.
[1048] MS m / e (ESI) 448 (MH ⁺ )
[1049] Example 67
[1050] Preparation Example 67a)
[1051]
[1052] 643 mg of 2-diethylphosphonopropionic acid and 973 mg of 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropionic acid ethyl ester were dissolved in 10 ml of N, N-dimethylformamide, and cyanofo 470 µl of diethyl sulfonate and 1.07 ml of triethylamine were added sequentially. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 1.310 g of 3- [3-([2- (diethoxyphosphoryl) propanoyl] aminomethyl-4-methoxyphenyl] -2-isopropoxypropionic acid ethyl ester were obtained.
[1053] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24-1.29 (m, 9H) 1.40 (dd, J = 7.2, 17.6 Hz , 3H) 2.79-2.94 (m, 3H) 3.50 (sept, J = 6.0 Hz, 1H) 3.84 (s, 3H) 3.98-4.2 (m, 7H) 4.43 (d, J = 4.8 Hz, 2H) 6.77 (d , J = 8.4Hz, 1H) 7.12 (d, J = 8.4Hz, 1H) 7.16 (s, 1H)
[1054] Example 67b)
[1055]
[1056] 3- [3-([(E) -3- (2-chlorophenyl) -2-methyl-propenoyl] aminomethyl) -4methoxyphenyl] -2-isopropoxy in the same manner as in Example 60 Propionic acid was obtained.
[1057] MS m / e (ESI) 446 (MH ⁺ )
[1058] Example 68
[1059]
[1060] 3- [3-([(E) -3- (2-methylphenyl) -2-methyl-propenoyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxy in the same manner as in Example 60 Propionic acid was obtained.
[1061] MS m / e (ESI) 426 (MH ⁺ )
[1062] Example 69
[1063]
[1064] 3- [3-([(E) -3- (4-chlorophenyl-2-methyl-propenoyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxy in the same manner as in Example 60 Propionic acid was obtained.
[1065] MS m / e (ESI) 446 (MH ⁺ )
[1066] Example 70
[1067]
[1068] 2-isopropoxy-3-4-methoxy-3-[((E) -2-methyl-3- [4- (trifluoromethyl) phenyl] -2-propene in the same manner as in Example 60 Noylamino) methyl] phenylpropionic acid was obtained.
[1069] MS m / e (ESI) 480 (MH ⁺ )
[1070] Example 71
[1071]
[1072] 3- [3-([(E) -3- (2,3-dichlorophenyl) -2-methyl-propenyl] aminomethyl) -4methoxyphenyl] -2-iso in the same manner as in Example 60 Propoxypropionic acid was obtained.
[1073] MS m / e (ESI) 480 (MH ⁺ )
[1074] Example 72
[1075]
[1076] 3-3-[((E) -3- [2-fluoro-3- (trifluoromethyl) phenyl] -2-methyl-2-propenoylamino) methyl]-in the same manner as in Example 60 4-methoxyphenyl-2-isopropoxypropionic acid was obtained.
[1077] NIS m / e (ESI) 498 (MH ⁺ )
[1078] Example 73
[1079]
[1080] 3- [3-([(E) -3- (3-fluoro-2-methylphenyl) -2-methyl-propenoyl] aminomethyl) -4-methoxyphenyl]-in the same manner as in Example 60 2-isopropoxypropionic acid was obtained.
[1081] MS m / e (ESI) 444 (MH ⁺ )
[1082] Example 74
[1083]
[1084] 3- [3-([(E) -3- (2,4-dichlorophenyl) -2-methyl-propenoyl] aminomethyl) -4-methoxyphenyl] -2- in the same manner as in Example 60 Isopropoxypropionic acid was obtained.
[1085] MS m / e (ESI) 480 (MH ⁺ )
[1086] Example 75
[1087]
[1088] 3- [3-([(E) -3- (2-fluoro-4-bromophenyl) -2-methyl-propenyl] aminomethyl) -4-methoxyphenyl in the same manner as in Example 60 ] -2-isopropoxypropionic acid was obtained.
[1089] MS m / e (ESI) 510 (MH ⁺ )
[1090] Example 76
[1091]
[1092] 3- [3-([(E) -3- (3,4-dichlorophenyl) -2-methyl-propenyl] aminomethyl) -4methoxyphenyl] -2-iso in the same manner as in Example 60 Propoxypropionic acid was obtained.
[1093] MS m / e (ESI) 480 (MH ⁺ )
[1094] Example 77
[1095]
[1096] 2-isopropoxy-3- [4-methoxy-3-([(E) -2-methyl-3- (1-naphthyl) -2-propenoyl] aminomethyl in the same manner as in Example 60 ) Phenyl] propionic acid was obtained.
[1097] MS m / e (ESI) 462 (MH ⁺ )
[1098] Example 78
[1099] Preparation Example 78a)
[1100]
[1101] 114 mg of propio-monic acid was dissolved in 8 ml of tetrahydrofuran, 13 mg of lithium hydride and 140 µl of ethyl chloroformate were sequentially added, followed by stirring at room temperature for 1 hour. A solution was added to 2 ml of 489 mg of tetrahydrofuran of 4- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropionate ethyl ester, 210 µl of triethylamine was added, and the mixture was stirred at room temperature overnight. . The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2-isopropoxy-3-4-methoxy-3-[(propioloylamino) methyl from the hexane-ethyl acetate (2: 1 → 3: 2) elution fraction. ] 230 mg of ethyl phenyl propionate were obtained.
[1102] ¹ H-NMR (CDCl ₃ ) δ: 0.98 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 2.76 (s, 1H) 2.87 (dd, J = 8.4, 14.0 Hz, 1H) 2.94 (dd, J = 4.8, 14.0 Hz, 1H) 3.51 (sept, J = 6.0 Hz, 1H) 3.85 (s, 3H) 4.01 (dd, J = 5.2, 8.4Hz, 1H) 4.12 (q, J = 8.0Hz, 2H) 4.45 (d, J = 6.0Hz, 2H) 6.35 (br, 1H) 6.80 (d, J = 8.0Hz, 1H) 7.13-7.18 (m, 2H)
[1103] Example 78b)
[1104]
[1105] 16 mg of 2-isopropoxy-3-4-methoxy-3-[(propioloylamino) methyl] phenylpropionate ethyl ester were dissolved in 0.6 ml of N, N-dimethylformamide, 15 mg of iodobenzene, and dichloro 3 mg of bistriphenylphosphine palladium, 2 mg of copper iodide, 3 mg of lithium chloride, and 0.1 ml of triethylamine were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the solvent was concentrated under reduced pressure. 0.5 ml of methanol and 0.1 ml of 5N-sodium hydroxide were added to the residue, and the mixture was stirred overnight at room temperature. The reaction mixture was made acidic with 5N hydrochloric acid, extracted with ethyl acetate, and the solvent was concentrated under reduced pressure. The residue was purified by HPLC to obtain 1.91 mg of 2-isopropoxy-3- (4-methoxy-3-[(3-phenyl-2-propinoyl) amino] methylphenyl) propionic acid.
[1106] MS m / e (ESI) 397 (MH ⁺ )
[1107] Example 79
[1108]
[1109] 2-Isopropoxy-3- [4-methoxy-3-([3- (4-methoxyphenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1110] MS m / e (ESI) 426 (MH ⁺ )
[1111] Example 80
[1112]
[1113] 2-Isopropoxy-3- [4-methoxy-3-([3- (4-methylphenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1114] MS m / e (ESI) 410 (MH ⁺ )
[1115] Example 81
[1116]
[1117] 2-Isopropoxy-3- [4-methoxy-3-([3- (4-fluorophenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1118] MS m / e (ESI) 414 (MH ⁺ )
[1119] Example 82
[1120]
[1121] 2-Isopropoxy-3- [4-methoxy-3-([3- (3-methoxyphenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1122] MS m / e (ESI) 426 (MH ⁺ )
[1123] Example 83
[1124]
[1125] 2-Isopropoxy-3- [4-methoxy-3-([3- (3-bromophenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1126] MS m / e (ESI) 475 (MH ⁺ )
[1127] Example 84
[1128]
[1129] 2-Isopropoxy-3-4-methoxy-3-[(3- [3- (trifluoromethyl) phenyl] -2-propinoylaminomethyl] propionic acid was obtained in the same manner as in Example 78.
[1130] MS m / e (ESI) 464 (MH ⁺ )
[1131] Example 85
[1132]
[1133] 2-Isopropoxy-3- [4-methoxy-3-([3- (3-methylphenyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1134] MS m / e (ESI) 410 (MH ⁺ )
[1135] Example 86
[1136]
[1137] 2-Isopropoxy-3- [4-methoxy-3-([3- (1-naphthyl) -2-propinoyl] aminomethyl) phenyl] propionic acid was obtained in the same manner as in Example 78.
[1138] MS m / e (ESI) 446 (MH ⁺ )
[1139] Example 87
[1140] Preparation Example 87a)
[1141]
[1142] 3- (3-[(tert-butoxycarbonyl) amino] methyl-2,4-dimethoxyphenyl)-using 3-bromo-2,6-dimethoxybenzaldehyde in the same manner as in Production Example 89e) 2-isopropoxypropionate ethyl ester was obtained.
[1143] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 2.87 (dd, J = 8.4, 14.0Hz, 1H) 2.98 (dd, J = 5.6, 14.0Hz, 1H) 3.51 (sept, J = 6.4Hz, 1H) 3.80 (s, 3H) 3.83 (s, 3H) 4.12- 4.17 (m, 3H) 4.40 (d, J = 5.2 Hz, 2H) 5.11 (br, 1H) 6.60 (d, J = 8.8 Hz, 1H) 7.15 (d, J = 8.8 Hz, 1H)
[1144] Example 87b)
[1145]
[1146] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-2,4-dimethoxyphenyl) -2-isopropoxypropionic acid ethyl ester was used for treatment in the same manner as in Example 38, -(3-[(2,4-dichlorobenzoyl) amino] methyl-2,4-dimethoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1147] MS m / e (ESI) 470 (MH ⁺ )
[1148] Example 88
[1149] Preparation Example 88a)
[1150]
[1151] 3- (3-[(tert-butoxycarbonyl) amino] methyl-4,6-dimethoxyphenyl)-using 5-bromo-2,4-dimethoxybenzaldehyde in the same manner as in Production Example 89e) 2-isopropoxypropionate ethyl ester was obtained.
[1152] ¹ H-NMR (CDCl ₃ )
[1153] δ: 0.98 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 1.26 (t, J = 6.8 Hz, 3H) 1.43 (s, 9H) 2.86 (dd, J = 8.8, 18.4 Hz, 1H) 2.98 (dd, J = 6.4, 13.6Hz, 1H) 3.51 (sept, J = 6.4Hz, 1H) 3.83 (s, 3H) 3.84 (s, 3H) 4.08-4.17 (m, 3H) 4.20 ( brs, 2H) 4.94 (br, 1H) 6.40 (s, 1H) 7.02 (s, 1H)
[1154] Example 88b)
[1155]
[1156] 3- (3-[(tert-butoxycarbonyl) amino] methyl-4,6-dimethoxyphenyl) -2-isopropoxypropionic acid ethyl ester was used and treated in the same manner as in Example 38 to give 3- (5-[(2,4-dichlorobenzoyl) amino] methyl-2,4-dimethoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1157] MS m / e (ESI) 470 (MH ⁺ )
[1158] Example 89
[1159] Preparation Example 89a)
[1160]
[1161] 10.67 g of 5-promo-2,3-dimethoxybenzaldehyde was dissolved in 100 ml of tetrahydrofuran and 100 ml of ethanol, 1 g of sodium borohydride was added and stirred overnight at room temperature. After adding 1N hydrochloric acid, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, 5-bromo-2,3-dimethoxybenzyl alcohol 10.27 g was obtained. 5.326 g of this crude product was dissolved in 50 ml of N, N-dimethylformamide, 1.8 g of imidazole and 5.9 g of third butylchlorodiphenylsilane were added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and [[5-bromo-2.3-dimethoxybenzyl) oxy] (third 10.72 g of butyl) diphenylsilane were obtained.
[1162] ¹ H-NMR (CDCl ₃ )
[1163] δ: 1.10 (s, 9H) 3.63 (s, 3H) 3.84 (s, 3H) 4.76 (s, 2H) 6.96 (d, J = 2.0 Hz, 1H) 7.33 (d, J = 1.6 Hz, 1H) 7.63- 7.45 (m, 6H) 7.68-7.71 (m, 4H)
[1164] Preparation Example 89b)
[1165]
[1166] 10.72 g of [(5-bromo-2,3-dimethoxybenzyl) oxy] (tertiary butyl) diphenylsilane was dissolved in 100 ml of tetrahydrofuran and cooled to -78 ° C under a nitrogen atmosphere. 16 ml of butyllithium (1.5 M hexane solution) was added, and after stirring for 30 minutes, 2.5 ml of 4-formylmorpholine was added. After stirring at −78 ° C. for 1 hour, 1N hydrochloric acid was added, extracted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 3-([1- (tert butyl) -1,1-diphenylsilyl] oxymethyl)-was extracted from the hexane-ethyl acetate (2: 1 → 3: 2) elution fraction. 9.4 g of 4,5-dimethoxybenzaldehyde was obtained.
[1167] ¹ H-NMR (CDCl ₃ )
[1168] δ: 1.12 (s, 9H) 3.77 (s, 3H) 3.91 (s, 3H) 4.84 (s, 2H) 7.39-7.44 (m, 7H) 7.69-7.72 (m, 5H) 9.91 (s, 1H)
[1169] Preparation Example 89c)
[1170]
[1171] 510 mg of 2-isopropoxyphosphono acetate diethyl was dissolved in 20 ml of tetrahydrofuran, and 370 mg of sodium hydride was added. Stir at room temperature for 30 minutes, and 3, [[1- (tert butyl) -1,1-diphenylsilyl] oxymethyl) -4,5-dimethoxybenzaldehyde 3.485 g of 5 ml of N, N-dimethylformamide Added. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. (E, Z) -3-[(1- (tertiary butyl) -1,1-diphenylsilyl] oxymethyl) -4,5-dimethoxyphenyl] -2-isopropoxy-2-propionic acid ethyl ester 5.01 g was obtained. 5.01 g of this crude product was dissolved in 30 ml of tetrahydrofuran, and 1 ml of acetic acid and 10 ml of tetrabutylammonium fluoride (1M solution) were sequentially added. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography, and (E, Z) -3- [hydroxymethyl) -4,5-dimethoxyphenyl] -2 from the hexane-ethyl acetate (2: 1 → 3: 2) elution fraction. 2.209 g of isopropoxy-2-propionate ethyl esters were obtained.
[1172] ¹ H-NMR (CDCl ₃ ) δ: 1.24-1.39 (m, 9H) 3.84, 3.87 (each s, 3H) 3.89, 3.92 (each s, 3H) 4.16, 4.29 (each q, J = 7.2 Hz, 2H) 4.27, 4.47 (each sept, J = 6.0 Hz, 1H) 4.65, 4.67 (each s, 2H) 6.16, 6.94 (each s, 1H) 6.79 (s, 1H) 7.23, 7.67 (each d, J = 2.0 Hz and 1.6 Hz, 1H)
[1173] Preparation Example 89d)
[1174]
[1175] 2.209 g of (E, Z) -3-[(hydroxymethyl) -4,5-dimethoxyphenyl] -2-isopropoxy-2-propionic acid ethyl ester was dissolved in 15 ml of toluene and diphenylphosphoryl azide 1.6 ml and 1.1 ml of diazabicyclo [5.4.0] undecene were added and stirred overnight at room temperature. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and (EZ) -3- [3- (azidemethyl) -4,5-dimethoxyphenyl]-from the hexane-ethyl acetate (2: 1 → 3: 2) elution fraction. 2-isopropoxy-2-propionate ethyl ester was obtained.
[1176] ¹ H-NMR (CDCl ₃ ) δ: 1.14 (t, J = 6.8 Hz, 3H) 1.30 (d, J = 7.2 Hz, 3H) 1.35 (d, J = 7.2 Hz, 3H) 3.84, 3.87 (each s, 3H) 3.90, 3.92 (each s, 3H) 4.16, 4.30 (eachq, J = 6.8 Hz, 2H) 4.35 (d, J = 11.2 Hz, 2H) 4.50 (sept, J = 6.4 Hz, 1H) 6.14, 6.93 ( each s, 1H) 6.75, 6.72 (each d, J = 2.0 Hz, 1H) 7.26, 7.64 (each d, J = 2.0 Hz, 1H)
[1177] Preparation 89e)
[1178]
[1179] 2.124 g of (E, Z) -3- [3- (azidemethyl) -4,5-dimethoxyphenyl] -2-isopropoxy-2-propionic acid ethyl ester was dissolved in 50 ml of ethyl acetate, and tertiary butyl 1.5 g of dicarbonate and 800 mg of 10% palladium carbon were added, followed by stirring at room temperature under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography, and 3- (3-[(tert-butoxy) was extracted from the hexane-ethyl acetate (5: 1 → 4: 1) elution fraction. Carbonyl) amino] methyl-4,5-dimethoxyphenyl) -2-isopropoxypropionate ethyl ester 1.93g was obtained.
[1180] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.26 (t, J = 6.8 Hz, 3H) 1.44 (s, 9H) 2.87 (dd, J = 8.4, 14.0Hz, 1H) 2.94 (dd, J = 4.8, 14.0Hz, 1H) 3.51 (sept, J = 6.4Hz, 1H) 3.82 (s, 3H) 3.84 (s, 3H) 4.02 ( dd, J = 4.8, 8.4 Hz, 1H) 4.13-4.22 (m, 2H) 4.29 (d, J = 6.0 Hz, 2H) 4.94 (br, 1H) 6.76 (s, 1H) 6.78 (s, 1H)
[1181] Example 89f)
[1182]
[1183] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4,5-dimethoxyphenyl) -2-isopropoxypropionic acid ethyl ester was used for the treatment in the same manner as in Example 38, and 3- (3-[(2,4-dichlorobenzoyl) amino] methyl-4,5-dimethoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1184] MS m / e (ESI) 470 (MH ⁺ )
[1185] Example 90
[1186] Preparation Example 90a)
[1187]
[1188] 300 ml of methanol was dissolved in 39.1 g of 2-benzyloxy-5-formyl-benzoic acid methyl esters, 60 ml of trimethyl orthoformate and 2 g of paratosyl acid were added, and the mixture was heated to reflux for 4 hours. After cooling to room temperature, 5 ml of triethylamine was added and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 39.08 g of methyl 2- (penyloxy) -5- (dimethoxymethyl) benzoic acid were obtained.
[1189] ¹ H-NMR (CDCl ₃ )
[1190] δ: 3.32 (6H, s) 3.88 (s, 3H) 5.19 (s, 2H) 5.37 (s, 1H) 7.03 (d, J = 8.0 Hz, 1H) 7.33-7.41 (m, 3H) 7.47-7.53 (m , 3H) 7.91 (s, 1H)
[1191] Preparation Example 90b)
[1192]
[1193] Under ice-cooling, 7 g of aluminum hydride hydride was suspended in 200 ml of tetrahydrofuran, and a 100 ml solution of 39.08 g of tetrahydrofuran of 2- (benzyloxy) -5- (dimethoxymethyl) benzoic acid methyl ester was added. After stirring for 5 minutes, water, 15% sodium hydroxide and water were added and filtered. The filtrate was concentrated under reduced pressure to obtain 35.15 g of 2- (benzyloxy) -5- (dimethoxymethyl) benzyl alcohol. This crude product was dissolved in 250 ml of toluene, 40 g of diphenylphosphoryl azide and 22 ml of diazabicyclo [5.4.0] undecene were added and stirred overnight at room temperature. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 17.4 g of 4- (benzyloxy) -3- (azidemethyl) dimethoxymethylbenzene from the hexane-ethyl acetate (15: 1) elution fraction. This was left to stand at room temperature for one month, and purified by silica gel column chromatography to obtain 9.39 g of 4-benzyloxy) -3- (azidemethyl) benzaldehyde from the hexane-ethyl acetate (12: 1) elution fraction.
[1194] ¹ H-NMR (CDCl ₃ ) δ: 4.48 (s, 2H) 5.22 (s, 2H) 7.90 (d, J = 8.8 Hz, 1H) 7.37-7.45 (m, 5H) 7.84-7.86 (m, 2H) 9.90 (s, 1H)
[1195] Preparation Example 90c)
[1196]
[1197] 12.9 g of 2-isopropoxyphosphonoacetic acid diethyl was dissolved in 100 ml of tetrahydrofuran, and 1.7 g of sodium hydride was added under ice cooling. It stirred at room temperature for 30 minutes, and added the 20 ml solution of 9.39 g of N, N- dimethylformamide of 3, 4- (benzyloxy) -3- (azidemethyl) benzaldehyde. After stirring at room temperature for 4 hours, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 16.7 g of (E, Z) -3- [azidemethyl-4- (benzyloxy) phenyl] -2-isopropoxy-2-propionate ethyl ester was obtained. 12.46 g of this crude product was dissolved in ethanol, 8.3 g of third butyldicarbonate and 3 g of 10% palladium carbon were added, and the mixture was stirred at room temperature under hydrogen atmosphere for 1.5 days. The reaction mixture was filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography, and 3- (3-[(tert-butoxycarbonyl) amino was extracted from hexane-ethyl acetate (4: 1). ] 6.2 g of methyl-4-hydroxyphenyl) -2-isopropoxypropionate ethyl ester was obtained.
[1198] ¹ H-NMR (CDCl ₃ ) δ: 0.99 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 2.84 (dd, J = 8.4, 13.6Hz, 1H) 2.90 (dd, J = 5.0, 13.6Hz, 1H) 3.50 (sept, J = 6.4Hz, 1H) 3.98 (dd, J = 5.6, 8.4Hz, 1H) 4.12 (q, J = 6.8 Hz, 2H) 4.19 (d, J = 6.4 Hz, 2H) 5.22 (br, 1H) 6.86 (d, J = 8.4 Hz, 1H) 6.94 (d, J = 2.0 Hz, 1H) 7.08 (dd, = 2.0, 8.0Hz, 1H) 8.77 (br, 1H)
[1199] Preparation Example 90d)
[1200]
[1201] 402 mg of 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionate ethyl ester was dissolved in 5 ml of acetonitrile and 200 mg of N-bromosuccimid was added. Added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (3-promo-5-[(tert-butoxycarbonyl) amino] methyl-4-hydroxyphenyl) from the hexane-ethyl acetate (5: 1) eluting fraction. 433 mg of 2-isopropoxypropionate ethyl esters were obtained.
[1202] ¹ H-NMR (CDCl ₃ ) δ: 0.98 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 6.8 Hz, 3H) 1.44 (s, 9H) 2.80 (dd, J = 8.4, 13.6Hz, 1H) 2.88 (dd, J = 7.2, 14.0Hz, 1H) 3.51 (sept, J = 6.4Hz, 1H) 3.97 (dd, J = 4.8, 8.4Hz, 1H) 4.16 -4.22 (m, 2H) 4.24 (d, J = 6.8 Hz, 2H) 5.20 (br, 1H) 6.96 (d, J = 1.6 Hz, 1H) 7.35 (d, J = 2.0 Hz, 1H) 8.45 (br, 1H)
[1203] Preparation Example 90e)
[1204]
[1205] 944 mg of 3- (3-propo-5-[(tert-butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionic acid ethyl ester was dissolved in 5 ml of N, N-dimethylformamide 0.15 ml of iodomethane and 500 mg of potassium carbonate were added sequentially. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (3-bromo-5-[(tert-butoxycarbonyl) amino] methyl-4-methoxyphenyl from the hexane-ethyl acetate (4: 1) eluting fraction. 876 mg of) -2-isopropoxypropionate ethyl ester were obtained.
[1206] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.45 (s, 9H) 2.86 (dd, J = 8.4, 14.0 Hz, 1H ) 2.93 (dd, J = 4.4, 14.0 Hz, 1H) 3.51 (sept, J = 6.4 Hz, 1H) 3.74 (s, 3H) 3.84 (s, 3H) 4.02 (dd, J = 4.8, 8.4 Hz, 1H) 4.34 (d, J = 6.0 Hz, 2H) 4.95 (br, 1H) 7.12 (d, J = 1.6 Hz, 1H) 7.37 (d, J = 2.0 Hz, 1H)
[1207] Example 90f)
[1208]
[1209] 3- (3-bromo-5-[(tertiary butoxycarbonyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropionic acid ethyl ester was used and treated in the same manner as in Example 38. , 3- (3-bromo-5-[(2,4-dichlorobenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1210] MS m / e (ESI) 520 (MH ⁺ )
[1211] Example 91
[1212] Preparation Example 91a)
[1213]
[1214] 876 mg of 3- (3-bromo-5-[(tertiary butoxycarbonyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropionic acid ethyl ester was dissolved in 5 ml of propionitrile and sodium cyanide 182 mg, tetrakistriphenylphosphinepalladium 214 mg, and copper iodide 70 mg were added, and it heated and refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added, and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3- (3-cyano-5-[(tert-butoxycarbonyl) amino] methyl from the hexane-ethyl acetate (4: 1) elution fraction. 586 mg of 4-methoxyphenyl) -2-isopropoxypropionate ethyl ester were obtained.
[1215] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 6.8 Hz, 3H) 1.45 (s, 9H) 2.89 (dd, J = 8.4, 14.0Hz, 1H) 2.97 (dd, J = 4.4, 14.0Hz, 1H) 3.53 (sept, J = 6.4Hz, 1H) 4.00 (dd, J = 4.8, 8.4Hz, 1H) 4.07 (s, 3H) 4.21-4.27 (m, 2H) 4.30 (s, 2H) 4.94 (br, 1H) 7.40 (d, J = 2.4 Hz, 1H) 7.42 (d, J = 0.8 Hz, 1H)
[1216] Example 91b)
[1217]
[1218] 3- (3-cyano-5-[(tertiary butoxycarbonyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropionic acid ethyl ester was treated in the same manner as in Example 38, , 3- (3-cyano-5-[(2,4-dichlorobenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1219] MS m / e (ESI) 465 (MH ⁺ )
[1220] Example 92
[1221] Preparation Example 92a)
[1222]
[1223] 12 g of 5-bromo-2-chlorobenzoic acid was dissolved in 60 ml of tetrahydrofuran, and 148.3 g of boranetetrahydrofuran complex (1M tetrahydrofuran solution) was added. It stirred at room temperature for 2.5 days. 1N hydrochloric acid was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 11.46 g of 5-bromo-2-chlorobenzyl alcohol was obtained. . This crude product was treated in the same manner as in Production Example 89e) to obtain 3- (3-[(tertiary butoxycarbonyl) amino] methylphenyl) -2-isopropoxypropionate ethyl ester.
[1224] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 1.46 (s, 9H) 2.93 (dd, J = 8.4, 14.0Hz, 1H) 3.07 (dd, J = 4.8, 14.0Hz, 1H) 3.49 (sept, J = 6.4Hz, 1H) 4.04 (dd, J = 4.8, 8.4Hz, 1H) 4.12 -4.19 (m, 2H) 4.30 (d, J = 5.2 Hz, 2H) 4.80 (br, 1H) 7.12-7.16 (m, 3H) 7.23 (d, J = 8.0 Hz, 1H)
[1225] Example 92b)
[1226]
[1227] 3- (3-[(tertiary butoxycarbonyl) amino] methylphenyl) -2-isopropoxypropionic acid ethyl ester was used for the same treatment as in Example 38 to give 3- (3-[(2,4 -Dichlorobenzoyl) amino] methylphenyl) -2-isopropoxypropionic acid was obtained.
[1228] MS m / e (ESI) 410 (MH ⁺ )
[1229] Example 93
[1230] Preparation Example 93a)
[1231]
[1232] 3- (3-[(tert-butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionic acid ethyl ester soluble in 2 ml of 795 mg N, N-dimethylformamide, 0.3 g of iodoethane ml and 200 mg of potassium carbonate were added sequentially. After stirring at 50 ° C for 4 hours, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (3-[(tert-butoxycarbonyl) amino] methyl-4-ethoxyphenyl) -2-iso from the hexane-ethyl acetate (8: 1) eluting fraction. 185 mg of propoxypropionate ethyl esters were obtained.
[1233] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.8 Hz, 3H) 1.42 (t, J = 6.8 Hz, 3H) 1.45 (s, 9H) 2.86 (dd, J = 8.4, 14.0 Hz, 1H) 2.93 (dd, J = 4.8, 14.0 Hz, 1H) 3.49 (sept, J = 6.4 Hz, 1H) 3.98-4.06 (m, 3H) 4.13-4.21 (m, 2H) 4.29 (d, J = 5.2 Hz, 2H) 4.99 (br, 1H) 6.75 (d, J = 8.4 Hz, 1H) 7.14 (d, J = 8.8 Hz, 1H) 7.14 (s, 1H)
[1234] Example 93b)
[1235]
[1236] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-ethoxyphenyl) -2-isopropoxypropionic acid was treated in the same manner as in Example 38, and 3- (3 -[(2,4-dichlorobenzoyl) amino] methyl-4-ethoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1237] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.45 (t, J = 7.2 Hz, 3H) 2.92 (dd, J = 8.0 , 14.0Hz, 1H) 3.07 (dd, J = 4.4, 14.0Hz, 1H) 3.58 (sept, J = 6.0Hz, 1H) 4.06-4.15 (m, 3H) 4.64 (d, J = 6.0Hz, 2H) 6.81 (d, J = 8.4Hz, 1H) 6.88 (br, 1H) 7.15 (dd, J = 2.4,8.4Hz, 1H) 7.27 (d, J = 8.4Hz, 2H) 7.42 (d, J = 2.4Hz, 1H ) 7.68 (d, J = 8.4 Hz, 1H)
[1238] MS m / e (ESI) 454 (MH ⁺ )
[1239] Example 94
[1240] Preparation Example 94a)
[1241]
[1242] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-propoxyphenyl) -2-isopropoxypropionic acid ethyl ester was obtained by the same method as in Production Example 93.
[1243] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.05 (t, J = 6.8 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 6.8 Hz, 3H) 1.44 (s, 9H) 1.78-1.86 (m, 2H) 2.86 (dd, J = 8.4, 14.0 Hz, 1H) 2.93 (dd, J = 4.8, 14.0 Hz, 1H) 3.50 (sept, J = 6.4Hz, 1H) 3.93 (t, J = 6.4Hz, 2H) 4.00 (dd, J = 4.8, 8.4Hz, 1H) 4.14-4.21 (m, 2H) 4.30 (d, J = 5.2Hz, 2H) 4.98 ( br, 1H) 6.75 (d, J = 8.4 Hz, 1H) 7.09 (dd, J = 2.0, 8.4 Hz, 1H) 7.13 (s, 1H)
[1244] Example 94b)
[1245]
[1246] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-propoxyphenyl) -2-isopropoxypropionic acid ethyl ester was used for the treatment in the same manner as in Example 38 to give 3- (3 -[(2,4-dichlorobenzoyl) amino] methyl-4-propoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1247] ¹ H-NMR (CDCl ₃ ) δ: 1.05 (t, J = 7.2 Hz, 3H) 1.06 (d, J = 6.0 Hz, 3H) 1.18 (d, J = 6.0 Hz, 3H) 1.80-1.87 (m, 2H ) 2.91 (dd, J = 8.0, 14.0 Hz, 1H) 3.07 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.97 (t, J = 7.2 Hz, 2H) 4.12 (dd, J = 4.4, 8.0Hz, 1H) 4.65 (d, J = 6.0Hz, 2H) 6.81-6.84 (m, 2H) 7.15 (dd, J = 2.4,8.4Hz, 1H) 7.25 (d, J = 2.4Hz, 1H) 7.28-7.33 (m, 1H) 7.42 (d, J = 2.4Hz, 1H) 7.67 (d, J = 9.6Hz, 1H)
[1248] MS m / e (ESI) 470 (MH ⁺ )
[1249] Example 95
[1250] Preparation Example 95a)
[1251]
[1252] In the same manner as in Production Example 93, 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionate ethyl ester was obtained.
[1253] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.8 Hz, 3H) 1.33 (d, J = 6.0 Hz, 6H) 1.44 (s, 9H) 1.78-1.86 (m, 2H) 2.86 (dd, J = 8.4, 14.0 Hz, 1H) 2.92 (dd, J = 4.8, 14.0 Hz, 1H) 3.50 (sept, J = 6.0 Hz, 1H) 4.00 (dd, J = 4.8, 8.4 Hz, 1H) 4.13-4.21 (m, 2H) 4.26 (d, J = 5.2 Hz, 2H) 4.54 (sept, J = 6.0 Hz, 1H) 4.96 ( br, 1H) 6.77 (d, J = 8.4 Hz, 1H) 7.08 (dd, J = 2.4, 8.4 Hz, 1H) 7.13 (s, 1H)
[1254] Example 95b)
[1255]
[1256] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionic acid was treated in the same manner as in Example 38, and 3- ( 3-[(2,4-dichlorobenzoyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1257] MS m / e (ESI) 470 (MH ⁺ )
[1258] Example 96
[1259] Preparation Example 96a)
[1260]
[1261] In the same manner as in Production Example 93, 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionate ethyl ester was obtained. .
[1262] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.8 Hz, 3H) 1.44 (s, 9H) 1.63 -1.65 (m, 2H) 1.75-1.90 (m, 6H) 2.85 (dd, J = 8.4, 14.0 Hz, 1H) 2.92 (dd, J = 4.8, 14.0 Hz, 1H) 3.50 (sept, J = 6.0 Hz, 1H) 4.00 (dd, J = 4.8, 8.4Hz, 1H) 4.10-4.21 (m, 2H) 4.25 (d, J = 5.2Hz, 2H) 4.76-4.79 (m, 1H) 4.95 (br, 1H) 6.75 ( d, J = 8.4Hz, 1H) 7.07 (d, J = 8.4Hz, 1H) 7.12 (s, 1H)
[1263] Example 96b)
[1264]
[1265] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionic acid was treated in the same manner as in Example 38, and 3- ( 3-[(2.4-dichlorobenzoyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionic acid was obtained.
[1266] MS m / e (ESI) 494 (MH ⁺ )
[1267] Example 97
[1268] Preparation Example 97a)
[1269]
[1270] 329 mg of 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2-isopropoxypropionate ethyl ester was dissolved in 4 ml of toluene, 110 mg of 4-fluorophenylboronic acid, 74 mg of tetrakistriphenylphosphine palladium, and 440 mg of potassium carbonate were added, and it stirred overnight at 100 degreeC under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3- (3-[(third) from the elution fraction of hexane-ethyl acetate (6: 1). 262 mg of butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (4-fluorophenyl) phenylpropoxypropionate ethyl ester was obtained.
[1271] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.4 Hz, 3H) 1.18 (d, J = 6.4 Hz, 3H) 1.26 (t, J = 7.2 Hz, 3H) 1.43 (s, 9H) 2.99 (dd, J = 8.8, 13.6Hz, 1H) 3.04 (dd, J = 5.6, 13.2Hz, 1H) 3.56 (sept, J = 6.4Hz, 1H) 4.08-4.24 (m, 5H) 4.60 (br 1H) 7.05 -7.15 (m, 4H) 7.19-7.30 (m, 3H)
[1272] Example 97b)
[1273]
[1274] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (4-fluorophenyl) phenylpropoxypropionate ethyl ester Was processed in the same manner as in Example 38 to obtain 3- (3-[(2,4-dichlorobenzoyl) amino] methyl-4- (4-fluorophenyl) phenyl) -2-isopropoxypropionic acid .
[1275] MS m / e (ESI) 504 (MH ⁺ )
[1276] Example 98
[1277] Preparation Example 98a)
[1278]
[1279] 501 mg of 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionic acid ethyl ester was dissolved in 7 ml of pyridine and trifluoromethanesulfonic anhydride under ice cooling. 270 μl was added. After stirring for 1 hour at room temperature, 100 µl of trifluoromethanesulfonic anhydride was added. After stirring for 2 hours, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with 1N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 663 mg of 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2-isopropoxypropionate ethyl ester was obtained.
[1280] ¹ H-NMR (CDCl ₃ ) δ: 0.92 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.8 Hz, 3H) 1.46 (s, 9H) 2.91 -3.04 (m, 2H) 3.51 (sept, J = 6.4 Hz, 1H) 4.02 (dd, J = 4.4, 8.8 Hz, 1H) 4.16-4.23 (m, 2H) 4.40 (d, J = 6.0 Hz, 2H) 4.95 (br, 1H) 7.17-7.20 (m, 1H) 7.24-7.25 (m, 1H) 7.40 (s, 1H)
[1281] Preparation Example 98b)
[1282]
