azole derivative, intermediate compound, method for producing azole derivative, agricultural or hort

专利摘要:
The present invention relates to a plant disease controlling agent having low toxicity to humans and animals, and with excellent handling safety, showing excellent controlling effects on various plant diseases and high antibiotic action against disease-causing microorganisms. of plants. A compound represented by the general formula (I), given below, or an N-oxide or agrochemically acceptable salt thereof.
公开号:BR112020002160A2
申请号:R112020002160-1
申请日:2018-11-13
公开日:2020-07-28
发明作者:Ryo HARIGAE；Atsushi Ito；Taiji Miyake；Toru Yamazaki
申请人:Kureha Corporation；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to a novel azole derivative, an intermediate compound thereof and a method for producing the azole derivative. The invention also relates to an agricultural or horticultural chemical agent and a protective agent for industrial materials, which contain the azole derivative as an active component. [BACKGROUND OF THE INVENTION]
[0002] [0002] Until now, agricultural or horticultural chemical agents that have low toxicity to humans and animals, excellent handling safety and high control effects on various plant diseases have been required. Azol-based germicides are known as an agricultural or horticultural chemical agent having a high controlling effect.
[0003] [0003] It is necessary to provide a plant disease controlling agent having low toxicity to humans and animals, and with excellent handling safety, showing excellent controlling effects on various plant diseases and high antibiotic action against disease-causing microorganisms of plants.
[0004] [0004] In view of the problems described above, the present invention was created, and its objective is to provide a compound capable of responding to the demands described above.
[0005] [0005] In order to solve the problem described above, the present inventors have diligently studied; as a result, they found that the azole derivative shown by the general formula (I), described below, has excellent activities and reduced chemical damage, and completed the present invention.
[0006] [0006] The azole derivative of the present invention is a compound represented by the general formula (I) described below, an N-oxide thereof, or an agrochemically acceptable salt: [Chemical Formula 1] in the general formula (I), A is N or CH; D is a hydrogen, a halogen group or SRD; where RD is hydrogen, a cyano group, a C1-C6-alkyl group, a C1-C6-haloalkyl group, a C2-C6-alkenyl group, a C2-C6-haloalkenyl group, a C2-C6-alkynyl group, or a C2-C6-haloalkynyl group;
[0007] [0007] The azole derivative of the present invention has excellent germicidal action for many microorganisms capable of causing plant diseases, and has reduced chemical damage to plants. The chemical agent containing the azole derivative of the present invention as an active ingredient, therefore, exhibits a high controlling effect on various plant diseases, and exerts effects to reduce chemical injury.
[0008] [0008] The agricultural or horticultural chemical agent containing the azole derivative of the present invention as an active ingredient regulates the growth of various agricultural products or garden plants in order to increase yields, and exerts effects to increase the quality thereof.
[0009] [0009] Additionally, the protective agent for an industrial material containing the azole derivative of the present invention as an active ingredient exerts effects to more effectively protect industrial materials against various harmful microorganisms that attack industrial materials.
[0010] [0010] Preferred embodiments for carrying out the present invention are explained below. It should be noted that the described embodiments are only typical embodiments of the present invention, and that the scope of the present invention should not be limited thereto.
[0011] [0011] The azole derivative of the present invention is an azole derivative represented by the following general formula (I) (hereinafter called "azole derivative (I)").
[0012] [0012] In the general formula (I), A is N or CH, preferably N. D is a hydrogen, a halogen group or SRD, and RD is hydrogen, a cyano group, a C1-C6-alkyl group, a C1-C6-haloalkyl, a C2-C6-alkenyl group, a C2-C6-haloalkenyl group, a C2-C6-alkynyl group or a C2-C6-haloalkynyl group. D is preferably hydrogen.
[0013] [0013] The C1-C6-alkyl group is a linear or branched alkyl group having from 1 to 6 carbon atoms, and includes, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a 1-methylpropyl group, a 2-methylpropyl group, a 1-ethylpropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a 2-methylbutyl group, a 3-group, 3-dimethylbutyl, a 2,2-dimethylbutyl group, a 1,1-dimethylbutyl group, a pentyl group, a 1-methylpentyl group, a neopentyl group, and a 1,1-dimethylethyl group.
[0014] [0014] The C2-C6-alkenyl group is a linear or branched alkenyl group having from 2 to 6 carbon atoms, and includes, for example, an ethenyl group, a 2-propenyl group, a 1-methyl-2- propenyl, a 2-methyl-2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 3-methyl-2-butenyl group, a 1-methyl-2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 2-pentenyl group, a 1-hexenyl group and a 5-hexenyl group.
[0015] [0015] The C2-C6-alkynyl group is a linear or branched alkynyl group having from 2 to 6 carbon atoms, and includes, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl, a 2-butynyl group, a 3-butynyl group, a pentynyl group, and a 1-hexynyl group.
[0016] [0016] The C1-C6-haloalkyl group, the C2-C6-haloalkenyl group and the C2-C6-haloalkynyl group are groups in which one or more hydrogen atoms are replaced by halogen atoms at substitutable sites on the C1-C6 group -alkyl, in the C2-C6-alkenyl group and in the C2-C6-alkynyl group described above, respectively, and when two or more halogen groups are substituted, the halogen group may be the same or different. The halogen group may include a chloro group, a bromo group, an iodo group and a fluorine group, such as a chloromethyl group, a 2-chloroethyl group, a 2,3-dichloropropyl group, a bromomethyl group, a chlorodifluoromethyl group, a trifluoromethyl and a 3,3,3-trifluoropropyl group.
[0017] [0017] R1 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1- C4-alkyl, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, a phenyl-C2-C4-alkynyl group, or COXR5. The C1-C6-alkyl group, the C2-C6-alkenyl group and the C2-C6-alkynyl group in R1 can be exemplified by the groups shown as examples of the organic group represented by RD. R1 is preferably hydrogen, the C1-C6-alkyl group, the C2-C6-alkenyl group, the C2-C6-alkynyl group or the COXR5, more preferably the hydrogen, the C1-C6-alkyl group or the COXR5 and, most preferably, the hydrogen or the C1-C6-alkyl group.
[0018] [0018] The C3-C8-cycloalkyl group is a cyclic alkyl having from 3 to 8 carbon atoms, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclo -heptyl and a cyclooctyl group.
[0019] [0019] The C3-C8-cycloalkyl-C1-C4-alkyl group is a group in which a cyclic cycloalkyl group having from 3 to 8 carbon atoms is bonded to a linear or branched alkyl group having from 1 to 4 carbon atoms , and includes, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a 2-cyclopropylethyl group, a 1-cyclopropylethyl group,
[0020] [0020] The phenyl-C1-C4-alkyl group is a group in which a linear or branched alkyl group having from 1 to 4 carbon atoms is replaced by a phenyl group, and includes, for example, a phenylmethyl group, a 2-phenylethyl, a 3-phenylpropyl group and a 4-phenylbutyl group.
[0021] [0021] The phenyl-C2-C4-alkenyl group is a group in which a linear or branched alkenyl group having from 2 to 4 carbon atoms is attached to a phenyl group, and includes, for example, a phenylethenyl group, a phenyl-1-propenyl, a phenylisopropenyl group and a phenylbutenyl group.
[0022] [0022] The phenyl-C2-C4-alkynyl group is a group in which an alkynyl group having from 2 to 4 carbon atoms is attached to a phenyl group, and includes, for example, a phenylethynyl group, a phenyl-1 group -propynyl, a phenyl-2-propynyl group, a phenyl-1-butynyl group, a phenyl-2-butynyl group, a phenyl-3-butynyl group and a phenyl-3-butynyl group.
[0023] [0023] R5 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1- C4-alkyl, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, or a phenyl-C2-C4-alkynyl group. They can be exemplified by the groups shown as examples of the organic groups represented by RD and R1. R5 is preferably hydrogen, the C1-C6-alkyl group, the C2-C6-alkenyl group, or the C2-C6-alkynyl group, more preferably hydrogen or the C1-C6-alkyl group.
[0024] [0024] X is a single bond, -O- or -NR6-, and R6 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3 group -C8-cycloalkyl, a C3-C8-cycloalkyl-C1-C4-alkyl group, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group or a phenyl-C2-C4 group -alkynyl. They can be exemplified by the groups shown as examples of the organic groups represented by RD and R1. R6 is preferably hydrogen, the C1-C6-alkyl group, the C2-C6-alkenyl group or the C2-C6-alkynyl group, more preferably hydrogen. R5 and R6 can form a ring.
[0025] [0025] R2 is -OR7 or -NR8R9, preferably -OR7. Each of R7, R8 and R9 is independently a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8 group - cycloalkyl-C1-C4-alkyl, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group or a phenyl-C2-C4-alkynyl group. They can be exemplified by the groups shown as examples of the organic groups represented by RD and R1. R8 and R9 may form a ring.
[0026] [0026] R7 is preferably the C1-C6-alkyl group.
[0027] [0027] The aliphatic group R1, R2, R5, R6, R7, R8 and R9 may have 1, 2, 3, or the maximum possible number of one or more of the same or different Ra groups, and Ra is independently selected from a group halogen, a cyano group, a nitro group, a C1-C4-alkoxy group and a C1-C4-haloalkoxy group. The C1-C4-alkoxy group is a linear or branched alkoxy group having from 1 to 4 carbon atoms, and includes, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n group. -butoxy, a sec-butoxy group and a tert-butoxy group.
[0028] [0028] The C1-C4-alkoxy group may be substituted by one or more halogen groups at substitutable sites, and when two or more halogen groups are substituted, the halogen group may be the same or different.
[0029] [0029] E is a phenyl group or a 6-membered heteroaromatic ring having one or two N atoms. E is preferably the phenyl group. The form in which E is the phenyl group is represented by the following general formula (I'). The form represented by the following general formula (I") is preferred.
[0030] [0030] R3 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, -SOR10 or -SF5. The halogen group, the C1-C4-alkyl group, the C1-C4-haloalkyl group, the C1-C4-alkoxy group, and the C1-C4-haloalkoxy group can be exemplified by the groups shown as examples of the organic groups represented by RD, R1 or Ra. R3 is preferably the halogen group, the cyano group, the C1-C4-alkyl group, the C1-C4-haloalkyl group, the C1-C4-alkoxy group, -SOR10 or -SF5, more preferably the halogen group , the cyano group, the C1-C4-alkyl group, the C1-C4-haloalkyl group or the C1-C4-alkoxy group. R10 is a C1-C4-alkyl group or a C1-C4-haloalkyl group. When E is the phenyl group, the substitution site of R3 is the 2-position, the 3-position, the 5-position or the 6-position, preferably the 2-position. n is 0, 1, 2 or 3, preferably 1. When E is the 6-membered heteroaromatic ring including one or two N atoms, the substitution site of R3 is the 2-position, 3-position, 5-position or 6-position, provided the N atom is not bonded, preferably the 2-position. In that case, n is 0, 1 or 2, preferably 1.
[0031] [0031] R4 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4haloalkyl group, a C1-C4-alkoxy group , a C1-C4-haloalkoxy group, a C1-C4-alkylamino group, a C1-C4-dialkylamino group, a C1-C4-alkylacylamino group, -SOR10 or -SF5. The halogen group, the C1-C4-alkyl group, the C1-C4-haloalkyl group, the C1-C4-alkoxy group, the C1-C4-haloalkoxy group, and -SOR10 can be exemplified by the groups shown as examples of the represented organic groups. by RD, R1 and R3. R4 is preferably the halogen group, the nitro group, the amino group, the C1-C4-alkyl group, the C1-C4-haloalkyl group, the C1-C4-alkoxy group, the C1-C4-haloalkoxy group, the C1-C4-alkylamino group, the C1-C4-dialkylamino group, the C1-C4-alkylacylamino group, -SOR10 or -SF5, more preferably the halogen group, the C1-C4-alkyl group, the C1-C4 group -haloalkyl, the C1-C4-alkoxy group or the C1-C4-haloalkoxy group.
[0032] [0032] The C1-C4-alkylamino group is an amino group in which one of the hydrogen atoms in an amino group is replaced by a linear or branched alkyl group having from 1 to 4 carbon atoms, and includes, for example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group and a tert-butylamino group.
[0033] [0033] The C1-C4-dialkylamino group is an amino group in which two of the hydrogen atoms in an amino group are both replaced by linear or branched alkyl groups having from 1 to 4 carbon atoms, and includes, for example, a N,N-dimethylamino group, an N,N-diethylamino group, an N,N-di-n-propylamino group, an N,N-diisopropylamino group and an N,N-di-tert-butylamino group.
[0034] [0034] The C1-C4-alkylacylamino group is an amino group in which one or two of the hydrogen atoms in an amino group are replaced by a linear or branched alkylacyl group having from 1 to 4 carbon atoms, and includes, for example, example, a methylacylamino group, an ethylacylamino group, an n-propylacylamino group, an isopropylacylamino group, a tert-butylacylamino group, a
[0035] [0035] The cycloalkyl group or the part of the phenyl group in R1, R2, R5, R6, R7, R8 and R9, or the part of the phenyl group in R3 and R4 may have 1, 2, 3, 4, 5 or the maximum possible number of one or more of the same or different Rb groups, and Rb is independently selected from a halogen group, a cyano group, a nitro group, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1 group -C4-haloalkyl and a C1-C4-haloalkoxy group. The halogen group, the C1-C4-alkyl group, the C1-C4-alkoxy group, the C1-C4-haloalkyl group, and the C1-C4-haloalkoxy group can be exemplified by the groups shown as examples of the organic groups represented by RD, R1 and Ra.
[0036] [0036] Y is an oxygen atom, -CH2O-, -OCH2-, -NH-, -N(-C1-C4-alkyl)-, -N(-C3-C6-cycloalkyl)- or -S(O )p-, which is attached to any sites of a phenyl group to which (R 3 )n is attached, where p is 0, 1 or 2 and is preferably the oxygen atom.
[0037] [0037] Y is attached to an ortho position, a meta position or a para position of the phenyl group, wherein R3 is substituted, and is preferably attached to the meta position or the para position.
[0038] [0038] Z is an aromatic hydrocarbon group which is a phenyl group or a naphthyl group, or a 5-membered or 6-membered heteroaromatic ring group, or a 9-membered or 10-membered heteroaromatic ring group formed by 2 rings, containing of 1 to 4 heteroatoms selected from O, N and S. Z is preferably the phenyl group or a 5-membered or 6-membered heteroaromatic ring having 1 to 3 heteroatoms selected from N and S, more preferably the phenyl group .
[0039] [0039] The 5-membered or 6-membered heteroaromatic ring group includes, for example, a furyl group, a pyrazolyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a pyrrolyl group , an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an iso-oxazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group and a triazinyl group.
[0040] [0040] The 9-membered or 10-membered heteroaromatic ring group formed by 2 rings may include an indolyl group, an isoindolyl group, a benzoimidazolyl group, a quinolinyl group, an isoquinolinyl group, a quinoxalinyl group, a cinolinyl group, a benzopyranyl and a pteridinyl group.
[0041] [0041] m R4 groups are attached to any substitution sites, and are preferably attached to a 2-position, a 3-position, a 4-position or a 5-position. When Z is an aromatic hydrocarbon group, then m is 1 , 2, 3, 4 or 5; and when Z is a heteroaromatic ring, then m is 0, 1, 2, 3 or 4.
[0042] [0042] The azole derivatives, which are particularly preferred examples of the azole derivative (I), are shown in Tables 1 to 8, described below.
[0043] [0043] R1, R2, R3, R4 and Y in Table 1, below, correspond to R1, R2, R3, R4 and Y in the following chemical formula (Ia), respectively.
[0044] [0044] R1, R2, R3, R4 and Y in Table 2, below, correspond to R1, R2, R3, R4 and Y in the following chemical formula (IIa) and chemical formula (IIb), respectively.
[0045] [0045] R1, R2, R3, R4, Y, Z2, Z3 and Z4 in Table 3, below, correspond to R1, R2, R3, R4, Y, Z2, Z3 and Z4 in the following chemical formula (IIIa), respectively .
[0046] [0046] Z2, Z3 and Z4 in the Table show an unsubstituted state, before the substitution of R4, in the form of a ring structure, and in the chemical formula (IIIa), a carbon, which is substituted by R4, is also represented by "CH".
[0047] [0047] R1, R2, R3, Y, R4, Z2, Z3, Z4, Z5 and Z6 in Table 4, below, correspond to R1, R2, R3, Y, R4, Z2, Z3, Z4, Z5 and Z6 in following chemical formula (IIIb), respectively.