[1283] 334 mg of 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2-isopropoxypropionate ethyl ester was dissolved in 4 ml of dioxane, , 280 mg of 2-tributylstanylfuran, 75 mg of tetrakistriphenylphosphine palladium and 83 mg of lithium chloride were added, and the mixture was stirred overnight at 80 ° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(from eluent fraction of hexane-ethyl acetate (7: 1). 180 mg of trifluoromethyl) sulfonyl] oxyphenyl) -2- (2-furyl) propoxypropionate ethyl ester was obtained.
[1284] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.4 Hz, 3H) 1.26 (t, J = 6.8 Hz, 3H) 1.46 (s, 9H) 2.95 (dd, J = 8.8, 13.6Hz, 1H) 3.02 (dd, J = 4.8, 14.0Hz, 1H) 3.51 (sept, J = 6.4Hz, 1H) 4.06 (dd, J = 4.8, 8.8Hz, 1H) 4.19 (q, J = 6.8Hz, 2H) 4.47 (s, 2H) 4.95 (br 1H) 6.52 (d, J = 20Hz, 2H) 6.98 (s, 1H) 7.21 (d, J = 8.4Hz, 1H) 7.32 ( s, 1H) 7.51-7.53 (m, 2H)
[1285] Example 98c)
[1286]
[1287] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (2-furyl) propoxypropionate ethyl ester The same procedure as in Example 38 was carried out to obtain 3- (3-[(2,4-dichlorobenzoyl) amino] methyl-4- (2-furyl) phenyl) -2-isopropoxypropionic acid.
[1288] MS m / e (ESI) 476 (MH ⁺ )
[1289] Example 99
[1290] Preparation Example 99a)
[1291]
[1292] 7.4 g of 2-methoxy-3-hydroxymethylpyridine was dissolved in 100 ml of toluene, 13.8 ml of diphenylphosphoryl azide and 9.5 ml of diazabicyclo [5.4.0] undecene were added, followed by stirring at room temperature overnight. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 9.5 g of [(2-methoxy-3-pyridyl) methyl] azide was obtained.
[1293] ¹ H-NMR (CDCl ₃ ) δ: 4.00 (s, 3H) 4.35 (s, 2H) 6.89-6.92 (m, 1H) 7.55-7.57 (m, 1H) 8.15-8.16 (m, 1H)
[1294] Preparation Example 99b)
[1295]
[1296] 9.5 g of [(2-methoxy-3-pyridyl) methyl] azide was dissolved in 100 ml of ethyl acetate, 13 g of third butyldicarbonate and 3 g of 10% palladium carbon were added thereto, and stirred at room temperature under a hydrogen atmosphere for 3 hours. did. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography, and extracted from hexane-ethyl acetate (5: 1 → 4: 1) elution fraction with third butyl N-[(2-meth). 6.84 g of oxy-3-pyridyl) methyl] carbamate was obtained. 2.916 g of this crude product was dissolved in 30 ml of acetonitrile and 2.19 g of N-bromosuccimid was added. After stirring for 3 days at room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with a mixture of diethyl ether, ethyl acetate and hexane to obtain 1.185 g of N-[(5-bromo-2-methoxy3-pyridyl) methyl] carbamate.
[1297] ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9H) 3.94 (s, 3H) 4.22 (d, J = 6.0 Hz, 2H) 5.02 (br, 1H) 7.62 (s, 1H) 8.01 (s, 1H )
[1298] Preparation Example 99c)
[1299]
[1300] 1.009 g of N-[(5-bromo-2-methoxy-3-pyridyl) methyl] carbamate, 45 mg of dichlorobistriphenylphosphinepalladium, 325 mg of sodium formate, 17 mg of anhydrous N, N- It dissolved in 3 ml of dimethylformamide, and stirred at 110 degreeC for 2.5 hours in carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 401 mg of tert-butyl N-[(5-formyl-2-methoxy-3-pyridyl) methyl] carbamate was extracted from the hexane-ethyl acetate (3.5: 1) elution fraction. Got it.
[1301] ¹ H-NMR (CDCl ₃ ) δ: 1.46 (s, 9H) 4.08 (s, 3H) 4.31 (d, J = 6.0 Hz, 2H) 5.02 (br, 1H) 8.01 (d, J = 2.4 Hz, 1H) 8.54 (d, J = 2.0 Hz, 1H)
[1302] Preparation Example 99d)
[1303]
[1304] 510 mg of ethyl 2-isopropoxyphosphonoacetic acid diethyl was dissolved in 5 ml of tetrahydrofuran, and 70 mg of sodium hydride was added. It stirred at room temperature for 15 minutes, and added 2 ml of N, N- dimethylformamide solution of 40lmg of N-[(5-formyl-2-methoxy-3-pyridyl) methyl] carbamate. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 8 ml of ethyl acetate and 2 ml of ethanol, 200 mg of 10% palladium carbon was added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was concentrated, the residue was purified by silica gel column chromatography, and 3- (5-[(tert-butoxy) was extracted from hexane-ethyl acetate (4: 1 → 2.5: 1) elution fraction. 514 mg of carbonyl) amino] methyl-6-methoxy-3-pyridyl) -2-isopropoxypropionate ethyl ester were obtained.
[1305] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 1.45 (s, 9H) 2.85 (dd, J = 8.4, 14.0Hz, 1H) 2.92 (dd, J = 4.8, 14.0Hz, 1H) 3.52 (sept, J = 6.0 Hz) 3.96 (s, 3H) 3.99 (dd, J = 4.8, 8.4Hz , 1H) 4.17-4.24 (m, 4H) 5.03 (br, 1H) 7.47 (s, 1H) 7.93 (d, J = 2.0 Hz, 1H)
[1306] Example 99e)
[1307]
[1308] 3- (5-[(tert-butoxycarbonyl) amino] methyl-6-methoxy-3-pyridyl) -2-isopropoxypropionic acid ethyl ester was used for treatment in the same manner as in Example 38, 3- (5-[(2,4-dichlorobenzoyl) amino] methyl 6-methoxy-3-pyridyl-2-isopropoxypropionic acid was obtained.
[1309] MS m / e (ESI) 441 (MH ⁺ )
[1310] Example 100
[1311] Preparation Example 1OOa)
[1312]
[1313] 253 mg of 3- (3-propo5-[(tertiary butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionic acid ethyl ester was dissolved in 3 ml of acetonitrile and N-iodosuccinic acid 157 mg of mid was added. After stirring at room temperature for 2.5 days, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (3-iodo-5-[(tert-butoxycarbonyl) amino] methyl-4-hydroxyphenyl from the hexane-ethyl acetate (4: 1) elution fraction. 100 mg of) -2-isopropoxypropionate ethyl ester were obtained.
[1314] ¹ H-NMR (CDCl ₃ ) δ: 0.99 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 6.8 Hz, 3H) 1.44 (s, 9H) 2.80 (dd, J = 8.0, 13.6Hz, 1H) 2.86 (dd, J = 5.6, 13.6Hz, 1H) 3.50 (sept, J = 6.4Hz, 1H) 3.96 (dd, J = 5.2, 8.8Hz, 1H) 4.15 -4.23 (m, 5H) 6.96 (d, J = 1.6Hz, 1H) 7.58 (d, J = 1.6Hz, 1H)
[1315] Preparation Example 10b)
[1316]
[1317] 305 mg of 3- (3-iodo-5-[(tertiary butoxycarbonyl) amino] methyl-4-hydroxyphenyl) -2-isopropoxypropionic acid ethyl ester in 3 ml of N, N-dimethylformamide Then, 120 mg of trimethylsilylacetylene, 70 mg of tetrakistriphenylphosphine palladium, 11.5 mg of copper iodide, and 0.5 ml of triethylamine were added and stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-3-[(tert-butoxycarbonyl) amino] methyl-4-hydroxy-5- [2- (from elution fraction of hexane-ethyl acetate (6: 1). 165 mg of 1,1,1-trimethylsilyl) -1-ethynyl] phenyl-2-isopropoxypropionate ethyl ester was obtained.
[1318] ¹ H-NMR (CDCl ₃ ) δ: 0.27 (s, 9H) 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.4 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 2.80 (dd, J = 9.2, 14.4 Hz, 1H) 2.88 (dd, J = 5.2, 14.0 Hz, 1H) 3.49 (sept, J = 6.4 Hz, 1H) 3.96 (dd, J = 4.8, 8.8 Hz, 1H) 4.13-4.21 (m, 3H) 4.24 (d, J = 6.0 Hz, 2H) 5.11 (br, 1H) 7.05 (d, J = 1.6 Hz, 1H) 7.19 (d, J = 2.4 Hz, 1H)
[1319] Preparation Example 10c)
[1320]
[1321] 3-3-[(tertiary butoxycarbonyl) amino] methyl-4-hydroxy-5- [2- (1,1,1-trimethylsilyl) -1-ethynyl] phenyl-2-isopropoxy 165 mg of ethyl propionate was dissolved in 2 ml of tetrahydrofuran, 40 µl of acetic acid and 0.5 ml of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 3-3-[(tert-butoxycarbonyl) amino] methyl-4-hydroxy-5- (1-to-1) from the hexane-ethyl acetate (3: 1) elution fraction. 122 mg of thynyl) phenyl-2-isopropoxypropionic acid esters were obtained.
[1322] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.4 Hz, 3H) 1.26 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 2.81 (dd, J = 9.2, 14.4Hz, 1H) 2.88 (dd, J = 5.2, 14.0Hz, 1H) 3.36 (s, 1H) 3.50 (sept, J = 6.4Hz, 1H) 3.97 (dd, J = 4.8, 8.8 Hz, 1H) 4.15-4.22 (m, 2H) 4.23 (d, J = 6.8 Hz, 2H) 7.04 (s, 1H) 7.20 (s, 1H)
[1323] Preparation Example 100d)
[1324]
[1325] 3-3-[(tert-butoxycarbonyl) amino] methyl-4-hydroxy-5- (1-ethynyl) phenyl-2-isopropoxypropionate ethyl ester 121mg 2 N, N-dimethylformamide It dissolved in and 50 mg of potassium carbonate was added. After stirring overnight at 60-70 ° C, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3- (7-[(tert-butoxycarbonyl) amino] methylbenzo [b] furan-5-yl)-from the hexane-ethyl acetate (6: 1) eluting fraction. 57 mg of 2-isopropoxypropionate ethyl ester were obtained.
[1326] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 6.8 Hz, 3H) 1.46 (s, 9H) 3.01 (dd, J = 8.8, 14.0Hz, 1H) 3.08 (dd, J = 5.2, 14.0Hz, 1H) 3.49 (sept, J = 6.4Hz, 1H) 4.07 (dd, J = 5.2, 8.4Hz, 1H) 4.12 -4.19 (m, 2H) 4.60 (brs, 2H) 5.01 (br, 1H) 6.72 (s, 1H) 7.13 (s, 1H) 7.39 (d, J = 1.6 Hz, 1H) 7.61 (d, J = 2.0 Hz , 1H)
[1327] Example 1OOe)
[1328]
[1329] 3- (7-[(tert-butoxycarbonyl) amino] methylbenzo [b] furan-5-yl) -2-isopropoxypropionic acid ethyl ester was used for treatment in the same manner as in Example 38, -(7-[(2,4-dichlorobenzoyl) amino] methylbenzo [b] furan-5-yl-2-isopropoxypropionic acid was obtained.
[1330] MS m / e (ESI) 451 (MH ⁺ )
[1331] Example 101
[1332] Preparation Example 1
[1333]
[1334] 29 mg of 3- (7-[(tert-butoxycarbonyl) amino] methylbenzo [b] furan-5-yl) -2-isopropoxypropionate ethyl ester were dissolved in ethanol, and 30 mg of 10% palladium carbon was added thereto. It stirred at room temperature under hydrogen atmosphere for 3 days. The reaction mixture was filtered through Celite and the filtrate was concentrated to give 3- (7-[(tert-butoxycarbonyl) amino] methyl-2,3-dihydrobenzo [b] furan-5-yl) -2- 27 mg of isopropoxypropionate ethyl esters were obtained.
[1335] ¹ H-NMR (CDCl ₃ ) δ: 0.99 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (t, J = 6.8 Hz, 3H) 1.45 (s, 9H) 2.85 (dd, J = 8.4, 14.0Hz, 1H) 2.92 (dd, J = 4.8, 14.0Hz, 1H) 3.17 (t, J = 5.2Hz, 2H) 3.50 (sept, J = 6.0Hz, 1H) 3.98 (dd , J = 4.8, 8.4Hz, 1H) 4.13-4.20 (m, 2H) 4.24 (brs, 2H) 4.57 (t, J = 5.2Hz, 2H) 4.97 (br, 1H) 6.91 (s, 1H) 7.00 (s , 1H)
[1336] Example 10 lb)
[1337]
[1338] Example 38 using ethyl 3- (7-[(tert-butoxycarbonyl) amino] methyl-2,3-dihydrobenzo [b] furan-5-yl) -2-isopropoxypropionate By the same method, 3- (7-[(2,4-dichlorobenzoyl) amino] methyl 2,3-dihydrobenzo [b] furan-5-yl) -2-isopropoxypropionic acid was obtained.
[1339] MS m / e (ESI) 481 (MH ⁺ )
[1340] Example 102
[1341]
[1342] 3- [2,4-dimethoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) was treated in the same manner as in Example 87. Phenyl] -2-isopropoxypropionic acid was obtained.
[1343] MS m / e (ESI) 499 (MH ⁺ )
[1344] Example 103
[1345]
[1346] 3- [2,4-dimethoxy-5-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) was treated in the same manner as in Example 88. Phenyl] -2-isopropoxypropionic acid was obtained.
[1347] MS m / e (ESI) 499 (MH ⁺ )
[1348] Example 104
[1349]
[1350] 3- [3,4-dimethoxy-5-([(5-methyl-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl] in the same manner as in Example 89; 2-isopropoxypropionic acid was obtained.
[1351] MS m / e (ESI) 499 (MH ⁺ )
[1352] Example 105
[1353]
[1354] Treated in the same manner as in Example 90, and 3- [3-bromo-4-methoxy-5-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] Aminomethyl) phenyl] -2-isopropoxypropionic acid was obtained.
[1355] MS m / e (ESI) 548 (MH ⁺ )
[1356] Example 106
[1357]
[1358] 3- [3-cyano-4-methoxy-5-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] was treated in the same manner as in Example 91. Aminomethyl) phenyl] -2-isopropoxypropionic acid was obtained.
[1359] MS m / e (ESI) 494 (MH ⁺ )
[1360] Example 107
[1361]
[1362] Treated in the same manner as in Example 92, 2-isopropoxy3- [3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl] Propionic acid was obtained.
[1363] MS m / e (ESI) 439 (MH ⁺ )
[1364] Example 108
[1365]
[1366] 3- [4-ethoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl1aminomethyl) phenyl] was treated in the same manner as in Example 93. 2-isopropoxypropionic acid was obtained.
[1367] MS m / e (ESI) 483 (MH ⁺ )
[1368] Example l09
[1369]
[1370] Treated in the same manner as in Example 94, and 3- [4-propoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonylaminomethyl) phenyl]- 2-isopropoxypropionic acid was obtained.
[1371] MS m / e (ESI) 497 (MH ⁺ )
[1372] Example 110
[1373]
[1374] Treated in the same manner as in Example 95, and 3- [4-isopropoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl ] -2-isopropoxypropionic acid was obtained.
[1375] MS m / e (ESI) 497 (MH ⁺ )
[1376] Example 111
[1377]
[1378] 3- [4-cyclopentyloxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl was treated in the same manner as in Example 96. ] -2-isopropoxypropionic acid was obtained.
[1379] MS m / e (ESI) 523 (MH ⁺ )
[1380] Example 112
[1381]
[1382] 3- [4- (4-fluorophenyl) -3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] was treated in the same manner as in Example 97. Aminomethyl) phenyl] -2-isopropoxypropionic acid was obtained.
[1383] MS m / e (ESI) 533 (MH ⁺ )
[1384] Example 113
[1385]
[1386] Treated in the same manner as in Example 98, and 3- [4- (4-furyl 3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl ] -2-isopropoxypropionic acid was obtained.
[1387] MS m / e (ESI) 505 (MH ⁺ )
[1388] Example 114
[1389]
[1390] Treatment was carried out in the same manner as in Example 99, and 2-isopropoxy-3- [6-methoxy-5-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl ] Aminomethyl) -3-pyridyl] propionic acid was obtained.
[1391] MS m / e (ESI) 470 (MH ⁺ )
[1392] Example 115
[1393]
[1394] Treated in the same manner as in Example 100, 2-isopropoxy-3- [7-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) benzo [b] furan-5-yl] propionic acid was obtained.
[1395] MS m / e (ESI) 479 (MH ⁺ )
[1396] Example 116
[1397]
[1398] Treated in the same manner as in Example 101, 2-isopropoxy-3- [7-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl)- 2,3-dihydrobenzo [b] furan-5-yl] propionic acid was obtained.
[1399] MS m / e (ESI) 480 (MH ⁺ )
[1400] Example 117
[1401]
[1402] The same procedure as in Example 93 was carried out to obtain 3- (3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4-ethoxyphenyl) -2-isopropoxypropionic acid.
[1403] MS m / e (ESI) 498 (MH ⁺ )
[1404] Example 118
[1405]
[1406] Treatment was carried out in the same manner as in Example 93 to obtain 3- (3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4-ethoxyphenyl) -2-isopropoxypropionic acid.
[1407] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.34 (d, J = 6.0 Hz, 6H) 1.43 (t, J = 7.2 Hz, 3H) 2.90 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 4.06 (q, J = 7.2 Hz, 2H) 4.11 (dd, J = 4.4, 8.0 Hz, 1H) 4.56 (sept, J = 6.0 Hz, 1H) 4.62 (d, J = 5.6 Hz, 2H) 6.79 (d, J = 8.8 Hz, 1H) 6.81 ( dd, J = 2.4,8.4Hz, 1H) 6.87 (d, J = 2.8Hz, 1H) 7.07 (br, 1H) 7.12 (dd, J = 2.4, 8.4Hz, 1H) 7.23 (d, J = 2.4Hz, 1H) 7.74 (d, J = 8.4 Hz, 1H)
[1408] MS m / e (ESI) 478 (MH ⁺ )
[1409] Example 119
[1410]
[1411] By the same method as in Example 93, 3- (3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4-ethoxyphenyl) -2-isopropoxypropionic acid was obtained.
[1412] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.43 (t, J = 7.2 Hz, 3H) 1.61-1.65 (m, 2H ) 1.74-1.94 (m, 6H) 2.90 (dd, J = 8.0, 14.0 Hz, 1H) 3.05 (dd, J = 4.4, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 4.06 (q, J = 7.2Hz, 2H) 4.10 (dd, J = 4.4, 8.0Hz, 1H) 4.62 (d, J = 5.6Hz, 2H) 4.74-4.77 (m, 1H) 6.78 (d, J = 8.0Hz, 1H) 6.80 (dd, J = 2.4, 8.4 Hz, 1H) 6.86 (d, J = 2.4 Hz, 1H) 7.08 (brt, J = 5.6 Hz, 1H) 7.12 (dd, J = 2.4, 8.4 Hz, 1H) 7.23 ( d, J = 2.4Hz, 1H) 7.73 (d, J = 8.4Hz, 1H)
[1413] MS m / e (ESI) 504 (MH ⁺ )
[1414] Example 120
[1415]
[1416] Treatment was carried out in the same manner as in Example 93, to 3-3-[([2- (4-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- The oxyphenyl-2-isopropoxypropionic acid was obtained.
[1417] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.48 (t, J = 7.2 Hz, 3H) 2.04 (s, 3H) 2.71 (s, 3H) 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 4.08-4.13 (m, 3H) 4.59 (d, J = 5.6 Hz, 2H) 4.74-4.77 (m, 1H) 6.53 (brt, J = 6.4 Hz, 1H) 6.81 (d, J = 8.4 Hz, 1H) 7.13 (dd, J = 2.4, 8.4 Hz, 1H) 7.21 (d, J = 2.4 Hz, 1H) 7.24 (d, J = 8.0 Hz, 2H) 7.80 (d, J = 8.4 Hz, 2H)
[1418] MS m / e (ESI) 497 (MH ⁺ )
[1419] Example 121
[1420]
[1421] Treatment in the same manner as in Example 93, yielding 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- Ethoxyphenyl-2-isopropoxypropionic acid was obtained.
[1422] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.48 (t, J = 7.2 Hz, 3H) 2.75 (s, 3H) 2.92 (dd, J = 8.0, 14.0Hz, 1H) 3.06 (dd, J = 4.4, 14.0Hz, 1H) 3.59 (sept, J = 6.0Hz, 1H) 4.08-4.13 (m, 3H) 4.60 (d, J = 6.0Hz, 2H) 6.61 (brt, J = 6.4Hz, 1H) 6.82 (d, J = 8.4Hz, 1H) 7.14 (dd, J = 2.4, 8.4Hz, 1H) 7.22 (d, J = 2.4Hz, 1H ) 7.35-7.40 (m, 1H) 7.48-7.51 (m, 1H) 8.24-8.27 (m, 1H)
[1423] MS m / e (ESI) 516 (MH ⁺ )
[1424] Example 122
[1425]
[1426] Treated in the same manner as in Example 93, and treating 3-3-[([2- (4-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- Ethoxyphenyl-2-isopropoxypropionic acid was obtained.
[1427] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.48 (t, J = 7.2 Hz, 3H) 2.71 (s, 3H) 2.92 (dd, J = 8.0, 14.0Hz, 1H) 3.06 (dd, J = 4.4, 14.0Hz, 1H) 3.59 (sept, J = 6.0Hz, 1H) 4.08-4.13 (m, 3H) 4.59 (d, J = 6.0Hz, 2H) 6.54 (brt, J = 5.6Hz, 1H) 6.82 (d, J = 8.4Hz, 1H) 7.14 (dd, J = 2.4, 8.4Hz, 1H) 7.21 (d, J = 2.4Hz, 1H ) 7.41 (d, J = 8.8 Hz, 2H) 7.86 (d, J = 8.8 Hz, 2H)
[1428] MS m / e (ESI) 516 (MH ⁺ )
[1429] Example 123
[1430]
[1431] Treatment in the same manner as in Example 93, yielding 3-3-[([2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]- 4-ethoxyphenyl-2-isopropoxypropionic acid was obtained.
[1432] MS m / e (ESI) 551 (MH ⁺ )
[1433] Example 124
[1434]
[1435] 3-4-ethoxy-3-[([5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] carbonylamino) by treatment in the same manner as in Example 93 Methyl] phenyl-2-isopropoxypropionic acid was obtained.
[1436] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.47 (t, J = 7.2 Hz, 3H) 2.05 (s, 3H) 2.92 (dd, J = 8.0, 14.0Hz, 1H) 3.06 (dd, J = 4.4, 14.0Hz, 1H) 3.57 (sept, J = 6.0Hz, 1H) 4.08-4.13 (m, 3H) 4.58 (d, J = 5.6 Hz, 2H) 6.50 (br, 1H) 6.82 (d, J = 8.0 Hz, 1H) 7.09 (dd, J = 3.6, 5.2 Hz, 1H) 7.13 (dd, J = 2.4, 8.0 Hz, 1H) 7.21 ( d, J = 2.0Hz, 1H) 7.48 (ddd, J = 1.2, 5.2, 33.6Hz, 1H)
[1437] MS m / e (ESI) 489 (MH ⁺ )
[1438] Example 125
[1439]
[1440] Treatment was carried out in the same manner as in Example 94, to obtain 3- (3-[(2-chloro4-propoxybenzoyl) amino] methyl-4-propoxyphenyl) -2-isopropoxypropionic acid.
[1441] MS m / e (ESI) 492 (MH ⁺ )
[1442] Example 126
[1443]
[1444] It processed in the same manner as in Example 94 to obtain 3- (3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionic acid.
[1445] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.05 (t, J = 7.2 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.33 (d, J = 6.0 Hz, 6H) 1.79-1.87 (m, 2H) 2.90 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 3.95 (t, J = 7.2 Hz, 2H) 4.11 (dd, J = 4.4, 8.0 Hz, 1H) 4.56 (sept, J = 6.0 Hz, 1H) 4.63 (d, J = 7.0 Hz, 2H) 6.79 (d, J = 8.8Hz, 1H) 6.81 (dd, J = 2.4, 8.8Hz, 1H) 6.86 (d, J = 2.8Hz, 1H) 6.99 (br, 1H) 7.11 (dd, J = 2.4, 8.4Hz, 1H) 7.23 (d, J = 2.0Hz, 1H) 7.72 (d, J = 8.4Hz, 1H)
[1446] MS m / e (ESI) 492 (MH ⁺ )
[1447] Example 127
[1448]
[1449] By the same method as in Example 94, 3- (3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4-propoxyphenyl-2-isopropoxypropionic acid was obtained.
[1450] MS m / e (ESI) 518 (MH ⁺ )
[1451] Example 128
[1452]
[1453] Treatment was carried out in the same manner as in Example 94, and 3-3-[([2- (4-methylphenyl-5-methyl-1,3-thiazol-4-yl) carbonylamino) methyl] -4-propoxy Phenyl-2-isopropoxypropionic acid was obtained.
[1454] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.09 (t, J = 7.2 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.82-1.91 (m, 2H ) 2.40 (s, 3H) 2.71 (s, 3H) 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.99 (t, J = 6.8 Hz, 2H) 4.12 (dd, J = 4.4, 8.0 Hz, 1H) 4.59 (d, J = 6.0 Hz, 2H) 6.46 (brt, J = 6.4 Hz, 1H) 6.82 (d, J = 8.2Hz, 1H) 7.14 (dd, J = 2.4, 8.8Hz, 1H) 7.22 (d, J = 2.4Hz, 1H) 7.24 (d, J = 8.0Hz, 2H) 7.80 (d, J = 8.4Hz , 2H)
[1455] MS m / e (ESI) 511 (MH ⁺ )
[1456] Example 129
[1457]
[1458] 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl) -4- in the same manner as in Example 94 Propoxyphenyl-2-isopropoxypropionic acid was obtained.
[1459] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.09 (t, J = 7.6 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.85-1.91 (m, 2H ) 2.74 (s, 3H) 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.99 (t, J = 6.4Hz, 2H) 4.12 (dd, J = 4.4, 8.0Hz, 1H) 4.60 (d, J = 6.0Hz, 2H) 6.57 (brt, J = 6.4Hz, 1H) 6.82 (d, J = 8.4Hz, 1H ) 7.14 (dd, J = 2.4, 8.4Hz, 1H) 7.22 (d, J = 2.4Hz, 1H) 7.35-7.40 (m, 2H) 7.48-7.51 (m, 1H) 8.24-8.27 (m, 1H)
[1460] MS m / e (ESI) 531 (MH ⁺ )
[1461] Example 130
[1462]
[1463] 3-3-[([2- (4-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- was treated in the same manner as in Example 94; Propoxyphenyl-2-isopropoxypropionic acid was obtained.
[1464] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.08 (t, J = 7.6 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.84-1.89 (m, 2H ) 2.70 (s, 3H) 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.05 (dd, J = 4.4, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.99 (t, J = 6.4Hz, 2H) 4.12 (dd, J = 4.4, 8.0Hz, 1H) 4.59 (d, J = 5.6Hz, 2H) 6.49 (brt, J = 6.4Hz, 1H) 6.82 (d, J = 8.4Hz, 1H ) 7.14 (dd, J = 2.4, 8.4Hz, 1H) 7.21 (d, J = 2.4Hz, 1H) 7.41 (d, J = 8.8Hz, 2H) 7.85 (d, J = 8.8Hz, 2H)
[1465] MS m / e (ESI) 531 (MH ⁺ )
[1466] Example 131
[1467]
[1468] 3-3-[(2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4 in the same manner as in Example 94 -Propoxyphenyl-2-isopropoxypropionic acid was obtained.
[1469] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.07 (t, J = 7.2 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.83-1.92 (m, 2H ) 2.73 (s, 3H) 2.92 (dd, J = 7.2, 14.0 Hz, 1H) 3.06 (dd, J = 4.0, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.99 (t, J = 6.4Hz, 2H) 4.12 (dd, J = 4.4, 8.0Hz, 1H) 4.60 (d, J = 5.6Hz, 2H) 6.55 (brt, J = 6.4Hz, 1H) 6.82 (d, J = 8.4Hz, 1H ) 7.14 (dd, J = 2.4, 8.4 Hz, 1H) 7.22 (d, J = 2.4 Hz, 1H) 7.36 (dd, J = 2.4, 8.8 Hz, 1H) 7.51 (d, J = 2.0 Hz, 1H) 8.26 (d, J = 8.4 Hz, 1H)
[1470] MS m / e (ESI) 565 (MH ⁺ )
[1471] Example 132
[1472]
[1473] 3-4-propoxy-3-[([5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] carbonylamino) by treatment in the same manner as in Example 94 Methyl] phenyl-2-isopropoxypropionic acid was obtained.
[1474] MS m / e (ESI) 503 (MH ⁺ )
[1475] Example 133
[1476]
[1477] The same procedure as in Example 95 was carried out to obtain 3- (3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionic acid.
[1478] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (t, J = 7.2 Hz, 3H) 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.35 (d, J = 6.0 Hz, 6H) 1.78-1.83 (m, 2H) 2.90 (dd, J = 7.2, 14.0 Hz, 1H) 3.05 (dd, J = 4.0, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 3.92 (t, J = 6.4 Hz, 2H) 4.10 (dd, J = 4.0, 7.2 Hz, 1H) 4.56-4.61 (m, 3H) 6.80 (d, J = 8.4 Hz, 1H) 6.83 (dd, J = 2.4, 8.4Hz, 1H) 6.89 (d, J = 2.4Hz, 1H) 7.04 (brt, J = 5.2Hz, 1H) 7.11 (dd, J = 2.4, 8.4Hz, 1H) 7.23 (d, J = 2.4Hz, 1H ) 7.74 (d, J = 8.8 Hz, 1H)
[1479] MS m / e (ESI) 492 (MH ⁺ )
[1480] Example 134
[1481]
[1482] The same procedure as in Example 95 was carried out to obtain 3- (3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4-isopropoxyphenyl-2-isopropoxypropionic acid.
[1483] MS m / e (ESI) 492 (MH ⁺ )
[1484] Example 135
[1485]
[1486] The same procedure as in Example 95 was carried out to obtain 3- (3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4-isopropoxyphenyl) -2-isopropoxypropionic acid.
[1487] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.35 (d, J = 6.0 Hz, 6H) 1.61-1.65 (m, 2H ) 1.75-1.94 (m, 6H) 2.90 (dd, J = 7.2, 14.0 Hz, 1H) 3.05 (dd, J = 4.0, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 4.10 (dd, J = 4.0, 7.2Hz, 1H) 4.60 (d, J = 5.6Hz, 3H) 4.76 (sept, J = 6.0Hz, 1H) 6.80 (d, J = 8.8Hz, 1H) 6.81 (d, J = 8.8Hz , 1H) 6.86 (d, J = 2.4Hz, 1H) 7.05 (brt, J = 5.6Hz, 1H) 7.11 (dd, J = 2.4, 8.4Hz, 1H) 7.23 (d, J = 2.0Hz, 2H) 7.73 (d, J = 8.8 Hz, 2H)
[1488] MS m / e (ESI) 518 (MH ⁺ )
[1489] Example 136
[1490]
[1491] 3-3-[([2- (4-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-iso is treated in the same manner as in Example 95 Propoxyphenyl-2-isopropoxypropionic acid was obtained.
[1492] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.39 (d, J = 6.0 Hz, 6H) 2.40 (s, 3H) 2.71 (s, 3H) 2.91 (dd, J = 7.2, 14.0 Hz, 1H) 3.05 (dd, J = 4.0, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 4.11 (dd, J = 4.0, 7.2Hz, 1H) 4.56 (d, J = 5.6Hz, 2H) 4.63 (sept, J = 6.0Hz, 1H) 6.53 (brt, J = 5.6Hz, 1H) 6.83 (d, J = 8.4Hz, 1H) 7.13 (dd, J = 2.4, 8.4Hz, 1H) 7.21 (d, J = 2.4Hz, 1H) 7.24 (d, J = 8.4Hz, 2H) 7.80 (d, J = 8.4Hz, 2H)
[1493] MS m / e (ESI) 511 (MH ⁺ )
[1494] Example 137
[1495]
[1496] Treatment in the same manner as in Example 95, yielding 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- Isopropoxyphenyl-2-isopropoxypropionic acid was obtained.
[1497] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.40 (d, J = 6.0 Hz, 6H) 2.75 (s, 3H) 2.92 (dd, J = 7.2, 14.0Hz, 1H) 3.05 (dd, J = 4.0, 14.0Hz, 1H) 3.60 (sept, J = 6.0Hz, 1H) 4.12 (dd, J = 4.0, 7.2Hz, 1H) 4.58 (d, J = 5.6Hz, 2H) 4.64 (sept, J = 6.0Hz, 1H) 6.63 (brt, J = 5.6Hz, 1H) 6.83 (d, J = 8.4Hz, 1H) 7.13 (dd, J = 2.4 , 8.4Hz, 1H) 7.21 (d, J = 2.4Hz, 1H) 7.35-7.39 (m, 2H) 7.48-7.50 (m, 1H) 8.25-8.27 (m, 1H)
[1498] MS m / e (ESI) 531 (MH ⁺ )
[1499] Example 138
[1500]
[1501] 3-3-[([2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]-for treatment in the same manner as in Example 95 4-isopropoxyphenyl-2-isopropoxypropionic acid was obtained.
[1502] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.40 (d, J = 6.0 Hz, 6H) 2.74 (s, 3H) 2.92 (dd, J = 7.2, 14.0Hz, 1H) 3.05 (dd, J = 4.0, 14.0Hz, 1H) 3.60 (sept, J = 6.0Hz, 1H) 4.12 (dd, J = 4.0, 7.2Hz, 1H) 4.56 (d, J = 5.6Hz, 2H) 4.64 (sept, J = 6.0Hz, 1H) 6.63 (brt, J = 5.6Hz, 1H) 6.83 (d, J = 8.4Hz, 1H) 7.13 (dd, J = 2.4 , 8.4Hz, 1H) 7.21 (d, J = 2.4Hz, 1H) 7.36 (dd, J = 2.0, 8.4Hz, 1H) 7.51 (d, J = 2.4Hz, 1H) 7.26 (d, J = 8.8Hz, 2H)
[1503] MS m / e (ESI) 565 (MH ⁺ )
[1504] Example 139
[1505]
[1506] 3-4-isopropoxy-3-[([5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] carbonylamino was treated in the same manner as in Example 95. ) Methyl] phenyl-2-isopropoxypropionic acid was obtained.
[1507] MS m / e (ESI) 503 (MH ⁺ )
[1508] Example 140
[1509]
[1510] By the same method as in Example 96, 3- (3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionic acid was obtained.
[1511] MS m / e (ESI) 513 (MH ⁺ )
[1512] Example 141
[1513]
[1514] The same procedure as in Example 96 was carried out to obtain 3- (3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionic acid.
[1515] MS m / e (ESI) 518 (MH ⁺ )
[1516] Example 142
[1517]
[1518] By the same method as in Example 96, 3- (3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4-cyclopentyloxyphenyl) -2-isopropoxypropionic acid was obtained.
[1519] MS m / e (ESI) 544 (MH ⁺ )
[1520] Example 143
[1521]
[1522] Treatment in the same manner as in Example 96, yielding 3-3-[([2- (4-methylphenyl5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-cyclopentyloxy Phenyl-2-isopropoxypropionic acid was obtained.
[1523] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.65-1.69 (m, 2H) 1.77-2.10 (m, 6H) 2.40 ( s, 3H) 2.71 (s, 3H) 2.91 (dd, J = 7.2, 14.0 Hz, 1H) 3.06 (dd, J = 4.0, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 4.11 (dd , J = 4.0, 7.2Hz, 1H) 4.54 (d, J = 5.6Hz, 2H) 4.82-4.85 (m, 1H) 6.44 (br, 1H) 6.82 (d, J = 8.4Hz, 1H) 7.12 (dd, J = 2.4, 8.4Hz, 1H) 7.20 (d, J = 2.4Hz, 1H) 7.24 (d, J = 7.2Hz, 2H) 7.80 (d, J = 8.0Hz, 2H)
[1524] MS m / e (ESI) 537 (MH ⁺ )
[1525] Example 144
[1526]
[1527] 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- was treated in the same manner as in Example 96; Cyclopentyloxyphenyl-2-isopropoxypropionic acid was obtained.
[1528] MS m / e (ESI) 557 (MH ⁺ )
[1529] Example 145
[1530]
[1531] 3-3-[([2- (4-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- was treated in the same manner as in Example 96; Cyclopentyloxyphenyl-2-isopropoxypropionic acid was obtained.
[1532] MS m / e (ESI) 557 (MH ⁺ )
[1533] Example 146
[1534]
[1535] 3-3-[([2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl-1 in the same manner as in Example 96 4-cyclopentyloxyphenyl-2-isopropoxypropionic acid was obtained.
[1536] MS m / e (ESI) 591 (MH ⁺ )
[1537] Example 147
[1538]
[1539] 3-4-cyclopentyloxy-3-[([5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] carbonylamino was treated in the same manner as in Example 96. ) Methyl] phenyl noisopropoxypropionic acid was obtained.
[1540] MS m / e (ESI) 529 (MH ⁺ )
[1541] Example 148
[1542]
[1543] By the same method as in Example 98, 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (2-furyl) phenyl] -2-isopropoxypropionic acid was obtained.
[1544] MS m / e (ESI) 500 (MH ⁺ )
[1545] Example 149
[1546]
[1547] By the same method as in Example 98, 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (2-furyl) phenyl] -2-isopropoxypropionic acid was obtained. .