[0048] [0048] Z2, Z3, Z4, Z5 and Z6 in the Table show an unsubstituted state, before the substitution of R4, in the form of a ring structure, and in the chemical formula (IIIb), a carbon, which is substituted by R4 is also represented by "CH".
[0049] [0049] R2, R3, R4, Z2, Z3, Z6, Z7, Z8, Z9 and Z10 in Table 5, below, correspond to R2, R3, R4, Z2, Z3, Z6, Z7, Z8, Z9 and Z10 in following chemical formula (IIIc), respectively.
[0050] [0050] Z6 in the Table shows an unsubstituted state, before the substitution of R4, in the form of a ring structure and in the chemical formula (IIIc), a carbon, which is substituted by R4, is also represented by "CH ".
[0051] [0051] R2, R3, R4, Z2, Z4, Z5, Z6 and Z8 in Table 6, below, correspond to R2, R3, R4, Z2, Z4, Z5, Z6 and Z8 in the following chemical formula (IIId), respectively .
[0052] [0052] Z4, Z5, Z6 and Z8 in the Table show an unsubstituted state, before the substitution of R4, in the form of a ring structure, and in the chemical formula (IIId), a carbon, which is substituted by R4 , is also represented by "CH".
[0053] [0053] R2, R3, R4, Z2, Z3, Z4, Z5, Z6 and Z7 in Table 7, below, correspond to R2, R3, R4, Z2, Z3, Z4, Z5, Z6 and Z7 in the following chemical formula ( IIIe), respectively.
[0054] [0054] Z5, Z6 and Z7 in the Table show an unsubstituted state, before the substitution of R4, in the form of a ring structure, and in the chemical formula (IIIe), a carbon, which is substituted by R4, is also represented by "CH".
[0055] [0055] R2, R3, R4, Z2, Z3, Z4 and Z5 in Table 8, below, correspond to R2, R3, R4, Z2, Z3, Z4 and Z5 in the following chemical formula (IIIf), respectively.
[0056] [0056] Z2 in the Table shows an unsubstituted state, before the substitution of R3, in the form of a ring structure, and in the chemical formula (IIIa), a carbon, which is substituted by R3, is also represented by " CH".
[0057] [0057] Agrochemically acceptable salts of the azole derivative (I) include cationic salts in which the cation and anion do not exert particularly bad influences on the effects of the azole derivative (I), and acid addition salts of an acid of the same. The particularly preferred cation may include alkali metal ions (preferably sodium and potassium), alkaline earth metals (preferably calcium, magnesium and barium) and transition metals (preferably manganese, copper, zinc and iron). If desired, ammonium ions which may have 1 to 4 C1-C4-alkyl substituents and/or a phenyl substituent or benzyl substituent (preferably diisopropyl ammonium, tetramethyl ammonium, tetrabutyl ammonium, trimethylbenzyl ammonium), and phosphonium, sulfonium ions (preferably tri(C1-C4-alkyl)sulfonium), and sulfoxonium ions (preferably tri(C1-C4-alkyl)sulfoxonium) are also preferred. Anions of useful acid addition salts are mainly chloride ions, bromide ions, fluoride ions, hydrogen sulfate ions, sulfate ions, dihydrogen phosphate ions, hydrogen phosphate ions, phosphate ions, nitrate ions, bicarbonate ions, carbonate ions, hexafluorosilicate ions , hexafluorophosphate ions, benzoate ions, and C1-C4-alkanoic acid anions, preferably formate ions, acetate ions, propionate ions, and butyrate ions. They can be formed by reacting the azole derivative (I) with a corresponding anionic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid).
[0058] [0058] The azole derivative (I) can be produced by any of the three methods shown below. In the method for producing the azole derivative explained below, the explanation is made by using a specific aspect of the azole derivative (I) for the sake of convenience, but other aspects can be produced by altering the starting materials.
[0059] [0059] R1, R2, R3, R4, R7, A and D in the following scheme correspond to R1, R2, R3, R4, R7, A and D in a general formula (I) described above, respectively.
[0060] [0060] The azole derivative (I) can be produced according to the following general scheme 1 from compounds obtained by a known technique.
[0061] [0061] (Step 1-1) In production method 1, a phenol compound represented by the general formula a (hereinafter referred to as "Phenol a") is reacted with an acetophenone compound represented by the general formula b (hereinafter referred to as "Phenol a"). hereinafter called "Acetophenone b") in the presence of a base to obtain a compound represented by the general formula c (hereinafter called "Compound c"), in Scheme 1 described above.
[0062] [0062] (Step 1-2) Compound c obtained is reacted with iodine in a suitable solvent such as dimethyl sulfoxide (DMSO). A suitable base, such as carbonate, is added thereto, and it is reacted with dialkyl sulfate (R7OS(=O)2OR7) or R7-LG, to obtain a compound represented by the general formula d1 (hereinafter referred to as " Compound d1"). Here, the carbonate includes sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, preferably potassium carbonate. LG is a nucleophilically substitutable leaving group, for example a leaving group selected from halogen groups, alkylsulfonyloxy groups and arylsulfonyloxy groups, preferably the halogen groups, more preferably a bromo group and an iodine group.
[0063] [0063] (Step 1-3) Compound d1 is reacted with a methyltriphenyl phosphonium halide in any solvent such as toluene, tetrahydrofuran (THF) or DMSO in the presence of a base such as potassium or sodium tert-butoxide hydrogenated to obtain an acrylic acid ester compound represented by the general formula e (hereinafter referred to as "Acrylate e").
[0064] [0064] (Step 1-4) Acrylate e is reacted with an aqueous solution of hydrogen peroxide or a mixture thereof with sodium carbonate or urea in a solvent of methanol or acetonitrile, preferably in the presence of a base such as sodium hydrogen carbonate or potassium carbonate, to obtain an epoxide compound represented by the general formula f1 (hereinafter referred to as "Epoxide Compound f1").
[0065] [0065] (Step 1-5) The epoxide compound f1 is reacted with a sodium azole in an organic solvent, preferably dimethylformamide (DMF), to obtain a compound represented by the general formula IA, which is a compound represented by general formula (I), where R1 is hydrogen and D is hydrogen (hereinafter referred to as "Compound IA").
[0066] [0066] (Step 1-6) In a suitable case, compound IA is subsequently reacted with R1-LG, preferably a suitable solvent such as THF, in the presence of a base such as NaH, to obtain a compound represented by general formula IB (hereinafter referred to as "Compound IB"). Here, LG is a nucleophilically substitutable leaving group, for example a leaving group selected from halogen groups, alkylsulfonyloxy groups and arylsulfonyloxy groups, preferably a bromo group or an iodo group.
[0067] [0067] (Step 1-7) Compound IB is reacted with an electrophile, such as sulfur, iodine, iodine monochloride, or dibromotetrafluoroethane, in the presence of a strong base, such as lithium butyl, lithium diisopropylamide, or hexamethyl disyl azide. potassium to obtain a compound represented by the general formula IC
[0068] [0068] The azole derivative (I) of the present invention can be produced according to the following general scheme 2 from compounds obtained by a known technique.
[0069] [0069] (Step 2-1) In production method 2, Phenol a is reacted with a halobenzene compound represented by the general formula g, or a phenol compound represented by the general formula i is reacted with a halobenzene compound represented by general formula h, if desired, in the presence of CuX, preferably in the presence of a base to obtain a compound represented by general formula j (hereinafter referred to as "Compound j"), in general scheme 2, described above . Here, X is a chloro group, a bromo group or an iodo group.
[0070] [0070] (Step 2-2) Compound j is reacted with alkyl chloroglyoxylate in the presence of a Lewis acid, preferably aluminum chloride or iron(III) chloride to obtain Compound d. Compound d can be obtained in the same manner as in production method 1, or it can be introduced into Compound I.A, I.B or I.C as in production method 1.
[0071] [0071] (Step 2-3) Compound d2 is reacted with a compound selected from trimethylsulfonium halide, trimethylsulfonium methylsulfate, trimethylsulfoxonium halide, and trimethylsulfoxonium methylsulfate in the presence of a base, such as halogenated sodium, sodium tert-butoxide, or cesium carbonate to obtain Epoxide Compound f2.
[0072] [0072] (Step 2-4) Epoxide Compound f2 is reacted with sodium azole in an organic solvent such as DMF to obtain Compound ID, which is a compound represented by the general formula (I), where R1 is hydrogen and D is hydrogen. Compound I.D can be converted to a derivative.
[0073] [0073] The azole derivative (I) of the present invention can be produced according to the following general scheme 3 from compounds obtained by a known technique.
[0074] [0074] (Step 3-1) In production method 3, Phenol a is reacted with a halobenzene compound represented by the general formula k, or a phenol compound represented by the general formula l is reacted with a halobenzene compound represented by general formula h to obtain a compound represented by general formula m (hereinafter referred to as "Compound m"), in general scheme 3, described above. Here, X1 is a bromo group or an iodine group.
[0075] [0075] (Step 3-2) Compound m is converted to an organic metal agent by reaction with a transmetallating agent such as butyl lithium or isopropyl magnesium chloride, followed by reaction with dialkyl oxalate (COOR7)2 to form get Compound d1. Compound d1 can be obtained in the same manner as in production method 1 or production method 2, or it can be introduced into Compound I.A, I.B, I.C or I.D as in production method 1 or production method 2.
[0076] [0076] (Step 3-3) Compound d1 is reacted with trimethylsulfonium halide, trimethylsulfonium methylsulfate, trimethylsulfoxonium halide, or trimethylsulfoxonium methylsulfate in the presence of sodium azole to obtain Compound IA, which is a compound represented by the formula general (I), where R1 is hydrogen and D is hydrogen. Compound I.A can be converted to a derivative.
[0077] [0077] As described above, in production methods 1 to 3, the explanation is made using the specific aspect of the azole derivative (I) for the sake of convenience, and the present invention is not limited thereto. For example, in production methods 1 to 3, the embodiment represented by the general formula (I) in which Z is the phenyl group, but Z is not limited to the phenyl group, is explained. For example, when a commercially available compound, in which a naphthyl group, or a 5-membered or 6-membered heteroaromatic ring, or a 9-membered or 10-membered heteroaromatic ring formed by 2 rings containing from 1 to 4 heteroatoms selected from O, N and S, to which a hydroxyl group and a preferred R4 are attached, is used as a starting material instead of Phenol a, an azole derivative (I) in which Z is a group other than the phenyl group can be produced from the same way as in production methods 1 to 3.
[0078] [0078] In production methods 1 to 3, the embodiment represented by the general formula (I) is explained in which E is the phenyl group, but E is not limited to the phenyl group. For example, when a compound in which a keto group, a fluoro group and a preferred R3 are attached to a 6-membered heteroaromatic ring containing 1 or 2 N atoms is used as a starting material instead of Acetophenone b, a derivative of azole (I) in which E is a group other than the phenyl group can be produced in the same manner as in production method 1.
[0079] [0079] Furthermore, according to the method presented below, an azole derivative (I) in which E is a group other than the phenyl group can be produced in the same way as in production method 2. ⋅ To use a compound in which a chloro group, a bromo group or an iodo group and a preferred R 3 are attached to a 6-membered heteroaromatic ring containing 1 or 2 N atoms, instead of the halobenzene compound represented by the general formula g.
[0080] [0080] Furthermore, according to the method presented below, an azole derivative (I) in which E is a group other than the phenyl group can be produced in the same way as in production method 3. ⋅ To use a compound in which a first halogen group selected from a chloro group, a bromo group and an iodo group, a second halogen group selected from a bromo group and an iodo group and a preferred R3 are bonded to a 6-membered heteroaromatic ring containing 1 or 2 N atoms in place of the halobenzene compound represented by the general formula k. ⋅ To use a compound in which a bromo group or an iodo group, a hydroxyl group and a preferred R3 are attached to a 6-membered heteroaromatic ring containing 1 or 2 N atoms instead of the phenol compound represented by the general formula I.
[0081] [0081] In production methods 1 to 3, Y in a general formula (I) is an oxygen atom, but Y is not limited to the oxygen atom. For example, when a commercially available compound in which -CH2OH, -OCH3, -NH2, -N(-C1-C4-alkyl)H, -N(-C3-C6-cycloalkyl)H or -S(O)pH is bonded to Z in a general formula (I) is used as a starting material instead of Phenol a, an azole derivative (I) in which Y is a group other than the oxygen atom can be produced in the same way as in the methods production 1 to 3.
[0082] [0082] The N-oxide form can be produced from Compound I according to a conventional oxidation method, for example, by treating Compound I with an organic acid peroxide such as methyl acid.
[0083] [0083] Preferred intermediate compounds in the production of the azole derivative may include compounds represented by the following general formula (IV) (hereinafter referred to as "Intermediate Compound (IV)").
[0084] [0084] Here, R2, R4, Y, Z and m, in the general formula (IV), are equal to R2, R4, Y, Z and m in the general formula (I), respectively.
[0085] [0085] Compound d1 in Scheme 1 and Compound d2 in Schemes 2 and 3 are an aspect of intermediate Compound (IV). When Intermediate Compound (IV) is used, therefore, an azole derivative (I) can be produced with reference to Schemes 1 to 3, described above.
[0086] [0086] As shown in Scheme 1 described above, the compound represented by the general formula (IV) wherein R2 is a group represented by -OR7 (hereinafter called "Intermediate Compound (VI)") can be produced from of a compound represented by the following general formula (V) (hereinafter referred to as "Intermediate Compound (V)").
[0087] [0087] Here, R7, R4, Y, Z and m, in the general formula (VI), are equal to R7, R4, Y, Z and m in the general formula (I), respectively. Similarly, R4 , Y, Z and m in general formula (V) are equal to R4 , Y, Z and m in general formula (I), respectively.
[0088] [0088] Specifically, Intermediate Compound (VI) can be produced in a manner in which, with the use of an R7-halogenated compound, iodine and a carbonate, Intermediate Compound (V) is changed to Intermediate Compound (VI) in dimethyl sulfoxide.
[0089] [0089] The azole derivative (I) has an imidazolyl group or a 1,2,4-triazolyl group and therefore can form an acid addition salt of an inorganic acid or an organic acid, or a complex of metal. The derivative, accordingly, can be used as a part of an acid addition salt or metal complex in an agricultural or horticultural chemical agent, or the like, as an active ingredient.
[0090] [0090] The agricultural or horticultural chemical agent in the present embodiment shows the controlling effect on various plant diseases.
[0091] [0091] Examples of applicable diseases may include the diseases described below. In parentheses, after each disease, the main pathogenic microorganisms that cause the disease are described: Asian soybean rust (Phakopsora pachyrhizi, Phakopsora meibomiae), soybean brown spot (Zymoseptoria glycines), soybean purple spot (Cercospora kikuchii), brown leaf spot on soybean (Alternaria sp.), anthracnose on soybean (Collectotrichum truncatum), frog-eye leaf spot on soybean (Cercospora sojina), Rhizoctonia root rot of soybean (Rhizoctonia solani), leaf rot on soybean (Rhizoctonia solani), soybean melanose (Diaporthe phaseolorum), soybean Phytophthora (Phytophthora soybean (Phytophthora soybean) stem rot), Phoma/black cinnamon leaf spot of rape (Leptosphaeria maculans, Leptosphaeria biglobosa), light rapeseed leaf spot (Pyrenopeziza brassicae), rapeseed cruciferous hernia (Plasmodiophora brassicae), rape whorl wilt (Verticillium longisporum), rapeseed smut (Alternaria spp), rice blast (Pyricularia oryzae ), brown leaf spot of rice (Cochliobolus miyabeanus), bacterial blight of rice (Xanthomonas oryzae), sheath blight of rice (Rhizoctonia solani), stem rot of rice (Helminthosporium sigmoideun), "Bakanae" disease of rice (Gibberella fujikuroi ), rice root rot (Pythium aphanidermatum), rice seedling damping-off (Pythium graminicola), barley powdery mildew (Erysiphe graminis f. sp hordei), stem rust of barley (Puccinia graminis), linear rust of barley (Puccinia striiformis), striated leaf spot of barley (Pyrenophora graminea), scald of barley (Rhynchosporium secalis), loose char of barley (Ustilago nuda) ), reticular blotch of barley (Pyrenophora teres), ear rot of barley (Fusarium graminearum, Microdochium nivale),
[0092] [0092] The agricultural or horticultural chemical agent of the present embodiment can be used for a germicide. The agricultural or horticultural chemical agent of the present embodiment shows a particularly excellent controlling effect on ear fusariosis diseases in the wheat family, such as wheat speckled leaf spot and barley leaf blight, among the diseases described above. For this reason, the agricultural or horticultural chemical agent is preferably used to control the wheat family, but is not limited to that.