[1548] MS m / e (ES1) 500 (MH ⁺ )
[1549] Example 150
[1550]
[1551] By the same method as in Example 98, 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (2-furyl) phenyl] -2-isopropoxypropionic acid was obtained. .
[1552] MS m / e (ESI) 526 (MH ⁺ )
[1553] Example 151
[1554]
[1555] 3-4- (2-furyl) -3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonyl by treatment in the same manner as in Example 98 Amino) methyl] phenyl-2-isopropoxypropionic acid was obtained.
[1556] MS m / e (ESI) 519 (MH ⁺ )
[1557] Example 152
[1558]
[1559] 3-4- (2-furyl 3-[([5-methyl-2- (2-chlorophenyl) -1,3-thiazol-4-yl] carbonylamino was treated in the same manner as in Example 98. ) Methyl] phenyl-2-isopropoxypropionic acid was obtained.
[1560] MS m / e (ESI) 539 (MH ⁺ )
[1561] Example 153
[1562] Preparation Example 153a)
[1563]
[1564] 3- (3-[(tertiarybutoxycarbonyl) amino] methyl-4- [trifluoromethyl) sulfonyl] oxyphenyl) -2- (2-thienylpropoxypropionic acid in the same manner as in Preparation Example 97 Ethyl ester was obtained.
[1565] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.0 Hz, 3H) 1.18 (d, J = 6.4 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 1.46 (s, 9H) 2.91 -3.06 (m, 2H) 3.51 (sept, J = 6.4 Hz, 1H) 4.10 (dd, J = 4.8, 8.8 Hz, 1H) 4.16-4.24 (m, 2H) 4.40 (d, J = 5.6 Hz, 2H) 4.69 (br 1H) 7.01 (d, J = 6.0 Hz, 1H) 7.08 (d, J = 5.2 Hz, 1H) 7.13-7.20 (m, 2H) 7.24-7.35 (m, 2H)
[1566] Example 153b)
[1567]
[1568] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (2-thienyl) propoxypropionate ethyl ester And the same procedure as in Example 98 to obtain 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4- (2-thienyl) phenyl] -2-isopropoxypropionic acid.
[1569] MS m / e (ESI) 492 (MH ⁺ )
[1570] Example 154
[1571]
[1572] It treated like Example 153 and obtained 3- [3-((2-chloro-4-propoxybenzoyl) amino] methyl-4- (2-thienyl) phenyl] -2-isopropoxypropionic acid.
[1573] MS m / e (ESI) 516 (MH ⁺ )
[1574] Example 155
[1575]
[1576] It treated like Example 153 and obtained 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (2-thienyl) phenyl] -2-isopropoxypropionic acid.
[1577] MS m / e (ESI) 516 (MH ⁺ )
[1578] Example 156
[1579] Preparation Example 156a)
[1580]
[1581] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (5-methyl-2- in the same manner as in Preparation Example 97 Thienyl) propoxypropionate ethyl ester was obtained.
[1582] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.4 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 1.46 (s, 9H) 2.51 (s, 3H) 2.91-3.05 (m, 2H) 3.51 (sept, J = 6.4 Hz, 1H) 4.07 (dd, J = 4.8, 8.8 Hz, 1H) 4.18-4.29 (m, 2H) 4.40 (br, 2H ) 4.70 (br 1H) 6.73 (s, 1H) 7.11-7.19 (m, 2H) 7.23-7.30 (m, 2H)
[1583] Example 156b)
[1584]
[1585] 3- [3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (5-methyl-2-thienyl) ethyl propoxypropionate Treatment was carried out as in Example 153 using an ester, and 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4- (5-methyl-2-thienyl) phenyl 1-2-isopropoxy Propionic acid was obtained.
[1586] MS m / e (ESI) 506 (MH ⁺ )
[1587] Example 157
[1588]
[1589] Treated as in Example 156, 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (5-methyl-2-thienyl) phenyl] -2-isopropoxypropionic acid Got.
[1590] HS m / e (ESI) 530 (MH ⁺ )
[1591] Example 158
[1592]
[1593] Treated as in Example 156, 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (5-methyl-2-thienyl) phenyl) -2-isopropoxy Propionic acid was obtained.
[1594] MS m / e (ESI) 530 (MH ⁺ )
[1595] Example 159
[1596] Preparation Example 159a)
[1597]
[1598] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (5-chloro-2- in the same manner as in Preparation Example 97 Thienyl) propoxypropionate ethyl ester was obtained.
[1599] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.4 Hz, 3H) 1.25 (t, J = 7.2 Hz, 3H) 1.45 (s, 9H) 2.51 (s, 3H) 2.91-3.05 (m, 2H) 3.50 (sept, J = 6.0 Hz, 1H) 4.08 (dd, J = 4.8, 8.8 Hz, 1H) 4.21-4.24 (m, 2H) 4.38-4.41 (m , 2H) 4.69 (br 1H) 6.78 (d, J = 3.6Hz, 1H) 7.17-7.20 (m, 2H) 7.25 (d, J = 8.0Hz, 1H) 7.31 (s, 1H)
[1600] Example 159b)
[1601]
[1602] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (5-chloro-2-thienyl) propoxypropionate ethyl The esters were treated in the same manner as in Example 153, and 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4- (5-chloro-2-thienyl) phenyl] -2-isopro Foxypropionic acid was obtained.
[1603] MS m / e (ESI) 526 (MH ⁺ )
[1604] Example 160
[1605]
[1606] Treated as in Example 159, 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (5-chloro-2-thienyl) phenyl] -2-isopropoxypropionic acid Got.
[1607] MS m / eESD 550 (MH ⁺ )
[1608] Example 161
[1609]
[1610] Treated as in Example 159, 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (5-chloro-2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1611] MS m / e (ESI) 550 (MH ⁺ )
[1612] Example 162
[1613] Preparation Example 162a)
[1614]
[1615] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (4-methyl-2- in the same manner as in Preparation Example 97 Thienyl) propoxypropionate ethyl ester was obtained.
[1616] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.4 Hz, 3H) 1.26 (t, J = 7.2 Hz, 3H) 1.45 (s, 9H) 2.29 (s, 3H) 2.94-3.05 (m, 2H) 3.54 (sept, J = 6.0 Hz, 1H) 4.08 (dd, J = 4.8, 8.8 Hz, 1H) 4.12-4.24 (m, 2H) 4.40 (br, 2H ) 4.70 (br 1H) 6.82 (s, 1H) 7.14-7.19 (m, 2H) 7.28 (d, J = 9.6 Hz, 1H) 7.31 (s, 1H)
[1617] Example 162b)
[1618]
[1619] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (4-methyl-2-thienyl) ethyl propoxypropionate Treatment was carried out as in Example 153 with an ester, and 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4- (4-methyl-2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1620] MS m / e (ESI) 506 (MH ⁺ )
[1621] Example 163
[1622]
[1623] Treated as in Example 162, 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (4-methyl-2-thienyl) phenyl] -2-isopropoxypropionic acid Got.
[1624] MS m / e (ESI) 530 (MH ⁺ )
[1625] Example 164
[1626]
[1627] Treated as in Example 162, 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (4-methyl-2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1628] MS m / e (ESI) 530 (MH ⁺ )
[1629] Example 165
[1630] Preparation Example 165a)
[1631]
[1632] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (3-thienyl) prop in the same manner as in Preparation Example 97 Foxy propionic acid ethyl ester was obtained.
[1633] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.4 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 1.44 (s, 9H) 2.95 -3.06 (m, 2H) 3.55 (sept, J = 6.0 Hz, 1H) 4.09 (dd, J = 4.8, 8.8 Hz, 1H) 4.14-4.25 (m, 2H) 4.32 (d, J = 5.6 Hz, 2H) 4.64 (br 1H) 7.10-7.11 (m, 1H) 7.18-7.25 (m, 3H) 7.30 (s, 1H) 7.37 (dd, J = 2.1, 5.2 Hz, 1H)
[1634] Example 165b)
[1635]
[1636] 3- (3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (3-thienyl) propoxypropionate ethyl ester It treated like Example 153, and obtained 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4- (3-thienyl) phenyl] -2-isopropoxypropionic acid.
[1637] MS m / e (ESl) 492 (MH ⁺ )
[1638] Example 166
[1639]
[1640] It processed like Example 165, and obtained 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (3-thienyl) phenyl] -2-isopropoxypropionic acid.
[1641] MS m / e (ESI) 516 (MH ⁺ )
[1642] Example 167
[1643]
[1644] It processed like Example 165, and obtained 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- [3-thienyl] phenyl] -2-isopropoxypropionic acid.
[1645] MS m / e (ESI) 516 (MH ⁺ )
[1646] Example 168
[1647] Preparation Example 168a)
[1648]
[1649] 3- (3-[(tertiarybutoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (3-furyl) propoxy in the same manner as in Preparation Example 97 Ethyl propionate was obtained.
[1650] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 7.2 Hz, 3H) 1.45 (s, 9H) 2.93 -3.04 (m, 2H) 3.54 (sept, J = 6.0 Hz, 1H) 4.08 (dd, J = 6.8, 8.0 Hz, 1H) 4.18-4.26 (m, 2H) 4.30-4.41 (m, 2H) 4.67 (br 1H) 6.52 (d, J = 4.0 Hz, 1H) 7.13-7.19 (m, 2H) 7.25-7.28 (m, 2H) 7.49 (d, J = 4.0 Hz, 1H)
[1651] Example 168b)
[1652]
[1653] 3- [3-[(tertiary butoxycarbonyl) amino] methyl-4-[(trifluoromethyl) sulfonyl] oxyphenyl) -2- (3-furyl) propoxypropionate ethyl ester Example 153), to obtain 3- [3-[(2.4-dichlorobenzoyl) amino] methyl-4- (3-furyl) phenyl] -2-isopropoxypropionic acid.
[1654] MS m / e (ESI) 476 (MH ⁺ )
[1655] Example 169
[1656]
[1657] It processed like Example 168, and obtained 3- [3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4- (3-furyl) phenyl] -2-isopropoxypropionic acid.
[1658] MS m / e (ESI) 500 (MH ⁺ )
[1659] Example 170
[1660]
[1661] It treated like Example 168, and obtained 3- [3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4- (3-furyl) phenyl] -2-isopropoxypropionic acid.
[1662] MS m / e (ESI) 5QO (MH ⁺ )
[1663] Example 171
[1664]
[1665] Treated as in Example 153, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4- (2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1666] MS m / e (ESI) 51 O (MH ⁺ )
[1667] Example 172
[1668]
[1669] It processed like Example 153, and obtained 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (2-thienyl) phenyl] -2-isopropoxypropionic acid.
[1670] MS m / e (ESI) 542 (MH ⁺ )
[1671] Example 173
[1672]
[1673] Treated as in Example 153, 2-isopropoxy-3- [3-[([5-methyl-2- [4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (2-thienyl) phenyl] propionic acid was obtained.
[1674] MS m / e (ESI) 535 (MH ⁺ )
[1675] Example 174
[1676]
[1677] Treated as in Example 156, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4- (5-methyl-2-thienyl) phenyl] -2 Isopropoxypropionic acid was obtained.
[1678] MS m / e (ESI) 524 (MH ⁺ )
[1679] Example 175
[1680]
[1681] Treated as in Example 156, 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (5-methyl-2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1682] MS m / e (ESI) 556 (MH ⁺ )
[1683] Example 176
[1684]
[1685] Treated as in Example 156, 2-isopropoxy-3- [3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (5-methyl-2-thienyl) phenyl] propionic acid was obtained.
[1686] MS m / e (ESI) 549 (MH ⁺ )
[1687] Example 177
[1688]
[1689] Treated as in Example 159, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl; aminomethyl) -4- (5-chloro-2-thienyl) phenyl] -2 Isopropoxypropionic acid was obtained.
[1690] MS m / e (ESI) 544 (MH ⁺ )
[1691] Example 178
[1692]
[1693] Treated as in Example 159, 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (5-chloro-2-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1694] MS m / e (ESI) 576 (MH ⁺ )
[1695] Example 179
[1696]
[1697] Treated as in Example 159, 2-isopropoxy-3- [3-[([5-methyl-2- [4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (5-chloro-2-thienyl) phenyl] propionic acid was obtained.
[1698] MS m / e (ESI) 569 (MH ⁺ )
[1699] Example 180
[1700]
[1701] Treated as in Example 162, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4- (4-methyl-2-thienyl) phenyl] -2 Isopropoxypropionic acid was obtained.
[1702] MS m / e (ESI) 524 (MH ⁺ )
[1703] Example 181
[1704]
[1705] Example 162), 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (4-methyl-2-thienyl) phenyl] -2-isopro Foxypropionic acid was obtained.
[1706] MS m / e (ESI) 556 (MH ⁺ )
[1707] Example 182
[1708]
[1709] Treated as in Example 162, 2-isopropoxy-3- [3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (4-methyl-2-thienyl) phenyl] propionic acid was obtained.
[1710] MS m / e (ESI) 549 (MH ⁺ )
[1711] Example 183
[1712]
[1713] Treated as in Example 165, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4- (3-thienyl) phenyl] -2-isopropoxy Propionic acid was obtained.
[1714] MS m / e (ESI) 510 (MH ⁺ )
[1715] Example 184
[1716]
[1717] It processed like Example 165, and obtained 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl] amino] methyl-4- (3-thienyl) phenyl] -2-isopropoxypropionic acid.
[1718] HS m / e (ESI) 542 (MH ⁺ )
[1719] Example 185
[1720]
[1721] Treated as in Example 165, 2-isopropoxy-3- [3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (3-thienyl) phenyl] propionic acid was obtained.
[1722] MS m / e (ES1) 535 (MH ⁺ )
[1723] Example 186
[1724]
[1725] Treated as in Example 168, 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4- (3-furyl) phenyl] -2-isopropoxypropionic acid Got.
[1726] MS m / e (ESI) 494 (MH ⁺ )
[1727] Example 187
[1728]
[1729] It processed like Example 168, and obtained 3- [3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4- (3-furyl) phenyl] -2-isopropoxypropionic acid.
[1730] MS m / e (ESI) 526 (MH ⁺ )
[1731] Example 188
[1732]
[1733] Treated as in Example 168, 2-isopropoxy-3- [3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl ] -4- (3-furyl) phenyl] propionic acid was obtained.
[1734] MS m / e (ESI) 519 (MH ⁺ )
[1735] Example 189
[1736] Preparation Example 189a)
[1737]
[1738] 2.95 g of benzyl 5-formyl-2-methoxybenzoate and 5 g of triphenylphosphoranilideneacetaldehyde were mixed in toluene and stirred at 80 ° C for 7 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1), and benzyl 2-methoxy-5- (3-oxo-1-propenyl) benzoate (EZ mixture) 2.0 g was obtained as a yellow solid.
[1739] ¹ H-NMR (CDCl ³ ) δ: 3.95 + 3.97 (s, 3H) 5.37 (s, 2H) 6.61 + 6.64 (s, J = 8.0Hz, 1H) 6.90-7.07 (m, 2H) 7.33-7.47 (m , 5H) 7.62 + 7.70 (dd, J = 2.0,8.0 Hz, 1H) 7.95 + 8.02 (d, J = 2.0 Hz, 1H)
[1740] Example 189b)
[1741]
[1742] 0.77 g of triethyl-2-phosphonobutylate was dissolved in N, N-dimethylformamide, 115 mg of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. 0.6 g of benzyl 2-methoxy-5-(-3-oxo-1-propenyl) benzoate (E-Z mixture) dissolved in N, N-dimethylformamide was added, and the mixture was stirred at room temperature for 2 hours. Water and ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1). The obtained product was dissolved in ethanol, 10% palladium carbon was added, hydrogen substituted, and the mixture was stirred at room temperature for 7 hours. The palladium carbon was filtered off, and the solvent was distilled off under reduced pressure to obtain 0.47 g of 5- [4- (ethoxycarbonyl) hexyl] -2-methoxybenzoic acid as a colorless oil.
[1743] ¹ H-NMR (CDCl ₃ ) δ: 0.50 (t, J = 8.0Hz, 3H) 1.17 (t, J = 8.0Hz, 3H) 1.38-1.58 (m, 6H) 2.20 (m, 1H) 2.54 (t, J = 8.0 Hz, 2H) 3.99 (s, 3H) 4.07 (q, J = 8.0 Hz, 2H) 7.90 (d, J = 8.0 Hz, 1H) 7.29 (dd, J = 2.0, 8.0 Hz, 1H) 7.91 ( d, J = 2.0 Hz, 1H)
[1744] Example 189c)
[1745]
[1746] The reaction was carried out in the same manner as in Example 1c) and d) using 0.47 g of 5- [4- (ethoxycarbonyl) hexyl] -2-methoxybenzoic acid and 0.279 of 4- (trifluoromethyl) benzylamine. By doing this, 0.21 g of 2-ethyl-5- [4-methoxy-3-([4- (trifluoromethyl) benzyl] aminocarbonyl) phenyl] pentanoic acid was obtained as a colorless amorphous.
[1747] ¹ H-NMR (CDCl ₃ ) δ: 0.85 (t, J = 8.0 Hz, 3H) 1.42-1.59 (m, 6H) 2.27 (m, 1H) 2.53 (m, 2H) 3.85 (s, 3H) 4.66 (d , J = 6.0 Hz, 2H) 6.90 (d, J = 7.0 Hz, 1H) 7.26 (m, 1H) 7.47 (d, J = 8.0 Hz, 2H) 7.59 (d, J = 8.0 Hz, 2H) 8.04 (d , J = 2.0Hz, 1H) 8.34 (bs, 1H)
[1748] Example 190
[1749] Preparation Example 190a)
[1750]
[1751] 5- (5-ethoxy-4-isopropoxy-5-oxopentyl) -2-methoxybenzoic acid was obtained in the same manner as in Production Example 189a) and Example 189a).
[1752] ¹ H-NMR (CDCl ₃ ) δ: 1.13 (d, J = 6.0 Hz, 3H) 1.19 (d, J = 6.0 Hz, 3H) 1.27 (t, J = 8.0 Hz, 3H) 1.54-1.74 (m, 4H ) 2.62 (t, J = 8.0Hz, 2H) 3.58 (sept, J = 6.0Hz, 1H) 3.88 (m, 1H) 4.05 (s, 3H) 4.18 (q, J = 8.0Hz, 2H) 6.98 (d, J = 8.0 Hz, 1H) 7.37 (dd, J = 2.0,8.0 Hz, 1H) 8.00 (d, J = 2.0 Hz, 1H)
[1753] Example 190b)
[1754]
[1755] Example 1c), d using 0.35 g of 5- (5-ethoxy-4-isopropoxy-5-oxopentyl) -2-methoxybenzoic acid and 0.18 g of 4- (trifluoromethyl) benzylamine In the same manner as in), 0.18 g of 5-3-[(benzylamino) carbonyl] -4-methoxyphenyl1-isopropoxypentanoic acid was obtained as a colorless amorphous.
[1756] ¹ H-NMR (CDCl ₃ ) δ: 1.20 (d, J = 6.0 Hz, 3H) 1.21 (d, J = 6.0 Hz, 3H) 1.67-1.80 (m, 4H) 2.63 (t, J = 8.0 Hz, 2H ) 3.69 (sept, J = 6.0 Hz, 1H) 3.92 (s, 3H) 3.96 (m, 1H) 4.70 (d, J = 6.0 Hz, 2H) 6.98 (d, J = 8.0 Hz, 1H) 7.26 (m, 1H) 7.47 (d, J = 8.0 Hz, 1H) 7.59 (d, J = 8.0 Hz, 2H) 8.04 (d, J = 2.0 Hz, 1H) 8.33 (bs, 1H)
[1757] Example 191
[1758]
[1759] 2- (4-methoxy-3-([2- (2.4-dichlorophenyl] acetyl] amino] benzyl) butanoic acid was obtained by the same method as in Example 17.
[1760] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 8.0 Hz, 3H) 1.55-1.64 (m, 2H) 2.58 (m, 1H) 2.68 (dd, J = 4.5,14.0 Hz, 1H) 2.89 ( dd, J = 7.0, 14.0 Hz, 1H) 3.78 (s, 3H) 3.82 (s, 2H) 6.73 (d, J = 8.0 Hz, 1H) 6.84 (dd, J = 2.0, 8.0 Hz, 1H) 7.26 (m , 1H) 7.35 (d, J = 8.0 Hz, 2H) 7.45 (d, 2.0 Hz, 1H) 7.88 (s, 1H) 8.19 (d, J = 2.0 Hz, 1H)
[1761] Example 192
[1762]
[1763] 2-isopropoxy-3- (4-methoxy-3-([2- (3-fluoro) -4-trifluoromethyl) phenyl] acetyl) amino) phenylpropane by the same method as in Example 14. Got acid.
[1764] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.65 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.58 (sept, J = 6.0 Hz, 1H) 3.78 (s, 2H) 3.80 (s, 3H) 4.13 (m, 1H) 6.77 (d, J = 8.0 Hz, 1H) 6.92 ( dd, J = 2.0, 8.0Hz, 1H) 7.25 (m, 2H) 7.61 (t, J = 8.0Hz, 1H) 7.76 (s, 1H) 8.24 (d, J = 2.0Hz, 1H)
[1765] Example 193
[1766]
[1767] 2-Isopropoxy-3- (4-methoxy-3-([2- (2,4-dichlorophenyl) acetyl] amino) phenylpropanoic acid was obtained by the same method as in Example 14.
[1768] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.88 (dd, J = 7.0, 14.0 Hz, 1H) 3.05 (dd, J = 4.5, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 3.80 (s, 3H) 3.83 (s, 2H) 4.12 (m, 1H) 6.76 (d, J = 8.0 Hz, 1H) 6.90 ( dd, J = 2.0, 8.0 Hz, 1H) 7.27 (dd, J = 2.0, 8.0 Hz, 1H) 7.36 (d, J = 8.0 Hz, 1H) 7.46 (d, J = 2.0 Hz, 1H) 7.86 (s, 1H) 8.26 (d, J = 2.0 Hz, 1H)
[1769] Example 194
[1770]
[1771] 2- (4-methoxy-3- (2-oxo-2- [2,4-difluoroanilino] ethyl) benzyl) butanoic acid was obtained by the same method as in Example 22.
[1772] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 8.0 Hz, 3H) 1.57-1.66 (m, 2H) 2.57 (m, 1H) 2.70 (dd, J = 7.0, 14.0 Hz, 1H) 2.89 ( dd, J = 4.5, 14.0 Hz, 1H) 3.69 (s, 2H) 3.92 (s, 3H) 6.76-6.87 (m, 3H) 7.09-7.12 (m, 2H) 8.22-8.29 (m, 2H)
[1773] Example 195
[1774]
[1775] 2- (4-methoxy-3- (2-oxo-2- [2-methyl-4- (trifluoromethyl] anilino] ethyl) benzyl) butanoic acid was obtained by the same method as in Example 22.
[1776] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (t, J = 8.0 Hz, 3H) 1.55-1.70 (m, 2H) 2.10 (m, 1H) 2.57 (dd, J = 4.5,14.0 Hz, 1H) 2.89 ( dd, J = 7.0, 14.0Hz, 1H) 3.73 (s, 3H) 3.89 (s, 2H) 6.88 (d, J = 8.0Hz, 1H) 7.12-7.15 (m, 2H) 7.26 (t, J = 8.0Hz , 1H) 7.39 (d, J = 8.0 Hz, 2H) 7.63 (s, 1H) 8.03 (d, J = 8.0 Hz, 1H)
[1777] Example 196
[1778] Example 196a)
[1779]
[1780] Ethyl 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) phenyl) -2- by the same method as in Example 122a) -c) Propenoate was obtained.
[1781] ¹ H-NMR (CDCl ₃ ) δ: 1.17 (t, J = 8.0 Hz, 3H) 1.34 (t, J = 8.0 Hz, 3H) 2.56 (q, J = 8.0 Hz, 2H) 3.77 (s, 3H) 3.96 (s, 3H) 4.26 (q, J = 8.0 Hz, 2H) 6.98 (d, J = 8.0 Hz, 1H) 7.22 (dd, J = 2.0, 8.0 Hz, 1H) 7.31 (d, J = 8.0 Hz, 1H ) 7.37 (dd, J = 2.0, 8.0 Hz, 1H) 7.58 (s, 1H) 8.22 (bs, 1H) 8.37 (d, J = 8.0 Hz, 1H)
[1782] Example 196b)
[1783]
[1784] 0.9 g of 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) phenyl) -2-propenoate was added to 15 ml of ethanol and 15 ml of ethyl acetate. It melt | dissolved and added 0.6 g of palladium carbon poisoned with ethylenediamine. The reaction solution was stirred at room temperature under a hydrogen atmosphere for 5 hours, and then palladium carbon was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 0.44 g of ethyl 2- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) benzyl) butanoate was colorless oil. Obtained as.
[1785] ¹ H-NMR (CDCl ₃ ) δ: 0.90 (t, J = 8.0 Hz, 3H) 1.14 (t, J = 8.0 Hz, 3H) 1.50-1.68 (m, 2H) 2.54 (m, 2H) 2.68 (dd, J = 4.5, 14.0 Hz, 1H) 2.86 (dd, J = 4.5, 14.0 Hz, 1H) 3.72 (s, 2H) 3.88 (s, 3H) 4.05 (q, J = 8.0 Hz, 2H) 6.85 (d, J = 8.0 Hz, 1H) 7.10 (m, 2H) 7.20 (d, J = 8.0 Hz, 1H) 7.26 (d, J = 8.0 Hz, 1H) 8.30 (bs, 1H) 8.37 (d, J = 8.0 Hz, 1H )
[1786] Example 196c)
[1787]
[1788] 0.27 g of ethyl 2- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) benzyl) butanoate was dissolved in 100 ml of ethanol, and 1 ml of 5N sodium hydroxide was added. After stirring the reaction solution at room temperature for 24 hours, water was added and the aqueous layer was extracted with diethyl ether. The aqueous layer was made acidic with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and 2- (4-methoxy-3-12-oxo-2- [2,4-dichloroanilino] ethyl) benzyl) Butanoic acid was obtained as a colorless oil.
[1789] ¹ H-NMR (CDCl ₃ ) δ: 0.89 (t, J = 8.0 Hz, 3H) 1.49-1.62 (m, 2H) 2.50 (m, 2H) 2.64 (dd, J = 4.5, 14.0 Hz, 1H) 2.84 ( dd, J = 4.5, 14.0 Hz, 1H) 3.72 (s, 2H) 3.88 (s, 3H) 6.80 (d, J = 8.0 Hz, 1H) 7.06 (m, 2H) 7.12 (dd, J = 2.0, 8.0 Hz , 1H) 7.22 (d, J = 8.0 Hz, 1H) 8.23 (s, 1H) 8.28 (d, J = 8.0 Hz, 1H)
[1790] Example 197
[1791] Preparation Example 197a)
[1792]
[1793] 1 g of sodium hydride was suspended in tetrahydrofuran, 3 g of acetophenone dissolved in tetrahydrofuran was added, and stirred at room temperature for 30 minutes. Furthermore, 3.7 g of diethyl oxalate was added and it heated and refluxed for 1 hour. The reaction solution was ice-cooled, water and ammonium chloride solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropylethyl was added to the residue, and the crystals were filtered to obtain 2.37 g of ethyl- (Z) -4-hydroxy-2-oxo-4-phenyl-3-butanoate.
[1794] ¹ H-NMR (DMSO-d ₆ ) δ: 1.15 (t, J = 8.0 Hz, 3H) 4.18 (q, J = 8.0 Hz, 2H) 6.55 (s, 1H) 7.35-7.48 (m, 3H) 7.80 ( m, 2H)
[1795] Preparation Example 197b)
[1796] 0.67 g of ethyl- (Z) -4-hydroxy-2-oxo-4-phenyl-3-butanoate was dissolved in 10 ml of acetic acid, and 0.17 g of methylhydrazine was added. After heating and refluxing the reaction solution for 2 hours, acetic acid was distilled off under reduced pressure. Ethyl acetate and tetrahydrofuran were added to the residue, dissolved, washed with a sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and hexane: ethyl acetate 9: 1, 0.12 g of ethyl 1-methyl-3-phenyl-1H-5-pyrazolecarboxylate, hexane: ethyl acetate 4: 1, ethyl 1- 0.55 g of methyl-5-phenyl-1H-3-pyrazolecarboxylate was obtained.
[1797]
[1798] Ethyl 1-methyl-3-phenyl-1H-5-pyrazolecarboxylate
[1799] ¹ H-NMR (CDCl ₃ ) δ: 1.42 (t, J = 8.0Hz, 3H) 4.21 (s, 3H) 4.38 (q, J = 8.0Hz, 2H) 7.11 (s, 1H) 7.32 (t, J = 8.0 Hz, 1H) 7.40 (t, J = 8.0 Hz, 2H) 8.79 (d, J = 8.0 Hz, 2H)
[1800]
[1801] Ethyl 1-methyl-5-phenyl-1H-3-pyrazolecarboxylate
[1802] ¹ H-NMR (CDCl ₃ ) δ: 1.41 (t, J = 8.0 Hz, 3H) 3.95 (s, 3H) 4.43 (q, J = 8.0 Hz, 2H) 6.85 (s, 1H) 7.40-7.53 (m, 5H)
[1803] Preparation Example 197c)
[1804]
[1805] 0.12 g of ethyl 1-methyl-3-phenyl-1H-5-pyrazolecarboxylate was dissolved in 5 ml of ethanol, 1 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.11 g of 1-methyl-3-phenyl-1H-5-pyrazolecarboxylic acid.
[1806] ¹ H-NMR (CDCl ₃ ) δ: 4.22 (s, 3H) 7.22 (s, 1H) 7.33 (t, J = 8.0 Hz, 1H) 7.40 (t, J = 8.0 Hz, 2H) 8.80 (d, J = 8.0 Hz, 2H)
[1807] Example 197d)
[1808]
[1809] 2-isopropoxy-3- [4-methoxy-3-([(1-methyl-3-phenyl-1H-5-pyrazolyl) carbonyl] amino by the same method as in Example 19d) and e) Ethyl) phenyl] propanoic acid was obtained.
[1810] ¹ H-NMR (CDCl ₃ ) δ: 1.06 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.94 (dd, J = 7.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.5, 14.0, 1H) 3.88 (s, 3H) 4.12 (dd, J = 4.0, 7.0 Hz, 1H) 4.20 (s, 3H) 4.57 (d, J = 6.0 Hz, 3H) 6.57 (bs, 1H) 6.73 (s, 1H) 6.84 (d, J = 2.0 Hz, 1H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.32 (d, J = 8.0 Hz, 1H ) 7.39 (m, 2H) 7.76 (m, 2H)
[1811] Example 198
[1812] Preparation Example 198a)
[1813]
[1814] 0.55 g of ethyl 1-methyl-5-phenyl-1H-3-pyrazolecarboxylate was dissolved in 10 ml of ethanol, 2 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.5 g of 1-methyl-5-phenyl-1H-3-pyrazolecarboxylic acid.
[1815] ¹ H-NMR (CDCl ₃ ) δ: 3.91 (s, 3H) 6.82 (s, 1H) 7.34-7.45 (m, 5H)
[1816] Example 198b)
[1817]
[1818] 2-isopropoxy-3- [4-methoxy-3-([(1-methyl-5-phenyl-1H-3-pyrazolyl) carbonyl] by the same method as in Example 19d) and e). Aminoethyl) phenyl] propanoic acid was obtained.
[1819] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.5, 14.0, 1H) 3.55 (sept, J = 6.0 Hz, 1H) 3.86 (s, 3H) 3.88 (s, 3H) 4.09 (dd, J = 4.0, 7.0 Hz, 1H) 4.60 (d, J = 6.0 Hz, 3H) 6.80 (d, J = 6.0 Hz, 1H) 6.84 (s, 1H) 7.12 (dd, J = 2.0, 8.0 Hz, 1H) 7.23 (d, J = 2.0 Hz, 1H) 7.32 (bs, 1H ) 7.39-7.57 (m, 5H)
[1820] Example 199
[1821] Preparation Example 199a)
[1822]
[1823] 1 g of phenylacetylene and 1.48 g of 2-chloro-2-hydroxyiminoacetic acid ethyl ester were dissolved in 20 ml of chloroform, 1.4 g of potassium carbonate was added and stirred at room temperature for 16 hours. Water and ammonium chloride solution were added to the reaction solution, Citron was ethyl alcohol. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 9: 1) to obtain 1.2 g of ethyl 5-phenyl-4-isoxazole carboxylate.
[1824] ¹ H-NMR (CDCl ₃ ) δ: 1.35 (t, J = 8.0 Hz, 3H) 4.40 (q, J = 8.0 Hz, 2H) 6.85 (s, 1H) 7.36-7.50 (m, 3H) 7.68-7.80 ( m, 2H)
[1825] Preparation Example 199 b)
[1826]
[1827] 0.4 g of ethyl 5-phenyl-4-isoxazole carboxylate was dissolved in 10 ml of ethanol, 2 ml of 5N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.25 g of 5-phenyl-3-isoxazole carboxylic acid.
[1828] ¹ H-NMR (DMSO-d ₆ ) δ: 7.32 (s, 1H) 7.48-7.57 (m, 3H) 7.92 (m, 2H)
[1829] Example 199c)
[1830]
[1831] 2-isopropoxy-3- [4-methoxy-3-([(5-phenyl-3-isoxazolyl) carbonyl] aminoethyl) phenyl] by the same method as in Example 19d) and e). Propanic acid was obtained.
[1832] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.5 Hz, 3H) 1.16 (d, J = 6.5 Hz, 3H) 2.90 (dd, J = 7.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.56 (sept, J = 6.0 Hz, 1H) 3.87 (s, 3H) 4.10 (dd, J = 4.5, 7.0 Hz, 1H) 4.61 (d, J = 6.0 Hz, 2H) 6.82 (d, J = 8.0 Hz, 1H) 6.96 (s, 1H) 7.15 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.36 (bs, 1H) 7.47 (m, 3H) 7.78 (m, 2H)
[1833] Example 200
[1834] Preparation Example 200a)
[1835]
[1836] 1-methyl-5- (2-pyridyl) -1H-3-pyrazolecarboxylic acid was obtained in the same manner as in Production Example 197a), b) and 198).
[1837] ¹ H-NMR (DMSO-d ₆ ) δ: 4.18 (s, 3H) 7.22 (s, 1H) 7.40 (t, J = 6.0 Hz, 1H) 7.85-7.94 (m, 2H) 8.68 (d, J = 4.0 Hz, 1H) 12.75 (s, 1H)
[1838] Example 200b)
[1839]
[1840] 2-isopropoxy-3-4-methoxy-3-[([1-methyl-5- (2-pyridyl) -1H-3-pyrazolyl) by the same method as in Example 19d) and e) ] Carbonylamino) methyl-1-phenylpropanoic acid was obtained.
[1841] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.5 Hz, 3H) 1.34 (d, J = 6.5 Hz, 3H) 2.90 (dd, J = 7.0, 14.0 Hz, 1H) 3.05 (dd, J = 4.5, 14.0 Hz, 1H) 3.55 (sept, J = 6.0 Hz, 1H) 3.87 (s, 3H) 4.09 (dd, J = 4.5, 7.0 Hz, 1H) 4.24 (s, 3H) 4.60 (d, J = 6.0 Hz, 2H) 6.81 (d, J = 8.0 Hz, 1H) 7.14 (m, 2H) 7.23 (m, 2H) 7.34 (bs, 1H) 7.64 (d, J = 8.0 Hz, 1H) 7.85 (bs, 1H ) 8.70 (d, J = 4.0 Hz, 1H)
[1842] Example 201
[1843] Preparation Example 20la)
[1844]
[1845] 1-Methyl-3- (2-pyridyl) -1H-5-pyrazolecarboxylic acid was obtained in the same manner as in Production Example 197a) -c).
[1846] ¹ H-NMR (DMSO-d ₆ ) δ: 4.13 (s, 3H) 7.26 (s, 1H) 7.32 (dd, J = 4.0, 8.0 Hz, 1H) 7.82 (t, J = 8.0 Hz, 1H) 7.91 ( d, J = 8.0 Hz, 1H) 8.57 (d, J = 4.0 Hz, 1H)
[1847] Example 20 lb)
[1848]
[1849] 2-isopropoxy-3-4-methoxy-3-[([1-methyl-3- (2-pyridyl) -1H-5-pyrazolyl) by the same method as in Example 19d) and e) ] Carbonylamino) methyl] phenylpropanoic acid was obtained.
[1850] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.5 Hz, 3H) 1.10 (d, J = 6.5 Hz, 3H) 2.75-3.00 (m, 2H) 3.57 (sept, J = 6.0 Hz, 1H ) 3.81 (s, 3H) 4.05 (dd, J = 4.5, 7.0 Hz, 1H) 4.21 (s, 3H) 4.52 (d, J = 6.0 Hz, 2H) 6.75 (d, J = 8.0 Hz, 1H) 7.08 ( m, 2H) 7.15 (bs, 1H) 7.45 (bs, 1H) 7.84 (s, 1H) 8.04 (t, J = 8.0 Hz, 1H) 8.24 (d, J = 8.0 Hz, 1H) 8.70 (d, J = 4.0 Hz, 1H)
[1851] Example 202
[1852] Preparation Example 202a)
[1853]
[1854] 2.33 ml of ethyl 2-chloroacetoacetic acid and 1.5 g of thiopropionamide were dissolved in 30 ml of ethanol, and the mixture was stirred at room temperature for 16 hours. The reaction solution was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 14: 1) to obtain 0.8 g of ethyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate.
[1855] ¹ H-NMR (CDCl ₃ ) δ: 1.34-1.60 (m, 6H) 2.98 (q, J = 8.0 Hz, 2H) 3.70 (s, 3H) 4.29 (q, J = 8.0 Hz, 2H)
[1856] Preparation Example 202 b)
[1857]
[1858] 0.8 g of ethyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml of ethanol, 2 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.8 g of 2-ethyl-5-methyl-1,3-thiazole-4-carboxylic acid.