[0093] [0093] The agricultural or horticultural chemical agent of the present embodiment can be used on all plants. Examples of applicable plants may include the following: Gramineae family such as rice, wheat, barley, rye, oats, triticale, corn, sorghum, sugar cane, grass, bentgrass grass (Agrostis), bermuda grass, blue grass ( Festuca) and ryegrass; Leguminosae family, such as soybeans, peanuts, red beans, peas, adzuki beans and alfalfa; family Convolvulaceae, such as sweet potato; family Solanaceae, such as red pepper, bell pepper, tomato, eggplant, potato and tobacco; family Polygonaceae, such as buckwheat; family Asteraceae, such as sunflower; family Araliaceae, such as ginseng; family Brassicaceae, such as rapeseed, chard, turnip, cabbage and Japanese horseradish; family Chenopodiaceae, such as sugar beet; family Malvaceae, such as cotton; family Rubiaceae, such as coffee; family Sterculiaceae, such as cocoa; family Theaceae, such as tea leaf; family Cucurbitaceae, such as watermelon, melon, cucumber and pumpkin; family Liliaceae, such as onions, chives and garlic; family Rosaceae, such as strawberry, apple, almond, apricot, plum, yellow peach, Japanese plum, peach and pear; family Apiaceae, such as carrots; family Araceae, such as yam; family Anacardiaceae, such as mango; family Bromeliaceae, such as pineapple; family Caricaceae, such as papaya; family Ebenaceae, such as persimmon; family Ericaceae, such as blueberry; family Juglandaceae, such as pecans; Musaceae family, such as bananas; family Oleaceae, such as olive; Arecaceae family, such as coconut and date palm; family Rutaceae, such as mandarin orange, orange, grapefruit and lemon; family Vitaceae, such as grape; flowers and ornamental plants; and trees in addition to fruit trees and other ornamental plants.
[0094] [0094] Additionally, the azole derivative (I) shows an excellent effect of effectively protecting industrial materials against various harmful micro-organisms that attack industrial materials and hence it can be used as a protective agent for industrial materials. Examples of microorganisms may include the microorganisms described below.
[0095] [0095] Aspergillus sp., which are paper/pulp spoilage microorganisms (including biofilm-forming microorganisms); Aspergillus sp., which are fiber-decaying microorganisms, such as Trichoderma sp., Penicillium sp., Geotrichum sp., Chaetomium sp., Cadophora sp., Ceratostomella sp., Cladosporium sp., Corticium sp., Lentinus sp., Lenzites sp., Phoma sp., Polysticus sp., Pullularia sp., Stereum sp., Trichosporium sp., Aerobacter sp., Bacillus sp., Desulfovibrio sp., Pseudomonas sp., Flavobacterium sp. and Micrococcus sp.; Tyromyces palustris, which are wood-degrading microorganisms, such as Penicillium sp., Chaetomium sp., Myrothecium sp., Curvularia sp., Gliomastix sp., Memnoniella sp., Sarcopodium sp., Stschybotrys sp., Stemphylium sp., Zygorhynchus sp., bacillus sp. and Staphylococcus sp.; Aspergillus sp., which are leather-deteriorating microorganisms, such as Coriolus versicolor, Aspergillus sp., Penicillium sp., Rhizopus sp., Aureobasidium sp., Gliocladum sp., Cladosporium sp., Chaetomium sp. and Trichoderma sp.; Aspergillus sp., which are rubber/plastic spoilage microorganisms, such as Penicillium sp., Chaetomium sp., Cladosporium sp., Mucor sp., Paecilomycessp., Pilobus sp.,
[0096] [0096] The present invention is not limited to each embodiment described above, and various changes may be made within the scope shown in the claims. Additionally, embodiments in which the technical means disclosed in different embodiments are suitably combined are within the technical scope of the present invention.
[0097] [0097] The agricultural or horticultural chemical agent is used by mixing the azole derivative (I), which is the active ingredient, with a solid carrier or a liquid carrier (diluent), a surfactant and other pharmaceutical preparation adjuvants and the like , and forming the pharmaceutical preparation in various states, for example, a powdered agent, a hydrating agent, a granular agent and an emulsion.
[0098] [0098] The pharmaceutical preparation is prepared so that the azole derivative (I) is contained in an amount of from 0.1 to 95% by weight, preferably from 0.5 to 90% by weight, more preferably from 2 to 80% by weight as the active ingredient. Examples of the solid carrier, the liquid carrier and the surfactant, which are used as the adjuvant of the pharmaceutical preparation, are described below. First, the solid carrier is used as a powder carrier or a granular carrier. Examples thereof may include minerals such as clay, talc, diatomaceous earth,
[0099] [0099] The liquid vehicle may include aliphatic solvents (paraffin), aromatic solvents (xylene, alkyl benzene, alkyl naphthalene and the like), mixed solvents (coal oil), machine oil (purified aliphatic hydrocarbon with high boiling temperature), alcohols (ethanol, isopropanol, cyclohexanol and the like), polyhydric alcohols (ethylene glycol, diethylene glycol, propylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol and the like), polyhydric alcohol derivatives (glycol ether based on propylene and the like), ketones (acetone, cyclohexanone, γ-butyrolactone and the like), esters (fatty acid methyl esters (coconut oil fatty acid methyl ester), ethylhexyl lactate, propylene carbonate, methyl ester of dibasic acid (succinic acid dimethyl ester, glutamic acid dimethyl ester, adipic acid dimethyl ester and the like)), nitrogen-containing vehicles (N-alkyl pyrrolidones), oils and fats (coconut oil, o soybean oil, rapeseed oil and the like), amide-based solvents (dimethyl formamide, (N,N-dimethyl octanamide, N,N-dimethyl decan-1-amide, 5-(dimethylamino)-4-acid methyl ester
[0100] [0100] Examples of the surfactant are described below. The nonionic surfactant may include, for example, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene resin acid ester, polyoxy ethylene fatty acid diester, polyoxy ethylene alkyl ether, polyoxy ethylene alkyl phenyl ether, polyoxy ethylene dialkyl phenyl ether, polyoxy ethylene alkyl phenyl ether formalin condensate, polyoxy ethylene/polyoxy propylene block polymer, polymer ether polyoxyethylene/polyoxypropylene alkyl block, polyoxyethylene alkylamine, polyoxyethylene fatty acid amide, polyoxyethylene fatty acid bisphenyl ether, polyoxyethylene benzylphenyl (or phenylphenyl)ether, polyethylene styrylphenyl (or phenylphenyl)ether, ester-type silicone polyoxy ethylene ether and fluorine-based surfactants, polyoxy ethylene castor oil, polyoxy hydrogenated castor oil ethylene and the like. The anionic surfactant may include sulfate salts, such as alkyl sulfate, polyoxyethylene alkyl ether sulfate, polyoxyethylene alkylphenyl ether sulfate, benzyl (or styryl) phenyl (or phenylphenyl) ether sulfate, polyoxyethylene, polyoxyethylene, polymer sulfate in polyoxypropylene block; sulfonate salts such as paraffin (alkane) sulfonate, α-olefin sulfonate, dialkyl sulfosuccinate, alkyl benzenesulfonate, mono or dialkyl naphthalenesulfonate, naphthalenesulfonate formalin condensate, alkyl diphenyl ether disulfonate, lignin sulfonate, polyoxyethylene alkyl phenyl ether and polyoxyethylene alkyl ether sulfosuccinic acid half-ester; fatty acid salts such as fatty acid, N-methyl fatty acid sarcosinate and resin acid; phosphate salts such as polyoxyethylene alkyl ether phosphate, polyoxyethylene mono or dialkyl phenyl ether phosphate, polyoxyethylene benzylate (or styrylate) phenyl (or phenylphenyl) ether phosphate, polyoxyethylene/polyoxypropylene block polymer, phosphatidylcholine phosphatidyl ethanolimine ( lecithin) and alkyl phosphate. The cationic surfactant may include ammonium salts, such as alkyl trimethyl ammonium chloride, methyl polyoxyethylene alkyl ammonium chloride, alkyl N-methyl pyridium bromide, mono- or di-alkyl methylated ammonium chloride, and alkyl pentamethyl propylenediamine dichloride; benzalkonium salts such as alkyl dimethyl benzalkonium chloride and benzethonium chloride (octylphenoxy ethoxyethyl dimethylbenzyl ammonium chloride).
[0101] [0101] Other adjuvants for pharmaceutical preparation may include inorganic salts, such as sodium and potassium, which are used as a pH controlling agent; fluorine or silicone based defoaming agents; water-soluble salts such as sodium chloride; water-soluble polymers such as xanthan gum, guar gum, carboxymethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, acrylic polymers, polyvinyl alcohol, starch derivatives and polysaccharides, algic acid and its salts, which are used as a thickener; metal salts of stearic acid, sodium tripolyphosphate, sodium hexametaphosphorate; and preservatives, coloring agents, antioxidants, ultraviolet absorbing agents, chemical damage reducing agents and the like.
[0102] [0102] The pharmaceutical preparation may be used as is, or used upon dilution with a diluent such as water, in order to set a predetermined concentration. When it is diluted, the concentration of the azole derivative (I) is desirably within a range of 0.001 to 1.0%.
[0103] [0103] The amount of the azole derivative (I) used is 20 to 5,000 g, more preferably 50 to 2,000 g per hectare (h) of agricultural or horticultural land, such as a farm, paddy field, orchard or stove. The concentration and amount of use vary depending on the dosage form, the time of use, the use, the place of use and the target crop and therefore it is possible to increase or decrease them without adhering to the range described above.
[0104] [0104] The agricultural or horticultural chemical agent in the present embodiment may be used in a state in which it is combined with another known active ingredient,
[0105] [0105] Active ingredient suitable for germicidal use may include, for example, sterol biosynthesis inhibitor compounds, benzimidazole based compounds, succinate dehydrogenase inhibitor compounds (SDHI compounds), strobilurin based compounds, phenylamide based compounds, dicarboxyimide based compounds, anilinopyrimidine based compounds, compounds having multiple reactive points, antibiotics, carbamate based compounds, quinoline based compounds, organic phosphorus based compound, carboxamide based compounds and the like.
[0106] [0106] The sterol biosynthesis inhibitor compound may include azaconazole, bitertanol, bromuconazole, difenoconazole, cyproconazole, diniconazole, fenbuconazole, fluquinconazole, flutriafol, hexaconazole, imazalil, imibenconazole, metconazole, ipconazole, myclobutanil, pefurazoate, penconazole, prochloraz, propiconazole, prothioconazole, epoxiconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole, flusilazole, oxpoconazole, mefentrifluconazole, ipfentrifluconazole, 1-((1H-1,2,4-triazol-1-yl)methyl)-5-( 4-chlorobenzyl)-2-(chloromethyl)-2-methylcyclopentan-1-ol, methyl 2-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-chlorobenzyl)-2 -hydroxy-1-methylcyclopentane-1-carboxylate, fenpropimorph, fenpropidine, spiroxamine, tridemorph, bupirimate, fenarimol, pyrifenox, triforine and the like.
[0107] [0107] The benzimidazole-based compound may include carbendazime, benomyl, thiabendazole, thiophanate-methyl, fuberidazole and the like.
[0108] [0108] Succinate dehydrogenase inhibitor compounds (SDHI compounds) may include bixaphene, benzovindiflupyr, boscalide, fluopyram, flutolanil, fluxapyroxad, furametpyr, isofetamide, isopyrazam, mepronil, penflufen, pentiopyrad, sedaxane, tiflumide, fluindapyr, pyraziflumide, piflumetophene, benodanil , carboxym, pyrapropoin, inpirfluxam, isoflucipram and oxycarboxim.
[0109] [0109] The strobilurin-based compound may include azoxy-strobin, dimoxy-strobin, enestrobin, phenamistrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orisastrobin, picoxy-strobin, pyraclostrobin, trifloxy-strobin, madestrobin, pyribencarb, pyroxy-strobin, pyrametostrobin, fluphenoxy-strobin, enoxastrobin, coumoxy-strobin, triclopyricarb and the like.
[0110] [0110] The phenylamide-based compound may include benalaxyl, benalaxyl M or chiralaxyl, metalaxyl, metalaxyl M or mefenoxam and oxadixyl and the like.
[0111] [0111] The dicarboxyimide based compound may include procymidone, iprodione, vinclozolin and the like.
[0112] [0112] The anilinopyrimidine-based compound may include cyprodinil, mepanipyrim, pyrimethanil and the like.
[0113] [0113] The compound having multiple reactive points may include mancozeb, maneb, methyram, propineb, thiram (thiuram), zineb, ziram, amobam, anilazine, dithianone, fluazinam, pencicuron, cincozene, trifluanid, dodaine, guazatine, iminoctadine (acetate of iminoctadine, iminoctadine albesilate), copper compounds (e.g. copper oxychloride, cupric hydroxide, basic copper sulfate, copper sulfate, organic copper (copper oxide), copper nonylphenolsulfonate, DBEDC and the like), hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate), metallic silver, fentin, sulfur, captan, chlorothalonil (TPN), folpet and the like.
[0114] [0114] The antibiotic may include kasugamycin, polyoxin, streptomycin, validamycin, oxytetracycline and the like.
[0115] [0115] The carbamate-based compound may include bentiavalicarb (isopropyl bentiavalicarb), diethofencarb, iprovalicarb, propamocarb, tolprocarb and the like.
[0116] [0116] The quinoline-based compound may include oxolinic acid, pyroquilone, quinoxyphene, tebufloquin and the like.
[0117] [0117] The phosphorus-based organic compound may include dinocap, edifenphos (EDDP), fosetyl (fosetyl-aluminium), iprobenphos (IBP), meptyldinocap, tolclofos-methyl and the like.
[0118] [0118] The carboxamide-based compound may include carpropamide, ethaboxam, phenoxanil, silthiopham, thiadinyl, isothianil and the like.
[0119] [0119] Other compounds for germicidal use may include ametoctradine, amisulbrome, cyazofamide, cyflufenamide, cymoxanil, diclocimet, diclomezine, famoxadone, phenamidone, phenexamide, phenitropam, fludioxonil, fluopicolide, flusulfamide, flutianil, halpim, isoprothiolane, isothianil, mandipropamide, metraphenone , oxathiapiproline, phthalide, proquinazide, valifenalate, zoxamide, diclobenthiazox, fenpicoxamide, picarbutrazox, quinofumeline, dimethomorph, flumorph, bupirimate, ferimzone, acibenzolar (acibenzolar-S-methyl), etridiazole, himhexazole, probenazole, tricyclazole, phenpyrazamine, teclophthalam, hydroxy- isoxazole, fluoroimide, pyriophenone, diflumetorime, quinomethionate, aminopyrifen, diclobentiazox, Lentinula hyphae extract, biotic pesticides (Agrobacterium radiobacter, Pseudomonas fluorescens, Pseudomonas rhodesiae, Bacillus subtilis, Bacillus simplex, Bacillus amyloliquefaciens, non-pathogenic Erwinia carotovora, Lactobacillus plantarum, Varia. paradoxus) and the like.
[0120] [0120] The preferred active ingredient for insecticidal use may include, for example, organic phosphorus-based compounds, carbamate-based compounds, pyrethroid-based compounds, nereistoxin-based compounds, neonicotinoid-based compounds, benzoylurea-based compounds, and other compounds insect proliferation controllers, chlorinated organic compounds, naturally derived compounds and the like.
[0121] [0121] Organic phosphorus-based compounds include acephate, azinphos-methyl, cadusaphos, chloroethoxyphos, chlorfenvinphos, chlorpyrifos, cyanophos, demetone-S-methyl, diazinone, dichlorvos (DDVP), dicrotophos, dimethoate, disulfotone, ethione, ethoprophos, EPN , phenamiphos, phenitrothione (MEP), phenthione (MPP), phosthiazate, imitiaphos, isophenphos, isoxathione, malathione, methamidophos, methidathione, mevinphos, monocrotophos, omethoate, oxidementon methyl, parathion, parathione-methyl, phentoate, phorate, phosalone, phosmet, phosphamidone, foxime, pyrimiphos-methyl, profenophos, prothiophos, pyraclophos, pyridafenthione, quinalphos, tebupyrinphos, terbuphos, triazophos, trichlorphone (DEP) and the like.
[0122] [0122] The carbamate-based compound includes alaniccarb, aldicarb, benfuracarb, BPMC, carbaryl (NAC), carbofuran, carbosulfan, cartape, phenoxycarb (BPMC), formatanate, isoisoprocarb (MIPC), methiocarb, methomyl, oxamyl, pirimicarb, thiodicarb, XMC, bendiocarb, ethiofencarb, fenobcarb, fenothiocarb, furathiocarb, metholcarb, xylylcarb and the like.