[1859] ¹ H-NMR (CDCl ₃ ) δ: 1.40 (t, J = 8.0 Hz, 3H) 3.74 (s, 3H) 4.03 (q, J = 8.0 Hz, 2H)
[1860] Example 202c)
[1861]
[1862] 3- [3-([(2-ethyl-5-methyl-1,3-thiazol-4-yl) carbonyl] aminoethyl) -4-meth by the same method as in Example 19d) and e) Oxyphenyl] -2-isopropoxypropanoic acid was obtained.
[1863] ¹ H-NMR (CDCl ₃ ) δ: 0.98 (d, J = 6.5 Hz, 3H) 1.10 (d, J = 6.5 Hz, 3H) 1.30 (t, J = 8.0 Hz, 3H) 2.56 (s, 3H) 2.82 -3.01 (m, 4H) 3.51 (sept, J = 6.0 Hz, 1H) 3.80 (s, 3H) 4.04 (dd, J = 4.5, 7.0 Hz, 1H) 4.48 d, J = 6.0 Hz, 2H) 6.31 (bs , 1H) 6.75 (d, J = 8.0 Hz, 1H) 6.08 (dd, J = 2.0, 8.0 Hz, 1H) 7.13 (d, J = 2.0 Hz, 1H)
[1864] Example 203
[1865] Preparation Example 203a)
[1866]
[1867] 10 ml of ethyl 2-chloroacetoacetic acid and 10 g of thiobenzamide were dissolved in 100 ml of ethanol and heated to reflux for 4 hours. The reaction solution was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 14: 1) to obtain 17 g of ethyl 5-methyl-2-phenyl-1,3-thiazole-4-carboxylate.
[1868] ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J = 8.0 Hz, 3H) 2.78 (s, 3H) 4.35 (q, J = 8.0 Hz, 2H) 7.45 (m, 3H) 7.95 (m, 2H)
[1869] Preparation Example 203b)
[1870]
[1871] 0.8 g of ethyl 5-methyl-2-phenyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml of ethanol, 2 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.8 g of 5-methyl-2-phenyl-1,3-thiazole-4-carboxylic acid.
[1872] ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3H) 7.52 (m, 3H) 7.96 (m, 2H)
[1873] Example 203c)
[1874]
[1875] 2-isopropoxy-3- [4-methoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) by the same method as in Example 19d), e) ) Carbonyl] aminoethyl) phenyl] propanoic acid.
[1876] ¹ H-NMR (CDCl ₃ ) δ: 0.99 (d, J = 6.5 Hz, 3H) 1.10 (d, J = 6.5 Hz, 3H) 2.65 (s, 3H) 2.86 (dd, J = 7.0, 14.0 Hz, 1H ) 3.00 (dd, J = 4.5, 14.0 Hz, 1H) 3.52 (sept, J = 6.0 Hz, 1H) 3.82 (s, 3H) 4.05 (dd, J = 4.5, 7.0 Hz, 1H) 4.51 (d, J = 6.0 Hz, 2H) 6.42 (bs, 1H) 6.77 (d, J = 8.0 Hz, 1H) 7.09 (dd, J = 2.0, 8.0 Hz, 1H) 7.16 (d, J = 2.0 Hz, 1H) 7.37 (m, 3H) 7.85 (m, 2H)
[1877] Example 204
[1878] Example 204a)
[1879]
[1880] Example 1a of 3.1 g of N- (2,4-dichlorophenyl) -2- (5-formyl-2-methoxyphenyl) acetamide and 3.3 g of ethyl 2- (diethylphosphoryl) -2-ethyl acetate In the same manner as in the above), and 2.6 g of 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) phenyl) -2-propenoate Got.
[1881] ¹ H-NMR (CDCl ₃ ) δ: 1.26 (d, J = 6.0 Hz, 6H) 1.35 (t, J = 8.0 Hz, 3H) 3.75 (s, 2H) 3.94 (s, 3H) 4.27 (q, J = 8.0 Hz, 2H) 4.41 (sept, J = 6.0 Hz, 1H) 6.95 (m, 2H) 7.20 (d, J = 8.0 Hz, 1H) 7.30 (d, J = 8.0 Hz, 1H) 7.79 (d, J = 2.0 Hz, 1H) 7.85 (dd, J = 2.0, 8.0 Hz, 1H) 8.18 (bs, 1H) 8.38 (d, J = 8.0 Hz, 1H)
[1882] Example 204b)
[1883]
[1884] 2-ethyl-3- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) phenyl) -2-propenoate by the same method as in Example 196b) 0.3 g of ethyl 2- (4-methoxy-3- (2-oxo-2- [2,4-dichloroanilino] ethyl) penyl) butanoate was obtained from 2 g.
[1885] ¹ H-NMR (CDCl ₃ ) δ: 0.88 (d, J = 6.0 Hz, 3H) 1.06 (d, J = 6.0 Hz, 3H) 1.15 (t, J = 8.0 Hz, 3H) 2.85 (m, 2H) 3.43 (sept, J = 6.0 Hz, 1H) 3.65 (s, 3H) 3.82 (s, 3H) 3.94 (dd, J = 4.0, 8.0 Hz, 1H) 4.09 (q, J = 8.0 Hz, 2H) 6.80 (d, J = 8.0Hz, 1H) 7.13 (m, 3H) 7.23 (d, J = 8.0Hz, 1H) 8.22 (s, 1H) 8.28 (d, J = 8.0Hz, 1H)
[1886] Example 204c)
[1887]
[1888] 0.3 g of ethyl 2- (4-methoxy-3- (2-oxo-2- [2.4-dichloroanilino] ethyl) benzyl) butanoate was dissolved in 10 ml of ethanol, and 1 ml of 5N sodium hydroxide was added. After refluxing for 10 minutes, the mixture was acidified with 1N hydrochloric acid under ice cooling. The aqueous layer was extracted with ethyl acetate and washed with saturated brine. 2- (4-methoxy-3- (2-oxo-2- [4- (trifluoromethyl) anilino] ethyl) benzyl) butanoic acid by drying the organic layer with anhydrous magnesium sulfate and distilling off the solvent under reduced pressure 0.19 g was obtained.
[1889] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.0 Hz, 3H) 1.08 (d, J = 6.0 Hz, 3H) 2.86 (dd, J = 7.0, 14.0 Hz, 1H) 3.00 (dd, J = 4.5, 14.0 Hz, 1H) 3.49 (sept, J = 6.0 Hz, 1H) 3.67 (s, 3H) 3.84 (s, 3H) 4.04 (dd, J = 4.5, 7.0 Hz, 1H) 6.82 (d, J = 8.0 Hz, 1H) 7.12 (m, 3H) 7.23 (d, J = 8.0 Hz, 1H) 8.20 (s, 1H) 8.28 (d, J = 8.0 Hz, 1H)
[1890] Example 205
[1891] Preparation Example 205a)
[1892]
[1893] 5- (2-chlorophenyl) -4-isoxazole carboxylic acid was obtained by the same method as in Preparation Example 199.
[1894] ¹ H-NMR (CDCl ₃ ) δ: 7.40 (s, 1H) 7.43 (m, 2H) 7.56 (m, 1H) 8.00 (dd, J = 2.0, 8.0 Hz, 1H)
[1895] Example 205b)
[1896]
[1897] Example 19d), 3-3-[([5- (2-chlorophenyl) -3-isoxazolyl] carbonylamino) methyl] -4-methoxyphenyl-2-iso by the same method as in Propoxypropanoic acid was obtained.
[1898] ¹ H-NMR (CDCl ₃ ) δ: 0.98 (d, J = 6.0 Hz, 3H) 1.09 (d, J = 6.0 Hz, 3H) 2.84 (dd, J = 7.0, 14.0 Hz, 1H) 3.00 (dd, J = 4.5, 14.0 Hz, 1H) 3.50 (sept, J = 6.0 Hz, 1H) 3.81 (s, 3H) 4.05 (dd, J = 4.5, 7.0 Hz, 1H) 4.46 (d, J = 7.0 Hz, 2H) 6.76 (d, J = 8.0 Hz, 1H) 7.08 (dd, J = 2.0, 8.0 Hz, 1H) 7.16 (d, J = 2.0 Hz, 1H) 7.29-7.35 (m, 2H) 7.46 (dd, J = 4.0, 7.5 Hz, 1H) 7.85 (dd, J = 4.0, 7.5 Hz, 1H)
[1899] Example 206
[1900] Preparation Example 206a)
[1901] 2 ml of ethyl 2,4-dioxo valerate and 1.2 g of phenylhydrazine were dissolved in 20 ml of acetic acid, and the mixture was stirred at 100 ° C for 2 hours. The acetic acid was distilled off under reduced pressure, ethyl acetate was added to the residue, washed with sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was treated by silica gel column chromatography, hexane: ethyl acetate 14: 1, 0.37 g of ethyl 3-methyl-1-phenyl-1H-5-pyrazolecarboxylate, hexane: ethyl acetate 9: 1 ethyl 5- 0.46 g of methyl-1-phenyl-1H-3-pyrazolecarboxylate was obtained.
[1902]
[1903] Ethyl 3-methyl-1-phenyl-1H-5-pyrazolecarboxylate
[1904] ¹ H-NMR (CDCl ₃ ) δ: 1.22 (t, J = 8.0 Hz, 3H) 2.35 (s, 3H) 4.22 (q, J = 8.0 Hz, 2H) 6.80 (s, 1H) 7.42 (m, 5H)
[1905]
[1906] Ethyl 5-methyl-1-phenyl-1H-3-pyrazolecarboxylate
[1907] ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J = 8.0 Hz, 3H) 2.34 (s, 3H) 4.41 (q, J = 8.0 Hz, 2H) 6.74 (s, 1H) 7.40-7.50 (m, 5H)
[1908] Preparation Example 206b)
[1909]
[1910] 0.37 g of ethyl 3-methyl-1-phenyl-1H-5-pyrazolecarboxylate was dissolved in 10 ml of ethanol, 1 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.26 g of 3-methyl-1-phenyl-1H-5-pyrazolecarboxylic acid.
[1911] ¹ H-NMR (CDCl ₃ ) δ: 2.35 (s, 3H) 6.87 (s, 1H) 7.40 (m, 5H)
[1912] Example 206
[1913]
[1914] 2-isopropoxy-3- [4-methoxy-3-([(3-methyl-1-phenyl-1H-5-pyrazolyl) carbonyl] amino by the same method as Example 19d), e) Ethyl) phenyl] propanoic acid was obtained.
[1915] ¹ H-NMR (CDCl ₃ ) δ: 0.98 (d, J = 6.0 Hz, 3H) 1.09 (d, J = 6.0 Hz, 3H) 2.62 (s, 3H) 2.84 (dd, J = 7.0, 14.0 Hz, 1H ) 2.96 (dd, J = 4.5, 14.0 Hz, 1H) 3.51 (sept, J = 6.0 Hz, 1H) 3.64 (s, 3H) 4.03 (dd, J = 4.5, 7.0 Hz, 1H) 4.38 (d, J = 7.0 Hz, 2H) 6.23 (bs, 1H) 6.67 (d, J = 8.0 Hz, 1H) 7.05-7.08 (m, 2H) 7.24-7.32 (m, 5H)
[1916] Example 207
[1917] Preparation Example 207a)
[1918]
[1919] 5-Methyl-1-phenyl-1H-3-pyrazolecarboxylic acid was obtained by the same method as in Production Example 206b).
[1920] ¹ H-NMR (CDCl ₃ ) δ: 2.35 (s, 3H) 6.79 (s, 1H) 7.42-7.52 (m, 5H)
[1921] Example 207b)
[1922]
[1923] 2-isopropoxy-3- [4-methoxy-3-([(5-methyl-1-phenyl-1H-3-pyrazolyl) carbonyl] amino by the same method as Example 19d), e) Ethyl) phenyl] propanoic acid was obtained.
[1924] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.09 (d, J = 6.0 Hz, 3H) 2.60 (s, 3H) 2.82 (dd, J = 7.0, 14.0 Hz, 1H ) 2.97 (dd, J = 4.5, 14.0 Hz, 1H) 3.47 (sept, J = 6.0 Hz, 1H) 3.76 (s, 3H) 4.01 (dd, J = 4.5, 7.0 Hz, 1H) 4.51 (d, J = 7.0 Hz, 2H) 6.67 (s, 1H) 6.71 (d, J = 8.0 Hz, 1H) 7.04 (dd, J = 8.0, 2.0 Hz, 1H) 7.15 (d, J = 2.0 Hz, 1H) 7.27 (bs, 1H) 7.35-7.38 (m, 3H) 7.41-7.46 (m, 2H)
[1925] Example 208
[1926] Example 208a)
[1927]
[1928] N1- (5-[(2.4-dioxo-1,3-thiazolan-5-ylidene) methyl] -2-methoxybenzyl) -2-fluoro by the same method as in Example 28a) -c) Rho-4-chlorobenzamide was obtained.
[1929] ¹ H-NMR (DMSO-d ₆ ) δ: 3.74 (s, 2H) 3.85 (s, 3H) 7.12 (d, J = 8.0 Hz, 1H) 7.23 (d, J = 8.0 Hz, 1H) 7.44 (bs, 1H) 7.50 (t, J = 8.0 Hz, 1H) 7.66 (s, 1H) 7.90 t, J = 8.0 Hz, 1H 9.98 (s, 1H)
[1930] Example 208b)
[1931]
[1932] 0.3 g of N1- (5-[(2,4-dioxo-1,3-thiazolan-5-ylidene) methyl] -2-methoxybenzyl) -2-fluoro-4-chlorobenzamide It was dissolved in 20 ml and 20 mg of iodine was added. While heating the reaction solution under reflux, 400 mg of magnesium was added for 10 minutes. The reaction solution was ice-cooled, acidified with 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropylethyl was added to the residue, and the crystals were filtered to give N1- (4-chloro-2-fluorophenyl) -2-2-methoxy-5-[(2-methylene-4-oxo-1,3- 80 mg of thiazolan-5-yl) methyl-1-phenylacetamide was obtained.
[1933] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 10.0, 14.0 Hz, 1H) 3.27 (m, 1H) 3.65 (s, 2H) 3.73 (s, 3H) 4.81 (m, 1H) 6.91 (d, J = 8.0 Hz, 1H) 7.08-7.11 (m, 2H) 7.22 (m, 1H) 7.47 (m, 1H) 7.89 (m, 1H) 9.84 (s, 1H)
[1934] Example 209
[1935] Preparation Example 209a)
[1936]
[1937] 5-Methyl-2- (3-pyridyl) -1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 203.
[1938] ¹ H-NMR (CDCl ₃ ) δ: 2.67 (s, 3H) 7.54 (dd, J = 4.0, 8.0 Hz, 1H) 8.31 (d, J = 8.0 Hz, 1H) 8.70 (d, J = 4.0 Hz, 1H ) 9.51 (s, 1H)
[1939] Example 209b)
[1940]
[1941] 2-isopropoxy-3-4-methoxy-3-[([5-methyl-2- (3-pyridyl) -1,3-thiazole- in the same manner as in Example 19d) and e) 4-yl] carbonylamino) methyl-1-phenylpropanoic acid was obtained.
[1942] ¹ H-NMR (CDCl ₃ ) δ: 1.01 (d, J = 6.0 Hz, 3H) 1.11 (d, J = 6.0 Hz, 3H) 2.66 (s, 3H) 2.87 (dd, J = 7.0, 14.0 Hz, 1H ) 2.99 (dd, J = 4.5, 14.0 Hz, 1H) 3.55 (sept, J = 6.0 Hz, 1H) 3.83 (s, 3H) 4.06 (dd, J = 4.5, 7.0 Hz, 1H) 4.52 (d, J = 7.0 Hz, 2H) 6.59 (bs, 1H) 6.78 (d, J = 8.0 Hz, 1H) 6.91 (s, 1H) 7.09-7.26 (m, 2H) 7.40 (m, 1H) 7.60 (m, 1H) 8.56 ( d, J = 7.0 Hz, 1H)
[1943] Example 210
[1944] Preparation Example 210a)
[1945]
[1946] 3.7 g of 1-methyl-3-phenylimidazole was dissolved in tetrahydrofuran, and 18.7 ml of n-butyllithium (1.5 mol / L hexane solution) was added dropwise under cooling at -50 ° C. The reaction temperature was raised to -20 deg. C and then cooled to -50 deg. After adding 3.6 ml of N, N-dimethylformamide, the cooling device was removed, and the reaction temperature was raised to room temperature. An ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 1.9 g of 1-methyl-5-phenyl-IH-2-imidazolecarboxyaldehyde.
[1947] ¹ H-NMR (DMSO-d ₆ ) δ: 3.98 (s, 3H) 7.28 (t, J = 8.0Hz, 1H) 7.40 (t, J = 8.0Hz, 2H) 8.82 (d, J = 8.0Hz, 2H ) 8.10 (s, 1H) 9.75 (s, 1H)
[1948] Preparation Example 210b)
[1949]
[1950] 1 g of I-methyl-5-phenyl-1 H-2-imidazole carboxyaldehyde was dissolved in 15 ml of dimethyl sulfoxide, and 3 ml of potassium hydrogen phosphate (1 mol / l) was added. An aqueous solution of 1.5 g of sodium chlorite was added, and stirred at room temperature for 20 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 1: 4 → ethyl acetate: methanol = 3: 1), and 90 mg of 1-methyl-5-phenyl-1H-2-imidazolecarboxylic acid Got.
[1951] ¹ H-NMR (DMSO-d ₆ ) δ: 4.00 (s, 3H) 7.26 (t, J = 8.0 Hz, 1H) 7.42 (t, J = 8.0 Hz, 2H) 7.75 (s, 1H) 8.82 (d, J = 8.0Hz, 2H)
[1952] Example 210c)
[1953]
[1954] 2-isopropoxy-3- [4-methoxy-3-([(1-methyl-5-phenyl-1H-2-imidazolyl) carbonyl] by the same method as in Example 19d), e) Aminoethyl) phenyl] propanoic acid was obtained.
[1955] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.06 (d, J = 6.0 Hz, 3H) 2.84 (dd, J = 7.0, 14.0 Hz, 1H) 2.97 (dd, J = 4.5, 14.0 Hz, 1H) 3.48 (sept, J = 6.0 Hz, 1H) 3.81 (s, 3H) 4.02 (m, 1H) 4.03 (s, 3H) 4.52 (d, J = 7.0 Hz, 2H) 6.75 ( d, J = 8.0Hz, 1H) 6.91 (s, 1H) 7.06 (dd, J = 2.0, 8.0Hz, 1H) 7.16 (m, 2H) 7.21 (m, 1H) 7.31 (t, J = 7.5Hz, 2H ) 7.68 (d, J = 7.5 Hz, 2H)
[1956] Example 211
[1957]
[1958] N1- (2,4-dichlorophenyl) -2-2-methoxy-5-[(2-methylene-4-oxo-1) by the same method as Example 28a) -c), 208a) and b) , 3-thiazolan-5-yl) methyl-1-phenylacetamide was obtained.
[1959] ¹ H-NMR (DMSO-d ₆ ) δ: 3.00 (dd, J = 10.0, 14.0 Hz, 1H) 3.32 (m, 1H) 3.65 (s, 2H) 3.76 (s, 3H) 4.82 (dd, J = 4.5 , 10.0 Hz, 1H) 6.93 (d, J = 8.0 Hz, 1H) 7.11 (m, 2H) 7.38 (dd, J = 2.5, 8.0 Hz, 1H) 7.64 (d, J = 2.5 Hz, 1H) 7.80 (d , J = 8.0 Hz, 1H) 9.42 (s, 1H)
[1960] Example 212
[1961] Preparation Example 212a)
[1962]
[1963] 2- (2-ethyl 4-pyridyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 203.
[1964] ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (t, J = 8.0 Hz, 3H) 2.69 (s, 3H) 2.83 (q, J = 8.0 Hz, 2H) 7.70 (d, J = 6.0 Hz, 1H ) 7.78 (s, 1H) 8.60 (d, J = 6.0Hz, 1H)
[1965] Example 212b)
[1966]
[1967] Example 19d), e) 3-3-[([2- (2-ethyl-4-pyridyl-5-methyl-1,3-thiazol-4-yl] carbonylamino) Methyl] -4-methoxyphenyl-2-isopropoxypropanoic acid was obtained.
[1968] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.18 (d, J = 6.0 Hz, 3H) 1.37 (d, J = 7.5 Hz, 3H) 2.72 (s, 3H) 2.94 (m, 3H) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.61 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.12 (dd, J = 4.5, 7.0 Hz, 1H) 4.59 ( d, J = 7.0Hz, 2H) 6.55 (bs, 1H) 6.84 (d, J = 7.0Hz, 1H) 7.18 (d, J = 7.0Hz, 1H) 7.22 (s, 1H) 7.63 (m, 1H) 7.72 (s, 1H) 8.62 (d, J = 5.0 Hz, 1H)
[1969] Example 213
[1970] Preparation Example 213a)
[1971]
[1972] 6.7 g of benzamide oxime and 5 ml of ethyl propioate were dissolved in methanol and heated to reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and ethyl (Z) -3-([(Z) -1-amino-1-phenylmethylidine] 4.5 g of aminooxy) -2-propenoate was obtained.
[1973] ¹ H-NMR (CDCl ₃ ) δ: 1.30 (t, J = 8.0 Hz, 3H) 4.17 (q, J = 8.0 Hz, 2H) 4.90 (d, J = 6.0 Hz, 1H) 5.25 (bs, 2H) 7.38 (d, J = 6.0 Hz, 1H) 7.40-7.50 (m, 3H) 7.65 (m, 2H)
[1974] Preparation Example 213b)
[1975]
[1976] 4.5 g of (Z) -3-([(Z) -1-amino-1-phenylmethylidine] aminooxy) -2-propenoate was dissolved in 30 ml of diphenylethyl and heated at 200 ° C. for 5 hours. Hexane was added to the reaction mixture, and the solid was filtered. The residue was purified by silica gel column chromatography to obtain hexane: ethyl acetate = 1: 1 → dichloromethane: methanol = 50: 1) and 3.5 g of ethyl 2-phenyl-1H-5-imidazole carboxylate.
[1977] ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J = 8.0 Hz, 3H) 4.38 (q, J = 8.0 Hz, 2H) 7.43 (m, 3H) 7.78 (s, 1H) 7.90 (m, 2H)
[1978] Preparation Example 213c)
[1979] 3.5 g of ethyl 2-phenyl-1H-5-imidazole carboxylate was dissolved in 30 ml of N, N-dimethylformamide, 0.71 g of sodium hydride was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled again, 1.5 ml of methyl iodide was added, and the mixture was stirred at room temperature for 30 minutes. Water and ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and hexane: ethyl acetate = 8: 1, 0.6 g of ethyl 1 -methyl-2-phenyl-1H-4-imidazole carboxylate, and hexane: ethyl acetate = 1: 1 2.2 g of ethyl 1-methyl-2-phenyl-1H-5-imidazolecarboxylate were obtained.
[1980]
[1981] Ethyl 1-methyl-2-phenyl-1H-4-imidazolecarboxylate
[1982] ¹ H-NMR (CDCl ₃ ) δ: 1.37 (t, J = 8.0 Hz, 3H) 3.94 (s, 3H) 4.34 (q, J = 8.0 Hz, 2H) 7.46 (m, 3H) 7.60 (m, 2H) 7.83 (s, 1 H)
[1983]
[1984] Ethyl 1-methyl-2-phenyl-1H-5-imidazolecarboxylate
[1985] ¹ H-NMR (CDCl ₃ ) δ: 1.39 (t, J = 8.0 Hz, 3H) 3.77 (s, 3H) 4.39 (q, J = 8.0 Hz, 2H) 7.45 (m, 3H) 7.64 (m, 2H) 7.68 (s, 1 H)
[1986] Preparation Example 213d)
[1987]
[1988] 2.2 g of ethyl 1-methyl-2-phenyl-1H-5-imidazole carboxylate was dissolved in 20 ml of ethanol, 2 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 1.1 g of 1-methyl-2-phenyl-1H-5-imidazolecarboxylic acid.
[1989] ¹ H-NMR (CDCl ₃ ) δ: 3.77 (s, 3H) 7.52 (m, 3H) 7.71 (m, 2H) 8.06 (s, 1H)
[1990] Example 213e)
[1991]
[1992] 2-isopropoxy-3- [4-methoxy-3-([(1-methyl-2-phenyl-1H-5-imidazolyl) carbonyl] by the same method as in Example 19d), e) Aminoethyl) phenyl) propanoic acid was obtained.
[1993] ¹ H-NMR (CDCl ₃ ) δ: 0.82 (d, J = 6.0 Hz, 3H) 0.97 (d, J = 6.0 Hz, 3H) 2.66 (dd, J = 7.0, 14.0 Hz, 1H) 2.79 (dd, J = 4.5, 14.0 Hz, 1H) 3.41 (sept, J = 6.0 Hz, 1H) 3.76 (s, 3H) 3.78 (s, 3H) 3.91 (dd, J = 4.5, 7.0 Hz, 1H) 4.37 (d, J = 7.0 Hz, 2H) 6.87 (d, J = 8.0 Hz, 1H) 7.05-7.08 (m, 2H) 7.46-7.53 (m, 3H) 7.72 (d, J = 6.5 Hz, 1H) 7.82 (s, 1H) 8.13 (bs, 1 H)
[1994] Example 214
[1995] Preparation Example 214a)
[1996]
[1997] 0.6 g of ethyl 1-methyl-2-phenyl-1H-4-imidazole carboxylate was dissolved in 10 ml of ethanol, 1 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and then the organic layer extracted with ethyl acetate and tetrahydrofuran was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure. 0.5 g of imidazole carboxylic acid was obtained.
[1998] 1 H-NMR (CDCl ₃ ) δ: 3.86 (s, 3H) 7.52 (m, 3H) 7.68 (m, 2H) 7.83 (s, 1H)
[1999] Example 214b)
[2000]
[2001] 2-isopropoxy-3- [4-methoxy-3-([(1-methyl-2-phenyl-1H-4-imidazolyl) carbonyl] by the same method as in Example 19d), e) Aminoethyl) phenyl) propanoic acid was obtained.
[2002] ¹ H-NMR (CDCl ₃ ) δ: 0.84 (d, J = 6.0 Hz, 3H) 0.99 (d, J = 6.0 Hz, 3H) 2.70 (dd, J = 7.0, 14.0 Hz, 1H) 2.84 (dd, J = 4.5, 14.0 Hz, 1H) 3.44 (sept, J = 6.0 Hz, 1H) 3.79 (s, 3H) 3.90 (s, 3H) 3.96 (dd, J = 4.5, 7.0 Hz, 1H) 4.40 (d, J = 7.0 Hz, 2H) 6.90 (d, J = 8.0 Hz, 1H) 7.11 (m, 2H) 7.56-7.64 (m, 3H) 7.70-7.76 (m, 1H) 8.10 (s, 1H) 8.97 (bs, 1H)
[2003] Example 215
[2004] Preparation Example 215a)
[2005]
[2006] 2- (2-chlorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2007] ¹ H-NMR (DMSO-d ₆ ) δ: 2.68 (s, 3H) 7.48-7.55 (m, 2H) 7.65 (d, J = 8.0Hz, 1H) 8.24 (dd, J = 2.0, 8.0Hz, 1H) 13.50 (bs, 1 H)
[2008] Example 2 I5b)
[2009]
[2010] 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxy by the same method as in Example 38 Phenyl-2-isopropoxycarboxylic acid was obtained.
[2011] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.74 (s, 3H) 2.93 (dd, J = 7.0, 14.0 Hz, 1H ) 3.07 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.13 (dd, J = 4.5, 7.0 Hz, 1H) 4.59 (d, J = 7.0 Hz, 2H) 6.84 (d, J = 8.0 Hz, 1H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.23 (d, J = 2.0 Hz, 1H) 7.35-7.38 (m, 2H) 7.48- 7.51 (m, 1H) 8.23-8.26 (m, 1H)
[2012] Example 216
[2013] Preparation Example 216a)
[2014]
[2015] 2- (4-Chlorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2016] ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3H) 7.56 (d, J = 8.0 Hz, 2H) 7.98 (d, J = 8.0 Hz, 2H)
[2017] Example 216b)
[2018]
[2019] 3-3-[([2- (4-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxy by the same method as in Example 38 Phenyl-2-isopropoxycarboxylic acid was obtained.
[2020] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.70 (s, 3H) 2.93 (dd, J = 7.0, 14.0 Hz, 1H ) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.90 (s, 3H) 4.13 (dd, J = 4.5, 7.0 Hz, 1H) 4.58 (d, J = 7.0 Hz, 2H) 6.52 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.41 (d, J = 9.0 Hz, 2H) 7.86 (d, J = 9.0Hz, 2H)
[2021] Example 217
[2022] Preparation Example 217a)
[2023]
[2024] 5-Methyl-2- (2-thienyl) -1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2025] ¹ H-NMR (DMSO-d ₆ ) δ: 2.60 (s, 3H) 7.08 (dd, J = 4.0, 5.0 Hz, 1H) 7.77 (d, J = 8.0 Hz, 1H) 7.80 (d, J = 5.0 Hz , 1H) 38 (bs, 1H)
[2026] Example 217b)
[2027]
[2028] 2-isopropoxy-3-4-methoxy-3-[([5-methyl-2- (2-thienyl) -1,3-thiazol-4-yl] by the same method as in Example 38. Carbonylamino) methyl-1-phenylpropanoic acid was obtained.
[2029] ¹ H-NMR (CDCl ₃ ) δ: 1.05 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.67 (s, 3H) 2.93 (dd, J = 7.0,14.0 Hz, 1H ) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.11 (dd, J = 4.5, 7.0 Hz, 1H) 4.57 (d, J = 7.0 Hz, 2H) 6.49 (bs, 1H) 6.83 (d, J = 8.0 Hz, 1H) 7.08 (dd, J = 4.0, 5.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 ( d, J = 2.0 Hz, 1H) 7.43 (dd, J = 1.0, 5.0 Hz, 1H) 7.52 (dd, J = 1.0, 4.0 Hz, 1H)
[2030] Example 218
[2031] Preparation Example 218a)
[2032]
[2033] 20.6 g of (±) -Z-α-phosphonoglycine trimethyl ester was dissolved in 200 ml of dichloromethane, and 8.9 ml of 1,8-diazabicyclo [5.4.0] -7-undecene was added. The reaction solution was stirred at room temperature for 15 minutes, tert-butyl-N- (5-formyl-2-methoxybenzyl) carbamate was dissolved in 50 ml of dichloromethane, and stirred at room temperature for 16 hours. The reaction solution was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give methyl (Z) -2-[(benzyloxy) carbonyl] amino-3- (3-[(tert-butoxycarbonyl 21 g of) amino] methyl-4-methoxyphenyl) -2-propenoate was obtained.
[2034] ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9H) 3.80 (s, 3H) 3.86 (s, 3H) 4.25 (s, 2H) 4.90 (bs, 1H) 5.13 (s, 2H) 6.78 (d, J = 8.0 Hz, 1H) 7.35 (m, 5H) 7.42 (m, 1H) 7.49 (m, 1H)
[2035] Preparation Example 218b)
[2036]
[2037] Methyl (Z) -2-[(benzyloxy) carbonyl] amino-3- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxyphenyl) -2-propenoate It dissolved in, 0.7 g of 10% palladium carbon was added, and it stirred for 16 hours in hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) methyl-2-amino-3- (3-[(tert-butoxycarbonyl) amino] methyl-4- 3.4 g of methoxyphenyl) propanoate were obtained.
[2038] ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H) 2.80 (dd, J = 7.0,14.0 Hz, 1H) 3.69 (dd, J = 4.5,14.0 Hz, 1H) 3.72 (s, 3H) 3.82 ( s, 3H) 4.27 (d, J = 6.0 Hz, 2H) 5.00 (bs, 1H) 6.79 (d, J = 8.0 Hz, 1H) 7.06 (m, 2H)
[2039] Preparation Example 218c)
[2040]
[2041] 3.4 g of methyl 2-amino-3- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxyphenyl) propanoate was dissolved in 30 ml of chloroform, 1.7 ml of acetic acid and 1.35 of isoamyl nitrite. ml was added, and it stirred at 60 degreeC for 20 minutes. The reaction solution was ice-cooled, water was added, and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1), and 1- [1- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxybenzyl) -2- 2.5 g of methoxy-2-oxoethyl] -1-diazine-1-ium were obtained.
[2042] ¹ H-NMR (CDCl ₃ ) δ: 1.43 (s, 9H) 3.78 (s, 3H) 3.82 (s, 3H) 4.27 (d, J = 6.0 Hz, 1H) 5.00 (bs, 1H) 6.79 (d, J = 8.0 Hz, 1H) 7.11 (m, 2H)
[2043] Example 218d)
[2044]
[2045] 2 g of 1- [1- (3-[(tert-butoxycarbonyl) amino] methyl-4-methoxybenzyl) -2-methoxy-2-oxoethyl] -1-diazine-1-ium n Dissolve in 30 ml of propanol and add 25 mg of rhodium (II) acetate. After stirring for 1 hour at room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1). By treating the obtained product in the same manner as in Example 38, 3- [3-[(2,4-dichlorobenzoyl) amino] methyl-4-methoxyphenyl) -2-propoxypropanoic acid was obtained.
[2046] ¹ H-NMR (CDCl ₃ ) δ: 0.87 (d, J = 8.0 Hz, 3H) 1.58 (q, J = 8.0 Hz, 2H) 2.97 (dd, J = 7.0, 14.0 Hz, 1H) 3.09 (dd, J = 4.5, 14.0 Hz, 1H) 3.38 (m, 1H) 3.52 (m, 1H) 3.85 (s, 3H) 4.07 (dd, J = 4.5, 7.0 Hz, 1H) 4.60 (d, J = 7.0 Hz, 2H) 6.82 (m, 2H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.30 (dd, J = 2.0, 8.0 Hz, 1H) 7.40 (d, J = 2.0 Hz, 1H) 7.40 (d, J = 2.0 Hz, 1H) 7.65 (d, J = 8.0 Hz, 1H)
[2047] Example 219
[2048] Preparation Example 219a)
[2049]
[2050] 2- (4-methylphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2051] ¹ H-NMR (CDCl ₃ ) δ: 2.40 (s, 3H) 2.77 (s, 3H) 7.25 (d, J = 8.0 Hz, 2H) 7.85 (d, J = 8.0 Hz, 2H)
[2052] Example 219b)
[2053]
[2054] 3-3-[([2- (4-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl by the same method as in Example 38. 2-isopropoxycarboxylic acid was obtained.
[2055] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.40 (s, 3H) 2.70 (s, 3H) 2.93 (dd, J = 7.0, 14.0 Hz, 1H) 3.07 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.13 (dd, J = 4.5, 7.0 Hz, 1H) 4.58 (d, J = 7.0 Hz, 2H) 6.49 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.24 (d, J = 8.0 Hz, 2H) 7.81 (d, J = 8.0 Hz, 2H)
[2056] Example 220
[2057] Preparation Example 220a)
[2058]
[2059] 2- (3-chloro4-fluorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2060] ¹ H-NMR (CDCl ₃ ) δ: 2.80 (s, 3H) 7.23 (d, J = 8.0 Hz, 1H) 7.84 (m, 1H) 8.09 (dd, J = 2.0, 8.0 Hz, 1H)
[2061] Example 220b)
[2062]
[2063] 3-3-[([2- (3-chloro4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2064] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.18 (d, J = 6.0 Hz, 3H) 2.70 (s, 3H) 2.94 (dd, J = 7.0, 14.0 Hz, 1H ) 3.07 (dd, J = 4.5, 14.0 Hz, 1H) 3.61 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.13 (dd, J = 4.5, 7.0 Hz, 1H) 4.58 (d, J = 7.0 Hz, 2H) 6.52 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.21-7.23 (m, 2H) 7.76-7.80 (m, 1H ) 8.02 (dd, J = 2.0, 8.0 Hz, 1H)
[2065] Example 221
[2066] Preparation Example 221a)
[2067]
[2068] 2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2069] ¹ H-NMR (DMSO-d ₆ ) δ: 2.67 (s, 3H) 7.60 (dd, J = 2.0, 8.0 Hz, 1H) 7.86 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 8.0 Hz , 1H)
[2070] Example 221b)
[2071]
[2072] 3-3-[([2- (2,4-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- by the same method as in Example 38 Methoxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2073] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.72 (s, 3H) 2.94 (dd, J = 7.0, 14.0 Hz, 1H ) 3.07 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.13 (dd, J = 4.5, 7.0 Hz, 1H) 4.59 (d, J = 7.0 Hz, 2H) 6.52 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.33 (d, J = 2.0 Hz, 1H) 7.36 (dd, J = 2.0, 8.0Hz, 1H) 7.51 (d, J = 2.0Hz, 1H) 8.24 (d, J = 8.0Hz, 1H)
[2074] Example 222
[2075] Preparation Example 222a)
[2076]
[2077] 2- (2-methylphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2078] ¹ H-NMR (CDCl ₃ ) δ: 2.61 (s, 3H) 2.82 (s, 3H), 7.27-7.33 (m, 2H) 7.37 (d, J = 8.0Hz, 1H) 7.80 (d, J = 8.0Hz , 1H)
[2079] Example 222b)
[2080]
[2081] 3-3-[([2- (2-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl by the same method as in Example 38 2-isopropoxycarboxylic acid was obtained.
[2082] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.57 (s, 3H) 2.72 (s, 3H) 2.94 (dd, J = 7.0, 14.0 Hz, 1H) 3.07 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.12 (dd, J = 4.5, 7.0 Hz, 1H) 4.59 (d, J = 7.0 Hz, 2H) 6.51 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.16 (dd, J = 2.0, 8.0 Hz, 1H) 7.24 (d, J = 2.0 Hz, 1H) 7.26-7.38 (m, 3H) 7.70 (dd, J = 2.0, 8.0 Hz, 1H)
[2083] Example 223
[2084] Preparation Example 223a)
[2085]
[2086] 2- (4-methoxyphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2087] ¹ H-NMR (DMSO-d ₆ ) δ: 2.63 (s, 3H) 3.80 (s, 3H) 7.04 (d, J = 8.0 Hz, 2H) 7.90 (d, J = 8.0 Hz, 2H)
[2088] Example 223b)
[2089]
[2090] 3-3-[([2- (4-methoxyphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylaminomethyl] -4-methoxy by the same method as in Example 38 Phenyl-2-isopropoxycarboxylic acid was obtained.
[2091] ¹ H-NMR (CDCl ₃ ) δ: 1.05 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.69 (s, 3H) 2.93 (dd, J = 7.0, 14.0 Hz, 1H ) 3.05 (dd, J = 4.5, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.86 (s, 3H) 3.89 (s, 3H) 4.12 (dd, J = 4.5, 7.0 Hz, 1H) 4.58 (d, J = 7.0 Hz, 2H) 6.49 (bs, 1H) 6.83 (d, J = 8.0 Hz, 1H) 6.94 (d, J = 8.0 Hz, 2H) 7.17 (dd, J = 2.0, 8.0 Hz , 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.86 (d, J = 8.0 Hz, 2H)
[2092] Example 224
[2093] Preparation Example 224a)
[2094]
[2095] 2- (3-methylphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2096] ¹ H-NMR (CDCl ₃ ) δ: 2.42 (s, 3H) 2.81 (s, 3H) 7.32 (m, 2H) 7.76 (dd, J = 2.0, 8.0 Hz, 1H) 7.82 (d, J = 2.0 Hz, 1H)
[2097] Example 224b)
[2098]
[2099] 3-3-[([2- (3methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl- by the same method as in Example 38. 2-isopropoxycarboxylic acid was obtained.
[2100] ¹ H-NMR (CDCl ₃ ) δ: 1.07 (d, J = 6.0 Hz, 3H) 1.17 (d, J = 6.0 Hz, 3H) 2.41 (s, 3H) 2.71 (s, 3H) 2.93 (dd, J = 7.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.5, 14.0 Hz, 1H) 3.60 (sept, J = 6.0 Hz, 1H) 3.89 (s, 3H) 4.12 (dd, J = 4.5, 7.0 Hz, 1H) 4.58 (d, J = 7.0 Hz, 2H) 6.49 (bs, 1H) 6.84 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.23 (d, J = 2.0 Hz, 1H) 7.25-7.34 (m, 2H) 7.70 (d, J = 8.0 Hz, 2H) 7.76 (bs, 1H)
[2101] Example 225
[2102] Preparation Example 225a)
[2103]
[2104] 2- (4-fluorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2105] ¹ H-NMR (CDCl ₃ ) δ: 2.85 (s, 3H) 7.16 (t, J = 8.0 Hz, 1H) 7.87 (t, J = 8.0 Hz, 1H)
[2106] Example 225b)
[2107]
[2108] 3-3-[([2- (4-fluorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-meth by the same method as in Example 38 The oxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2109] MS m / e (ESI) (MH ⁺ ) 487
[2110] Example 226
[2111] Preparation Example 226a)
[2112]
[2113] 20 g of methyl dichloroacetate and 8 g of acetaldehyde were dissolved in 50 ml of anhydrous diethyl ether, and 25 g of 28% sodium methylate was added dropwise under ice cooling. The reaction solution was stirred for 2 hours under ice cooling, followed by addition of water and saturated brine, and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in 60 ml of methanol, 8.5 g of thiourea was added, and the mixture was heated to reflux for 4 hours. The reaction solution was ice-cooled, water and ammonia water were added to pH 9, dichloromethane was added, and the mixture was extracted. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-&gt; l: 1), and methyl-2-amino-5-methyl-1, 2.8 g of 3-thiazole-4-carboxylate was obtained.
[2114] ¹ H-NMR (CDCl ₃ ) δ: 2.61 (s, 3H) 3.88 (s, 3H) 5.02 (bs, 2H)
[2115] Preparation Example 226b)
[2116]
[2117] 2.8 g of methyl-2-amino-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 30 ml of methanol and 7 ml of hydrobromic acid, and an aqueous solution of 1.2 g of sodium nitrite was added dropwise under ice cooling. The reaction solution was stirred for 30 minutes under ice-cooling, then added to 1.3 g of cuprous bromide hydrobromic acid 7 g solution previously heated to 60 ° C., and stirred at 60 ° C. for 1 hour. The reaction solution was ice-cooled, water was added, and the mixture was extracted with diethyl ether. The organic layer was extracted with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.47 g of methyl-2-bromo-5-methyl-1,3-thiazole-4-carboxylate.
[2118] ¹ H-NMR (CDCl ₃ ) δ: 2.74 (s, 3H) 3.93 (s, 3H)
[2119] Preparation Example 226c)
[2120]
[2121] 0.3 g of methyl-2-bromo-5-methyl-1,3-thiazole-4-carboxylate and 0.29 of 3-chlorophenylboronic acid are dissolved in toluene, 0.15 g of tetrakistriphenylphosphinepalladium and carbonic acid 0.7 g of potassium was added. The reaction solution was heated to reflux for 4 hours under a nitrogen atmosphere. The reaction solution was cooled, filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.2 g of methyl-2- (3-methylphenyl])-5-methyl-1,3-thiazole-4-carboxylate.
[2122] ¹ H-NMR (CDCl ₃ ) δ: 2.83 (s, 3H) 3.97 (s, 3H) 7.38 (m, 2H) 7.77 (dd, J = 2.0, 8.0 Hz, 1H) 7.94 (d, J = 2.0 Hz, 1H)
[2123] Preparation Example 226d)
[2124]
[2125] 0.2 g of methyl-2- (3-methylphenyl) -5-methyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml of methanol, 1 ml of 5N sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 0.2 g of 2- (3-methylphenyl) 5-methyl-1,3-thiazole-4-carboxylic acid.
[2126] ¹ H-NMR (DMSO-d ₆ ) δ: 2.73 (s, 3H) 7.55 (m, 2H) 7.83 (d, J = 8.0 Hz, 1H) 7.93 (d, J = 2.0 Hz, 1H)
[2127] Example 226e)
[2128]
[2129] 3-3-[([2- (3-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl by the same method as in Example 38 2-isopropoxycarboxylic acid was obtained.
[2130] HS m / e (ESD 503 (MH ⁺ )
[2131] Example 227
[2132] Preparation Example 227a)
[2133]
[2134] 2- (3-5-dichlorophenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 226.
[2135] ¹ H-NMR (DMSO-d ₆ ) δ: 2.74 (s, 3H) 8.75 (s, 1H) 8.90 (s, 2H)
[2136] Example 227b)
[2137]
[2138] 3-3-[([2- (3-5-dichlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4- by the same method as in Example 38 Methoxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2139] MS m / e (ESI) 537 (MH ⁺ )
[2140] Example 228
[2141] Preparation Example 228a)
[2142]
[2143] 5-Methyl-2- (5-methyl-2-thienyl) -1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 226.
[2144] ¹ H-NMR (CDCl ₃ ) δ: 2.53 (s, 3H) 2.81 (s, 3H) 6.74 (d, J = 5.0 Hz, 1H) 7.28 (d, J = 5.0Hz, 1H)
[2145] Example 228b)
[2146]
[2147] 2-Isopropoxy-3-4-methoxy-3-[([5-methyl-2- (5-methyl-2-thienyl) -1,3-thiazole- in the same manner as in Example 38 4-yl] carbonylamino) methyl-1-phenylpropanoic acid was obtained.
[2148] MS m / e (ESI) 489 (MH ⁺ )
[2149] Example 229
[2150] Preparation Example 229a)
[2151]
[2152] 5-Methyl-2- (3-thienyl) -1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 226.
[2153] ¹ H-NMR (CDCl ₃ ) δ: 2.84 (s, 3H) 7.41 (dd, J = 1.0, 5.0 Hz, 1H) 7.50 (d, J = 1.0 Hz, 1H) 7.81 (d, J = 5.0 Hz, 1H )
[2154] Example 229b)
[2155]
[2156] 2-isopropoxy-3-4-methoxy-3-[([5-methyl-2 (3-thienyl) -1,3-thiazol-4-yl] carrine in the same manner as in Example 38 Bonylamino) methyl-1-phenylpropanoic acid was obtained.
[2157] MS m / e (ESI) 475 (MH ⁺ )
[2158] Example 230
[2159] Preparation Example 230a)
[2160]
[2161] 2- (5-chloro-2-thienyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 226.
[2162] ¹ H-NMR (CDCl ₃ ) δ: 2.83 (s, 3H) 6.92 (d, J = 5.0 Hz, 1H) 7.24 (d, J = 5.0 Hz, 1H)
[2163] Example 230b)
[2164]
[2165] 3-3-[([2- (5-chloro-2-thienyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2166] MS m / e (ESI) 509 (MH ⁺ )
[2167] Example 231
[2168] Preparation Example 231a)
[2169]
[2170] 2 g of 1-cyclopentanecarboxamide was dissolved in tetrahydrofuran, 4.3 g of Lawson's reagent was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography to obtain 1.8 g of 1-cyclopentanecarbothioamide.
[2171] ¹ H-NMR (CDCl ₃ ) δ: 1.64 (m, 2H) 1.78-1.94 (m, 4H) 2.00 (m, 2H) 2.95 (qui, J = 6.0 Hz, 1H) 6.86 (bs, 1H) 7.50 (bs , 1H)
[2172] Preparation Example 231 b)
[2173]
[2174] 2-cyclopentyl-5-methyl-1,3-thiazole-4-carboxylic acid was obtained by treating ethyl 2-chloroacetoacetic acid and 1-cyclopentanecarbothioamide as raw materials in the same manner as in Production Example 203. .
[2175] ¹ H-NMR (CDCl ₃ ) δ: 1.70-1.88 (m, 6H) 2.20 (m, 2H) 2.72 (s, 3H) 3.42 (qui, J = 6.0 Hz, 1H)
[2176] Example 231c)
[2177]
[2178] 3- [3-([(2-cyclopentyl-5-methyl-1,3-thiazol-4-yl) carbonyl] aminomethyl])-4-methoxyphenyl] by the same method as in Example 38] 2-isopropoxypropanoic acid was obtained.
[2179] MS m / e (ESI) 461 (MH ⁺ )
[2180] Example 232
[2181] Preparation Example 232a)
[2182]
[2183] 2-cyclohexyl-5-methyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 231.
[2184] ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.55 (m, 5H) 1.75 (m, 1H) 1.86 (m, 2H) 2.13 (m, 2H) 2.72 (s, 3H) 2.96 (qui, J = 6.0Hz , 1H)
[2185] Example 232b)
[2186]
[2187] 3- [3-([(2-cyclohexyl-5-methyl-1,3-thiazol-4-yl) carbonyl] aminomethyl])-4-methoxyphenyl] by the same method as in Example 38] 2-isopropoxypropanoic acid was obtained.
[2188] MS m / e (ESI) (MH ⁺ ) 475
[2189] Example 233
[2190] Preparation Example 233a)
[2191]
[2192] 2- (2-methylphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 231.
[2193] ¹ H-NMR (CDCl ₃ ) δ: 2.61 (s, 3H) 2.82 (s, 3H) 7.30 (m, 2H) 7.37 (d, J = 8.0Hz, 1H) 7.80 (dd, J = 2.0, 8.0Hz, 1H)
[2194] Example 233b)
[2195]
[2196] 3-3-[([2- (2-methylphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl by the same method as in Example 38 2-isopropoxycarboxylic acid was obtained.
[2197] MS m / e (ESI) 482 (MH ⁺ )
[2198] Example 234
[2199] Preparation Example 234a)
[2200]
[2201] 2- (2-methoxyphenyl) -5-methyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 231.
[2202] ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3H) 4.02 (s, 3H) 7.10 (t, J = 8.0 Hz, 1H) 7.25 (d, J = 8.0 Hz, 1H) 7.55 (t, J = 8.0Hz, 1H) 8.28 (d, J = 8.0Hz, 1H)
[2203] Example 234b)
[2204]
[2205] 3-3-[([2- (2-methoxyphenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-meth by the same method as in Example 38 Toxylphenyl-2-isopropoxycarboxylic acid was obtained.
[2206] MS m / e (ESI) 498 (MH ⁺ )
[2207] Example 235
[2208] Preparation Example 235a)
[2209]
[2210] 2 g of 2-cyano-3-methylpyridine was dissolved in 30 ml of pyridine and 12 ml of triethylamine, and hydrogen sulfide gas was bubbled for 2 hours. The reaction solution was stirred at 50 ° C. for 2 hours in a clogged tube, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2.6 g of 3-methyl-2-pyridinecarbothioamide.
[2211] ¹ H-NMR (CDCl ₃ ) δ: 2.76 (s, 3H) 7.28 (m, 1H) 7.62 (d, J = 8.0 Hz, 1H) 8.37 (d, J = 4.0 Hz, 1H)
[2212] Preparation Example 235b)
[2213]
[2214] 5-Methyl-2- (3-methyl-2-pyridyl) -1, by treating in the same manner as in Production Example 203 using ethyl 2-chloroacetoacetic acid and 3-methyl-2-pyridinecarbothioamide as raw materials 3-thiazole-4-carboxylic acid was obtained.
[2215] ¹ H-NMR (DMSO-d ₆ ) δ: 2.66 (s, 3H) 2.71 (s, 3H) 7.42 (dd, J = 4.0, 8.0 Hz, 1H) 7.80 (d, J = 8.0 Hz, 1H) 8.44 ( d, J = 4.0 Hz, 1H)
[2216] Example 235c)
[2217]
[2218] 3-3-[([2- (3-methyl-2-pyridyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxypropanoic acid was obtained.
[2219] MS m / e (ESI) 484 (MH ⁺ )
[2220] Example 236
[2221] Preparation Example 236a)
[2222]
[2223] 2 g of 3-picolin was dissolved in 30 ml of dichloromethane, 5.6 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 4: 1) to obtain 2.4 g of 3-pyridine N-oxide.
[2224] ¹ H-NMR (CDCl ₃ ) δ: 2.31 (s, 3H) 7.10 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 4.0,8.0 Hz, 1H) 8.07 (m, 2H)
[2225] Preparation Example 236b)
[2226]
[2227] 2.4 g of 3-pyridine N-oxides were dissolved in 30 ml of acetonitrile, 3.5 ml of trimethylsilylcyanide and 2.4 ml of dimethylcarbamoyl chloride were added, and the mixture was heated to reflux for 2 hours. The reaction solution was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The obtained product was processed according to Production Example 235a) to obtain 0.2 g of 5-methyl-2-pyridinecarbothioamide.
[2228] ¹ H-NMR (CDCl ₃ ) δ: 2.41 (s, 3H) 7.63 (d, J = 8.0 Hz, 1H) 8.34 (bs, 1H) 8.60 (d, J = 8.0 Hz, 1H)
[2229] Preparation Example 236c)
[2230]
[2231] 2- (5-ethyl-2-pyridyl) -5-methyl-1,3 by treating in the same manner as in Production Example 203 using 2-chloroacetoacetic acid and 5-methyl-2-pyridinecarbothioamide as raw materials -Thiazole-4-carboxylic acid was obtained.
[2232] ¹ H-NMR (DMSO-d ₆ ) δ: 2.35 (s, 3H) 2.65 (s, 3H) 7.78 (dd, J = 2.0, 8.0 Hz, 1H) 8.02 (d, J = 8.0 Hz, 1H) 8.48 ( d, J = 2.0 Hz, 1H)
[2233] Example 236d)
[2234]
[2235] 3-3-[([2- (5-methyl-2-pyridyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxypropanoic acid was obtained.
[2236] MS m / e (ESI) 484 (MH ⁺ )
[2237] Example 237
[2238] Preparation Example 237a)
[2239]
[2240] 2- (2-chlorophenyl) -5-ethyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 203.
[2241] ¹ H-NMR (CDCl ₃ ) δ: 1.37 (t, J = 8.0 Hz, 3H) 3.24 (q, H = 8.0 Hz, 2H) 7.40 (m, 2H) 7.52 (m, 1H) 8.35 (m, 1H)
[2242] Example 237b)
[2243]
[2244] 3-3-[([2- (2-chlorophenyl) -5-ethyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxy by the same method as in Example 38 Phenyl-2-isopropoxycarboxylic acid was obtained.
[2245] MS m / e (ESI) 517 (MH ⁺ )
[2246] Example 238
[2247] Preparation Example 238a)
[2248]
[2249] 2- (4-Chlorophenyl) -5-ethyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 203.
[2250] ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (t, J = 8.0 Hz, 3H) 3.08 (q, H = 8.0 Hz, 2H) 7.57 (d, J = 8.0 Hz, 2H) 8.00 (d, J = 8.0 Hz, 2H)
[2251] Example 238b)
[2252]
[2253] 3-3-[([2- (4-chlorophenyl) -5-ethyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxy by the same method as in Example 38 Phenyl-2-isopropoxycarboxylic acid was obtained.
[2254] MS m / e (ESI) 517 (MH ⁺ )
[2255] Example 239
[2256] Preparation Example 239a)
[2257]
[2258] 2- (4-methylphenyl) -5-ethyl-1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Production Example 203.
[2259] ¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (t, J = 8.0 Hz, 3H) 2.35 (s, 3H) 3.07 (q, H = 8.0 Hz, 2H) 7.30 (d, J = 8.0 Hz, 2H ) 7.86 (d, J = 8.0 Hz, 2H)
[2260] Example 239b)
[2261]
[2262] 3-3-[([2- (4-methylphenyl) -5-ethyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl by the same method as in Example 38. 2-isopropoxycarboxylic acid was obtained.
[2263] MS m / e (ESI) 497 (MH ⁺ )
[2264] Example 240
[2265] Preparation Example 240a)
[2266]
[2267] 5-Ethyl-2- (3-methyl-2-pyridyl) -1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 235.
[2268] ¹ H-NMR (DMSO-d ₆ ) δ: 1.27 (t, J = 8.0 Hz, 3H) 2.74 (s, 3H) 3.10 (q, H = 8.0 Hz, 2H) 7.42 (dd, J = 4.0, 8.0 Hz , 1H) 7.81 (d, J = 8.0 Hz, 1H) 8.48 (d, J = 4.0 Hz, 1H)
[2269] Example 240b)
[2270]
[2271] 3-3-[([2- [3-methyl-2-pyridyl) -5-ethyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxypropanoic acid was obtained,
[2272] MS m / e (ESI) 498 (MH ⁺ )
[2273] Example 241
[2274] Preparation Example 241a)
[2275]
[2276] 2- (5-methyl-2-pyridyl) -5-ethyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Production Example 236a-c).
[2277] ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (t, J = 8.0 Hz, 3H) 2.35 (s, 3H) 3.09 (q, H = 8.0 Hz, 2H) 7.79 (d, J = 8.0 Hz, 1H ) 7.81 (d, J = 8.0 Hz, 1H) 8.49 (s, 1H)
[2278] Example 241b)
[2279]
[2280] 3-3-[([2- (5-methyl-2-pyridyl) -5-ethyl-1,3-thiazol-4-yl] carbonylamino) methyl]-by the same method as in Example 38 4-methoxyphenyl-2-isopropoxypropanoic acid was obtained.
[2281] MS m / e (ESI) 498 (MH ⁺ )
[2282] Example 242
[2283] Preparation Example 242a)
[2284]
[2285] 2- (3-Chloro-4-fluorophenyl) -5-ethyl-1,3-thiazole-4-carboxylic acid was obtained by the same method as in Preparation Example 203.
[2286] ¹ H-NMR (CDCl ₃ ) δ: 1.35 (t, J = 8.0 Hz, 3H) 3.20 (q, H = 8.0 Hz, 2H) 7.21 (d, J = 8.0 Hz, 1H) 7.83 (m, 1H) 8.10 (dd, J = 2.0, 8.0 Hz, 1H)
[2287] Example 242b)
[2288]
[2289] 3-3-[([2- (3-chloro4-fluorophenyl] -5-ethyl 1,3-thiazol-4-yl] carbonylamino) methyl] -4 by the same method as in Example 38 -Methoxyphenyl-2-isopropoxycarboxylic acid was obtained.
[2290] MS m / e (ESI) 535 (MH ⁺ )
[2291] Example 243
[2292] Preparation Example 243a)
[2293]
[2294] 5-Ethyl-2- (2-thienyl) -1,3-thiazole-4-carboxylic acid was obtained in the same manner as in Preparation Example 203.
[2295] ¹ H-NMR (CDCl ₃ ) δ: 1.33 (t, J = 8.0 Hz, 3H) 3.18 (q, H = 8.0 Hz, 2H) 7.10 (dd, J = 4.0, 5.0 Hz, 1H) 7.47 (d, J = 4.0 Hz, 1H) 7.60 (d, J = 5.0Hz, 1H)
[2296] Example 243b)
[2297]
[2298] 2-isopropoxy-3-4-methoxy-3-[([5-ethyl-2- (2-thienyl) -1,3-thiazol-4-yl] by the same method as in Example 38. Carbonylamino) methyl-1-phenylpropanoic acid was obtained.
[2299] MS m / e (ESI) 489 (MH ⁺ )
[2300] Example 244
[2301] Example 244a)
[2302]
[2303] Following the preparation example 1a) using 4-methoxy-3- (2- [4- (trifluoromethyl) phenoxy] ethyl) benzaldehyde, the ethyl 2- was prepared by the same method as in preparation example 1b). Isopropoxy-3- (4-methoxy-3-2- [4- (trifluoromethyl) phenoxy] ethylphenyl) propanoate was obtained.
[2304] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 7.2 Hz, 3H) 2.79 (dd, J = 8.4 , 14.0Hz, 1H) 2.95 (dd, J = 4.8, 14.0Hz, 1H) 3.08 (t, J = 7.6Hz, 2H) 3.50 (sept, J = 6.0Hz, 1H) 3.82 (s, 3H) 4.00 (dd , J = 4.8, 8.4Hz, 1H) 4.15-4.20 (m, 4H) 6.78 (d, J = 8.0Hz, 1H) 6.96 (d, J = 8.8Hz, 2H) 7.09 (s, 1H) 7.10 (d, J = 8.0Hz, 1H) 7.52 (d, J = 8.8Hz, 2H)
[2305] Example 244b)
[2306]
[2307] Ethyl 2-isopropoxy-3- (4-methoxy-3-2- [4- (trifluoromethyl) phenoxy] ethylphenyl) propanoate was treated as in Example 1e) and 2-iso Propoxy-3- (4-methoxy-3-2- [4- (trifluoromethyl) phenoxy] ethylphenyl) propanoic acid was obtained.
[2308] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.89 (dd, J = 7.6, 14.0 Hz, 1H) 3.07 (dd, J = 4.0, 14.0Hz, 1H) 3.09 (t, J = 7.6Hz, 2H) 3.56 (sept, J = 6.0Hz, 1H) 3.83 (s, 3H) 4.10 (dd, J = 4.0, 7.6Hz, 1H) 4.17 (t, J = 7.6Hz, 2H) 6.80 (d, J = 8.0Hz, 1H) 6.96 (d, J = 8.8Hz, 2H) 7.09 (s, 1H) 7.09 (d, J = 8.0Hz, 1H) 7.52 (d, J = 8.8 Hz, 2H)
[2309] Example 245
[2310] Example 245a)
[2311]
[2312] Production Example 1a) was followed by 4-methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzaldehyde, followed by ethyl 2-isopro in the same manner as in Production Example 1b). Foxy-3- [4-methoxy-3-([4- (trifluoromethyl) benzyl] oxymethyl) phenyl] propanoate was obtained.
[2313] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.23 (t, J = 7.2 Hz, 3H) 2.79 (dd, J = 8.4 , 14.0Hz, 1H) 2.95 (dd, J = 4.8, 14.0Hz, 1H) 3.50 (sept, J = 6.0Hz, 1H) 3.82 (s, 3H) 4.00 (dd, J = 4.8, 8.4Hz, 1H) 4.15 -4.20 (m, 2H) 4.58 (s, 2H) 4.64 (s, 2H) 6.79 (d, J = 8.0 Hz, 1H) 7.16 (dd, J = 2.4, 8.0 Hz, 1H) 7.28 (d, J = 2.4 Hz, 1H) 7.49 (d, J = 8.0 Hz, 2H) 7.60 (d, J = 8.4 Hz, 2H)
[2314] Example 245b)
[2315]
[2316] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (trifluoromethyl) benzyl] oxymethyl) phenyl] propanoate was treated as in Example 1e) and 2-iso Propoxy-3- [4-methoxy-3-([4- (trifluoromethyl) benzyl] oxymethyl) phenyl] propanoic acid was obtained.
[2317] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 7.6, 14.0 Hz, 1H) 3.09 (dd, J = 4.0, 14.0Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 3.81 (s, 3H) 4.12 (dd, J = 4.0, 7.6Hz, 1H) 4.59 (s, 2H) 4.64 (s, 2H) 6.80 (d, J = 8.0 Hz, 1H) 7.14 (dd, J = 2.4, 8.0 Hz, 1H) 7.28 (d, J = 2.4 Hz, 1H) 7.50 (d, J = 8.4 Hz, 2H) 7.60 (d, J = 8.4 Hz, 2H)
[2318] Example 246
[2319]
[2320] 40 mg of sodium hydride was dissolved in 2 ml of tetrahydrofuran, and 0.51 g of tetrahydrofuran solution (1 ml of ethyl 3- [3- (hydroxymethyl) -4-methoxyphenyl] -2-isopropoxypropanoate was dissolved under ice cooling). ) And 0.25 mg of 4-chlorobenzyl bromide were added in this order, and the mixture was stirred at room temperature for 15 hours. The reaction solution was cooled on ice, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 0.19 g from the hexane-ethyl acetate (4: 1) elution fraction. The obtained 0.19 g was treated like Example 1e), and 0.17 g of 3- (3-[(4-chloromethyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2321] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 7.6, 14.0 Hz, 1H) 3.09 (dd, J = 4.0, 14.0Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 3.81 (s, 3H) 4.12 (dd, J = 4.0, 7.6Hz, 1H) 4.59 (s, 2H) 4.60 (s, 2H) 6.80 (d, J = 8.0 Hz, 1H) 7.13 (dd, J = 2.4, 8.0 Hz, 1H) 7.27 (d, J = 2.4 Hz, 1H) 7.32 (s, 4H)
[2322] Example 247
[2323] Preparation Example 247a)
[2324]
[2325] 2.2 g of ethyl 3- [3- (hydroxymethyl])-4-methoxyphenyl] -2-isopropoxypropanoate was dissolved in 15 ml of dimethoxyethane, 1.2 ml of phosphorus tribromide was added under ice-cooling, and room temperature It stirred at 4 hours. The reaction solution was diluted with ethyl and washed with water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and ethyl 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 2.6 was extracted from the hexane-ethyl acetate (4: l) elution fraction. g was obtained.
[2326] ¹ H-NMR (CDCl ₃ ) δ: 0.97 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.24 (t, J = 7.2 Hz, 3H) 2.88 (dd, J = 8.4 , 14.0 Hz, 1H) 2.95 (dd, J = 5.2, 14.0 Hz, 1H) 3.50 (sept, J = 6.0 Hz, 1H) 3.87 (s, 3H) 4.00 (dd, J = 5.2, 8.4 Hz, 1H) 4.11 -4.21 (m, 2H) 4.53 (d, J = 2.4 Hz, 2H) 6.79 (d, J = 8.8 Hz, 1H) 7.08 (d, J = 8.8 Hz, 1H) 7.12 (s, 1H)
[2327] Preparation Example 247b)
[2328]
[2329] 87 mg of lithium aluminum hydride was dissolved in 7.5 ml of tetrahydrofuran, and 0.50 g of tetrahydrofuran solution (2.5 ml) of ethyl 5-methyl-2-phenyl-1,3-thiazole-4-carboxylate was dissolved under ice cooling. It added and stirred at room temperature for 3 hours. After cooling the reaction solution, water and 1N hydrochloric acid were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 0.42 g of (5-methyl-2-phenyl-1,3-thiazol-4-yl) methanol from the hexane-ethyl acetate (2: 1) eluting fraction.
[2330] ¹ H-NMR (CDCl ₃ ) δ: 2.46 (s, 3H) 4.82 (s, 2H) 7.50-7.53 (m, 3H) 7.88-7.91 (m, 2H)
[2331] Example 247c)
[2332]
[2333] 24 mg of sodium hydride is dissolved in 2 ml of tetrahydrofuran, and 0.19 g of tetrahydrofuran solution (1 ml) of 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate under ice-cooling And tetrahydrofuran solution (1 ml) of (5-methyl-2-phenyl-1,3-thiazol-4-yl) methanol 0.12 mg was added in this order, and it stirred at room temperature for 15 hours. 2 ml of 1N sodium hydroxide aqueous solution was added to the reaction liquid, and it stirred at room temperature for 2 hours. The reaction solution was cooled on ice, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was concentrated, and then purified by HPLC using a water-acetonitrile-trifluoroacetic acid system as an eluting solvent in a column of reversed phase, and then 2-isopropoxy-3- (4-methoxy-3-[(5 0.13 g of -methyl-2-phenyl-1,3-thiazol-4-yl) methoxy] methylphenyl) propanoic acid was obtained.
[2334] MS m / e (ESI) 454 (MH ⁺ )
[2335] Example 248
[2336] Preparation Example 248a)
[2337]
[2338] (5-Butyl-2-pyridyl) methanol was obtained by the same method as Preparation Example 247b) using fusaric acid.
[2339] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 8.0 Hz, 3H) 1.31-1.40 (m, 2H) 1.56-1.65 (m, 2H) 2.63 (t, J = 8.0 Hz, 2H) 4.73 ( s, 2H) 7.14 (d, J = 8.0Hz, 1H) 7.50 (d, J = 8.0Hz, 1H) 8.39 (s, 1H)
[2340] Example 248b)
[2341]
[2342] In the same manner as in Example 247, using (5-butyl-2-pyridyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(5-butyl-2-pyridyl) methoxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2343] MS m / e (ESI) 416 (MH ⁺ )
[2344] Example 249
[2345] Preparation Example 249a)
[2346]
[2347] (4-Isopropoxyphenyl) methanol was obtained by the same method as Preparation Example 247b) using 4-isopropoxybenzoic acid.
[2348] ¹ H-NMR (CDCl ₃ ) δ: 1.34 (d, J = 6.4 Hz, 6H) 4.55 (sept, J = 6.4 Hz, 1H) 4.62 (s, 2H) 6.87 (d, J = 8.8 Hz, 2H) 7.22 (d, J = 8.8 Hz, 2H)
[2349] Example 249b)
[2350]
[2351] 2- in the same manner as in Example 247, using (4-isopropoxyphenyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate Isopropoxy-3- (3-[(4-isopropoxybenzyl) oxy] methyl-4-methoxy) propanoic acid was obtained.
[2352] MS m / e (ESI) 417 (MH ⁺ )
[2353] Example 250
[2354] Preparation Example 250a)
[2355]
[2356] Using 4-chloro-2-methoxybenzoic acid, (4-chloro-2-methoxyphenyl) methanol was obtained by the same method as in Production Example 247b).
[2357] ¹ H-NMR (CDCl ₃ ) δ: 3.83 (s, 3H) 4.62 (s, 2H) 6.85 (s, 1H) 6.94 (d, J = 8.0 Hz, 1H) 7.20 (d, J = 8.0 Hz, 1H)
[2358] Example 250b)
[2359]
[2360] Same method as in Example 247, using (4-chloro-2-methoxyphenyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(4-chloro-2-methoxybenzyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained by the above.
[2361] MS m / e (ESI) 423 (MH ⁺ )
[2362] Example 251
[2363] Preparation Example 251a)
[2364]
[2365] Using 2-chloro-4-methoxybenzoic acid, (2-chloro-4-methoxyphenyl) methanol was obtained by the same method as in Preparation Example 247b).
[2366] ¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 3H) 4.70 (s, 2H) 6.80 (d, J = 8.0 Hz, 1H) 6.95 (s, 1H) 7.37 (d, J = 8.0 Hz, 1H)
[2367] Example 251b)
[2368]
[2369] Same method as in Example 247, using [2-chloro-4-methoxyphenyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(2-chloro-4-methoxybenzyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained by the above.
[2370] MS m / e (ESI) 423 (MH ⁺ )
[2371] Example 252
[2372] Preparation Example 252a)
[2373]
[2374] [2-methoxy-4- (trifluoromethyl) phenyl] methanol was obtained by the same method as Preparation Example 247b) using 2-methoxy-4- (trifluoromethyl]) benzoic acid.
[2375] ¹ H-NMR (CDCl ₃ ) δ: 3.92 (s, 3H) 4.72 (s, 2H) 7.08 (s, 1H) 7.22 (d, J = 8.0 Hz, 1H) 7.42 (d, J = 8.0 Hz, 1H)
[2376] Example 252b)
[2377]
[2378] Same method as in Example 247, using (2-chloro-4-methoxyphenyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- [3-([2-fluoro-4- (trifluoromethyl) benzyl] oxymethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid was obtained by the above.
[2379] MS m / e (ESI) 457 (MH ⁺ )
[2380] Example 253
[2381] Preparation Example 253a)
[2382]
[2383] Using 4-phenoxybenzoic acid, (4-phenoxyphenyl) methanol was obtained by the same method as Preparation Example 247b).
[2384] ¹ H-NMR (CDCl ₃ ) δ: 4.72 (s, 2H) 7.00-7.02 (m, 4H) 7.12 (t, J = 8.0 Hz, 1H) 7.30-7.38 (m, 4H)
[2385] Example 253b)
[2386]
[2387] 2-iso in the same manner as in Example 247, using (4-phenoxyphenyl) methanol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate Propoxy-3- (4-methoxy-3-[(4-phenoxybenzyl) oxy] methylphenyl) propanoic acid was obtained.
[2388] MS m / e (ESI) 451 (MH ⁺ )
[2389] Example 254
[2390]
[2391] 3- (3) in the same manner as in Example 247, using 2,4-dichlorobenzyl alcohol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate -[(2,4-dichlorobenzyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2392] MS m / e (ESI) 427 (MH ⁺ )
[2393] Example 255
[2394]
[2395] Example 247, using 2-fluoro-4- (trifluoromethyl) benzyl alcohol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- [3-([2-fluoro-4- (trifluoromethyl) benzyl] oxymethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid was obtained by the same method as the above.
[2396] MS m / e (ESI) 445 (MH ⁺ )
[2397] Example 256
[2398]
[2399] In the same manner as in Example 247), using 4-chloro-2-fluorobenzyl alcohol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate -(3-[(4-chloro-2-fluorobenzyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2400] MS m / e (ESI) 411 (MH ⁺ )
[2401] Example 257
[2402]
[2403] 3- (3) in the same manner as in Example 247, using 3,4-dichlorobenzyl alcohol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate -[(3,4-dichlorobenzyl) oxy] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2404] MS m / e (ESI) 427 (MH ⁺ )
[2405] Example 258
[2406]
[2407] 2-isopropoxy in the same manner as in Example 247, using 4-isopropylbenzyl alcohol and 3- [3- (bromomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(4-isopropylbenzyl) oxy] methyl-4-methoxyphenyl) propanoic acid was obtained.
[2408] MS m / e (ESI) 401 (MH ⁺ )
[2409] Example 259
[2410]
[2411] Example 29) subsequent to Production Example 27c) using 4-methoxy-3- (2- [4- (trifluoromethyl) phenoxy] ethyl) benzaldehyde and 2,4-thiazolidinedione. 5- (4-methoxy-3-2- [4- (trifluoromethyl) phenoxy] ethylbenzyl) -1,3-thiazolan-2,4-dione was obtained in the same manner as the above.
[2412] ¹ H-NMR (DMSO-d ₆ ) δ: 3.09 (t, J = 7.2 Hz, 2H) 3.10 (dd, J = 9.2, 14.0 Hz, 1H) 3.45 (dd, J = 4.0, 14.0 Hz, 1H) 3.83 (s, 3H) 4.17 (t, J = 7.6 Hz, 2H) 4.49 (dd, J = 4.0, 9.2 Hz, 1H) 6.82 (d, J = 8.0 Hz, 1H) 6.96 (d, J = 8.8 Hz, 2H ) 7.08-7.10 (m, 2H) 7.52 (d, J = 8.8 Hz, 2H) 8.37 (brs, 1H)
[2413] Example 260
[2414]
[2415] Example 29) subsequent to Production Example 27c) using 4-methoxy-3-(([4- (trifluoromethyl) benzyl] oxy) methyl) benzaldehyde and 2,4-thiazolidinedione 5- [4-methoxy-3-([4- (trifluoromethyl) benzyl] oxymethyl) benzyl] -1,3-thiazolan-2,4-dione was obtained in the same manner as the above.
[2416] ¹ H-NMR (DMSO-d ₆ ) δ: 3.11 (dd, J = 10.0, 14.0 Hz, 1H) 3.47 (dd, J = 4.0, 14.0 Hz, 1H) 3.82 (s, 3H) 4.51 (dd, J = 4.0, 9.2 Hz, 1H) 4.58 (s, 2H) 4.66 (s, 2H) 6.82 (d, J = 8.0 Hz, 1H) 7.12 (dd, J = 2.4, 8.0 Hz, 1H) 7.24-7.28 (m, 1H ) 7.50 (d, J = 8.0 Hz, 2H) 7.61 (d, J = 8.0 Hz, 2H) 8.10 (brs, 1H)
[2417] Example 261
[2418] Preparation Example 26la)
[2419]
[2420] 7.7 g of tert-butyl N- (5-formyl-2-methoxybenzyl) carbamate and 2,4-thiazolidinedione3,4 g were dissolved in 100 ml of toluene, 0.28 g of piperidine and 0.24 g of acetic acid Was added, the Dean Stark apparatus was attached and it heated and refluxed for 3 hours. After cooling the reaction solution to room temperature, the precipitated crystals were filtered, washed with toluene, dried under reduced pressure, and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolane -5-ylidene) methyl] -2-methoxybenzylcarbamate was obtained. Subsequently obtained tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-ylidene) methyl] -2-methoxybenzylcarbamate was dissolved in 80 ml of dimethylformamide, 8.0 g of 10% palladium carbon was added thereto, and the mixture was stirred at 50 degrees and 15 kg / cm 2 for 20 hours under reduced pressure of hydrogen. The catalyst was filtered off, and the solvent was distilled off under reduced pressure, followed by addition of water and extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and tert-butylN-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl from hexane-ethyl acetate (1: 1) eluted fraction. ] -2-methoxybenzylcarbamate was obtained 8.2g.
[2421] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H) 3.11 (dd, J = 9.2, 14.0 Hz, 1H) 3.42 (dd, J = 3.6, 14.0 Hz, 1H) 3.83 (s, 3H) 4.26 ( d, J = 6.0Hz, 2H) 4.50 (dd, J = 3.6, 9.2Hz, 1H) 5.00-5.08 (m, 1H) 6.79 (d, J = 8.0Hz, 1H) 7.09-7.13 (m, 2H) 8.28 -8.33 (m, 1H)
[2422] Example 261b)
[2423]
[2424] To 8.2 g of tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylcarbamate, 40 ml of 4M HC1-dioxane was added, and 1 It stirred for hours. The reaction solution was concentrated and then dried under reduced pressure, tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride 6.0 g was obtained. Subsequently obtained tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride 0.20 g and 2-methoxy-4- 0.15 g of (trifluoromethyl) benzoic acid was dissolved in 25 ml of dimethylformamide, and 0.11 ml of diethyl cyanophosphonic acid and 0.10 ml of triethylamine were added under ice cooling. After stirring at room temperature for 16 hours, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with IN hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and extracted from hexane-ethyl acetate (2: 1) eluting fraction with N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2. 0.18 g of -methoxybenzyl-2-methoxy-4- (trifluoromethyl) benzamide was obtained.