[0123] [0123] The pyrethroid-based compound may include acrinathrin, allethrin, cypermethrin, bifenthrin, cycloprothrin, cyfluthrin, cypermethrin,
[0124] [0124] deltamethrin, dimefluthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flubrocitrinate, fulcitrinate, fluvalinate, halfenprox, cyhalothrin, metofluthrin, momfluorothrin, permethrin, profluthrin, tefluthrin, tralomethrin, cyfluthrin, kappa-bifenthrin, imiprothrin, pyrethrin, chloropralethrin, cyfluthrin - metofluthrin, cyphenothrin and the like.
[0125] [0125] The nereistoxin compound may include cartape, bensultape, thiocyclam, monosultape, bisultape and the like.
[0126] [0126] The neonicotinoid compound may include acetamiprid, clothianidin, dinotefran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam and the like.
[0127] [0127] The benzoylurea compound may include bistriflurone, chlorfluazurone, diflubenzuron, flucycloxurone, flufenoxurone, hexaflumurone, lufenurone, novalurone, noviflumurone, teflubenzuron, triflumurone and the like.
[0128] [0128] The other insect growth controlling compound may include buprofezin, chromafenozide, cyromazine, halofenozide, methoxyfenozide, tebufenozide, pyriproxyfen and the like.
[0129] [0129] The chlorinated organic compound may include aldrin, dieldrin, endosulfan, methoxychlor, lindane, DDT and the like.
[0130] [0130] The naturally derived compound may include abamectiona, viable spores derived from Bacillus thuringiensis and crystalline toxins from production and mixtures thereof, bensultape, emamectin benzoate, lepimectin, milbemectin, spinetorame, spinosad, machine oils, starch, reduced starch saccharified oil, rapeseed oil, sodium oleate, propylene glycol monofatty acid esters, fatty acid glyceride, ferric phosphate and the like.
[0131] [0131] Other compounds for insecticidal use may include avermectin, chlorantraniliprol, chlorfenapyr, cyantraniliprol, diafenthiuron, ethiprole, fipronil, flonicamide, flubendiamide, fluensulfone, flupyradifurone, indoxacarb, metaflumizone, meta-aldehyde, pymetrozine, pyridaryl, pyrifluquinazone, silafluofen, spirotetramate , sulfoxaflor, tolfenpyrade, afidopyropen, broflanilide, cyclaniliprol, dichloromezothiaz, furomethoquin, fluazaindolizine, fluhexafone, fluxametamide, pyriprole, tetraniliprol, triflumezopyrim, methoprene, ticlopyrazoflor, flupirimine, spiropidione, benzpyrimoxane, cyhalodiamide, sulfluramid and the like.
[0132] [0132] The preferred active ingredient for acaricide use (acaricide active component) may include, for example, acequinocil, amidoflumet, amitraz, azocycle tin, biphenazate, bromopropionate, propylate, chlorfeson, quinomethionate, phenisobromolate, benzoximate, clofentezine, cyenopyrafen, cyflumetofen , ci-
[0133] [0133] The active ingredient for nematicide use (nematicide active component) may include, for example DD (1,3-dichloropropene), DCIP (diisopropyl dichloro ether), methyl isothiocyanate, sodium carbam salt, cadusphos, phosthiazate , imitiaphos, morantel tartrate, levamisole hydrochloride, nemadectin, thioxazaphene and the like.
[0134] [0134] The active ingredient optimal for use as a plant growth regulator may include, for example, amino ethoxyvinyl glycine, chlormequat, chlorpropham, cyclanilide, dikegulac, daminozide, ethephon, flurprimidol, flumetraline, forchlorphenurone, gibberellin, maleic hydrazide salt, mepiquat chloride, methyl cyclopropene, benzylaminopurine, paclobutrazol, prohexadione, thidiazuron, tributyl phosphorotrithioate, trinexapac-ethyl, uniconazole and the like.
[0135] [0135] The agricultural or horticultural chemical agent in the present embodiment can be used in rural areas such as farms, rice paddies, lawns and orchards, and in non-rural areas. The agricultural or horticultural chemical agent in the present embodiment may also be used, in addition to stem and leaf treatments as a foliar application, through seed treatments, including bulb and tuber treatments, irrigation treatments and non-foliar treatments, as water surface treatment. The method for controlling plant diseases,
[0136] [0136] When the agent is used in seed treatment, the chemical agent is adhered to the seeds by mixing the hydrating agent and the powdered agent together and agitating them, or by immersing the seeds in the diluted hydrating agent. The treatment includes a coating treatment of the seeds. In the seed treatment, the amount of active ingredient used was, for example, from 0.01 to 10,000 g for 100 kg of the seeds, preferably from 0.1 to 1,000 g. Seeds treated with the agricultural or horticultural chemical agent are used in the same way as normal seeds.
[0137] [0137] When the agent is used in the irrigation treatment, the pits and their periphery are treated with the granular agent when the seedlings are transplanted, or similar. The soil around the seeds or plants is treated with the granulating agent and the hydrating agent. When irrigation treatment is carried out, the amount of active ingredient used is, for example, from 0.01 to 10,000 g, preferably from 0.1 to 1,000 g per square meter (m2) of agricultural or horticultural land.
[0138] [0138] When the agent is used in water surface treatment, the water surface of the rice field is treated with the granulating agent, or the like. When water surface treatment is carried out, the amount of active ingredient used is, for example, from 0.1 to 10,000 g per 10 ares(a) of rice paddy, preferably from 1 to 1,000 g.
[0139] [0139] When the agent is used in forage application, the amount of the active ingredient used is, for example, from 20 to 5,000, more preferably from 50 to 2,000 g, per hectare (ha) of agricultural or horticultural land, such as the farm, paddy field, orchard or greenhouse.
[0140] [0140] The concentration and amount of use vary depending on the dosage form, the time in which the use occurs, the use, the place of use and the target crop and therefore it is possible to increase or decrease them. without adhering to the range described above.
[0141] [0141] The protective agent for industrial material containing the azole derivative (I) as the active ingredient may contain various components in addition to the azole derivative (I). The protective agent for industrial material containing the azole derivative (I) as the active ingredient can be used by dissolving or dispersing it in a suitable liquid vehicle, or mixing it with a solid vehicle. The protective agent for industrial material containing the azole derivative (I) as the active ingredient may contain, if necessary, an emulsifier, a dispersant, a spreader, a penetrating agent, a wetting agent, a stabilizer and the like. Examples of the protective agent dosage form for industrial material containing the azole derivative (I) as the active ingredient may include a moisturizing agent, a powdered agent, a granular agent, a tablet, a paste, a suspension, an aerosol. and the like. The protective agent for industrial material containing the azole derivative (I) as the active ingredient may contain other germicides, insecticides, spoilage preventing agents and the like.
[0142] [0142] The liquid carrier is not particularly limited as long as it is not reacted with the active ingredient. The liquid carrier may include, for example, water, alcohols (e.g., methyl alcohol, ethyl alcohol, ethylene glycol, cellossolve, and the like), ketones (e.g., acetone, methyl ethyl ketone, and the like), ethers (e.g., ether dimethyl, diethyl ether, dioxane, tetrahydrofuran and the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene, methyl naphthalene and the like), aliphatic hydrocarbons (e.g. gasoline, kerosene, coal oil, machine oil, fuel oil and the like), acid amides (e.g. dimethylformamide, N-methyl pyrrolidone and the like), halogenated hydrocarbons (e.g. chloroform, tetrachloromethane and the like), esters (e.g. ethyl acetate ester, glycerin ester fatty acid and the like), nitriles (eg acetonitrile and the like), dimethyl sulfoxide and the like.
[0143] [0143] As a solid carrier, it is possible to use a granular or fine powder material of kaolin, bentonite, acid clay, pyrophyllite, talc, diatomaceous earth, calcite, urea or ammonium sulfate.
[0144] [0144] As an emulsifier or dispersant, it is possible to use surfactants such as soaps, alkyl sulfonates, alkylaryl sulfonates, dialkyl sulfosuccinate, quaternary ammonium salts, oxyalkyl amines, fatty acid esters, polyalkylene oxides, anhydrosorbitols and the like.
[0145] [0145] When the azole derivative (I) is contained in the pharmaceutical preparation as the active ingredient, the content thereof depends on the dosage form and the purpose for which it is intended, but can be adjusted to 0.1 to 99.9 % by weight based on the total amount of the pharmaceutical preparation. When it is actually used, it is preferred that a solvent, a diluent or an extender is suitably added thereto, so that the treatment concentration is generally from 0.005 to 5% by weight, preferably from 0.01 to 1% , by weight.
[0146] [0146] As explained above, the azole derivative (I) shows excellent germicidal action on many microorganisms that cause plant diseases. The agricultural or horticultural disease controlling agent containing the azole derivative (I) as the active ingredient has low toxicity for humans and animals as well as high safety in handling, and can show the high controlling effect on the various plant diseases.
[0147] [0147] The present invention is not limited to the embodiments described above, and various changes may be made within the scope shown in the claims. The modalities, obtained by combining technical means that are suitably modified within the scope shown in the claims, are therefore within the technical scope of the present invention. [SUMMARY OF THE INVENTION]
[0148] [0148] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein R1 is a hydrogen, a C1-C6-alkyl group, a C2-C6- alkenyl, a C2-C6-alkynyl group, or COXR5; R2 is -OR7; R5 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, or a C2-C6-alkynyl group; R6 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, or a C2-C6-alkynyl group; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR10, or -SF5; and R4 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group , a C1-C4-alkylamine group, a C1-C4-dialkylamine group, a C1-C4-alkylacylamine group, -SOR10, or -SF5.
[0149] [0149] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein R1 is a hydrogen, a C1-C6-alkyl group, or COXR5; R5 is a hydrogen or a C1-C6-alkyl group; R6 is a hydrogen; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR10, or -SF5; and R4 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group,
[0150] [0150] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein R1 is a hydrogen or a C1-C6-alkyl group; R7 is a C1-C6-alkyl group; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, or a C1-C4-alkoxy group; and R4 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, or a C1-C4-haloalkoxy group.
[0151] [0151] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein E is a phenyl group.
[0152] [0152] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein Z is a phenyl group, a naphthyl group, or a 5- or 6-membered heteroaromatic ring. members containing 1 to 3 heteroatoms selected from N and S.
[0153] [0153] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein Z is a phenyl group.
[0154] [0154] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein Y is an oxygen atom.
[0155] [0155] The azole derivative of the present invention is preferably a compound or salt thereof represented by the general formula (I), wherein A is N and D is hydrogen.
[0156] [0156] The azole derivative of the present invention is preferably a compound or salt thereof represented by the following general formula (II).
[0157] [0157] The method for producing the azole derivative of the present invention is preferably the method for producing the compound represented by the general formula (I) described above, containing a step of converting a compound represented by the following general formula (V) in a compound represented by the following general formula (VI) by using a dialkyl sulfate represented by the following general formula (VII) or R7-LG, in which LG is a nucleophilically substitutable leaving group, iodine and a carbonate in sulfoxide of dimethyl. LG is preferably a halogen group.
[0158] [0158] The present invention contains a method for producing a compound represented by the general formula (VI), described above, which is a production method containing converting a compound represented by the general formula (V) into a compound represented by the formula general (VI) by using a dialkyl sulfate represented by the general formula (VII), described above, or R7-LG, iodine and a carbonate in a dimethyl sulfoxide. Here, LG is a nucleophilically replaceable leaving group.
[0159] [0159] An agricultural or horticultural chemical agent or a protective agent for industrial material containing the azole derivative of the present invention as an active ingredient is encompassed within the scope of the present invention.
[0160] [0160] From this point forward, the present invention will be described in detail with reference to production examples, preparation examples and test examples. It should be noted that the present invention is not limited to the production examples, preparation examples and test examples given below, provided that the present invention does not depart from the main point.
[0161] [0161] 1.00 g of commercially available diphenyl ether was dissolved in 12 mL of methylene chloride, and the solution was cooled in an ice bath. The solution was added with 0.936 g of aluminum chloride and then dripped with 0.864 g of methyl chloroglyoxylate over 30 minutes. After stirring the mixture at the same temperature for 30 minutes, the mixture was poured into a mixed solution of ice and concentrated hydrochloric acid. The mixture was extracted with methylene chloride and the organic layer was washed with 2M hydrochloric acid, water and a saturated saline solution, and dried over anhydrous sodium sulfate. After a solvent was distilled off, the residue was purified by column chromatography (20 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 0.973 g of the title compound as a colorless liquid. The yield was 64.6%. 1
[0162] [0162] NMR (400 MHz, CDCl 3 ) δ: 8.00 (d,J = 9.0 Hz, 2H), 7.42 (dd,J = 8.5, 7.6 Hz, 2H), 7. 26-7.21 (m,1H), 7.08 (dd,J=8.5, 7.5Hz, 2H), 7.02 (d,J=9.0Hz, 2H), 3.96 (s, 3H).
[0163] [0163] 184 mg of sodium hydride was weighed into a 25 ml three-necked flask, and 7 ml of dimethyl sulfoxide (hereinafter called DMSO) was added thereto. After stirring the mixture at room temperature for 20 minutes, the mixture was cooled to 10°C and added little by little with 1.75 g of methyltriphenylphosphine bromide (MTPB). After the mixture was returned to room temperature and stirred again for 30 minutes, 0.938 g of methyl 2-oxo-2-(4-phenoxyphenyl)acetate, synthesized in the previous paragraph, was dissolved in 2 ml of DMSO and dripped for 5 minutes, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was added with water and extracted with toluene. The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 0.595 g of the title compound as a liquid. colorless. The yield was 63.9%.
[0164] [0164] NMR (400 MHz, CDCl 3 ) δ: 7.39 (d,J = 8.8 Hz, 2H), 7.34 (dd,J = 8.6, 7.4 Hz, 2H), 7, 15-7.10 (m, 1H), 7.04 (dd,J = 8.5, 1.0 Hz, 2H), 6.98 (d,J = 8.8 Hz, 2H), 3.83 (s, 3H).
[0165] [0165] 0.590 g of methyl 2-(4-phenoxy phenyl)acrylate, synthesized in the previous paragraph, was dissolved in 6 ml of acetonitrile and 6 ml of methanol, and the solution was cooled to 0 °C. The solution was added with 0.767 g of urea hydrogen peroxide adduct and 0.385 g of potassium carbonate, and stirred at room temperature for 7.25 hours. The mixture was added with 0.100 g of potassium carbonate and further stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was added with water and extracted with toluene, and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain 0.585 g of crude product as a colorless liquid. 0.560 g of crude product was dissolved in 8 ml of dimethylformamide (DMF), and the mixture was added with 0.144 g of triazole and 0.189 g of triazole sodium and stirred at 50°C for 1.5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/4), thus obtaining 0.484 g of the title compound as a white solid. The yield was 61.4%.
[0166] [0166] NMR (400 MHz, CDCl 3 ) δ: 8.17 (s, 1H), 7.91 (s, 1H), 7.60 (d,J = 8.9 Hz, 2H), 7.39- 7.34 (m, 2H), 7.17-7.12 (m, 1H), 7.04-6.99 (m, 2H), 7.01 (d,J = 8.9 Hz, 2H) , 5.03 (d,J = 14.0 Hz, 1H), 4.44 (d,J = 14.0 Hz, 1H), 4.36 (s, 1H), 3.83 (s, 3H) .
[0167] [0167] By the same operation as the synthesis of methyl 2-oxo-2-(4-phenoxyphenyl)acetate of Synthesis Example 1, 0.998 g of the title compound was obtained as a colorless liquid from of 1.21 g of 4-chlorodiphenyl ether. The yield was 58.0%. 1
[0168] [0168] NMR (400 MHz, CDCl 3 ) δ: 8.02 (d,J = 9.0 Hz, 2H), 7.38 (d,J = 9.0 Hz, 2H), 7.06-7, 00 (m, 4H), 3.97 (s, 3H).
[0169] [0169] By means of the same operation as the synthesis of methyl 2-(4-phenoxyphenyl)acrylate of Synthesis Example 1, 0.431 g of the title compound was obtained as a colorless liquid from 0.980 g of methyl 2-(4-(4-chlorophenoxy)phenyl)-2-oxoacetate. The yield was 44.3%. 1
[0170] [0170] NMR (400 MHz, CDCl 3 ) δ: 7.39 (d,J = 8.8 Hz, 2H), 7.30 (d,J = 9.0 Hz, 2H), 6.99-6, 94 (m, 4H), 3.83 (s, 3H).
[0171] [0171] By the same operation as the synthesis of Control Compound B of Synthesis Example 1, 0.276 g of the title compound was obtained as a white solid from 0.413 g of 2-(4-( methyl 4-chlorophenoxy)phenyl)acrylate. The yield was 51.6%.
[0172] [0172] NMR (400 MHz, CDCl 3 ) δ: 8.16 (s, 1H), 7.91 (s, 1H), 7.62 (d,J = 8.9 Hz, 2H), 7.31 ( d,J = 8.9 Hz, 2H), 6.99 (d,J = 8.9 Hz, 2H), 6.96 (d,J = 8.9 Hz, 2H), 5.02 (d, J = 14.0 Hz, 1H), 4.44 (s, 1H), 4.43 (d,J = 14.0 Hz, 1H), 3.83 (s, 3H).
[0173] [0173] 1.54 g of 2-chloro-4-fluoroacetophenone was dissolved in 16 ml of DMF, and the solution was added with 1.47 g of 2,4-dichlorophenol and 1.48 g of potassium carbonate, and stirred at 100°C for 0.75 hours. A bath temperature was raised to 120°C and the mixture was further stirred for 2 hours. The mixture was added with 0.144 g of 2,4-dichlorophenol and further stirred for 2 hours. Upon completion of the reaction, the mixture was added with toluene, and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (75 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.922 g of the title compound as a liquid. colorless viscous. The yield was 68.3%. 1
[0174] [0174] NMR (400 MHz, CDCl 3 ) δ: 7.64 (d,J = 8.7 Hz, 1H), 7.51 (d,J = 2.5 Hz, 1H), 7.29 (dd, J = 8.7, 2.5 Hz, 1H), 7.06 (d,J = 8.7 Hz, 1H), 6.92 (d,J = 2.5 Hz, 1H), 6.83 ( dd,J = 8.7, 2.5 Hz, 1H), 2.65 (s, 3H).
[0175] [0175] 1.86 g of 1-(2-chloro-4-(2,4-dichlorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotary evaporator flask, and added to 24 mL of DMSO for dissolution. The mixture was added with 4.76 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.69 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.17 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, the excess iodine was quenched with 60 ml of saturated aqueous sodium sulfite solution, 60 ml of toluene was added and the precipitated solution was filtered with celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.2786 g of the title compound as a pale yellow liquid. The yield was 60.5%. 1
[0176] [0176] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.7 Hz, 1H), 7.53 (d,J = 2.5 Hz, 1H), 7.32 (dd, J = 8.7, 2.5 Hz, 1H), 7.10 (d,J = 8.7 Hz, 1H), 6.92 (d,J = 2.5 Hz, 1H), 6.89 ( dd,J = 8.7, 2.5Hz, 1H), 3.95 (s, 3H).
[0177] [0177] 0.525 g of methyl-2-(2-chloro-4-(2,4-dichlorophenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 3 ml of dimethylacetamide (DMAc), and the The solution was added with 0.387 g of trimethylsulfoxonium iodide (TMSOI) and 0.174 g of sodium triazole and stirred at 40°C for 0.75 hour, and at 50°C for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/4), thus obtaining
[0178] [0178] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.49 (d,J = 2.5 Hz, 1H), 7.41 ( d,J = 8.8 Hz, 1H), 7.26 (dd,J = 8.7, 2.5 Hz, 1H), 7.00 (d,J = 8.7 Hz, 1H), 6, 94 (d,J = 2.5 Hz, 1H), 6.76 (dd,J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.92 (d,J = 14.3 Hz, 1H), 4.90 (brs, 1H), 3.79 (s, 3H).
[0179] [0179] 2.015 g of 2-chloro-4-fluoroacetophenone was dissolved in 21 ml of DMF, and the solution was added with 1.462 g of 4-methoxy phenol and 1.935 g of potassium carbonate, and stirred at 80 °C for 3.5 hours. The mixture was added with 0.435 g of 4-methoxy phenol and 0.484 g of potassium carbonate, and further stirred for 2.5 hours. Upon completion of the reaction, the mixture was added with toluene, and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (75 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 2.367 g of the title compound as a liquid. colorless viscous. The yield was 73.3%. 1
[0180] [0180] NMR (400 MHz, CDCl 3 ) δ: 7.62 (d,J = 8.7 Hz, 1H), 7.00 (d,J = 9.2 Hz, 2H), 6.94-6, 91 (m, 3H), 6.84 (dd,J = 8.7, 2.4 Hz, 1H), 3.83 (s, 3H), 2.64 (s, 3H).
[0181] [0181] 2.0879 g of 1-(2-chloro-4-(4-methoxyphenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotary evaporator flask and added to 30 ml of DMSO for dissolution. The mixture was added with 6.151 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 7.35 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.50 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, 60 ml of saturated aqueous sodium sulfite solution and 60 ml of toluene were added to the mixture, and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.6922 g of the title compound as a colorless solid. The yield was 69.9%. 1
[0182] [0182] NMR (400 MHz, CDCl 3 ) δ: 7.81 (d,J = 9.0 Hz, 1H), 7.02 (d,J = 9.2 Hz, 2H), 6.97-6, 89 (m, 4H), 3.94 (s, 3H), 3.83 (s, 3H). Synthesis of methyl 2-(2-chloro-4-(4-methoxyphenoxy)phenyl)acrylate
[0183] [0183] 210 mg of sodium hydride was weighed into a 25 ml three-neck flask, and 8 ml of DMSO was added thereto. After stirring the mixture at room temperature for 20 minutes, the mixture was cooled with ice and added little by little with 1.91 g of MTPB. After the mixture was returned to room temperature and stirred again for 30 minutes, 1.34 g of methyl 2-(2-chloro-4-(4-methoxyphenoxy)phenyl)-2-oxoacetate, synthesized in the previous paragraph, in 2 ml of DMSO and dripped for 2 minutes, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was added with water and extracted with toluene. The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (30 g of silica gel,
[0184] [0184] NMR (400 MHz, CDCl 3 ) δ: 7.16 (d,J = 8.5 Hz, 1H), 7.02 (d,J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 6.94-6.81 (m, 1H), 6.83 (dd,J = 8.5, 2.5 Hz, 1H), 6.48 (d,J = 1.5 Hz, 1H), 5.76 (d,J = 1.5 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H).
[0185] [0185] 0.8681 g of methyl 2-(2-chloro-4-(4-methoxyphenoxy)phenyl)acrylate, synthesized in the previous paragraph, was dissolved in 7 ml of acetonitrile and 9.4 ml of methanol, and the solution was cooled to 0 °C. The solution was added with 0.898 g of urea hydrogen peroxide adduct and 0.383 g of potassium carbonate, and stirred at room temperature for 5.5 hours. The mixture was added with 0.388 g of potassium carbonate and further stirred at room temperature for 1 hour. Upon completion of the reaction, the mixture was added with water and extracted with toluene, and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain 0.827 g of crude oxirane product as a colorless liquid.
[0186] [0186] 0.796 g of methyl 2-(2-chloro-4-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate, synthesized in the previous paragraph, was dissolved in 9.5 ml of DMF, and the solution was added with 0.167 g of triazole and 0.222 g of sodium triazole, and stirred at 50°C for 1.5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/4 → ethyl acetate → chloroform methanol 20/ 1), thereby obtaining 0.693 g of the title compound as a white solid. The yield was 63.0%. 1
[0187] [0187] NMR (400 MHz, CDCl 3 ) δ: 7.99 (s, 1H), 7.88 (s, 1H), 7.35 (d,J = 8.8 Hz, 1H), 6.98 ( d,J = 9.2 Hz, 2H), 6.93-6.89 (m, 3H), 6.76 (dd,J = 8.8, 2.5 Hz, 1H), 5.01 (d ,J = 14.3 Hz, 1H), 4.92 (d,J = 14.3 Hz, 1H), 4.83 (s, 1H), 3.82 (s, 3H), 3.79 (s , 3H).
[0188] [0188] After 761 mg of commercially available 1-(2-chloro-4-(4-chlorophenoxy)phenyl)-ethan-1-one and 10.8 mL of DMSO are added to and dissolved in a 100 mL rotary evaporator flask , the mixture was added with 2.21 g of iodine, heated to 100°C and stirred. After 3 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried with anhydrous sodium sulfate, the solvent was removed by distillation and 181 mg of a crude product was obtained as an orange liquid, but no target product was contained in the mixture. The aqueous layer was added with a 1N aqueous HCl solution to make it acidic, it was extracted three times with ethyl acetate and washed once with a saturated saline solution. After being dried over anhydrous sodium sulfate, the solvent was distilled off and the title compound was obtained as a crude product as a white solid (551.1 mg, 65.4% yield).
[0189] [0189] NMR (400 MHz, DMSO-d6) δ: 7.78 (d,J = 8.4 Hz, 1H), 7.50 (d,J = 8.8 Hz, 2H), 7.18 ( d,J = 8.8 Hz, 2H), 7.05 (d,J = 2.4 Hz, 1H), 7.00 (dd,J = 8.4, 2.4 Hz, 1H).
[0190] [0190] After 177 mg of 2-(2-chloro-4-(4-chlorophenoxy)phenyl)-2-oxoacetic acid and 1.1 mL of DMF were added to and dissolved in a 100 mL rotary evaporator flask, the mixture was added with 223 mg of cesium carbonate and 57 µl of methyl iodide and stirred. After 1 hour of starting the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 171.5 mg of crude α-ketoester product as a colorless liquid. Upon purification by column chromatography (5 g of silica gel, hexane:ethyl acetate = 9:1), the title compound was obtained as 161.4 mg of colorless viscous liquid compound (yield 87.1 %). 1
[0191] [0191] NMR (400 MHz, CDCl 3 ) δ: 7.87 (d,J = 8.7 Hz, 1H), 7.36 (d,J = 8.9 Hz, 2H), 7.03-6, 97 (m, 3H), 6.87 (dd,J = 8.7, 2.5 Hz, 1H), 3.91 (s, 3H). 13 CRMN (100 MHz, CDCl 3 ) δ: 165.3, 160 .5, 153.6, 135.8, 133.4, 130.2, 129.7, 124.0, 121.5, 120.2, 119.8, 115.5, 52.3.
[0192] [0192] After 130.4 mg of methyl 2-(2-chloro-4-(4-chlorophenoxy)phenyl)-2-oxoacetate, 68 µL of diiodomethane and 1.0 mL of THF are added to and dissolved in into a 50 mL rotary evaporator flask, the mixture was cooled in a dry ice acetone bath, added with 0.68 mL of isopropylmagnesium chloride and continuously stirred. After 0.5 hour from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with ethyl acetate. The extract was washed once with water and then washed once with saturated saline. After the extract was dried with anhydrous sodium sulfate, a solvent was distilled off to obtain 187.1 mg of crude 2-(2-chloro-4-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate product. methyl in the form of a colorless liquid. Upon purification by column chromatography (6 g of silica gel, hexane:ethyl acetate = 9:1), the title compound was obtained as 91.6 mg of a colorless viscous liquid mixture.
[0193] [0193] After 91.6 mg of a mixture of methyl 2-(2-chloro-4-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate and 1.2 ml of DMF are added to and dissolved in a flask to 100 ml rotary evaporator, the mixture was added with 43.7 mg of triazole sodium salt, heated to 40°C and stirred. The reaction was properly sampled and tracked by HPLC. After 4 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction and it was extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 187 mg of crude product as a colorless liquid. Upon purification by column chromatography (2 g of silica gel, hexane:ethyl acetate = 1:1), 27.0 mg of a colorless viscous liquid mixture was obtained. The mixture was crystallized from toluene to obtain the title compound (I-1) as 12.8 mg of white solid. 1
[0194] [0194] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.40 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 8.7 Hz, 2H), 6.99-6.95 (m, 3H), 6.81 (dd,J = 8.8 Hz, 1H), 5.0 (d,J = 14 .3 Hz, 1H), 4.93 (d,J = 14.3 Hz, 1H), 4.88 (br, 1H), 3.80 (s, 3H).
[0195] [0195] 46.4 mg of Compound (I-1), synthesized in Synthesis Example 5, was dissolved in 2 ml of ethyl acetate. The mixture was added with 19.0 mg of a 20% solution of sodium ethoxide/ethanol, and stirred at room temperature for 2 hours. The mixture was added with 11.6 mg of sodium tert-butoxide (STB) and stirred at room temperature for 1 hour, and added with 2 ml of ethanol and stirred for 2 hours. Upon completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off, and 45.4 mg of the title compound was obtained as a white solid by vacuum drying. The yield was 94.6%. 1
[0196] [0196] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.87 (s, 1H), 7.40 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 9.0 Hz, 2H), 6.98-6.94 (m, 3H), 6.80 (dd,J = 8.8, 2.6 Hz, 1H), 5.02 (d ,J = 14.3 Hz, 1H), 4.97 (d,J = 14.3 Hz, 1H), 4.76 (s, 1H), 4.25-4.19 (m, 2H), 1 .27 (t,J = 7.5 Hz, 3H).
[0197] [0197] 1.50 g of 2-chloro-4-fluoroacetophenone was dissolved in 16 ml of DMF and the solution was added with 1.704 g of 4-trifluoromethoxyphenol and 1.44 g of potassium carbonate, and stirred at 120° C for 2.5 hours. Upon completion of the reaction, the mixture was added with toluene, and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by column chromatography (75 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 2.627 g of the title compound as a liquid. colorless viscous. The yield was 91.3%. 1
[0198] [0198] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 1H), 7.26 (d,J = 9.0 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.01 (d,J = 2.4 Hz, 1H), 6.90 (dd,J = 8.6, 2.5 Hz, 1H), 2.66 ( s, 3H).
[0199] [0199] 2.61 g of 1-(2-chloro-4-(4-(trifluoromethoxy)phenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotaevaporator flask, and added with 25 ml of DMSO for dissolution. The mixture was added with 6.418 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 7.65 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.58 mL of iodomethane and stirred at 35 °C for 1.5 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.879 g of the title compound as a pale yellow liquid. The yield was 63.5%.
[0200] [0200] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.7 Hz, 1H), 7.28 (d,J = 9.1 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 7.00 (d,J = 2.4 Hz, 1H), 6.95 (dd,J = 8.7, 2.4 Hz, 1H), 3.95 ( s, 3H).
[0201] [0201] 0.563 g of methyl 2-(2-chloro-4-(4-(trifluoromethoxy)phenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 3 ml of DMF, and the solution was added with 0.320 g of trimethylsufoxonium bromide (TMSOB) and 0.177 g of sodium triazole, and stirred at 50°C for 2.5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/4), thus obtaining 0.172 g of the title compound (I-22) as a white solid. The yield was 25.1%. 1
[0202] [0202] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.41 (d,J = 8.8 Hz, 1H), 7.23 ( brd,J = 9.1 Hz, 2H), 7.03 (d,J = 9.1 Hz, 2H), 7.00 (d,J = 2.5 Hz, 1H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.94 (d,J = 14.3 Hz, 1H), 4.89 ( brs, 1H), 3.80 (s, 3H).
[0203] [0203] 1.53 g of 2-chloro-4-fluoroacetophenone was dissolved in 16 ml of N-methyl-2-pyrrolidone (NMP), and the solution was added with 2.15 g of 4--
[0204] [0204] NMR (400 MHz, CDCl 3 ) δ: 7.68-7.62 (m, 3H), 7.13 (d,J = 8.4 Hz, 2H), 7.06 (d,J = 2 .4 Hz, 2H), 6.95 (dd,J = 8.6, 2.5 Hz, 1H), 2.67 (s, 3H).
[0205] [0205] 1.56 g of 1-(2-chloro-4-(4-(trifluoromethyl)phenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotary evaporator flask, and 20 ml of DMSO was added for dissolution. The mixture was added with 4.01 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 4.76 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.0 mL of iodomethane and stirred at 35 °C for 1.5 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (37 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.064 g of the title compound as a pale yellow liquid. The yield was 60.0%.
[0206] [0206] NMR (400 MHz, CDCl 3 ) δ: 7.84 (d,J = 8.6 Hz, 1H), 7.69 (d,J = 8.5 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.04 (d,J = 2.4 Hz, 1H), 7.00 (dd,J = 8.6, 2.4 Hz, 1H), 3.96 ( s, 3H).
[0207] [0207] 0.508 g of methyl 2-(2-chloro-4-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 2.6 ml of DMF, and the The solution was added with 0.270 g of TMSOB and 0.170 g of sodium triazole, and stirred at 50°C for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.160 g of the title compound as pale yellow to white solids. The yield was 25.5%. 1
[0208] [0208] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.89 (s, 1H), 7.63 (d,J = 8.6 Hz, 2H), 7.46 ( d,J = 8.8 Hz, 1H), 7.08 (d,J = 8.6 Hz, 2H), 7.05 (d,J = 2.5 Hz, 1H), 6.88 (dd, J = 8.8, 2.5 Hz, 1H), 5.03 (d,J = 14.3 Hz, 1H), 4.95 (d,J = 14.3 Hz, 1H), 4.90 ( brs, 1H), 3.81 (s, 3H).