[2425] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0,14.0 Hz, 1H) 3.79 (s, 3H) 3.97 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.79 (dd, J = 4.0, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.08-7.13 (m, 2H) 7.37 (d, J = 8.0 Hz, 1H) 7.42 (s, 1H) 7.84 (d, J = 8.0 Hz, 1H) 8.64 (t, J = 6.0 Hz, 1H) 12.02 (brs, 1H)
[2426] Example 262
[2427]
[2428] Using 2-chloro-4-methoxybenzoic acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride , N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2-chloro-4-methoxy in the same manner as in Example 261) Benzamide was obtained.
[2429] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.78 (s, 3H) 3.79 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.79 (dd, J = 4.0, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 6.94-6.96 (m, 1H) 7.06 (d, J = 2.4 Hz, 1H) 7.08-7.13 (m, 2H) 7.43 (d, J = 8.0 Hz, 1H) 8.64 (t, J = 6.0 Hz, 1H) 12.02 (brs, 1H)
[2430] Example 263
[2431]
[2432] Example 261) with fusaric acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride In the same manner, N2-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-5-butyl-2-pyridinecarboxyamide was obtained.
[2433] ¹ H-NMR (DMSO-d ₆ ) δ: 0.89 (t, J = 7.2 Hz, 3H) 1.25-1.33 (m, 2H) 1.53-1.60 (m, 2H) 2.67 (t, J = 8.0 Hz, 2H) 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.79 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.77 (dd, J = 4.0 , 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.03 (d, J = 2.4 Hz, 1H) 7.10 (dd, J = 2.4, 8.4 Hz, 1H) 7.81 (dd, J = 2.0, 8.0 Hz, 1H) 7.95 (d, J = 8.0 Hz, 1H) 8.49 (d, J = 2.0 Hz, 1H) 8.89 (t, J = 6.0 Hz, 1H) 12.02 (brs, 1H)
[2434] Example 264
[2435]
[2436] Example 261 using 4-isopropoxybenzoic acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride N1-5-[(2.4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-4-isopropoxybenzamide was obtained by the same method as.
[2437] ¹ H-NMR (DMSO-d ₆ ) δ: 1.26 (d, J = 6.0 Hz, 6H) 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.79 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.69 (sept, J = 6.0 Hz, 1H) 4.79 (dd, J = 4.0, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H ) 6.95 (d, J = 8.4 Hz, 2H) 7.03 (s, 1H) 7.08 (d, J = 8.4 Hz, 1H) 7.84 (d, J = 8.4 Hz, 2H) 8.63 (t, J = 6.0 Hz, 1H ) 12.02 (brs, 1H)
[2438] Example 265
[2439]
[2440] 5-Methyl-2-phenyl-1,3-thiazole-4-carboxylic acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl]- N 4-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxy in the same manner as in Example 261 using 2-methoxybenzylamine hydrochloride Benzyl-5-methyl-2-phenyl-1,3-thiazole-4-carboxyamide was obtained.
[2441] ¹ H-NMR (DMSO-d ₆ )
[2442] δ: 2.61 (s, 3H) 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.79 (s, 3H) 4.37 (m, 2H) 4.77 (dd, J = 4.0, 9.6Hz, 1H) 6.93 (d, J = 8.4Hz, 1H) 7.08-7.13 (m, 2H) 7.46-7.52 (m, 3H) 7.90-7.95 (m, 2H) 8.61 (m, 1H) 12.02 (brs, 1 H)
[2443] Example 266
[2444]
[2445] Example 261) with 4-phenylbenzoic acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzylamine hydrochloride In the same manner, N1-5-[(2.4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-4-phenylbenzamide was obtained.
[2446] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.79 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.77 (dd, J = 4.0, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.08-7.13 (m, 2H) 7.39 (t, J = 7.2 Hz, 1H) 7.48 ( t, J = 7.6Hz, 2H) 7.72 (d, J = 7.6Hz, 2H) 7.76 (d, J = 8.0Hz, 2H) 7.99 (d, J = 8.0Hz, 2H) 8.87 (t, J = 6.0Hz , 1H) 12.02 (brs, 1H)
[2447] Example 267
[2448]
[2449] Example 261 using 4-phenoxybenzoic acid and tert-butyl N-5-[(2,4-dioxo-1,3-thiazolan5-yl) methyl] -2-methoxybenzylamine hydrochloride N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-4-phenoxybenzamide was obtained in the same manner as the above.
[2450] ¹ H-NMR (DMSO-d ₆ ) δ: 2.99 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.79 (s, 3H) 4.42 (d, J = 6.0 Hz, 2H) 4.77 (dd, J = 4.0, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.02 (d, J = 8.8 Hz, 2H) 7.05-7.10 (m, 4H) 7.20 ( t, J = 8.0 Hz, 1H) 7.43 (t, J = 8.0 Hz, 2H) 7.92 (d, J = 8.8 Hz, 2H) 8.76 (t, J = 6.0 Hz, 1H) 12.02 (brs, 1H)
[2451] Example 268
[2452]
[2453] Following Example 19d) using psaric acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate, in the same manner as in Example 19e) -[3-([(5-butyl-2-pyridyl) carbonyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid was obtained.
[2454] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 8.0 Hz, 3H) 1.00 (d, J = 6.0 Hz, 3H) 1.12 (d, J = 6.0 Hz, 3H) 1.31-1.40 (m, 2H ) 1.56-1.65 (m, 2H) 2.66 (t, J = 8.0 Hz, 2H) 2.88 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.4, 14.0 Hz, 1H) 3.53 (sept, J = 6.0Hz, 1H) 3.87 (s, 3H) 4.08 (dd, J = 4.4, 8.0Hz, 1H) 4.63 (d, J = 6.4Hz, 2H) 6.80 (d, J = 8.0Hz, 1H) 7.12 ( dd, J = 2.4, 8.0 Hz, 1H) 7.22 (d, J = 2.4 Hz, 1H) 7.63 (dd, J = 1.6, 8.0 Hz, 1H) 8.10 (d, J = 8.0 Hz, 1H) 8.35 (d, J = 1.6Hz, 1H)
[2455] Example 269
[2456]
[2457] Example 19e), followed by Example 19d) using 4-isopropoxybenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate In the same manner, 2-isopropoxy-3- (3-[(4-isopropoxybenzoyl) amino] methyl-4-methoxyphenyl) propanoic acid was obtained.
[2458] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.34 (d, J = 6.4 Hz, 6H) 2.90 (dd, J = 8.0 , 14.0Hz, 1H) 3.05 (dd, J = 4.4, 14.0Hz, 1H) 3.57 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.10 (dd, J = 4.4, 8.0Hz, 1H) 4.58 (d, J = 6.0Hz, 2H) 4.59-4.61 (m, 1H) 6.55-6.61 (m, 1H) 6.80 (d, J = 8.0Hz, 1H) 6.87 (d, J = 8.8Hz, 2H) 7.13 ( dd, J = 2.0, 8.0Hz, 1H) 7.22 (d, J = 2.0Hz, 1H) 7.69 (d, J = 8.8Hz, 2H)
[2459] Example 270
[2460]
[2461] The same method as Example 19e) following Example 19d) using 4-phenylbenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate 2-isopropoxy-3- (4-methoxy-3-[(4-phenylbenzoyl) amino] methylphenyl) propanoic acid was obtained.
[2462] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0Hz, 1H) 3.58 (sept, J = 6.0Hz, 1H) 3.88 (s, 3H) 4.11 (dd, J = 4.4, 8.0Hz, 1H) 4.63 (d, J = 6.4Hz, 2H) 6.68 -6.73 (m, 1H) 6.82 (d, J = 8.0Hz, 1H) 7.15 (dd, J = 2.0, 8.0Hz, 1H) 7.24 (d, J = 2.0Hz, 1H) 7.35-7.40 (m, 1H) 7.46 (t, J = 7.2 Hz, 2H) 7.59 (d, J = 7.2 Hz, 2H) 7.64 (d, J = 8.0 Hz, 2H) 7.82 (d, J = 8.0 Hz, 2H)
[2463] Example 271
[2464]
[2465] Following Example 19d) using 4-phenoxybenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate, the same procedure as in Example 19e) was performed. 2-isopropoxy-3- (4-methoxy-3-[(4-phenoxybenzoyl) amino] methylphenyl) propanoic acid was obtained by the method.
[2466] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.91 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.4, 14.0Hz, 1H) 3.57 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.10 (dd, J = 4.4, 8.0Hz, 1H) 4.59 (d, J = 6.0Hz, 2H) 6.60 -6.65 (m, 1H) 6.81 (d, J = 8.0 Hz, 1H) 6.98 (d, J = 8.0 Hz, 2H) 7.03 (d, J = 8.0 Hz, 2H) 7.13-7.18 (m, 2H) 7.22 ( d, J = 2.0Hz, 1H) 7.37 (t, J = 8.0Hz, 2H) 7.72 (d, J = 8.0Hz, 2H)
[2467] Example 272
[2468]
[2469] Following Example 19d) using 4-isopropylbenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate, the same as in Example 19e) 2-isopropoxy-3- (3-[(4-isopropylbenzoyl)) amino] methyl-4-methoxyphenyl) propanoic acid was obtained by the method.
[2470] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.25 (d, J = 6.0 Hz, 6H) 2.90 (dd, J = 8.0 , 14.0Hz, 1H) 2.92 (sept, J = 6.0Hz, 1H) 3.04 (dd, J = 4.4, 14.0Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.10 (dd , J = 4.4, 8.0Hz, 1H) 4.60 (d, J = 6.0Hz, 2H) 6.66-6.70 (m, 1H) 6.81 (d, J = 8.0Hz, 1H) 7.14 (dd, J = 2.0, 8.0Hz , 1H) 7.23 (d, J = 2.0 Hz, 1H) 7.26 (d, J = 8.0 Hz, 2H) 7.68 (d, J = 8.0 Hz, 2H)
[2471] Example 273
[2472]
[2473] Following Example 19d) using 2.4-dimethoxybenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate, the same procedure as in Example 19e) was performed. 3- (3-[(2,4-dimethoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained by the method.
[2474] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.4, 14.0 Hz, 1H) 3.56 (sept, J = 6.0 Hz, 1H) 3.85 (s, 3H) 3.88 (s, 3H) 3.92 (s, 3H) 4.09 (dd, J = 4.4, 8.0 Hz, 1H) 4.61-4.63 (m, 2H) 6.47 (d, J = 2.0 Hz, 1H) 6.59 (dd, J = 2.0, 8.8 Hz, 1H) 6.81 (d, J = 8.0 Hz, 1H) 7.13 (dd, J = 2.0 , 8.0Hz, 1H) 7.22 (d, J = 2.0Hz, 1H) 8.19 (d, J = 8.8Hz, 1H) 8.34-8.39 (m, 1H)
[2475] Example 274
[2476]
[2477] Example 38) using 4-cyclohexylbenzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(4-cyclohexylbenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained by the same method as the above.
[2478] MS m / e (ESI) 454 (MH ⁺ )
[2479] Example 275
[2480]
[2481] 4- (4'-ethylphenyl) benzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate In the same manner as in Example 38), 2-isopropoxy-3- [4-methoxy-3-([4- (4'-ethylphenyl) benzoyl] amino) methylphenyl] propanoic acid was obtained.
[2482] MS m / e (ESI) 476 (MH ⁺ )
[2483] Example 276
[2484]
[2485] Example 38 using 2-naphthalenecarboxylic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 2-isopropoxy-3- (4-methoxy-3-[(2-naphthylcarbonyl) amino] methylphenyl) propanoic acid was obtained in the same manner as the above.
[2486] MS m / e (ESI) 422 (MH ⁺ )
[2487] Example 277
[2488] Preparation Example 277a)
[2489]
[2490] 1.9 g of 2-chloro-4-hydroxybenzoic acid was dissolved in 20 ml of dimethylformamide, 1.8 g of methyl iodide and 1.2 g of potassium hydrogencarbonate were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and 1.7 g of methyl 2-chloro-4-hydroxybenzoate was obtained from the hexane-ethyl acetate (3: 1) eluting fraction.
[2491] Preparation Example 277b)
[2492]
[2493] 0.25 g of methyl 2-chloro-4-hydroxybenzoate was dissolved in 10 ml of dimethylformamide, 0.23 g of ethyl iodide and 0.21 g of potassium carbonate were added and stirred for 8 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 6 ml of methanol, 3 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 1.7 g of 2-chloro-4-ethoxybenzoic acid was obtained.
[2494] ¹ H-NMR (CDCl ₃ ) δ: 1.43 (t, J = 7.2 Hz, 3H) 4.10 (q, J = 7.2 Hz, 2H) 6.84 (dd, J = 2.8, 8.8 Hz, 1H) 6.99 (d, J = 2.8 Hz, 1H) 8.03 (d, J = 8.8Hz, 1H)
[2495] Example 277c)
[2496]
[2497] By using 2-chloro-4-ethoxybenzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(2-chloro-4-ethoxybenzoyl) amino] methyl-4-methoxyphenyl] 2-isopropoxypropanoic acid was obtained in the same manner as in Example 38).
[2498] MS m / e (ESI) 450 (MH ⁺ )
[2499] Example 278
[2500] Preparation Example 278a)
[2501]
[2502] Methyl 2-chloro-4-hydroxybenzoate and propyl iodide were used to obtain 2-chloro-4-propoxybenzoic acid in the same manner as in Preparation Example 277b).
[2503] ¹ H-NMR (CDCl ₃ ) δ: 1.05 (t, J = 7.2 Hz, 3H) 1.80-1.86 (m, 2H) 3.98 (t, J = 6.4 Hz, 2H) 6.84 (dd, J = 2.8, 8.8 Hz , 1H) 6.99 (d, J = 2.8 Hz, 1H) 8.03 (d, J = 8.8 Hz, 1H)
[2504] Example 278b)
[2505]
[2506] Example using 2-chloro-4-propoxybenzoic acid and 3- [3-([tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate In the same manner as in 38), 3- (3-[(2-chloro-4-propoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2507] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (t, J = 7.2 Hz, 3H) 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 1.76-1.85 (m, 2H ) 2.91 (dd, J = 8.0, 14.0 Hz, 1H) 3.06 (dd, J = 4.4, 14.0 Hz, 1H) 3.57 (sept, J = 6.0 Hz, 1H) 3.85 (s, 3H) 3.92 (t, J = 6.4 Hz, 2H) 4.10 (dd, J = 4.4, 8.0 Hz, 1H) 4.61 (d, J = 6.0 Hz, 2H) 6.80-6.89 (m, 3H) 6.95-7.02 (m, 1H) 7.14 (dd, J = 2.0, 8.0 Hz, 1H) 7.24 (d, J = 2.0 Hz, 1H) 7.74 (d, J = 8.8 Hz, 1H)
[2508] Example 279
[2509] Preparation Example 279a)
[2510]
[2511] Using 2-chloro-4-hydroxybenzoate methyl and isopropyl iodide, 2-chloro-4-isopropoxybenzoic acid was obtained in the same manner as in Production Example 277b).
[2512] ¹ H-NMR (CDCl ₃ ) δ: 1.37 (d, J = 6.0 Hz, 6H) 4.62 (sept, J = 6.0 Hz, 1H) 6.81 (dd, J = 2.8, 8.8 Hz, 1H) 6.99 (d, J = 2.8 Hz, 1H) 8.02 (d, J = 8.8Hz, 1H)
[2513] Example 279b)
[2514]
[2515] Using 2-chloro-4-isopropoxybenzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate, 3- (3-[(2-chloro-4-isopropoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 38).
[2516] MS m / e (ESI) 464 (MH ⁺ )
[2517] Example 280
[2518] Preparation Example 280a)
[2519]
[2520] Methyl 2-chloro-4-hydroxybenzoate and cyclopentyl bromide were obtained in the same manner as in Production Example 277b) to obtain 2-chloro-4-cyclopentyloxybenzoic acid.
[2521] ¹ H-NMR (CDCl ₃ ) δ: 1.76-1.98 (m, 8H) 4.78-4.82 (m, 1H) 6.81 (dd, J = 2.8, 8.8 Hz, 1H) 6.99 (d, J = 2.8 Hz, 1H) 8.02 (d, J = 8.8Hz, 1H)
[2522] Example 280b)
[2523]
[2524] Using 2-chloro-4-cyclopentyloxybenzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate, 3- (3-[(2-chloro-4-cyclopentyloxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 381.
[2525] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 1.72-1.95 (m, 8H) 2.91 (dd, J = 8.0, 14.0 Hz , 1H) 3.05 (dd, J = 4.4, 14.0 Hz, 1H) 3.56 (sept, J = 6.0 Hz, 1H) 3.85 (s, 3H) 4.10 (dd, J = 4.4, 8.0 Hz, 1H) 4.60 (d, J = 6.0 Hz, 2H) 4.74-4.77 (m, 1H) 6.79 -6.86 (m, 3H) 6.95-7.01 (m, 1H) 7.14 (dd, J = 2.0, 8.0 Hz, 1H) 7.24 (d, J = 2.0 Hz, 1H) 7.73 (d, J = 8.8Hz, 1H)
[2526] Example 281
[2527] Preparation Example 281a)
[2528]
[2529] 5.0 g of 4-chloro-2-hydroxybenzoic acid was dissolved in 25 ml of dimethylformamide, 14.5 g of ethyl iodide and 12 g of potassium carbonate were added, and the mixture was stirred at 70 ° C for 8 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and 3.8 g of ethyl 4-chloro-2-ethoxybenzoate was obtained from the hexane-ethyl acetate (2: 1) elution fraction.
[2530] ¹ H-NMR (CDCl ₃ ) δ: 1.48 (t, J = 7.2 Hz, 3H) 1.59 (t, J = 7.2 Hz, 3H) 4.10 (q, J = 7.2 Hz, 2H) 4.33 (q, J = 7.2 Hz, 2H) 6.92 (d, J = 2.0 Hz, 1H) 6.94 (dd, J = 2.0, 8.8 Hz, 1H) 7.73 (d, J = 8.8 Hz, 1H)
[2531] Preparation Example 281 b)
[2532]
[2533] 0.2 g of ethyl 4-chloro-2-ethoxybenzoate was dissolved in 5 ml of methanol, 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 0.20 g of 4-chloro-2-ethoxybenzoic acid.
[2534] ¹ H-NMR (CDCl ₃ ) δ: 1.59 (t, J = 7.2 Hz, 3H) 4.33 (q, J = 7.2 Hz, 2H) 7.04 (d, J = 2.0 Hz, 1H) 7.13 (dd, J = 2.0 , 8.8Hz, 1H) 8.13 (d, J = 8.8Hz, 1H)
[2535] Example 281c)
[2536]
[2537] By using 4-chloro-2-ethoxybenzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(4-chloro-2-ethoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 38).
[2538] MS m / e (ESI) 450 (MH ⁺ )
[2539] Example 282
[2540] Preparation Example 282a)
[2541]
[2542] 2,4-dihydroxybenzoic acid and ethyl iodide were obtained in the same manner as in Production Example 281b) following Production Example 281a) to obtain 2.4-diethoxybenzoic acid.
[2543] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (t, J = 7.2 Hz, 3H) 1.56 (t, J = 7.2 Hz, 3H) 4.10 (q, J = 7.2 Hz, 2H) 4.28 (q, J = 7.2 Hz, 2H) 6.51 (d, J = 2.0Hz, 1H) 6.62 (dd, J = 2.0, 8.8Hz, 1H) 8.12 (d, J = 8.8Hz, 1H)
[2544] Example 282b)
[2545]
[2546] Example 38, using 2,4-diethoxybenzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate In the same manner as in the above), 3- (3-[(2,4-diethoxybenzoyl)) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained.
[2547] MS m / e (ESI) 460 (MH ⁺ )
[2548] Example 283
[2549] Preparation Example 283a)
[2550]
[2551] 0.80 g of 2-hydroxy-4- (trifluoromethyl) benzaldehyde was dissolved in 8 ml of dimethylformamide, 0.78 g of ethyl iodide and 0.69 g of potassium carbonate were added, and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and 0.60 g of 2-ethoxy-4- (trifluoromethyl) benzaldehyde was obtained from the hexane-ethyl acetate (5: 1) eluting fraction.
[2552] ¹ H-NMR (CDCl ₃ ) δ: 1.57 (t, J = 7.2 Hz, 3H) 4.22 (q, J = 7.2 Hz, 2H) 7.22 (s, 1H) 7.29 (d, J = 8.0 Hz, 1H) 7.93 (d, J = 8.0Hz, 1H) 10.50 (s, 1H)
[2553] Preparation Example 283b)
[2554]
[2555] 0.60 g of 2-ethoxy-4- (trifluoromethyl) benzaldehyde was dissolved in 5 ml of dimethyl sulfoxide and 67 mg aqueous sodium dihydrogen phosphate (1 ml), and 0.35 g aqueous sodium chlorite (3 ml) was added dropwise. After stirring for 12 hours at room temperature, water was added and extracted with ethyl acetate. After washing with saturated brine and drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography to obtain 0.55 g of 2-ethoxy-4- (trifluoromethyl) benzoic acid from the hexane-ethyl acetate (2: 1) eluting fraction.
[2556] ¹ H-NMR (CDCl ₃ ) δ: 1.57 (t, J = 7.2 Hz, 3H) 4.22 (q, J = 7.2 Hz, 2H) 7.22 (s, 1H) 7.29 (d, J = 8.0 Hz, 1H) 7.93 (d, J = 8.0Hz, 1H) 10.50 (s, 1H)
[2557] Example 283c)
[2558]
[2559] 2-ethoxy-4- (trifluoromethyl) benzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate Using 3- [3-([2-ethoxy-4- (trifluoromethyl) benzoyl] aminomethyl) -4-methoxyphenyl1-2-isopropoxy in the same manner as in Example 38) Propanic acid was obtained.
[2560] MS m / e (ESI) 484 (MH ⁺ )
[2561] Example 284
[2562] Preparation Example 284a)
[2563]
[2564] Using 2-hydroxy-4- (trifluoromethyl) benzaldehyde and propyl iodide, 2-propoxy-4- (trifluoromethyl) benzaldehyde was obtained in the same manner as in Preparation Example 283a).
[2565] ¹ H-NMR (CDCl ₃ ) δ: 1.11 (t, J = 7.2 Hz, 3H) 1.88-1.96 (m, 2H) 4.10 (t, J = 7.2 Hz, 2H) 7.22 (s, 1H) 7.29 (d, J = 8.0Hz, 1H) 7.93 (d, J = 8.0Hz, 1H) 10.50 (s, 1H)
[2566] Preparation Example 284b)
[2567]
[2568] Using 2-propoxy-4- (trifluoromethyl) benzaldehyde, 2-propoxy-4- (trifluoromethyl) benzoic acid was obtained in the same manner as in Preparation Example 283b).
[2569] ¹ H-NMR (CDCl ₃ ) δ: 1.15 (t, J = 7.2 Hz, 3H) 1.94-2.04 (m, 2H) 4.30 (t, J = 7.2 Hz, 2H) 7.28 (s, 1H) 7.40 (d, J = 8.0Hz, 1H) 8.30 (d, J = 8.0Hz, 1H)
[2570] Example 284c)
[2571]
[2572] 2-propoxy-4- (trifluoromethyl) benzoic acid and 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate Using 2-isopropoxy-3- [4-methoxy-3-([2-propoxy-4- (trifluoromethyl) benzoyl] aminomethyl) phenyl] in the same manner as in Example 38). Got propanoic acid,
[2573] MS m / e (ESI) 498 (MH ⁺ )
[2574] Example 285
[2575] Preparation Example 285a)
[2576]
[2577] Ethyl 3-[-3 in the same manner as in Example 19d, using 4-bromobenzoic acid and ethyl 3- [3- (aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoate -([4-bromobenzoyl] amino) methyl] -4-methoxyphenyl) -2-isopropoxypropanoate was obtained. Subsequently, 1.1 g of ethyl 3-[-3-([4-bromobenzoyl] amino) methyl] -4-methoxyphenyl) -2-isopropoxypropanoate and 0.64 g of bis (pinacholate) diboron were then obtained. 56 mg of 1,1-bis (diphenylphosphino) ferrocenedichloropalladium and 0.68 g of potassium acetate were dissolved in 20 ml of dimethyl sulfoxide and stirred at 80 ° C. under nitrogen atmosphere for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added, the mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography and purified from hexane-ethyl acetate (1: 1) eluting fractions with ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5, 1.23 g of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] aminomethyl) phenyl] propanoate were obtained.
[2578] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (t, J = 6.4 Hz, 3H) 1.14 (d, J = 6.4 Hz, 3H) 1.21-1.27 (m, 3H) 1.35 (s, 12H) 2.88 (dd, J = 8.4, 14.0Hz, 1H) 2.94 (dd, J = 4.8, 14.0Hz, 1H) 3.50 (sept, J = 6.4Hz, 1H) 3.86 (s, 3H) 4.02 (dd, J = 4.8, 8.4Hz, 1H) 4.14-4.19 (m, 2H) 4.62 (d, J = 5.6 Hz, 2H) 6.65-6.70 (m, 1H) 6.81 (d, J = 8.4 Hz, 1H) 7.16 (dd, J = 2.4, 8.4 Hz , 1H) 7.22 (d, J = 2.4Hz, 1H) 7.73 (d, J = 8.0Hz, 2H) 7.85 (d, J = 8.0Hz, 2H)
[2579] Example 285b)
[2580]
[2581] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 53 mg of methyl) phenyl] propanoate, 21 mg of 4-bromofluorobenzene, 5.7 mg of 1,1-bis (diphenylphosphino) ferrocenedichloropalladium and 55 mg of potassium carbonate were dissolved in 1.5 ml of dimethoxyethane, and were in a nitrogen atmosphere. It stirred at 80 degreeC under 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and the mother liquor was distilled off under reduced pressure. The residue was dissolved in 2 ml of ethanol, 1 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was concentrated, and then purified by HPLC using a water-acetonitrile-trifluoroacetic acid system as an eluting solvent in a column of reversed phase to give 2-isopropoxy-3-4- [methoxy-3-4- (4 19 mg of '-fluorophenyl) benzoyl] amino) methylphenyl] propanoic acid were obtained.
[2582] MS m / e (ESI) 466 (MH ⁺ )
[2583] Example 286
[2584]
[2585] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 2-isopropoxy-3-4- [methoxy-3-([4- (4'-), in the same manner as in Example 285) using methyl) phenyl] propanoate and 4-bromochlorobenzene Chlorophenyl) benzoyl] amino) methylphenyl] propanoic acid.
[2586] MS m / e (ESI) 482 (MH ⁺ )
[2587] Example 287
[2588]
[2589] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino Methyl) phenyl] propanoate and 2-bromochlorobenzene, in the same manner as in Example 285), 2-isopropoxy-3-4- [methoxy-3-([4- (2'- Chlorophenyl) benzoyl] amino) methylphenyl] propanoic acid.
[2590] MS m / e (ESI) 482 (MH ⁺ )
[2591] Example 288
[2592]
[2593] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 2-isopropoxy-3-4- [methoxy-3-([4- (4'-), in the same manner as in Example 285) using methyl) phenyl] propanoate and 4-bromoanisole Methoxyphenyl) benzoyl] amino) methylphenyl] propanoic acid was obtained.
[2594] MS m / e (ESI) 478 (MH ⁺ )
[2595] Example 289
[2596]
[2597] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 2-isopropoxy-3-4- (methoxy-3-[(4- [4 ') in the same manner as in Example 285 using methyl) phenyl] propanoate and 4-bromobenzotrifluoride -(Trifluoromethyl) phenyl] benzoyl) amino] methylphenyl) propanoic acid was obtained.
[2598] MS m / e (ESl) 5I6 (MH ⁺ )
[2599] Example 290
[2600]
[2601] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 2-isopropoxy-3- [4-methoxy-3-[([4- (1,3) in the same manner as in Example 285) using methyl) phenyl] propanoate and 2-bromothiazole -Thiazol-2-yl) benzoyl] amino) methyl-1-phenyl] propanoic acid was obtained.
[2602] MS m / e (ESI) 455 (MH ⁺ )
[2603] Example 291
[2604]
[2605] Ethyl 2-isopropoxy-3- [4-methoxy-3-([4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoyl] amino 2-isopropoxy-3- [4-methoxy-3-[([4- (2-pyri) in the same manner as in Example 285) using methyl) phenyl] propanoate and 2-bromopyridine Dill) benzoyl] amino) methyl-1-phenyl) propanoic acid was obtained.
[2606] MS m / e (ESI) 449 (MH ⁺ )
[2607] Example 292
[2608] Preparation Example 292a)
[2609]
[2610] Methyl-2-chloro-4- (4,4,5,5-tetramethyl-) using 1.0 g of 4-bromo-2-chlorobenzoic acid followed by Preparation Example 277a) and in the same manner as Preparation Example 285) 0.91 g of 1,3,2-dioxaboran-2-yl) benzoate was obtained.
[2611] ¹ H-NMR (CDCl ₃ ) δ: 1.25 (s, 6H) 1.36 (s, 6H) 1.14 (d, J = 6.4 Hz, 3H) 3.94 (s, 3H) 7.70 (d, J = 8.0 Hz, 1H) 7.79 (d, J = 8.0 Hz, 1H) 7.84 (s, 1H)
[2612] Preparation Example 292b)
[2613]
[2614] Methyl-2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) benzoate 0.30 g, bromobenzene 0.19 g, 1,1-bis 57 mg of (diphenylphosphino) ferrocenedichloropalladium and 0.55 g of potassium carbonate were dissolved in 15 ml of dimethoxyethane and heated and refluxed under a nitrogen atmosphere for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added, the mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and methyl 2-chloro-4-phenylbenzoate was obtained from the hexane-ethyl acetate (5: 1) eluting fraction. Subsequently, methyl 2-chloro-4-phenylbenzoate obtained was dissolved in 4 ml of methanol, 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 0.12 g of 2-chloro-4-phenylbenzoic acid was obtained.
[2615] 1 H-NMR (CDCl 3) δ: 7.44-7.52 (m, 3H) 7.56-7.63 (m, 3H) 7.73 (d, J = 1.6 Hz, 3H) 8.05 (d, J = 8.0 Hz, 1H)
[2616] Example 292c)
[2617]
[2618] By using 2-chloro-4-phenylbenzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3-[(2-chloro-4-phenylbenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 38).
[2619] MS m / e (ESI) 482 (MH ⁺ )
[2620] Example 293
[2621] Preparation Example 293a)
[2622]
[2623] Preparation Example 292b using methyl-2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) benzoate and 4-bromochlorobenzene 2-chloro-4- (4'-chlorophenyl) benzoic acid was obtained in the same manner as).
[2624] ¹ H-NMR (DMSO-d ₆ ) δ: 7.54 (d, J = 8.8 Hz, 2H) 7.72 (dd, J = 1.6, 8.0 Hz, 2H) 7.78 (d, J = 8.8 Hz, 2H) 7.84 (d , J = 1.6Hz, 2H) 7.87 (d, J = 8.0Hz, 1H)
[2625] Example 293b)
[2626]
[2627] 2-Chloro-4- (4'-chlorophenyl) benzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropano 3- (3- [2-chloro-4- (4'-chlorophenyl) benzoyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxy using the same method as in Example 38) Propanic acid was obtained.
[2628] MS m / e (ESI) 516 (MH ⁺ )
[2629] Example 294
[2630] Preparation Example 294a)
[2631]
[2632] Preparation Example 292b) using methyl-2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) benzoate and 4-bromotoluene 2-Chloro-4- (4'-methylphenyl) benzoic acid was obtained in the same manner as the same.
[2633] ¹ H-NMR (CDCl ₃ ) δ: 2.42 (s, 3H) 7.29 (d, J = 8.0 Hz, 2H) 7.52 (d, J = 8.0 Hz, 2H) 7.56 (dd, J = 1.6, 8.4 Hz, 1H ) 7.71 (d, J = 1.6Hz, 1H) 8.09 (d, J = 8.4Hz, 1H)
[2634] Example 294b)
[2635]
[2636] 2-Chloro-4- (4'-methylphenyl) benzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate 3- (3- [2-chloro-4- (4'-methylphenyl) benzoyl] aminomethyl) -4-methoxyphenyl] -2-isopropoxypropanoic acid in the same manner as in Example 38) Got.
[2637] MS m / e (ESI) 496 (MH ⁺ )
[2638] Example 295
[2639] Preparation Example 295a)
[2640]
[2641] 0.50 g of ethyl 4-chloro-2-ethoxybenzoate, 0.31 g of phenylboronic acid, 85 mg of 1,1-bis (diphenylphosphino) ferrocenedichloronickel, and 1.4 g of potassium phosphate were dissolved in 8 ml of dioxane, and under nitrogen atmosphere. It stirred at 95 degreeC for 1 hour. After cooling the reaction solution to room temperature, ethyl acetate and water were added, the mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and ethyl 2-ethoxy-4-phenylbenzoate was obtained from the hexane-ethyl acetate (9: 1) eluting fraction. Subsequently, ethyl 2-ethoxy-4-phenylbenzoate obtained was dissolved in 4 ml of ethanol, 2 ml of 1N sodium hydroxide was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was ice-cooled, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and 0.22 g of 2-ethoxy-4-phenylbenzoic acid was obtained.
[2642] ¹ H-NMR (CDCl ₃ ) δ: 1.61 (t, J = 7.2 Hz, 3H) 4.42 (q, J = 7.2 Hz, 2H) 7.21 (d, J = 1.6 Hz, 1H) 7.36 (dd, J = 1.6 , 8.4Hz, 1H) 7.43-7.51 (m, 3H) 7.59-7.61 (m, 1H) 8.25 (d, J = 8.4Hz, 1H)
[2643] Example 295b)
[2644]
[2645] Using 2-ethoxy-4-phenylbenzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxypropanoate, 3- (3-[(2-ethoxy-4-phenylbenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was obtained in the same manner as in Example 38).
[2646] MS m / e (ESI) 492 (MH ⁺ )
[2647] Example 296
[2648] Preparation Example 296a)
[2649]
[2650] 2-Ethoxy-4- (4'-fluorophenyl) benzoic acid was obtained in the same manner as in Production Example 295) using ethyl 4-chloro-2-ethoxybenzoate and 4-fluorobenzeneboronic acid.
[2651] ¹ H-NMR (CDCl ₃ ) δ: 1.61 (t, J = 7.2 Hz, 3H) 4.42 (q, J = 7.2 Hz, 2H) 7.15-7.20 (m, 3H) 7.30 (dd, J = 1.6, 8.0 Hz , 1H) 7.55-7.59 (m, 2H) 8.24 (d, J = 8.0Hz, 1H)
[2652] Example 296b)
[2653]
[2654] 2-ethoxy-4- (4'-fluorophenyl]) benzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopro 3- (3- [2-ethoxy-4- (4'-fluorophenyl) benzoyl] aminomethyl) -4-methoxyphenyl]-in the same manner as in Example 38, using foxypropanoate 2-isopropoxypropanoic acid was obtained.
[2655] MS m / e (ESI) 510 (MH ⁺ )
[2656] Example 297
[2657] Preparation Example 297a)
[2658]
[2659] 2-Ethoxy-4- (4'-methoxyphenyl) benzoic acid was obtained in the same manner as in Production Example 295 using ethyl 4-chloro-2-ethoxybenzoate and 4-methoxybenzeneboronic acid.
[2660] ¹ H-NMR (CDCl ₃ ) δ: 1.61 (t, J = 7.2 Hz, 3H) 3.87 (s, 3H) 4.41 (q, J = 7.2 Hz, 2H) 7.01 (d, J = 8.0 Hz, 2H) 7.17 (d, J = 1.6Hz, 1H) 7.31 (dd, J = 1.6, 8.4Hz, 1H) 7.55 (d, J = 8.0Hz, 2H) 8.22 (d, J = 8.4Hz, 1H)
[2661] Example 297b)
[2662]
[2663] 2-ethoxy-4- (4'-methoxyphenyl) benzoic acid and ethyl 3- [3-([(tert-butoxycarbonyl) amino] methyl) -4-methoxyphenyl] -2-isopropoxy 3- (3- [2-ethoxy-4- (4'-methoxyphenyl]) benzoyl] aminomethyl) -4-methoxyphenyl] -2 in the same manner as in Example 38 using propanoate Isopropoxypropanoic acid was obtained.
[2664] MS m / e (ESI) 522 (MH ⁺ )
[2665] Example 298
[2666]
[2667] 3- [3-([2-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4-methoxyphenyl] -2-propoxypropanoic acid was obtained in the same manner as in Example 218.