[0209] [0209] 1.51 g of 2-chloro-4-fluoroacetophenone was dissolved in 16 ml of DMF, and the solution was added with 1.45 g of 4-tert-butylphenol and 1.45 g of potassium carbonate, and stirred at 110°C for 2.5 hours. After the reaction is complete,
[0210] [0210] NMR (400 MHz, CDCl 3 ) δ: 7.63 (d,J = 8.7 Hz, 1H), 7.40 (d,J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.99 (d,J = 2.4 Hz, 2H), 6.89 (dd,J = 8.7, 2.5 Hz, 1H), 2.65 ( s, 3H), 1.34 (s, 9H).
[0211] [0211] 1.586 g of 1-(4-(4-(tert-butyl)phenoxy)-2-chlorophenyl)ethan-1-one synthesized in the previous paragraph were weighed into a 100 mL rotary evaporator flask and added 18 mL of DMSO for dissolution. The mixture was added with 4.21 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.07 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.05 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (37 g of silica gel, hexane/ethyl acetate = 10/1),
[0212] [0212] NMR (400 MHz, CDCl 3 ) δ: 7.80 (d,J = 8.7 Hz, 1H), 7.43 (d,J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.97 (d,J = 2.4 Hz, 1H), 6.94 (dd,J = 8.7, 2.4 Hz, 1H), 3.94 ( s, 3H), 1.35 (s, 9H).
[0213] [0213] 0.465 g of methyl 2-(4-(4-(tert-butyl)phenoxy)-2-chlorophenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 2.5 ml of DMF, and the solution was added with 0.280 g of TMSOB and 0.135 g of sodium tert-butoxide, stirred at room temperature for 0.5 hour and stirred at 50°C for 0.5 hour. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 7/1), thus obtaining 0.0905 g of the title compound as a pale yellow to white liquid. The yield was 18.7%. 1
[0214] [0214] NMR (400 MHz, CDCl 3 ) δ: 7.38 (d,J = 8.6 Hz, 1H), 7.36 (d,J = 8.8 Hz, 2H), 6.99 (d, J = 2.4 Hz, 1H), 6.97 (d,J = 8.8 Hz, 2H), 6.89 (dd,J = 8.6, 2.4 Hz, 1H), 3.77 ( s, 3H), 3.57 (d,J = 6.4 Hz, 1H), 3.03 (d,J = 6.4 Hz, 1H), 1.33 (s, 9H).
[0215] [0215] 89.5 mg of methyl 2-(4-(4-(tert-butyl)phenoxy)-2-chlorophenyl)oxirane-2-carboxylate obtained in the previous paragraph was dissolved in 1 ml of DMF and the solution was added with 17.4 mg of triazole and 23.0 mg of triazole sodium and stirred at 50°C for 3 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (3 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 78.5 mg of the title compound as a white solid. The yield was 75.4%. 1
[0216] [0216] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.89 (s, 1H), 7.38 (d,J = 8.8 Hz, 2H), 7.37 ( d,J = 8.8 Hz, 1H), 6.98 (d,J = 2.5 Hz, 1H), 6.95 (d,J = 8.8 Hz, 2H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.2 Hz, 1H), 4.92 (d,J = 14.2 Hz, 1H), 4.79 ( brs, 1H), 3.79 (s, 3H), 1.33 (s, 9H).
[0217] [0217] 37.6 mg of tert-butyl 2-(2-chloro-4-((4-chlorobenzyl)oxy)phenyl)-2-oxoacetate was dissolved in 0.5 ml of DMF, and the solution was added with 11.3 mg of sodium triazole and 8.9 mg of triazole and stirred at 50°C for 8 hours. After completion of the reaction, the mixture was added with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (3 g of silica gel, hexane/ethyl acetate = 1/3), thereby obtaining 36.5 mg of the title compound as a a white solid. The yield was 82.7%.
[0218] [0218] NMR (400 MHz, CDCl 3 ) δ: 8.04 (s, 1H), 7.85 (s, 1H), 7.48 (d,J = 9.0 Hz, 2H), 7.37 ( d,J = 8.8 Hz, 1H), 6.99 (d,J = 2.5 Hz, 1H), 6.90 (d,J = 9.0 Hz, 2H), 6.80 (dd, J = 8.8, 2.5 Hz, 1H), 4.99 (d,J = 14.3 Hz, 1H), 4.95 (d,J = 14.3 Hz, 1H), 4.53 ( s, 1H), 1.46 (s, 9H).
[0219] [0219] 135 mg of compound (I-1), synthesized in Synthesis Example 5, was dissolved in 1 ml of methanol, and the solution was added with 2 ml of 2 mol/L aqueous sodium hydroxide solution and stirred at room temperature for 6.5 hours. Upon completion of the reaction, the mixture was adjusted with 1 mol/L hydrochloric acid to have a pH of 3 to 4, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and 115 mg of the title compound was obtained as a white solid by vacuum drying.
[0220] [0220] 49.9 mg of 2-(2-chloro-4-(4-chlorophenoxy)phenyl)2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoic acid obtained in paragraph above were dissolved in 1 ml of DMF and the solution was added with 58.7 mg of cesium carbonate. The mixture was added with 26.1 mg of 2-iodopropane and stirred at 50°C for 2 hours. The mixture was added with 17.0 mg of 2-iodopropane and further stirred at the same temperature for 3.5 hours. After completion of the reaction, the mixture was added with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (2.5 g of silica gel, hexane/ethyl acetate = 1/3), thereby obtaining 51.6 mg of the title compound under the form of a white solid. The yield was 93.4%. 1
[0221] [0221] NMR (400 MHz, CDCl 3 ) δ: 8.02 (s, 1H), 7.86 (s, 1H), 7.39 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 9.0 Hz, 2H), 6.98 (d,J = 2.5 Hz, 1H), 6.96 (d,J = 9.0 Hz, 2H), 6.80 (dd, J = 8.8, 2.5 Hz, 1H), 5.10 (sept,J = 6.3 Hz, 1H), 5.01 (d,J = 14.3 Hz, 1H), 4.94 ( d,J = 14.3 Hz, 1H), 4.74 (s, 1H), 1.26 (d,J = 6.3 Hz, 3H), 1.23 (d,J = 6.3 Hz, 3H).
[0222] [0222] 54.5 mg of 2-(2-chloro-4-(4-chlorophenoxy)phenyl)2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoic acid, obtained in the previous paragraph, were dissolved in 1 ml of DMF and the solution was added with 68.7 mg of cesium carbonate. The mixture was added with 16 µl of cyclopropylmethyl bromide and stirred at 50°C for 3 hours. The mixture was added with 16 µl of cyclopropylmethyl bromide and further stirred at the same temperature for 2 hours. After completion of the reaction, the mixture was added with ethyl acetate and the organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (3 g of silica gel, hexane/ethyl acetate = 1/2), thereby obtaining 38.2 mg of the title compound as a a white solid. The yield was 61.6%. 1
[0223] [0223] NMR (400 MHz, CDCl 3 ) δ: 8.02 (s, 1H), 7.87 (s, 1H), 7.41 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 9.0 Hz, 2H), 6.98 (d,J = 2.5 Hz, 1H), 6.96 (d,J = 9.0 Hz, 2H), 6.81 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.96 (d,J = 14.3 Hz, 1H),
[0224] [0224] 1.560 g of 2-chloro-4-fluoroacetophenone was dissolved in 16 ml of DMF, and the solution was added with 1.615 g of 3,4-dichlorophenol and 1.510 g of potassium carbonate, and stirred at 90 °C for 6 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.701 g of the title compound as a liquid. colorless viscous. The yield was 62.1%.
[0225] [0225] 1.70 g of 1-(2-chloro-4-(3,4-dichlorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotary evaporator flask, and added with 20 mL of DMSO for dissolution. The mixture was added with 4.37 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.212 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.1 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.175 g of the title compound as a pale yellow liquid. The yield was 60.6%. 1
[0226] [0226] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.6 Hz, 1H), 7.49 (d,J = 8.8 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 7.00 (d,J = 2.4 Hz, 1H), 6.97 (dd,J = 8.6, 2.4 Hz, 1H), 6.96 ( dd,J = 8.8, 2.8 Hz, 1H), 3.96 (s, 3H).
[0227] [0227] 0.813 g of methyl 2-(2-chloro-4-(3,4-dichlorophenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 4.5 ml of DMF, and the solution was added with 0.548 g of trimethylsulfoxonium iodide (TMSOI) and 0.247 g of triazole sodium salt at 0°C, and stirred for 30 minutes while returning to room temperature. The mixture was placed in a 50 °C bath and stirred for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.242 g of the title compound as a white solid. The yield was 24.2%. 1
[0228] [0228] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.88 (s, 1H), 7.43 (d,J = 8.8 Hz, 2H), 7.13 ( d,J = 2.8 Hz, 1H), 7.00 (d,J = 2.5 Hz, 1H), 6.89 (dd,J = 8.8, 2.8 Hz, 1H), 6, 83 (dd,J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.98 (s, 1H), 4.93 (d,J = 14.3 Hz, 1H), 3.80 (s, 3H).
[0229] [0229] 2.67 g of 3-trifluoromethoxy fluorobenzene was dissolved in 18 ml of NMP, and the solution was added with 2.39 g of 4-chloroiodobenzene, 6.55 g of cesium carbonate, 0.205 g of copper and 0.401 g of dimethyl glycine hydrochloride (DMG) and stirred at 90°C for 6 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (75 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.171 g of the title compound as a liquid. colorless viscous. The yield was 40.6%. 1
[0230] [0230] NMR (400 MHz, CDCl 3 ) δ: 7.35-7.28 (m, 3H), 7.00-6.94 (m, 3H), 6.93-6.88 (m, 1H) , 6.86-6.84 (m, 1H).
[0231] [0231] 1.17 g of 1-(4-chlorophenoxy)-3-(trifluoromethoxy)benzene, synthesized in the previous paragraph, were weighed into a 100 ml rotary evaporator flask and dissolved in 5.0 ml of methylene chloride. The solution was cooled to -20 °C and added with 0.523 g of aluminum chloride. Furthermore, the mixture was cooled to -40 °C and dripped with a solution obtained by dropping 0.487 g of methylglyoxalic acid chloride in 5 ml of methylene chloride for 9 minutes. The mixture was heated over 1 hour to -5°C. Upon completion of the reaction, the mixture was added with ice and concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. A solvent was distilled off and the residue was redissolved in 5.0 ml of methylene chloride. The mixture was cooled to -5°C and added with 0.548 g of aluminum chloride. The mixture was dripped with a solution, in which 0.499 g of methylglyoxalic acid chloride is dissolved in 5 ml of methylene chloride for 1 minute. The mixture was stirred for 2 hours while warming to room temperature. Upon completion of the reaction, the mixture was added with ice and concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. A solvent was distilled off and the residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 0.287 g of the title compound as a liquid. colorless viscous. The yield was 22.1%. 1
[0232] [0232] NMR (400 MHz, CDCl 3 ) δ: 7.94 (d,J = 9.3 Hz, 1H), 7.41 (d,J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 6.93-6.89 (m, 2H), 3.94 (s, 3H).
[0233] [0233] 0.259 g of methyl 2-(4-(4-chlorophenoxy)-2-(trifluoromethoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 1.5 ml of DMAc, and the solution was added with 0.171 g of TMSOI and 0.076 g of sodium triazole and stirred at room temperature for 0.5 hour and at 50°C for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (9 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining
[0234] [0234] NMR (400 MHz, CDCl 3 ) δ: 8.06 (s, 1H), 7.88 (s, 1H), 7.45 (d,J = 8.8 Hz, 1H), 7.35 ( d,J = 8.9 Hz, 2H), 6.98 (d,J = 8.9 Hz, 2H), 6.98-6.93 (m, 1H), 6.77(dd,J = 8 .8, 2.4 Hz, 1H), 5.01 (d,J = 14.2 Hz, 1H), 4.76 (d,J = 14.2 Hz, 1H), 4.70 (s, 1H ), 3.79 (s, 3H).
[0235] [0235] In a nitrogen atmosphere, 10.494 g of 1-bromo-2-cyano-4-fluorobenzene and 0.337 g of 4-chlorophenol were dissolved in 4.5 mL of NMP, and the solution was added with 0.420 g of potassium carbonate at room temperature, heated to 100°C, stirred for 23 hours and then stirred at 160°C for 1 hour. Thereafter, the reaction was quenched by adding water, the mixture was extracted with ethyl acetate, the organic layer was washed with water and a saturated saline solution, and then dried with anhydrous sodium sulfate. The solvent was distilled off and 0.845 g of crude product obtained was purified by column chromatography (20 g of silica gel, hexane/ethyl acetate = 19/1) to obtain a mixture containing the title compound as a product. main, in the form of 0.656 g of colorless oil. 1
[0236] [0236] NMR (400 MHz, CDCl 3 ) δ: 7.60 (d,J = 8.8 Hz, 1H), 7.39-7.36 (m, 2H), 7.21 (d,J = 2 .8 Hz, 1H), 7.08 (dd,J = 8.8, 2.8 Hz, 1H), 6.98-6.95 (m, 2H).
[0237] [0237] In a nitrogen atmosphere, 3 mL of a solution in tetrahydrofuran (THF) of 0.195 g of 1-bromo-4-(4-chlorophenoxy)-2-cyanobenzene, obtained in the previous paragraph, were cooled to 0 ° C, added with 0.5 mL of a THF solution of iPrMgCl·LiCl, warmed to room temperature and then stirred for 20 minutes. Then, the solution was cooled once to 0 °C, added with a THF solution of 0.08 mL of methyl 3-bromopyruvate, warmed to room temperature and stirred for 1 hour. After that, the solution was added with 1N aqueous hydrochloric acid solution to stop the reaction, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate water and saturated saline solution, and then dried with anhydrous sodium sulfate. The solvent was distilled off and 0.243 g of the crude product obtained was purified by column chromatography (10.0 g of silica gel, hexane/ethyl acetate = 9/1), thus obtaining 0.055 g of the title compound in the form of a pale yellow oil. The yield was 21.0%. 1
[0238] [0238] NMR (400 MHz, CDCl 3 ) δ: 7.63 (brs, 1H), 7.50 (d,J = 8.4 Hz, 1H), 7.36-7.34 (m, 3H), 7.26 (dd,J = 8.0, 2.0 Hz, 1H), 7.00 (d,J = 8.8 Hz, 2H), 4.12 (d,J = 12.0 Hz, 1H ), 3.83 (s, 3H), 3.72 (d,J = 11.6 Hz, 1H).
[0239] [0239] In an atmosphere of nitrogen, 0.011 g of sodium triazole was added to 2 mL of a DMF solution of 0.039 g of bromohydrin, and the mixture was heated to 40 °C and stirred for 1 hour and then stirred at 50°C for 2 hours. After the mixture was cooled to room temperature, the mixture was added with 0.004 g of sodium triazole, heated to 50 °C and stirred for 1 hour. After that, the mixture was added with a saturated aqueous ammonium chloride solution to stop the reaction and extracted with chloroform, and the organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate. The solvent was distilled off and 0.052 g of the crude product obtained was purified by column chromatography (6.3 g of silica gel, hexane/ethyl acetate = 1/1 → 1/4 → 0/1), obtaining if so 0.005 g of the title compound as a pale yellow oil. The yield was 10.4%. 1
[0240] [0240] NMR (400 MHz, CDCl 3 ) δ: 8.08 (s, 1H), 7.83 (s, 1H), 7.57 (d,J = 9.2 Hz, 2H), 7.36- 7.34 (m, 3H), 7.29-7.25 (m, 1H), 6.98 (d,J = 8.8 Hz, 1H), 5.04 (d,J = 14.4 Hz , 1H), 4.78 (d,J = 14.4 Hz, 1H), 3.81 (s, 3H).
[0241] [0241] After 825 mg of 4-fluoro-2-(trifluoromethyl)acetophenone and 7.2 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 567 mg of 4-chlorophenol and 663 mg of potassium carbonate, and heated and stirred in an oil bath at 120 °C. After 1.5 hours from the start of the reaction, the mixture was added with water to stop the reaction and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.33 g of the title compound as a brown liquid.