[2668] ¹ H-NMR (CDCl ₃ ) δ: 0.86 (t, J = 7.2 Hz, 3H) 1.51-1.61 (m, 2H) 2.97 (dd, J = 8.0, 14.0 Hz, 1H) 3.07 (dd, J = 4.4, 14.0Hz, 1H) 3.35 (dt, J = 6.4, 8.8Hz, 1H) 3.50 (dt, J = 6.4, 8.8Hz, 1H) 3.89 (s, 3H) 4.04 (dd, J = 4.4, 8.0Hz, 1H) 4.64 (d, J = 6.0 Hz, 2H) 6.82 (d, J = 8.0 Hz, 1H) 7.17 (dd, J = 2.0, 8.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1H) 7.38 (d, J = 12.0Hz, 1H) 7.37-7.45 (m, 1H) 7.52 (d, J = 8.0Hz, 1H) 8.23 (t, J = 8.0Hz, 1H)
[2669] Example 299
[2670]
[2671] 3- (3-[(4-chloro-2-fluorobenzoyl) amino] methyl-4-methoxyphenyl) -2-propoxypropanoic acid was obtained in the same manner as in Example 218.
[2672] MS m / e (ESI) 424 (MH ⁺ )
[2673] Example 300
[2674]
[2675] 3- [4-methoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) phenyl] -2- in the same manner as in Example 218 Propoxypropanoic acid was obtained.
[2676] MS m / e (ESI) 469 (MH ⁺ )
[2677] Example 301
[2678]
[2679] 3- (3-[(2-chloro-4-propoxy) amino] methyl-4-methoxyphenyl) -2-propoxypropanoic acid was obtained in the same manner as in Example 218.
[2680] MS m / e (ESI) 464 (MH ⁺ )
[2681] Example 302
[2682]
[2683] 3- [3-([2-chloro4- (cyclopentyloxy) benzoyl] aminomethyl) -4-methoxyphenyl] -2-propoxypropanoic acid was obtained in the same manner as in Example 218.
[2684] MS m / e (ESI) 4 O (MH ⁺ )
[2685] Example 303
[2686]
[2687] 3- (3-[(4-cyclohexylbenzoyl) amino] methyl-4-methoxyphenyl) -2-propoxypropanoic acid was obtained in the same manner as in Example 218.
[2688] MS m / e (ESI) 454 (MH ⁺ )
[2689] Example 304
[2690]
[2691] 3-3-[([2- (2-chlorophenyl) -5-methyl-1,3-thiazol-4-yl] carbonylamino) methyl] -4-methoxyphenyl in the same manner as in Example 218. 2-propoxypropanoic acid was obtained.
[2692] MS m / e (ESI) 503 (MH ⁺ )
[2693] Example 305
[2694]
[2695] 3-4-methoxy-3-[([5-methyl-2- (4-methylphenyl) -1,3-thiazol-4-yl] carbonylamino) methyl-1- in the same manner as in Example 218 Phenyl-2-propoxypropanoic acid was obtained.
[2696] MS m / e (ESI) 483 (MH ⁺ )
[2697] Example 306
[2698]
[2699] 3- (3-[(2,4-dichlorobenzoyl) amino] methyl-4-methoxyphenyl) -2-ethoxypropanoic acid was obtained in the same manner as in Example 218.
[2700] MS m / e (ESI) 426 (MH ⁺ )
[2701] Example 307
[2702]
[2703] 2-Ethoxy-3- [4-methoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) in the same manner as in Example 218 Phenyl] propanoic acid was obtained.
[2704] MS m / e (ESI) 455 (MH ⁺ )
[2705] Example 308
[2706]
[2707] 3- (3-[(2,4-dichlorobenzoyl) amino] methyl-4-methoxyphenyl) -2-isobutoxypropanoic acid was obtained in the same manner as in Example 218.
[2708] MS m / e (ESI) 454 (MH ⁺ )
[2709] Example 309
[2710]
[2711] 2-isobutoxy-3- [4-methoxy-3-([(5-methyl-2-phenyl-1,3-thiazol-4-yl) carbonyl] aminomethyl) in the same manner as in Example 218. Phenyl] propanoic acid was obtained.
[2712] MS m / e (ESI) 483 (MH ⁺ )
[2713] Example 310
[2714]
[2715] In the same manner as in Example 1d) and 1e), 2- [4-methoxy-3-([4- (trifluoromethoxy) benzoyl] aminomethyl) benzyl] butanoic acid was obtained.
[2716] δ: 0.94 (t, J = 7.2 Hz, 3H) 1.51-1.71 (m, 2H) 2.51-2.58 (m, 1H) 2.70 (dd, J = 5.8, 14.0 Hz, 1H) 2.88 (dd, J = 8.4, 14.0 Hz, 1H) 3.84 (s, 3H) 4.57 (d, J = 5.6 Hz, 2H) 6.75 (t, J = 5.6 Hz, 1H) 6.80 (d, J = 8.4 Hz, 1H) 7.09 (dd, J = 2.0, 8.4 Hz, 1H) 7.15 (d, J = 2.0 Hz, 1H) 7.23 (d, 8.4 Hz, 2H) 7.79 (dt, J = 2.0, 8.4 Hz, 2H)
[2717] Example 311
[2718]
[2719] In the same manner as in Example 1d) and 1e), 2- (4-methoxy-3-[(2-naphthylcarbonyl) amino] methylbenzyl) butanoic acid was obtained.
[2720] ¹ H-NMR (CDCl ₃ ) δ: 0.96 (t, J = 7.2 Hz, 3H) 2.53-2.62 (m, 1H) 2.73 (dd, J = 5.8, 14.0 Hz, 1H) 2.89 (dd, J = 8.6, 14.0Hz, 1H) 2.89 (dd, J = 8.6, 14.0Hz, 1H) 3.87 (s, 3H) 4.64 (d, J = 6.0Hz, 2H) 6.82 (d, J = 8.4Hz, 1H) 6.85 (t, J = 6.0Hz, 1H) 7.10 (dd, 2.2, 8.4Hz, 1H) 7.22 (d, J = 2.2Hz, 1H), 7.4-7.58 (m, 2H) 7.78-7.94 (m, 4H) 8.27 (s, 1H)
[2721] Example 312
[2722]
[2723] In the same manner as in Example 1d) and 1e), 2- [4-methoxy-3-([(1-methyl-1H-2-indylcarbonyl] aminomethyl) benzyl] butanoic acid was obtained.
[2724] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 7.2 Hz, 3H) 1.51-1.62 (m, 2H) 2.53-2.62 (m, 1H) 2.72 (dd, J = 6.4, 14.0 Hz, 1H) 2.89 (dd, J = 4.4, 14.0 Hz, 1H) 3.86 (s, 3H) 4.04 (s, 3H) 4.57 (d, J = 5.6 Hz, 2H) 6.77 (t, J = 5.6 Hz, 1H) 6.79-6.83 (m, 2H) 7.06-7.18 (m, 3H) 7.27-7.33 (m, 1H) 7.37 (d, J = 8.4 Hz, 1H) 7.61 (d, J = 8.0 Hz, 1H)
[2725] Example 313
[2726]
[2727] In the same manner as in Example 1d) and 1e), 2- (3-[(2,4-dimethoxybenzoyl) amino] methyl-4-methoxybenzyl) butanoic acid was obtained.
[2728] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.2 Hz, 3H) 1.50-1.71 (m, 2H) 2.49-2.58 (m, 1H) 2.70 (dd, J = 6.0, 14.0 Hz, 1H) 2.86 (dd, J = 4.4, 14.0 Hz, 1H) 3.84 (s, 3H) 3.86 (s, 3H) 3.90 (s, 3H) 4.59 (d, J = 6.0 Hz, 1H) 4.60 (d, J = 6.0 Hz , 1H) 6.46 (d, J = 2.4Hz, 1H) 6.58 (dd, J = 2.4, 8.8Hz, 1H) 6.78 (d, J = 8.4Hz, 1H) 7.05 (dd, J = 2.4, 8.4Hz, 1H ) 7.17 (d, J = 2.4Hz, 1H) 8.16 (d, J = 8.8Hz, 1H) 8.35 (t, J = 6.0Hz, 1H)
[2729] Example 314
[2730]
[2731] In the same manner as in Example 1d) and 1e), 2- [3-([(5-butyl-2-pyridyl) carbonyl] aminomethyl) -4-methoxybenzyl] butanoic acid was obtained.
[2732] ¹ H-NMR (CDCl ₃ ) δ: 0.90-1.00 (m, 6H) 1.30-1.42 (m, 2H) 1.50-1.71 (m, 4H) 2.50-2.59 (m, 1H) 2.65 (t, J = 8.0 Hz , 2H) 2.70 (dd, J = 6.4, 14.0 Hz, 1H) 2.86 (dd, J = 8.4, 14.0 Hz, 1H) 3.86 (s, 3H) 4.61 (d, J = 6.4 Hz, 2H) 6.78 (d, J = 8.4 Hz, 1H) 7.06 (dd, J = 2.4, 8.4 Hz, 1H) 7.17 (d, J = 2.4 Hz, 1H) 7.62 (dd, J = 2.0, 8.0 Hz, 1H) 8.10 (d, J = 8.0Hz, 1H) 8.35 (d, J = 2.0Hz, 1H) 8.42 (t, J = 6.4Hz, 1H)
[2733] Example 315
[2734]
[2735] In the same manner as in Example 1d) and 1e), 2- (4-methoxy-3-[(2,4,5-trimethoxybenzoyl) amino] methylbenzyl) butanoic acid was obtained.
[2736] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 7.6 Hz, 3H) 1.50-1.70 (m, 2H) 2.50-2.58 (m, 1H) 2.69 (dd, J = 6.0, 13.6 Hz, 1H) 2.88 (dd, J = 8.4, 13.6 Hz, 1H) 3.86 (s, 3H) 3.88 (s, 3H) 3.91 (s, 3H) 3.92 (s, 3H) 4.60 (d, J = 6.0 Hz, 2H) 6.49 ( s, 1H) 6.78 (d, J = 8.0 Hz, 1H) 7.06 (dd, J = 2.0, 8.0 Hz, 1H) 7.17 (d, J = 2.0 Hz, 1H) 7.75 (s, 1H) 8.45 (t, J = 6.0 Hz, 1H)
[2737] Example 316
[2738]
[2739] In the same manner as in Example 1d) and 1e), 2- (3- [2,4-dimethylbenzoylamino] methyl-4-methoxybenzyl) butanoic acid was obtained.
[2740] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.2 Hz, 3H) 1.50-1.71 (m, 2H) 2.31 (s, 3H) 2.36 (s, 3H) 2.50-2.59 (m, 1H) 2.70 (dd, J = 6.6, 14.0Hz, 1H) 2.88 (dd, J = 8.4, 14.0Hz, 1H) 3.81 (s, 3H) 4.54 (d, J = 6.0Hz, 1H) 4.55 (d, J = 6.0Hz , 1H) 6.29 (t, J = 6.0Hz, 1H) 6.78 (d, J = 8.6Hz, 1H) 6.98 (d, J = 7.6Hz, 1H) 7.00 (s, 1H) 7.08 (dd, J = 2.0, 8.6 Hz, 1H) 7.18 (d, J = 2.0 Hz, 1H) 7.24 (d, J = 7.6 Hz, 1H)
[2741] Example 317
[2742]
[2743] In the same manner as in Example 1d) and 1e), 2- [4-methoxy-3-([(5-methyl-2-pyrazinyl) carbonyl] aminomethyl) benzyl] butanoic acid was obtained.
[2744] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.2 Hz, 3H) 1.50-1.70 (m, 2H) 2.50-2.58 (m, 1H) 2.69 (dd, J = 6.8, 14.0 Hz, 1H) 2.88 (dd, J = 8.4, 14.0 Hz, 1H) 3.85 (s, 3H) 4.61 (d, J = 6.0 Hz, 2H) 6.79 (d, J = 8.4 Hz, 1H) 7.08 (dd, J = 2.0, 8.4 Hz, 1H) 7.15 (d, J = 2.0 Hz, 1H) 8.21 (t, J = 6.0 Hz, 1H) 8.36 (s, 1H) 9.26 (s, 1H)
[2745] Example 318
[2746]
[2747] In the same manner as in Example 1d) and 1e), 2- (4-methoxy-3-[(2-quinolylcarbonyl) amino] methylbenzyl) butanoic acid was obtained.
[2748] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 7.2 Hz, 3H) 1.50-1.70 (m, 2H) 2.51-2.60 (m, 1H) 2.70 (dd, J = 6.4, 13.4 Hz, 1H) 2.89 (dd, J = 8.6, 13.4 Hz, 1H) 3.87 (s, 3H) 4.68 (d, J = 6.4 Hz, 2H) 6.80 (d, J = 8.2 Hz, 1H) 7.07 (dd, J = 2.2, 8.2 Hz, 1H) 7.11 (d, J = 2.2 Hz, 1H) 7.69 (t, J = 8.0 Hz, 1H) 7.76 (t, J = 8.0 Hz, 1H) 7.97 (d, J = 8.0 Hz, 1H) 8.01 ( d, J = 8.0Hz, 1H) 8.62 (s, 1H) 8.67 (t, J = 6.4Hz, 1H) 9.15 (s, 1H)
[2749] Example 319
[2750]
[2751] In the same manner as in Example 1d) and 1e), 2- (4-methoxy-3-[(6-quinolylcarbonyl) amino] methylbenzyl) butanoic acid was obtained.
[2752] ¹ H-NMR (CDCl ₃ ) δ: 0.91 (t, J = 7.6 Hz, 3H) 1.47-1.70 (m, 2H) 2.47-2.56 (m, 1H) 2.69 (dd, J = 6.0, 14.0 Hz, 1H) 2.84 (dd, J = 8.8, 14.0 Hz, 1H) 3.79 (s, 3H) 4.57 (d, J = 6.0 Hz, 2H) 6.75 (d, J = 8.0 Hz, 1H) 6.84 (t, J = 6.0 Hz, 1H) 7.05 (dd, J = 2.0, 8.0 Hz, 1H) 7.17 (d, J = 2.0 Hz, 1H) 7.34 (dd, J = 4.4, 8.4 Hz, 1H) 7.88 (dd, J = 2.0, 8.8 Hz, 1H) 7.96 (t, J = 8.8Hz, 1H) 8.06 (d, J = 8.4Hz, 1H) 8.10 (s, 1H) 8.86 (d, J = 2.8Hz, 1H)
[2753] Example 320
[2754]
[2755] 2- (3-[(2,6-difluoro-4-methoxybenzoyl) amino] methyl-4-methoxybenzyl) butanoic acid was obtained.
[2756] ¹ H-NMR (CDCl ₃ ) δ: 0.95 (t, J = 7.6 Hz, 3H) 1.53-1.71 (m, 2H) 2.52-2.59 (m, 1H) 2.70 (dd, J = 6.6, 14.0 Hz, 1H) 2.88 (dd, J = 8.4, 14.0 Hz, 1H) 3.79 (s, 3H) 3.83 (s, 3H) 4.57 (d, J = 5.6 Hz, 1H) 4.57 (d, J = 5.6 Hz, 1H) 6.44 (s , 1H) 6.46 (s, 1H) 6.78 (d, J = 8.0 Hz, 1H) 7.07 (dd, J = 2.0, 8.0 Hz, 1H) 7.17 (d, J = 2.0 Hz, 1H)
[2757] Example 321
[2758]
[2759] In the same manner as in Example 1d) and 1e), 2- [4-methoxy-3-([(5-methoxypyridyl-2-pyridyl) carbonyl] aminomethyl) penyl] butanoic acid was prepared. Got it.
[2760] ¹ H-NMR (CDCl ₃ ) δ: 0.93 (t, J = 7.2 Hz, 3H) 1.48-1.70 (m, 2H) 2.48-2.57 (m, 1H) 2.69 (dd, J = 6.6, 13.6 Hz, 1H) 2.87 (dd, J = 8.4, 13.6 Hz, 1H) 3.85 (s, 3H) 3.89 (s, 3H) 4.59 (d, J = 6.0 Hz, 2H) 6.78 (d, J = 8.0 Hz, 1H) 7.06 (dd , J = 2.0, 8.0Hz, 1H) 7.16 (d, J = 2.0Hz, 1H) 7.26 (dd, J = 3.2, 8.4Hz, 1H) 8.14 (d, J = 8.4Hz, 1H) 8.19 (d, J = 3.2Hz, 1H) 8.30 (t, J = 6.0Hz, 1H)
[2761] Example 322
[2762]
[2763] In the same manner as in Example 1d) and 1e), 2- [3-([(3,5-dichloro-2-pyridyl) carbonyl] aminomethyl) -4-methoxybenzyl] butanoic acid was obtained. .
[2764] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.2 Hz, 3H) 1.51-1.70 (m, 2H) 2.50-2.59 (m, 1H) 2.69 (dd, J = 6.4, 13.6 Hz, 1H) 2.87 (dd, J = 8.4, 13.6 Hz, 1H) 3.85 (s, 3H) 4.57 (d, J = 6.4 Hz, 2H) 6.78 (d, J = 8.4 Hz, 1H) 7.07 (dd, J = 2.2, 8.4 Hz, 1H) 7.16 (s, 1H) 7.82 (d, J = 2.0 Hz, 1H) 8.09 (t, J = 6.4 Hz, 1H) 8.40 (d, J = 2.0 Hz, 1H)
[2765] Example 323
[2766]
[2767] Treatment was carried out in the same manner as in Examples 1d) and 1e), and 2- [3-([(4-chlorobenzo [b] furan-7-yl) carbonyl] aminomethyl) -4-methoxybenzyl] butanoic acid Got.
[2768] ¹ H-NMR (CDCl ₃ ) δ: 0.94 (t, J = 7.2 Hz, 3H) 1.50-1.71 (m, 2H) 2.50-2.60 (m, 1H) 2.71 (dd, J = 6.0, 13.8 Hz, 1H) 2.87 (dd, J = 8.8, 13.8 Hz, 1H) 3.89 (s, 3H) 4.69 (d, J = 6.0 Hz, 1H) 4.70 (d, J = 6.0 Hz, 1H) 6.81 (d, J = 8.4 Hz, 1H) 6.96 (d, J = 2.0 Hz, 1H) 7.08 (dd, J = 2.0, 8.4 Hz, 1H) 7.20 (d, J = 2.0 Hz, 1H) 7.33 (d, J = 8.0 Hz, 1H) 7.71 ( d, J = 2.0Hz, 1H) 8.01 (t, J = 6.0Hz, 1H) 8.04 (d, J = 8.0Hz, 1H)
[2769] Example 324
[2770]
[2771] Treatment was carried out in the same manner as in Example 1d) and 1e) to obtain 3- (3-[(4-cyanobenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid.
[2772] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 7.2, 14.0 Hz, 1H) 3.03 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.86 (s, 3H) 4.11 (dd, J = 4.4, 7.2 Hz, 1H) 4.60 (d, J = 6.0 Hz, 2H) 6.77 (br, 1H) 6.82 (d, J = 8.4 Hz, 1H) 7.16 (dd, J = 2.0, 8.4 Hz, 1H) 7.21 (d, J = 2.0 Hz, 1H) 7.70 (d, J = 8.0 Hz, 2H ) 7.84 (d, J = 8.0Hz, 2H)
[2773] Example 325
[2774]
[2775] Treatment was carried out in the same manner as in Examples 1d) and 1e), and 3- [3-([3-fluoro-4- (trifluoromethyl) benzoyl] aminomethyl) -4-methoxyphenyl] -2-iso Propoxypropanoic acid was obtained.
[2776] ¹ H-NMR (CDCl ₃ ) δ: 1.03 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.92 (dd, J = 7.4, 14.0 Hz, 1H) 3.03 (dd, J = 4.6, 14.0 Hz, 1H) 3.58 (sept, J = 6.0 Hz, 1H) 3.87 (s, 3H) 4.11 (dd, J = 4.6, 7.4 Hz, 1H) 4.60 (d, J = 6.0 Hz, 2H) 6.75 (br, 1H) 6.83 (d, J = 8.4 Hz, 1H) 7.17 (dd, J = 2.0,8.4 Hz, 1H) 7.21 (d, J = 2.0 Hz, 1H) 7.56-7.70 (m, 3H)
[2777] Example 326
[2778]
[2779] 3- (3-[(2-fluoro-4-methoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid by treatment in the same manner as in Examples 1d) and 1e) Got.
[2780] ¹ H-NMR (CDCl ₃ ) δ: 1.00 (d, J = 6.0 Hz, 3H) 1.14 (d, J = 6.0 Hz, 3H) 2.89 (dd, J = 8.0, 14.0 Hz, 1H) 3.04 (dd, J = 4.0, 14.0 Hz, 1H) 3.54 (sept, J = 6.0 Hz, 1H) 3.83 (s, 3H) 3.86 (s, 3H) 4.09 (dd, J = 4.0, 8.0 Hz, 1H) 4.62 (d, J = 6.0 Hz, 2H) 6.59 (dd, J = 2.4, 14.0 Hz, 1H) 6.77 (dd, J = 2.4, 8.8 Hz, 1H) 6.81 (d, J = 8.0 Hz, 1H) 7.13 (dd, J = 2.0, 8.4Hz, 1H) 7.21 (d, J = 2.0Hz, 1H) 7.27-7.36 (m, 1H) 8.05 (t, J = 8.8Hz, 1H)
[2781] Example 327
[2782]
[2783] By treating in the same manner as in Example 1d) and 1e), 3- (3-[(2-chloro-4-methoxybenzoyl) amino] methyl-4-methoxyphenyl) -2-isopropoxypropanoic acid was added. Got it.
[2784] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.6, 14.0 Hz, 1H) 3.05 (dd, J = 4.4, 14.0 Hz, 1H) 3.56 (sept, J = 6.0 Hz, 1H) 3.81 (s, 3H) 3.84 (s, 3H) 4.09 (dd, J = 4.4, 7.6 Hz, 1H) 4.61 (d, J = 5.6 Hz, 2H) 6.59 (dd, J = 2.4, 14.0 Hz, 1H) 6.80 (d, J = 8.4 Hz, 1H) 6.84 (dd, J = 2.8, 8.8 Hz, 1H) 6.88 (d, J = 2.8 Hz , 1H) 6.97 (t, J = 5.6 Hz, 1H) 7.14 (dd, J = 2.0, 8.4 Hz, 1H) 7.24 (d, J = 2.0 Hz, 1H) 7.74 (d, J = 8.8 Hz, 1H)
[2785] Example 328
[2786]
[2787] In the same manner as in Example 1d) and 1e), 2-isopropoxy-3- (4-methoxy-3-[(2, 4.6-trichlorobenzoyl) amino] methylphenyl) propanoic acid was obtained.
[2788] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.91 (dd, J = 7.6, 14.0 Hz, 1H) 3.05 (dd, J = 4.4, 14.0Hz, 1H) 3.57 (sept, J = 6.0Hz, 1H) 3.82 (s, 3H) 4.11 (dd, J = 4.4, 7.6Hz, 1H) 4.61 (d, J = 6.0Hz, 2H) 6.40 (br, 1H) 6.80 (d, J = 8.4 Hz, 1H) 7.16 (dd, J = 2.4, 8.4 Hz, 1H) 7.27 (d, J = 2.4 Hz, 1H) 7.26 (s, 1H) 7.32 (s, 1H)
[2789] Example 329
[2790]
[2791] 2-isopropoxy-3-4-methoxy-3-[([6- (trifluoromethyl) -3-pyridyl] carbonylamino) by treatment in the same manner as in Examples 1d) and 1e) Methyl] phenyl propanoic acid was obtained.
[2792] ¹ H-NMR (CDCl ₃ ) δ: 1.05 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.93 (dd, J = 7.2, 14.0 Hz, 1H) 3.04 (dd, J = 4.4, 14.0 Hz, 1H) 3.59 (sept, J = 6.0 Hz, 1H) 3.86 (s, 3H) 4.10 (dd, J = 4.4, 7.2 Hz, 1H) 4.63 (d, J = 6.0 Hz, 2H) 6.83 (d, J = 8.4Hz, 1H) 6.93 (br, 1H) 7.17 (dd, J = 2.0, 8.4Hz, 1H) 7.22 (d, J = 2.0Hz, 1H) 7.75 (d, J = 8.4Hz, 1H ) 8.29 (dd, J = 1.2, 8.4 Hz, 1H) 9.02 (s, 1H)
[2793] Example 330
[2794]
[2795] 3-3-[([3-chloro-5- (trifluoromethyl) -2-pyridyl] carbonylamino) methyl] -4-methoxyphenyl-2-isopropoxypropanoic acid was obtained.
[2796] ¹ H-NMR (CDCl ₃ ) δ: 1.02 (d, J = 6.0 Hz, 3H) 1.15 (d, J = 6.0 Hz, 3H) 2.90 (dd, J = 7.6, 14.0 Hz, 1H) 3.04 (dd, J = 4.4, 14.0Hz, 1H) 3.56 (sept, J = 6.0Hz, 1H) 3.86 (s, 3H) 4.09 (dd, J = 4.4, 7.6Hz, 1H) 4.61 (d, J = 6.0Hz, 2H) 6.82 (d, J = 8.2Hz, 1H) 7.15 (dd, J = 2.0, 8.2Hz, 1H) 7.23 (d, J = 2.0Hz, 1H) 8.05 (d, J = 0.8Hz, 1H) 8.14 (t, J = 6.0 Hz, 1H) 8.70 (d, J = 0.8Hz, 1H)
[2797] Example 331
[2798]
[2799] Treatment was carried out in the same manner as in Examples 1d) and 1e), and 3- [3-[[(2,4-dimethoxy-5-pyrimidinyl) carbonyl] aminomethyl-4-methoxyphenyl] -2- Isopropoxypropanoic acid was obtained.
[2800] ¹ H-NMR (CDCl ₃ ) δ: 1.04 (d, J = 6.0 Hz, 3H) 1.16 (d, J = 6.0 Hz, 3H) 2.91 (dd, J = 7.4, 14.0 Hz, 1H) 3.04 (dd, J = 4.2, 14.0Hz, 1H) 3.58 (sept, J = 6.0Hz, 1H) 3.89 (s, 3H) 4.10 (dd, J = 4.2, 7.4Hz, 1H) 4.60 (d, J = 6.0Hz, 2H) 6.82 (d, J = 8.4Hz, 1H) 7.14 (dd, J = 2.0, 8.4Hz, 1H) 7.19 (d, J = 2.0Hz, 1H) 7.96 (t, J = 6.0Hz, 1H) 9.10 (s, 1H )
[2801] Example 332
[2802] Preparation Example 332a)
[2803]
[2804] 3-bromo-4-fluorobenzaldehyde 259 was dissolved in 300 ml of methanol, 40 g of trimethyl orthoformate and 3 g of paratosylic acid were added, and the mixture was heated to reflux for 6 hours. The mixture was cooled on ice and 5 g of sodium bicarbonate was added thereto. Concentrated under reduced pressure, ethyl acetate was added to the residue, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 30 g of 2-bromo-4- (dimethoxymethyl) benzene. . This crude product was dissolved in 300 ml of tetrahydrofuran and cooled to -78 ° C under a nitrogen atmosphere. 60 ml of butyllithium (2.47 M hexane solution) were added. After stirring for 1 hour, 20 ml of N, N-dimethylformamide was added, and the temperature was raised to room temperature. Water was added to the mixture and extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 25 g of 2-fluoro-5- (dimethoxymethyl) benzaldehyde. This crude product was dissolved in 200 ml of ethanol, and 3.3 g of sodium borohydride was added under ice cooling. It stirred at room temperature for 2 hours, added water, and extracted with ethyl acetate. It dried with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure, and 25 g of 2-fluoro-5- (dimethoxymethyl) benzyl alcohols were obtained. This crude product was dissolved in 400 ml of toluene, 32 ml of diphenylphosphoryl azide and 22 ml of diazabicyclo [5.4.0] undecene were added, followed by stirring at room temperature for 12 hours. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 30 g of 2-azidemethyl-4-1.dimethoxymethyl) fluorobenzene was obtained. This crude product was dissolved in 500 ml of tetrahydrofuran, 50 ml of water and 45 g of triphenylphosphine were added, followed by stirring at 50 ° C for 3 hours. The solvent was distilled off under reduced pressure to obtain 70 g of 2-fluoro-5- (dimethoxymethyl) benzylamine. The crude product was dissolved in 200 ml of N, N-dimethylformamide, 55 g of third butyldicarbonate and 43 ml of triethylamine were added, followed by stirring at room temperature for 4 days. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was treated by silica gel column chromatography, and 30 g of third butyl N- [5- (dimethoxymethyl) -2-fluorobenzyl] carbamate was extracted from the hexane-ethyl acetate (10: 1 → 2: 1) elution fraction. Got it.
[2805] ¹ H-NMR (CDCl ₃ ) δ: 1.44 (s, 9H) 3.30 (s, 6H) 4.36 (d, J = 5.2 Hz, 2H) 4.90 (br, 1H) 5.34 (s, 1H) 7.02 (t, J = 9.2 Hz, 1H) 7.16-7.46 (m, 2H)
[2806] Preparation Example 332b)
[2807]
[2808] 30 g of third butyl N- [5- (dimethoxymethyl) -2-fluorobenzyl] carbamate was dissolved in 300 ml of tetrahydrofuran, 80 ml of 1N hydrochloric acid was added, and the mixture was stirred for 20 minutes under ice-cooling, saturated aqueous sodium bicarbonate solution. Was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 25 g of third butyl N- (2-fluoro-5-formyl) carbamate.
[2809] ¹ H-NMR (CDCl ₃ ) δ: 1.45 (s, 9H) 4.43 (d, J = 5.6 Hz, 2H) 4.98 (br, 1H) 7.19 (t, J = 8.8 Hz, 1H) 7.79-7.85 (m, 1H) 7.90 (dd, J = 2.0, 7.2 Hz, 1H)
[2810] Preparation Example 332c)
[2811]
[2812] Treatment was carried out in the same manner as in Production Example 261 using tert-butyl N- (2-fluoro-5-formyl) carbamate to obtain tert-butyl N-5-[(2,4-dioxo-1, 3-thiazolan-5-yl) methyl] -2-fluorobenzylcarbamate was obtained.
[2813] ¹ H-NMR (DMSO-d ₆ ) δ: 1.38 (s, 9H) 3.06 (dd, J = 9.2, 14.0 Hz, 1H) 3.34 (dd, J = 4.0, 14.0 Hz, 1H) 4.12 (d, J = 5.6 Hz, 2H) 4.81 (dd, J = 4.0, 9.2 Hz) 7.05-7.20 (m, 2H) 7.35 (t, J = 5.6 Hz, 1H) 7.93 (s, 1H)
[2814] Example 332d)
[2815]
[2816] Treatment was performed in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2,4-dichlorobenzamide Got.
[2817] ¹ H-NMR (CDCl ₃ ) δ: 3.17 (dd, J = 8.4, 14.4 Hz, 1H) 3.26 (dd, J = 4.4, 14.4 Hz, 1H) 4.45 (dd, J = 4.4, 8.4 Hz) 4.59 (d , J = 6.0 Hz, 2H) 6.61 (br, 1H) 6.96 (t, J = 9.2 Hz, 1H) 7.04-7.11 (m, 1H) 7.20-7.29 (m, 2H) 7.36 (d, J = 2.0 Hz, 1H) 7.80 (d, J = 8.4Hz, 1H)
[2818] Example 333
[2819]
[2820] Treatment was carried out in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2-chloro-4-meth Oxybenzamide was obtained.
[2821] ¹ H-NMR (CDCl ₃ ) δ: 3.15 (dd, J = 8.6, 14.0 Hz, 1H) 3.32 (dd, J = 4.2, 14.0 Hz, 1H) 3.76 (s, 3H) 4.44 (dd, J = 4.2, 8.6Hz, 1H) 4.59 (d, J = 6.4Hz, 2H) 6.76-6.86 (m, 3H) 6.95 (t, J = 8.4Hz, 1H) 7.03-7.08 (m, 1H) 7.27 (dd, J = 2.0 , 7.2Hz, 1H) 7.69 (d, J = 8.4Hz, 1H) 8.46 (br, 1H)
[2822] Example 334
[2823]
[2824] Treatment was carried out in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-2,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-4-chloro-2-meth Oxybenzamide was obtained.
[2825] ¹ H-NMR (DMSO-d ₆ ) δ: 3.07 (dd, J = 8.8, 14.0 Hz, 1H) 3.34 (dd, J = 4.4, 14.0 Hz, 1H) 3.90 (s, 3H) 4.47 (d, J = 6.0Hz, 2H) 4.82 (dd, J = 4.4, 8.8Hz, 1H) 7.00-7.30 (m, 5H) 7.70 (d, J = 8.0Hz, 1H) 8.63 (t, J = 5.6Hz, 1H) 12.03 ( s, 1 H)
[2826] Example 335
[2827]
[2828] Treatment was carried out in the same manner as in Example 261, to obtain N 3-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2-methoxynicotinamide Got.
[2829] ¹ H-NMR (CDCl ₃ ) δ: 3.07 (dd, J = 9.6, 14.0 Hz, 1H) 3.34 (dd, J = 4.4, 14.0 Hz, 1H) 3.97 (s, 3H) 4.50 (d, J = 6.0 Hz , 2H) 4.83 (dd, J = 4.4, 9.2 Hz, 1H) 7.08-7.20 (m, 3H) 8.07-8.14 (m, 1H) 8.26-8.33 (m, 1H) 8.74 (t, J = 6.0 Hz, 1H ) 12.03 (s, 1 H)
[2830] Example 336
[2831]
[2832] Treatment was performed in the same manner as in Example 261, whereby N 3-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2-methoxy-6 -Methylnicotinamide was obtained.
[2833] ¹ H-NMR (CDCl ₃ ) δ: 2.43 (3 H, s) 3.07 (dd, J = 9.4, 14.0 Hz, 1H) 3.40 (dd, J = 4.0, 14.0 Hz, 1H) 3.96 (s, 3H) 4.49 (d, J = 5.6Hz, 2H) 4.82 (dd, J = 4.0, 9.4Hz, 1H) 6.94-7.00 (m, 1H) 7.10-7.30 (m, 3H) 8.02-8.10 (m, 1H) 8.64 (t , J = 5.6Hz, 1H) 12.02 (s, 1H)
[2834] Example 337
[2835]
[2836] Treatment was carried out in the same manner as in Example 261, and N 3-5-[(2.4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2,6-dimethoxynicotinamide Got.
[2837] ¹ H-NMR (CDCl ₃ ) δ: 3.02-3.10 (m, 1H) 3.27-3.36 (m, 1H) 3.90 (d, J = 2.0 Hz, 3H) 4.10 (d, J = 2.0 Hz, 3H) 4.49 ( d, J = 5.6Hz, 2H) 4.79-4.84 (m, 1H) 6.48 (d, J = 8.0Hz, 1H) 7.08-7.27 (m, 3H) 8.13 (d, J = 8.0Hz, 1H) 8.48 (t , J = 5.6Hz, 1H) 12.01 (s, 1H)
[2838] Example 338
[2839]
[2840] The same procedure as in Example 261 was carried out to obtain N 3-5-[(2.4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2-ethoxynicotinamide .
[2841] ¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (t, J = 7.2 Hz, 3H) 3.07 (dd, J = 9.6, 14.0 Hz, 1H) 3.35 (dd, J = 4.4, 14.0 Hz, 1H) 4.43 (q, J = 7.2 Hz, 2H) 4.49 (d, J = 5.6 Hz, 2H) 4.85 (dd, J = 4.4, 9.6 Hz, 1H) 7.06-7.30 (m, 4H) 8.12 (dd, J = 2.0, 7.6Hz, 1H) 8.27 (dd, J = 2.0, 4.8Hz, 1H) 8.63 (t, J = 5.6Hz, 1H)
[2842] Example 339
[2843]
[2844] Treatment was performed in the same manner as in Example 261, whereby N 4-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-5-methyl-2- Phenyl-1,3-thiazole-4-carboxamide was obtained.
[2845] ¹ H-NMR (DMSO-d ₆ ) δ: 2.61 (s, 3H) 3.09 (dd, J = 9.6, 14.0 Hz, 1H) 3.35 (dd, J = 4.4, 14.0 Hz, 1H) 4.44 (d, J = 5.6 Hz, 2H) 4.85 (dd, J = 4.4, 9.6 Hz, 1H) 7.10-7.29 (m, 3H) 7.46-7.55 (m, 3H) 7.90-7.96 (m, 2H) 8.81 (t, J = 5.6 Hz , 1H) 12.03 (s, 1H)
[2846] Example 340
[2847]
[2848] Treatment was carried out in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-4-isopropylbenzamide was obtained. Got it.
[2849] ¹ H-NMR (CDCl ₃ ) δ: 1.25 (d, J = 7.2 Hz, 6H) 2.94 (sept, J = 7.2 Hz, 1H) 3.19 (dd, J = 8.8, 14.0 Hz, 1H) 3.36 (dd, J = 4.4, 14.0 Hz, 1H) 4.50 (dd, J = 4.4, 8.8 Hz, 1H) 4.64 (d, J = 6.0 Hz, 2H) 6.61 (t, J = 6.0 Hz, 1H) 7.00 (dd, J = 8.6 , 9.6 Hz, 1H) 7.08-7.14 (m, 1H) 7.25-7.35 (m, 3H) 7.68-7.74 (m, 2H) 9.04 (br, 1H)
[2850] Example 341
[2851]
[2852] Treatment was carried out in the same manner as in Example 261, whereby N7-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-4-chlorobenzo [b] Furan-7-carboxamide was obtained.
[2853] ¹ H-NMR (CDCl ₃ ) δ: 3.19 (dd, J = 8.8, 14.0 Hz, 1H) 3.39 (dd, J = 4.4, 14.0 Hz, 1H) 4.50 (dd, J = 4.4, 8.8 Hz, 1H) 4.76 (d, J = 6.0Hz, 2H) 6.98 (d, J = 2.0Hz, 1H) 7.03 (t, J = 9.0Hz, 1H) 7.10-7.16 (m, 1H) 7.30-7.42 (m, 2H) 7.77 ( d, J = 2.0Hz, 1H) 7.83 (t, J = 6.0Hz, 1H) 8.06 (d, J = 8.8Hz, 1H)
[2854] Example 342
[2855]
[2856] Treated in the same manner as in Example 261, and treating N1-5-[(2.4-dioxo-1,3-thiazolan-5-yl) methyl] -2-fluorobenzyl-2-fluoro-4- (tri Fluoromethyl) benzamide was obtained.
[2857] ¹ H-NMR (CDCl ₃ ) δ: 3.14 (dd, J = 8.8, 14.0 Hz, 1H) 3.33 (dd, J = 4.4, 14.0 Hz, 1H) 4.44 (dd, J = 4.4, 8.8 Hz, 1H) 4.62 (d, J = 5.6 Hz, 2H) 6.97 (t, J = 9.0 Hz, 1H) 7.04-7.16 (m, 2H) 7.23 (dd, J = 2.2, 7.2 Hz, 1H) 7.35 (d, J = 11.6 Hz , 2H) 7.48 (d, J = 8.0 Hz, 1H) 8.17 (t, J = 8.0 Hz, 1H)
[2858] Example 343
[2859]
[2860] Treatment was carried out in the same manner as in Example 261, whereby N3-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2,6-dimethoxynicotine An amide was obtained.
[2861] ¹ H-NMR (DMSO-d ₆ ) δ: 3.00 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.4, 14.0 Hz, 1H) 3.84 (s, 3H) 3.91 (s, 3H) 4.03 (s, 3H) 4.42 (d, J = 5.6 Hz, 2H) 4.80 (dd, J = 4.0, 9.6 Hz, 1H) 6.49 (d, J = 8.4 Hz, 1H) 6.95 (d, J = 8.4 Hz, 1H) 7.06-7.15 (m, 2H) 8.17 (d, J = 8.4 Hz, 1H) 8.40 (t, J = 5.6 Hz, 1H)
[2862] Example 344
[2863]
[2864] N3-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2-methoxynicotinamide was treated in the same manner as in Example 261. Got it.
[2865] ¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (dd, J = 9.6, 14.0 Hz, 1H) 3.30 (dd, J = 4.0, 14.0 Hz, 1H) 3.87 (s, 3H) 3.99 (s, 3H) 4.43 (d, J = 6.0 Hz, 2H) 4.80 (dd, J = 4.0, 9.6 Hz, 1H) 6.95 (d, J = 8.8 Hz, 1H) 7.05-7.20 (m, 3H) 8.13-8.20 (m, 1H ) 8.27-8.33 (m, 1H) 8.63 (t, J = 6.0 Hz, 1H) 12.01 (br, 1H)
[2866] Example 345
[2867]
[2868] Treatment was carried out in the same manner as in Example 261, whereby N2-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxypenzyl-6-methyl-2-pyridine Carboxamide was obtained.
[2869] ¹ H-NMR (DMSO-d ₆ ) δ: 2.54 (s, 3H) 2.98 (dd, J = 9.6, 14.0 Hz, 1H) 3.24-3.31 (m, 1H) 3.82 (s, 3H) 4.44 (d, J = 6.4Hz, 2H) 4.79 (dd, J = 4.4, 9.6Hz, 1H) 6.95 (d, J = 8.4Hz, 1H) 7.05 (d, J = 1.6Hz, 1H) 7.11 (dd, J = 1.6, 8.4 Hz, 1H) 7.45 (dd, J = 1.6, 6.8 Hz, 1H) 7.80-7.90 (m, 2H) 8.85 (t, J = 6.4 Hz, 1H) 11.99 (br, 1H)
[2870] Example 346
[2871]
[2872] Treatment was carried out in the same manner as in Example 261, whereby N2-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-3,5-dichloro-2 Pyridinecarboxamide was obtained.
[2873] ¹ H-NMR (DMSO-d ₆ ) δ: 2.98 (dd, J = 9.6, 14.0 Hz, 1H) 3.30 (dd, J = 4.6, 14.0 Hz, 1H) 3.79 (s, 3H) 4.38 (d, J = 6.0 Hz, 2H) 4.78 (dd, J = 4.6, 9.6 Hz, 1H) 6.94 (d, J = 8.2 Hz, 1H) 7.13 (d, J = 8.2 Hz, 1H) 7.15 (s, 1H) 8.35 (d, J = 2.0Hz, 1H) 8.64 (s, 1H) 8.94 (t, J = 6.0Hz, 1H) 12.02 (br, 1H)
[2874] Example 347
[2875]
[2876] Treatment was carried out in the same manner as in Example 261, whereby N2-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-3,5-dimethyl-2 Pyridinecarboxamide was obtained.
[2877] ¹ H-NMR (DMSO-d ₆ ) δ: 2.31 (s, 3H) 2.52 (s, 3H) 2.97 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 3.8, 14.0 Hz, 1H) 3.80 (s, 3H) 4.38 (d, J = 6.4 Hz, 2H) 4.77 (dd, J = 3.8, 9.6 Hz, 1H) 6.93 (d, J = 8.4 Hz, 1H) 7.06 (s, 1H) 7.10 (d , J = 8.4 Hz, 1H) 7.55 (s, 1H) 8.28 (s, 1H) 8.79 (t, J = 6.4 Hz, 1H)
[2878] Example 348
[2879]
[2880] Treatment was performed in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-4- (trifluoromethyl ) -1-benzenesulfonamide was obtained.
[2881] ¹ H-NMR (DMSO-d ₆ ) δ: 3.03 (dd, J = 9.0, 14.0 Hz, 1H) 3.30 (dd, J = 4.0, 14.0 Hz, 1H) 3.69 (s, 3H) 4.16 (d, J = 6.4Hz, 2H) 4.46 (dd, J = 4.0, 9.6Hz, 1H) 5.59 (t, J = 6.4Hz, 1H) 6.63 (d, J = 8.4Hz, 1H) 6.95 (d, J = 2.0Hz, 1H ) 7.03 (dd, J = 2.0, 8.4Hz, 1H) 7.64 (d, J = 8.4Hz, 2H) 7.85 (d, J = 8.4Hz, 2H) 8.95 (s, 1H)
[2882] Example 349
[2883]
[2884] Treatment was carried out in the same manner as in Example 261, whereby N 5-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2,4-dimethyl 5 Pyrimidinecarboxamide was obtained.
[2885] ¹ H-NMR (DMSO-d ₆ ) δ: 3.14 (s, 6H) 3.03 (dd, J = 9.6, 14.0 Hz, 1H) 3.30 (dd, J = 4.4, 14.0 Hz, 1H) 3.79 (s, 3H) 4.36-4.40 (m, 2H) 4.82 (dd, J = 4.4, 9.6 Hz, 1H) 6.94 (d, J = 8.8 Hz, 1H) 7.06-7.16 (m, 2H) 8.63 (s, 1H) 8.88 (t, J = 5.6 Hz, 1H) 12.00 (br, 1H)
[2886] Example 350
[2887]
[2888] Treatment was carried out in the same manner as in Example 261, whereby N5-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2,4-dimethoxy- 5-pyrimidinecarboxamide was obtained.
[2889] ¹ H-NMR (DMSO-d ₆ ) δ: 3.00 (dd, J = 9.6, 14.0 Hz, 1H) 3.28 (dd, J = 4.0, 14.0 Hz, 1H) 3.82 (s, 3H) 3.94 (s, 3H) 4.03 (s, 3H) 4.40 (d, J = 6.0 Hz, 2H) 4.79 (dd, J = 4.0, 9.6 Hz, 1H) 6.94 (d, J = 8.4 Hz, 1H) 7.05-7.15 (m, 2H) 8.36 (t, J = 6.0 Hz, 1H) 8.72 (s, 1H) 12.00 (br, 1H)
[2890] Example 351
[2891]
[2892] Treatment was performed in the same manner as in Example 261, whereby N1-5-[(2,4-dioxo-1,3-thiazolan-5-yl) methyl] -2-methoxybenzyl-2,4-dichloro-1 -Benzenesulfonamide was obtained.
[2893] ¹ H-NMR (DMSO-d ₆ ) δ: 2.96 (dd, J = 9.2, 14.4 Hz, 1H) 3.26 (dd, J = 4.0, 14.4 Hz, 1H) 3.79 (s, 3H) 4.15 (d, J = 5.6 Hz, 2H) 4.39 (dd, J = 4.0, 9.2 Hz, 1H) 5.82 (t, J = 5.6 Hz, 1H) 6.67 (d, J = 8.4 Hz, 1H) 6.70 (s, 1H) 7.02 (d, J = 8.4Hz, 1H) 7.28 (d, J = 8.4Hz, 1H) 7.88 (d, J = 8.4Hz, 1H) 8.16 (br, 1H)