[0242] [0242] 1.3257 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethan-1-one and 16 ml of DMSO were added to and dissolved in a 100 ml rotary evaporator flask at The mixture was added with 3.2500 g of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 hour from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.8714 g of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 hour, the reaction solution was cooled to room temperature, added with 0.80 mL of methyl iodide and stirred continuously. After 3.5 hours, the mixture was heated and stirred in a water bath at 35 °C. After 1 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.3677 g of crude ketoester product as a brown liquid. Upon purification by column chromatography (50 g of silica gel, hexane:ethyl acetate = 9:1), 840.2 mg of the title compound was obtained as an orange liquid compound. 1
[0243] [0243] NMR (400 MHz, CDCl 3 ) δ: 7.66 (d,J = 8.6 Hz, 1H), 7.41 (d,J = 9.0 Hz, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.14 (dd,J = 8.6, 2.4 Hz, 1H), 7.04 (d,J = 9.0 Hz, 2H), 3.94 ( s,3H).
[0244] [0244] 840 mg of methyl 2-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-oxoacetate and 12.2 ml of THF were added to a 50 ml three-neck flask, and cooled to -78°C in an acetone bath, and the mixture was dripped with 3.11 mL of methylmagnesium bromide and stirred continuously. After two hours of drip completion, the mixture was added with 5 mL of 1N hydrochloric acid, the aqueous layer was separated, and the THF of the organic layer was distilled off. The aqueous layer was extracted twice with toluene, combined with the THF distilled off from the organic layer, washed once with water, and washed once with a saturated saline solution. After the mixture was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 900 mg of crude hydroxyester product as a yellow liquid. Upon purification by column chromatography (30 g of silica gel, hexane:ethyl acetate = 4:1), 689 mg of the title compound were obtained as a yellow liquid compound. The yield was 78.5%. 1
[0245] [0245] NMR (400 MHz, CDCl 3 ) δ: 7.60 (d,J = 8.8 Hz, 1H), 7.37 (d,J = 2.7 Hz, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.09 (dd,J = 8.8, 2.7 Hz, 1H), 6.98 (d,J = 9.0 Hz, 2H), 3.74 ( s,3H), 3.66 (s, 1H), 1.87 (s, 3H).
[0246] [0246] After 651 mg of methyl 2-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-hydroxypropanoate and 13.0 mL of toluene were added to and dissolved in a 50 ml, the mixture was added with 165 mg of tosylate monohydrate and connected to a Dean-Stark tube to be dehydrated and refluxed. A saturated aqueous sodium hydrogen carbonate solution was added after 1.5 hours and extracted three times with toluene. The extract was washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 669 mg of a black liquid mixture. After 8.7 mL of toluene was added to and dissolved in a 50 mL rotary evaporator flask, the mixture was added with 90 µL of concentrated sulfuric acid and connected to a Dean-Stark tube to be dehydrated and refluxed. After 1 hour, the mixture was added with a saturated aqueous solution of sodium hydrogen carbonate, and extracted three times with toluene. The extract was washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 592 mg of a black liquid mixture. Purification by column chromatography (20 g of silica gel, hexane:ethyl acetate = 9:1) gave 689 mg of the title compound as a yellow liquid. The yield was 94.4%.
[0247] [0247] NMR (400 MHz, CDCl 3 ) δ: 7.35 (d,J = 8.9 Hz, 2H), 7.28 (d,J = 2.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.10 (dd,J = 8.4, 2.4 Hz, 1H), 7.01 (d,J = 8.9 Hz, 2H), 6.60 ( d,J = 1.1 Hz, 1H), 5.76 (d,J = 1.1 Hz, 1H), 3.74 (s, 3H).
[0248] [0248] After 570.0 mg of methyl 2-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acrylate (9) and 4.0 mL of acetonitrile are added to and dissolved in a rotary evaporator flask 100 ml, the mixture was added with 452 mg of potassium carbonate, 452 mg of urea-hydrogen peroxide and 4.0 ml of methanol, and stirred. After 2 hours, the mixture was added with a saturated aqueous solution of sodium sulfite and 1N hydrochloric acid, and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 590 mg of crude oxirane product as a colorless liquid. Upon purification by column chromatography (15 g of silica gel, hexane:ethyl acetate = 9:1), 459.5 mg of the title compound were obtained as a colorless liquid. The yield was 77.2%. 1
[0249] [0249] NMR (400 MHz, CDCl 3 ) δ: 7.58 (d,J = 8.6 Hz, 1H), 7.36 (d,J = 9.0 Hz, 2H), 7.26 (d, J = 2.2 Hz, 1H), 7.12 (dd,J = 8.6, 2.2 Hz, 1H), 7.01 (d,J = 9.0 Hz, 2H), 3.74 ( s, 3H), 3.64 (d,J = 6.2 Hz, 1H), 3.05 (d,J = 6.2 Hz, 1H).
[0250] [0250] After 454.6 mg of methyl 2-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)oxirane-2-carboxylate and 1.22 mL of DMF are added to and dissolved in a rotary evaporator flask of 100 ml, the mixture was added with 26.0 mg of sodium carbonate, and heated and stirred in an oil bath at 60 °C.
[0251] [0251] After 2 hours, the mixture was added with 22.3 mg of sodium triazole and continuously stirred. After 1.5 hours, the mixture was added with 103.5 mg of sodium carbonate and stirred continuously. After 2 hours, the mixture was added with 55.8 mg of sodium triazole and stirred continuously. After 4 hours, the mixture was extracted with saturated aqueous ammonium chloride solution and three times with toluene. The extract was washed twice with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 474 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (15 g of silica gel, hexane:ethyl acetate = 1:1→chloroform:ethyl acetate = 1:1), 314 mg of the title compound (I-122) were obtained under the form of a white solid compound. The yield was 58.2%. 1
[0252] [0252] NMR (400 MHz, CDCl 3 ) δ: 8.11 (s, 1H), 7.89 (s, 1H), 7.62 (d,J = 8.9 Hz, 1H), 7.38 ( d,J = 2.7 Hz, 1H), 7.36 (d,J = 9.0 Hz, 2H), 7.06 (dd,J = 8.9, 2.7 Hz, 1H), 6, 98 (d,J = 9.0 Hz, 2H), 5.08 (d,J = 14.1 Hz, 1H), 4.70 (d,J = 14.1 Hz, 1H), 4.67 ( s, 1H), 3.80 (s, 3H).
[0253] [0253] After 869 mg of 2-bromo-4-fluoroacetophenone and 7.2 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 567 mg of p-chlorophenol and 665 mg of carbonate potassium, and heated and stirred in an oil bath at 120 °C. After 2.5 hours from the start of the reaction, the mixture was added with water to stop the reaction and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.33 g of the title compound as a brown liquid. 1
[0254] [0254] NMR (400 MHz, CDCl 3 ) δ: 7.55 (d,J = 8.6 Hz, 1H), 7.36 (d,J = 8.8 Hz, 2H), 7.20 (d, J = 2.4 Hz, 1H), 7.00 (d,J = 8.8 Hz, 2H), 6.94 (dd,J = 8.6, 2.4 Hz, 1H), 2.64 ( s, 3H).
[0255] [0255] After 1.33 g of 1-(2-bromo-4-(4-chlorophenoxy)phenyl)ethan-1-one and 16 mL of DMSO were added to and dissolved in a 100 mL rotary evaporator flask, the mixture was added with 3.25 g of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 hour from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.87 g of potassium carbonate, and continuously stirred. After 0.5 h, the reaction solution was cooled to room temperature and then added with 0.80 mL of methyl iodide, heated in a 35°C water bath and stirred. After 1 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the mixture was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.49 g of crude ketoester product as a brown liquid. Upon purification by column chromatography (50 g of silica gel, hexane:ethyl acetate = 9:1), 1.05 g of the title compound was obtained as an orange liquid compound. The yield was 71.2%. 1
[0256] [0256] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.7 Hz, 1H), 7.52 (dd,J = 8.0, 1.6 Hz, 1H), 7, 35 (td,J = 7.9, 1.6 Hz, 1H), 7.25 (td,J = 7.9, 1.6 Hz, 1H), 7.16 (dd,J = 8.0, 1.6 Hz, 1H), 6.92 (d,J = 2.4 Hz, 1H), 6.89 (dd,J = 8.7, 2.4 Hz, 1H), 3.95 (s, 3H).
[0257] [0257] 1.0149 g of methyl 2-(2-bromo-4-(4-chlorophenoxy)phenyl)-2-oxoacetate and 14.3 ml of THF were added to a 50 ml three-neck flask, and cooled to -78°C in an acetone bath, and the mixture was dripped with 3.64 mL of methylmagnesium bromide and stirred continuously. After two hours of drip completion, the mixture was added with 5 mL of 2N hydrochloric acid, the aqueous layer was separated, and the THF of the organic layer was distilled off. The aqueous layer was extracted twice with toluene, combined with the THF distilled off from the organic layer, washed once with water, and washed once with a saturated saline solution. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.04 g of the crude hydroxyester product as a yellow liquid. Upon purification by column chromatography (35 g of silica gel, hexane:ethyl acetate = 4:1), 718.7 mg of the title compound was obtained as a colorless liquid. The yield was 67.9%. 1
[0258] [0258] NMR (400 MHz, CDCl 3 ) δ: 7.55 (d,J = 8.7 Hz, 1H), 7.33 (d,J = 9.0 Hz, 2H), 7.19 (d, J = 2.6 Hz, 1H), 6.97 (d,J = 9.0 Hz, 2H), 6.94 (dd,J = 8.7, 2.6 Hz, 1H), 3.79 ( s, 3H), 3.70 (s, 1H), 1.85 (s, 3H).
[0259] [0259] After 701 mg of methyl 2-(2-bromo-4-(4-chlorophenoxy)phenyl)-2-hydroxypropanoate (8) and 13.6 mL of toluene are added to and dissolved in a flask for a rotary evaporator. 50 ml, the mixture was added with 174 mg of tosylate monohydrate and connected to a Dean-Stark tube to be dehydrated and refluxed. A saturated aqueous sodium hydrogen carbonate solution was added after 1.5 hours and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 656 mg of crude unsaturated ester product as a black liquid. Upon purification by column chromatography (20 g of silica gel, hexane:ethyl acetate = 9:1), 634 mg of the title compound were obtained as a yellow liquid compound. The yield was 94.4%. 1
[0260] [0260] NMR (400 MHz, CDCl 3 ) δ: 7.34 (d,J = 9.0 Hz, 2H), 7.21 (d,J = 8.4 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.00 (d,J = 9.0 Hz, 2H), 6.93 (dd,J = 8.4, 2.5 Hz, 1H), 6.51 ( d,J = 1.3 Hz, 1H), 5.77 (d,J = 1.3 Hz, 1H), 3.79 (s, 3H).
[0261] [0261] After 596.0 mg of methyl 2-(2-bromo-4-(4-chlorophenoxy)phenyl)acrylate and 3.88 mL of acetonitrile were added to and dissolved in a 100 mL rotary evaporator flask, the mixture was added with 666 mg of potassium carbonate, 441 mg of urea-hydrogen peroxide and 3.88 mL of methanol, and stirred. After 2 hours, the mixture was added with a saturated aqueous solution of sodium sulfite and 2N hydrochloric acid, and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 465 mg of crude oxirane product as a colorless liquid. Purification by column chromatography (15 g of silica gel, hexane:ethyl acetate = 9:1) gave 439 mg of the title compound as a colorless liquid. The yield was 70.6%. 1
[0262] [0262] NMR (400 MHz, CDCl 3 ) δ: 7.38 (d,J = 8.5 Hz, 1H), 7.34 (d,J = 8.8 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 6.99 (d,J = 8.8 Hz, 2H), 6.94 (dd,J = 8.5, 2.4 Hz, 1H), 3.78 ( s, 3H), 3.62 (d,J = 6.3 Hz, 1H), 3.01 (d,J = 6.3 Hz, 1H).
[0263] [0263] After 455 mg of methyl 2-(2-bromo-4-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate and 1.22 ml of DMF are added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 22.3 mg of sodium triazole, and heated and stirred in an oil bath at 60°C. After 1.5 hours, the mixture was extracted with saturated aqueous ammonium chloride solution and three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 474 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (12 g of silica gel, chloroform:ethyl acetate = 1:1), 292 mg of the title compound (I-228) were obtained as a white solid compound. The yield was 57.2%. 1
[0264] [0264] NMR (400 MHz, CDCl 3 ) δ: 7.97 (s, 1H), 7.88 (s, 1H), 7.40 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 8.9 Hz, 2H), 7.18 (d,J = 2.5 Hz, 1H), 6.96 (d,J = 8.9 Hz, 2H), 6.85 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (s, 2H), 4.86 (s, 1H), 3.80 (s, 3H).
[0265] [0265] After 674 mg of m-fluorophenol, 954.0 mg of p-chloroiodobenzene (3) and 6.0 ml of NMP were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 76.5 mg of copper iodide and 2.61 g of cesium carbonate, and heated and stirred in an oil bath at 160 °C. After 4.5 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction and it was extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.39 g of diaryl ether crude product as a black liquid. Purification by column chromatography (70 g of silica gel, hexane) gave 355 mg of the title compound as a colorless liquid. The yield was 39.8%. 1
[0266] [0266] NMR (400 MHz, CDCl 3 ) δ: 7.32 (d,J = 9.0 Hz, 2H), 7.28 (d,J = 6.6 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.81 (tdd,J = 8.3, 2.4, 0.8 Hz, 1H), 6.76 (dd,J = 8.3, 2.3 Hz , 1H), 6.69 (td,J = 10.1, 2.4 Hz, 1H).
[0267] [0267] After 111 mg of 1-(4-chlorophenoxy)-3-fluorobenzene and 0.5 ml of dichloromethane were added to and dissolved in a 10 ml rotary evaporator flask, the mixture was added with 42 µl of acetyl chloride and 80.6 mg of aluminum chloride, and stirred. After 1.5 hours from the start of the reaction, the mixture was added with 2N hydrochloric acid to stop the reaction, and extracted three times with dichloromethane. 129 mg of crude phenoxy ketone product were obtained in the form of a colorless liquid. Upon purification by column chromatography (6.5 g of silica gel, hexane:ethyl acetate = 19:1), 97.7 mg of the title compound was obtained as a colorless liquid. The yield was 86.7%. 1
[0268] [0268] NMR (400 MHz, CDCl 3 ) δ: 7.89 (t,J = 8.7 Hz, 1H), 7.38 (d,J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 6.79 (dd,J = 8.7, 2.3 Hz, 1H), 6.66 (dd,J = 12.3, 2.3 Hz, 1H), 2.61 (d,J = 5.1 Hz, 3H).
[0269] [0269] 289 mg of 1-(4-(4-chlorophenoxy)-2-fluorophenyl)ethan-1-one and 4.4 ml of DMSO were added to and dissolved in a 50 ml rotary evaporator flask, the mixture was added with 888 mg of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 hour from the start of the reaction, the reaction solution was cooled to room temperature and then added with 1.0597 g of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 hour, the reaction solution was cooled to room temperature and then added with 218 µL of methyl iodide, heated with a water bath at 35 °C and stirred. After 1 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 266.7 mg of crude ketoester product as a yellow liquid. Upon purification by column chromatography (13 g of silica gel, hexane:ethyl acetate = 9:1), 176.3 mg of the title compound was obtained as a yellow liquid compound. The yield was 52.3%. 1
[0270] [0270] NMR (400 MHz, CDCl 3 ) δ: 7.92 (d,J = 8.7 Hz, 1H), 7.41 (d,J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 6.85 (dd, J = 8.7, 2.3, 0.6 Hz, 1H), 6.65 (dd, J = 12.1, 2.3 Hz , 1H), 3.95 (s, 3H).
[0271] [0271] After adding 176 mg of methyl 2-(4-(4-chlorophenoxy)-2-fluorophenyl)-2-oxoacetate and 3.0 mL of THF to a 25 mL three-necked flask, and cooling - up to -78°C in an acetone bath, the mixture was dripped with 0.76 mL of MeMgBr and stirred continuously. After 1.5 hours of drip completion, the mixture was dripped with 2N hydrochloric acid and extracted three times with ethyl acetate. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 184 mg of crude hydroxyester product as a yellow liquid. Upon purification by column chromatography (30 g of silica gel, hexane:ethyl acetate = 4:1), 119.4 mg of the title compound was obtained as a colorless liquid. The yield was 64.4%. 1
[0272] [0272] NMR (400 MHz, CDCl 3 ) δ: 7.47 (t,J = 8.8 Hz, 1H), 7.33 (d,J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 6.76 (ddd,J = 8.7, 2.5, 0.9 Hz, 1H), 6.66 (dd,J = 12.4, 2.5 Hz , 1H), 3.79 (s, 3H), 3.70 (d,J = 1.2 Hz, 1H), 2.04 (s, 3H).