权利要求:
Claims (18)
[1" claim-type="Currently amended] General formula

[Wherein, R ¹ is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or having 1 to 6 carbon atoms which may each have one or more substituents Hydroxyalkyl group of 6, hydroxyalkoxy group of 1 to 6 carbon atoms, hydroxyalkylthio group of 1 to 6 carbon atoms, aminoalkyl group of 1 to 6 carbon atoms, aminoalkoxy group of 1 to 6 carbon atoms, amino of 1 to 6 carbon atoms Alkylthio group, C1-C6 halogenated alkyl group, C1-C6 halogenated alkoxy group, C1-C6 halogenated alkylthio group, C2-C12 alkoxyalkyl group, C2-C12 alkoxyalkoxy group, C2 An alkoxyalkylthio group having 12 to 12, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkylthio group having 3 to 7 carbon atoms, and a carbon atom Alkenyl groups of 2 to 6, alkenyloxy groups of 2 to 6 carbon atoms, alkenylthio groups of 2 to 6 carbon atoms, alkynyl groups of 2 to 6 carbon atoms, alkynyloxy groups of 2 to 6 carbon atoms, alkynylthio groups of 2 to 6 carbon atoms , Aryl group having 6 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, arylthio group having 6 to 12 carbon atoms, alkylaryl group having 7 to 18 carbon atoms, alkylaryloxy group having 7 to 18 carbon atoms, and 7 to 18 carbon atoms. An alkylarylthio group, an aralkyl group having 7 to 18 carbon atoms, an aralkyloxy group having 7 to 18 carbon atoms, or an aralkylthio group having 7 to 18 carbon atoms; L is a single bond or a double bond or an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; M is a single bond or an alkylene group having 2 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; T is a single bond or an alkylene group having 1 to 3 carbon atoms, an alkenylene group having 2 to 3 carbon atoms or an alkynylene group having 2 to 3 carbon atoms, each of which may have one or more substituents; W is a 2,4-dioxothiazolidine-5-yl group, a 2.4-dioxothiazolidine-5-ylidene group, a carboxyl group, or -C0N (R ^w1 ) R ^w2 , wherein R ^w1 and R ^w2 are the same Or a hydrogen atom, a formyl group, or an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or an aromatic acyl group having 7 to 19 carbon atoms, respectively) However, in the above definition, when T is a single bond and W is a 2,4-dioxothiazolidin-5-yl group or a 2,4-dioxothiazolidine-5-ylidene group Except; Is a single bond or a double bond; X is an oxygen atom, an alkenylene group having 2 to 6 carbon atoms which may have one or more substituents, or a hydroxymethylene group, or a general formula -CQ-, where Q represents an oxygen atom or a sulfur atom, -CQNR ^x- Wherein Q is the same group as defined above, R ^x is a hydrogen atom, a formyl group, or an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or 7 to 19 carbon atoms, each of which may have one or more substitutions. Each represents an aromatic acyl group of-, -NR ^x CQ- (wherein Q and R ^x each represent the same group as defined above), -SO ₂ NR ^x- (where R ^x represents the same group as defined above), -NR ^x SO ₂ - (R ^x represents the same groups as defined above), or -NR CQNR ^{x1 x2} - (wherein Q is the same groups as defined above, R ^x1 or R ^x2 are the same or different and a hydrogen atom, a formyl group, or each Each can have more than l substitutions And an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or an aromatic acyl group having 7 to 19 carbon atoms, respectively), wherein, in the above definition, T is a single bond, Except X is an oxygen atom; Y may have one or more substituents, and may have an aromatic hydrocarbon group of 5 to 12 carbon atoms or an alicyclic hydrocarbon group of 3 to 7 carbon atoms which may have one or more heteroatoms; Ring Z further represents an aromatic hydrocarbon group having 5 to 6 carbon atoms which may further have a substituent of 0 to 4 and may have one or more heteroatoms; General formula

The group represented by (wherein the symbol in the formula represents the same group as the above definition), the general formula

A carboxylic acid derivative, a salt thereof, or an ester thereof, or a hydrate thereof, represented by (wherein, the symbol in the formula represents the same group as the above definition) is bonded to each other over three atoms on ring Z.
[2" claim-type="Currently amended] The method of claim 1,
In the general formula (I), carboxylic acid derivatives, salts thereof or esters thereof, or hydrates thereof, wherein W is carboxylic acid.
[3" claim-type="Currently amended] The method according to claim 1 or 2,
In the general formula (I), a carboxylic acid derivative, a salt thereof or an ester thereof, or a hydrate thereof, wherein R ¹ is each an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, each of which may have one or more substituents.
[4" claim-type="Currently amended] The method according to claim 1 or 2,
In the general formula (I), the ring Z is a benzene ring which may further have a substituent of 0 to 4, a carboxylic acid derivative thereof, a salt thereof, or an ester thereof or a hydrate thereof.
[5" claim-type="Currently amended] The method according to claim 1 or 2,
In the above formula (I), X represents a general formula -CQNR ^x- (where Q, R ^x represents the same group as the above definition) or -NR ^x CQ- (where Q, R ^x represents the same group as the above definition) Carboxylic acid derivatives, salts thereof or esters thereof, or hydrates thereof, represented by.
[6" claim-type="Currently amended] The method according to claim 1 or 2,
In the general formula (I), Y is a carboxylic acid derivative, salt or ester thereof, or hydrate thereof, wherein Y is an aromatic hydrocarbon group having 5 to 12 carbon atoms which may have one or more substituents.
[7" claim-type="Currently amended] The method according to claim 1 or 2,
In the general formula (I), carboxylic acid derivatives, salts or esters thereof, or hydrates thereof, wherein L or M is an alkylene group having 1 to 6 carbon atoms.
[8" claim-type="Currently amended] The method according to claim 1 or 2,
In the general formula (I), a carboxylic acid derivative, a salt thereof or an ester thereof, or a hydrate thereof, wherein T is an alkylene group having 1 to 3 carbon atoms.
[9" claim-type="Currently amended] The method according to claim 1 or 2,
In said general formula (I), R <^1> is a C1-C6 alkyl group and C1-C6 alkoxy group which may respectively have one or more substituents, Ring Z may further have a substituent of 0 to 4 Carboxylic acid derivatives, salts thereof or esters thereof, or hydrates thereof.
[10" claim-type="Currently amended] The method according to claim 1 or 9,
In formula (I), X represents formula -CQNR ^x- , where Q and R ^x represent the same group as the above definition, or -NR ^x CQ- (where Q and R ^x represents the same group as the above definition) Carboxylic acid derivatives, salts or esters thereof, or hydrates thereof, wherein Y is an aromatic hydrocarbon group having 5 to 12 carbon atoms which may have one or more substituents.
[11" claim-type="Currently amended] General formula

[Wherein, R ¹ is a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or having 1 to 6 carbon atoms which may each have one or more substituents Hydroxyalkyl group of 6, hydroxyalkoxy group of 1 to 6 carbon atoms, hydroxyalkylthio group of 1 to 6 carbon atoms, aminoalkyl group of 1 to 6 carbon atoms, aminoalkoxy group of 1 to 6 carbon atoms, amino of 1 to 6 carbon atoms Alkylthio group, a C1-C6 halogenated alkyl group, a C1-C6 halogenated alkoxy group, a C1-C6 halogenated alkylthio group, a C2-C12 alkoxyalkyl group, a C2-C12 alkoxyalkoxy group, a carbon number An alkoxyalkylthio group having 2 to 12 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkylthio group having 3 to 7 carbon atoms, and carbon Alkenyl groups of 2 to 6, alkenyloxy groups of 2 to 6 carbon atoms, alkenylthio groups of 2 to 6 carbon atoms, alkynyl groups of 2 to 6 carbon atoms, alkynyloxy groups of 2 to 6 carbon atoms, alkynylthio groups of 2 to 6 carbon atoms , Aryl group having 6 to 12 carbon atoms, aryloxy group having 6 to 12 carbon atoms, arylthio group having 6 to 12 carbon atoms, alkylaryl group having 7 to 18 carbon atoms, alkylaryloxy group having 7 to 18 carbon atoms, and 7 to 18 carbon atoms. An alkylarylthio group, an aralkyl group having 7 to 18 carbon atoms, an aralkyloxy group having 7 to 18 carbon atoms, or an aralkylthio group having 7 to 18 carbon atoms; L is a single bond or a double bond or an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; M is a single bond or an alkylene group having 1 to 6 carbon atoms, an alkenylene group having 2 to 6 carbon atoms or an alkynylene group having 2 to 6 carbon atoms, each of which may have one or more substituents; T is a single bond or an alkylene group having 1 to 3 carbon atoms, an alkenylene group having 2 to 3 carbon atoms or an alkynylene group having 2 to 3 carbon atoms, each of which may have one or more substituents; W is a 2,4-dioxothiazolidine-5-yl group, a 2,4-dioxothiazolidine-5-ylidene group, a carboxyl group, or -CON (R ^w1 ) R ^w2 , where R ^w1 , R ^w2 is A hydrogen atom, a formyl group, or an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or an aromatic acyl group having 7 to 19 carbon atoms, each of which is the same or different, and may each have one or more substitutions. Wherein, in the above definition, T is a single bond and W is a 2,4-dioxothiazolidin-5-yl group or a 2,4-dioxothiazolidine-5-ylidene group Except when; Is a single bond or a double bond; X is an oxygen atom, an alkenylene group having 2 to 6 carbon atoms which may have one or more substituents, or a hydroxymethylene group, or a general formula -CQ-, where Q represents an oxygen atom or a sulfur atom, -CQNR ^x- Wherein Q is the same group as defined above, R ^x is a hydrogen atom, a formyl group, or an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms, or 7 to 19 carbon atoms, each of which may have one or more substitutions. Each represents an aromatic acyl group of-, -NR ^x CQ- (wherein Q and R ^x each represent the same group as the above definition), -SO ₂ NR ^x- (where R ^x represents the same group as the above definition), -NR ^x SO ₂ - (R ^x represents the same groups as defined above), or -NR CQNR ^{x1 x2} - (wherein Q is the same groups as defined above, R ^x1 or R ^x2 are the same or different and each represents a hydrogen atom, a formyl group, or Each one has more than one substitution Group represented by an alkyl group having 1 to 6 carbon atoms, an aliphatic acyl group having 2 to 7 carbon atoms or an aromatic acyl group having 7 to 19 carbon atoms, respectively), wherein, in the above definition, T is a single bond, Except X is an oxygen atom; Y may have one or more substituents, and may have an aromatic hydrocarbon group of 5 to 12 carbon atoms or an alicyclic hydrocarbon group of 3 to 7 carbon atoms which may have one or more heteroatoms; Ring Z further represents an aromatic hydrocarbon group having 5 to 6 carbon atoms which may further have a substituent of 0 to 4 and may have one or more heteroatoms; General formula

The group represented by (wherein the symbol in the formula represents the same group as the above definition), the general formula

(Wherein the symbols in the formulas refer to the same groups as the above definitions), the groups represented by the above formulas are bonded to each other over three atoms on ring Z. Medicine made.
[12" claim-type="Currently amended] The method of claim 11,
A medicament that is a medicament based on the dual agonist action of PPARα and γ.
[13" claim-type="Currently amended] The method of claim 11,
A medicament that is a medicament based on the triple agonist action of PPARα, β and γ.
[14" claim-type="Currently amended] The method according to any one of claims 11 to 13,
A drug that is an insulin resistance improver.
[15" claim-type="Currently amended] The method according to any one of claims 11 to 13,
Medication that prevents and treats diabetes.
[16" claim-type="Currently amended] The method according to any one of claims 11 to 13,
Medication that prevents and treats X syndrome.
[17" claim-type="Currently amended] A method for preventing, treating or improving a disease in which the dual agent action of PPARα and γ or the triple agent action of PPARα, β and γ is effective, by administering to a patient a pharmacologically effective amount of the compound of claim 1, a salt thereof, or an ester thereof or a hydrate thereof. .
[18" claim-type="Currently amended] Use of the compound of claim 1, a salt thereof, or an ester thereof, or a hydrate thereof, for use in the prevention, treatment and improvement of a disease in which the action of the dual agent of PPARα and γ or the action of the triple agent of PPARα, β and r is effective.

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同族专利:

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公开号 | 公开日

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AU776267B2|2004-09-02|

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US6884821B1|2005-04-26|

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AU7449900A|2001-05-10|

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CN1377336A|2002-10-30|

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JP4571766B2|2010-10-27|

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CA2385081C|2010-02-16|

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KR100694686B1|2007-04-23|

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WO2001025181A1|2001-04-12|

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CN1228327C|2005-11-23|

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TWI262185B|2006-09-21|

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CA2385081A1|2001-04-12|

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NZ517719A|2004-10-29|

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EP1216980A4|2010-12-08|

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EP1216980A1|2002-06-26|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1999-10-01|Priority to JPJP-P-1999-00282079

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1999-10-01|Priority to JP28207999

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1999-12-27|Priority to JP36944299

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1999-12-27|Priority to JPJP-P-1999-00369442

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2000-02-16|Priority to JP2000038795

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2000-02-16|Priority to JPJP-P-2000-00038795

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2000-04-06|Priority to JPJP-P-2000-00104260

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2000-04-06|Priority to JP2000104260

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2000-09-29|Application filed by 에자이 가부시키가이샤

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2002-11-22|Publication of KR20020087383A

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2007-04-23|Application granted

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2007-04-23|Publication of KR100694686B1

优先权:

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申请号 | 申请日 | 专利标题

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JPJP-P-1999-00282079|1999-10-01|

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JP28207999|1999-10-01|

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JP36944299|1999-12-27|

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JPJP-P-1999-00369442|1999-12-27|

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JP2000038795|2000-02-16|

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JPJP-P-2000-00038795|2000-02-16|

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JPJP-P-2000-00104260|2000-04-06|

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JP2000104260|2000-04-06|