[0273] [0273] After 119 mg of methyl 2-(4-(4-chlorophenoxy)-2-fluorophenyl)-2-hydroxypropanoate and 2.8 ml of toluene were added to and dissolved in a 50 ml rotary evaporator flask, the The mixture was added with 35.4 mg of tosylate monohydrate and connected to a Dean-Stark tube to be dehydrated and refluxed. A saturated aqueous solution of sodium hydrogen carbonate was added after 1.25 hours and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 109.7 mg of the title compound as a brown liquid. 1
[0274] [0274] NMR (400 MHz, CDCl 3 ) δ: 7.34 (d,J = 8.9 Hz, 2H), 7.23 (t,J = 8.4 Hz, 1H), 7.00 (d, J = 8.9 Hz, 2H), 6.76 (ddd,J = 8.4, 2.4, 0.7 Hz, 1H), 6.69 (dd,J = 11.1, 2.4 Hz , 1H), 6.49 (d,J = 1.1 Hz, 1H), 5.87 (d,J = 1.1 Hz, 1H), 3.81 (s, 3H).
[0275] [0275] After 110 mg of methyl 2-(4-(4-chlorophenoxy)-2-(fluorophenyl)acrylate and 0.92 ml of acetonitrile were added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 158 mg of potassium carbonate, 104 mg of urea-hydrogen peroxide and 0.92 ml of methanol, and stirred.After 2 hours, the mixture was added with a saturated aqueous solution of sodium sulfite, and extracted three times with toluene. The extract was washed once with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 124 mg of the crude oxirane product under form of a yellow liquid. Upon purification by column chromatography (6 g of silica gel, hexane:ethyl acetate = 9:1), 68.3 mg of the title compound were obtained as a colorless liquid compound Yield was 54.4%.1
[0276] [0276] NMR (400 MHz, CDCl 3 ) δ: 7.34 (t,J = 8.4 Hz, 1H), 7.34 (d,J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 6.76 (ddd,J = 8.4, 2.4, 0.8 Hz, 1H), 6.70 (dd,J = 10.9, 2.4 Hz , 1H), 3.78 (s, 3H), 3.51 (d,J = 6.4 Hz, 1H), 3.05 (d,J = 6.4 Hz, 1H).
[0277] [0277] After 68.3 mg of methyl 2-(4-(4-chlorophenoxy)-2-fluorophenyl)oxirane-2-carboxylate and 0.63 ml of DMF are added to and dissolved in a 50 ml rotary evaporator flask , the mixture was added with 24.1 mg of sodium triazole and heated and stirred in an oil bath at 50 °C. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 46.9 mg of the crude azole product as a colorless liquid. Purification by column chromatography (2.5 g of silica gel, chloroform:ethyl acetate = 1:1) gave 25.4 mg of the title compound (I-334) as a solid compound. White. The yield was 30.6%. 1
[0278] [0278] NMR (400 MHz, CDCl 3 ) δ: 8.13 (s, 1H), 7.89 (s, 1H), 7.47 (t,J = 8.8 Hz, 1H), 7.35 ( d,J = 8.9 Hz, 2H), 6.98 (d,J = 8.9 Hz, 2H), 6.74 (dd,J = 8.8, 2.5 Hz, 1H), 6, 68 (dd,J = 12.7, 2.5 Hz, 1H), 5.11 (d,J = 14.1 Hz, 1H), 4.74 (d,J = 14.1 Hz, 1H), 4.61 (s, 1H), 3.82 (s, 3H).
[0279] [0279] After 541 mg of m-cresol and 7.5 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 1.79 g of p-chloroiodobenzene, 3.26 g of carbonate of cesium and 95.6 mg of copper (I) iodide, and heated and stirred in an oil bath at 90 °C. After 6 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with hexane. The extract was washed twice with water and washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.61 g of diaryl ether crude product as a brown liquid. Purification by column chromatography (50 g of silica gel, hexane) gave 314.4 mg of the title compound as a colorless liquid. The yield was 28.7%. 1
[0280] [0280] NMR (400 MHz, CDCl 3 ) δ: 7.28 (d,J = 8.8 Hz, 2H), 7.22 (t,J = 7.8 Hz, 1H), 6.94-6, 90 (m, 3H), 6.82-6.78 (m, 2H), 2.33 (s, 3H).
[0281] [0281] After 314 mg of 1-(4-chlorophenoxy)-3-methylbenzene and 1.44 ml of dichloromethane were added to and dissolved in a 50 ml rotary evaporator flask, the mixture was added with 158 µl of methyl chloroglyoxylate and 231 mg of aluminum chloride, and stirred. After 1 hour of starting the reaction, the mixture was added with water to stop the reaction, and extracted three times with chloroform. 436 mg of crude ketoester product were obtained in the form of a colorless liquid. Purification by column chromatography (6.5 g of silica gel, hexane:ethyl acetate = 9:1) gave 323 mg of the title compound as a colorless liquid. The yield was 73.7%. 1
[0282] [0282] NMR (400 MHz, CDCl 3 ) δ: 7.88 (d,J = 8.0 Hz, 1H), 7.35 (d,J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 6.85-6.81 (m, 1H), 6.64 (s, 1H), 3.70 (s, 3H), 2.34 (s, 3H).
[0283] [0283] After 53.7 mg of 55% sodium hydride and 1.8 ml of DMSO were added to a 25 ml rotary evaporator flask and cooled in an ice bath, the mixture was added with 492 mg of sodium bromide. methyltriphenylphosphonium (MTPB), warmed to room temperature, and stirred. After 30 minutes, the mixture was dripped with a DMSO solution (0.5 mL) of 323 mg of methyl 2-(4-(4-chlorophenoxy)-2-methylphenyl)-2-oxoacetate, and stirred continuously. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 636 mg of crude unsaturated ester product as an orange solid. Purification by column chromatography (30 g of silica gel, hexane:ethyl acetate = 9:1) gave 240 mg of the title compound as a colorless liquid. The yield was 74.7%. 1
[0284] [0284] NMR (400 MHz, CDCl 3 ) δ: 7.31-7.20 (m, 2H), 6.89-6.93 (m, 2H), 6.90 (d,J = 9.0 Hz , 2H), 6.68 (s, 1H), 6.30 (d,J = 1.4 Hz, 1H), 5.77 (d,J = 1.4 Hz, 1H), 3.62 (s , 3H), 2.30 (s, 3H).
[0285] [0285] After 239.7 mg of methyl-2-(4-(4-chlorophenoxy)-2-methylphenyl)acrylate, 1.98 ml of acetonitrile and 1.98 ml of methanol are added to a 100° rotary evaporator flask. mL and cooled in an ice bath, the mixture was added with 110 mg of potassium carbonate and 232 mg of urea-hydrogen peroxide, warmed to room temperature, and stirred. After 22 hours, the mixture was added with a saturated aqueous solution of sodium sulfite, and extracted three times with toluene. The extract was washed once with water and was washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 179 mg of the title compound as a yellow liquid.
[0286] [0286] After 179 mg of methyl 2-(4-(4-chlorophenoxy)-2-methylphenyl)oxirane-2-carboxylate crude product and 2.25 ml of DMF are added to and dissolved in a 100° rotaevaporator flask ml, the mixture was added with 38.8 mg of triazole and 51.5 mg of triazole sodium, and heated and stirred in an oil bath at 50 °C. After 2.5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 212 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (10 g of silica gel, chloroform:ethyl acetate = 1:1), 25.4 mg of the title compound (I-2) was obtained as a white solid compound. 2 The process yield was 23.8%. 1
[0287] [0287] NMR (400 MHz, CDCl 3 ) δ: 8.06 (s, 1H), 7.87 (s, 1H), 7.33-7.27 (m, 3H), 6.94-6.88 (m, 3H), 6.66 (s, 1H), 5.01 (d,J = 14.1 Hz, 1H), 4.85 (d,J = 14.1 Hz, 1H), 4.42 (s, 1H), 3.55 (s, 3H), 2.27 (s, 3H).
[0288] [0288] After 621 mg of m-methoxy phenol and 7.5 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 1.7888 g of p-chloroiodobenzene, 3.27 g of cesium carbonate and 95.6 mg of copper(I) iodide, and heated and stirred in an oil bath at 90 °C. After 6 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with hexane. The extract was washed twice with water and washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.58 g of diaryl ether crude product as a brown liquid. Purification by column chromatography (50 g of silica gel, hexane) gave 303 mg of the title compound as a colorless liquid. The yield was 25.8%. 1
[0289] [0289] NMR (400 MHz, CDCl 3 ) δ: 7.29 (d,J = 9.0 Hz, 2H), 7.23 (t,J = 8.3 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.67 (ddd, J = 8.3, 2.4, 0.8 Hz, 1H), 6.59-6.54 (m, 2H), 3.78 (s, 3H).
[0290] [0290] After 303 mg of 1-(4-chlorophenoxy)-3-methoxybenzene and 1.29 ml of dichloromethane were added to and dissolved in a 50 ml rotary evaporator flask, the mixture was added with 142 µl of methyl chloroglyoxylate and 231 mg of aluminum chloride, and stirred. After 1 hour of starting the reaction, the mixture was added with water to stop the reaction, and extracted three times with chloroform. 424 mg of crude ketoester product were obtained in the form of a colorless liquid. Upon purification by column chromatography (21 g of silica gel, hexane:ethyl acetate = 7:1), 206 mg of the title compound were obtained as a colorless liquid. The yield was 49.8%. 1
[0291] [0291] NMR (400 MHz, CDCl 3 ) δ: 7.98 (d,J = 8.9 Hz, 1H), 7.35 (d,J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.76 (dd,J = 8.9, 2.3 Hz, 1H), 6.27 (d,J = 2.3 Hz, 1H), 3.78 ( s, 3H), 3.70 (s, 3H).
[0292] [0292] After 32.8 mg of 55% sodium hydride and 1.1 mL of DMSO were added to a 10 mL rotary evaporator flask and cooled in an ice bath, the mixture was added with 299 mg of MTPB, warmed to room temperature, and stirred. After 30 minutes, the mixture was dripped with a DMSO solution (0.3 ml) of 206 mg of methyl 2-(4-(4-chlorophenoxy)-2-methoxyphenyl)-2-oxoacetate, and stirred continuously. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 411 mg of crude unsaturated ester product as a brown solid. Purification by column chromatography (20 g of silica gel, hexane:ethyl acetate = 7:1) gave 139 mg of the title compound as a colorless liquid. The yield was 68.1%. 1
[0293] [0293] NMR (400 MHz, CDCl 3 ) δ: 7.30-7.24 (m,3H), 6.92 (d,J = 9.0 Hz, 2H), 6.69 (dd,J = 8 .5, 2.5 Hz, 1H), 6.40 (d,J = 2.5 Hz, 1H), 6.28 (d,J = 1.4 Hz, 1H), 5.87 (d,J = 1.4 Hz, 1H), 3.75 (s, 3H), 3.62 (s, 3H).
[0294] [0294] After 139.4 mg of 2-(4-(4-chlorophenoxy)-2-methoxyphenyl)acrylate, 1.09 ml of acetonitrile and 1.09 ml of methanol are added to a 50 ml rotary evaporator flask and cooled in an ice bath, the mixture was added with 60.9 mg of potassium carbonate and 128 mg of urea-hydrogen peroxide, warmed to room temperature, and stirred. After 22 hours, the mixture was added with a saturated aqueous solution of sodium sulfite, and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 104 mg of the title compound as a yellow liquid.
[0295] [0295] After 104 mg of methyl 2-(4-(4-chlorophenoxy)-2-methylphenyl)oxirane-2-carboxylate and 1.24 ml of DMF are added to and dissolved in a 100 ml rotary evaporator flask, the The mixture was added with 21.5 mg of triazole and 28.3 mg of triazole sodium, and heated and stirred in an oil bath at 50 °C. After 2.5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 119 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (10 g of silica gel, chloroform:ethyl acetate = 1:1), 101 mg of the title compound (I-3) was obtained as a colorless viscous liquid. 2 The process yield was 59.8%. 1
[0296] [0296] NMR (400 MHz, CDCl 3 ) δ: 8.07 (s, 1H), 7.87 (s, 1H), 7.35 (d,J = 8.8 Hz, 1H), 7.31 ( d,J = 9.0 Hz, 2H), 6.92 (d,J = 9.0 Hz, 2H), 6.64 (dd,J = 8.8, 2.5 Hz, 1H), 6, 37 (d,J = 2.5 Hz, 1H), 5.00 (d,J = 14.1 Hz, 1H), 4.84 (d,J = 14.1 Hz, 1H), 4.40 ( s, 1H), 3.71 (s, 3H), 3.56 (s, 3H).
[0297] [0297] After 692 mg of 2-chloro-4-fluoroacetophenone and 7.2 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 568 mg of 2-chlorophenol and 664 mg of carbonate potassium, and heated and stirred in an oil bath at 120 °C. After 1.5 hours from the start of the reaction, the mixture was added with water to stop the reaction and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.1159 g of the title compound as a brown liquid. 1
[0298] [0298] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.7 Hz, 1H), 7.51 (dd,J = 8.0, 1.6 Hz, 1H), 7, 32 (td,J = 7.5, 1.6 Hz, 1H), 7.22 (td,J = 7.5, 1.6 Hz, 1H), 7.12 (dd,J = 8.0, 1.6 Hz, 1H), 6.93 (d,J = 2.4 Hz, 1H), 6.83 (dd,J = 8.7, 2.4 Hz, 1H), 2.65 (s, 3H).
[0299] [0299] After 1.12 g of 1-(2-chloro-4-(2-chlorophenoxy)phenyl)ethan-1-one and 16 mL of DMSO were added to and dissolved in a 100 mL rotary evaporator flask, the mixture was added with 3.25 g of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 h from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.87 g of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 h, the reaction solution was cooled to room temperature and then added with 0.80 mL of methyl iodide, heated in a 35°C water bath and stirred. After 1 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 946 mg of crude ketoester product as a brown liquid. Purification by column chromatography (45 g of silica gel, hexane:ethyl acetate = 9:1) gave 474.9 mg of the title compound as an orange liquid. 2 The process yield was 36.5%. 1
[0300] [0300] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.7 Hz, 1H), 7.52 (dd,J = 8.0, 1.6 Hz, 1H), 7, 35 (td,J = 7.9, 1.6 Hz, 1H), 7.25 (td,J = 7.9, 1.6 Hz, 1H), 7.16 (dd,J = 8.0, 1.6 Hz, 1H), 6.92 (d,J = 2.4 Hz, 1H), 6.89 (dd,J = 8.7, 2.4 Hz, 1H), 3.95 (s, 3H).
[0301] [0301] After 26.9 mg of 55% sodium hydride, 1.0 mL of DMSO and 133 mg of trimethylsulfoxonium iodide were added to a 25 mL rotary evaporator flask and stirred in an ice bath, the mixture was added with 1.5 mL of methyl 2-(2-chloro-4-(2-chlorophenoxy)phenyl)-2-oxoacetate DMSO solution and continuously stirred at room temperature. After 1.5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 208 mg of crude oxirane product as a brown liquid. Purification by column chromatography (10 g of silica gel, hexane:ethyl acetate = 9:1) gave 59.2 mg of the title compound as a colorless liquid. The yield was 34.5%. 1
[0302] [0302] NMR (400 MHz, CDCl 3 ) δ: 7.49 (dd,J = 8.0, 1.6 Hz, 1H), 7.38 (d,J = 8.5 Hz, 1H), 7. 29 (td,J = 7.6, 1.5 Hz, 1H), 7.18 (td,J = 7.6, 1.6 Hz, 1H), 7.09 (dd,J = 8.0, 1.5 Hz, 1H), 6.96 (d,J = 2.5 Hz, 1H), 6.84 (dd,J = 8.5, 2.5 Hz, 1H), 3.77 (s, 3H), 3.51 (d,J = 6.4 Hz, 1H), 3.05 (d,J = 6.4 Hz, 1H).
[0303] [0303] After 59.2 mg of methyl 2-(2-chloro-4-(2-chlorophenoxy)phenyl)oxirane-2-carboxylate and 0.70 mL of DMF are added to and dissolved in a 100 ml, the mixture was added with 12.8 mg of triazole and 16.0 mg of triazole sodium, and heated and stirred in an oil bath at 50 °C. After 2 hours, the oil bath was heated to 60°C with continuous stirring. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 64.3 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (3 g of silica gel, chloroform:ethyl acetate = 1:1), 59.0 mg of the title compound (I-19) was obtained as a white solid compound. The yield was 82.8%. 1
[0304] [0304] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.48 (dd,J = 8.0, 1.6 Hz, 1H), 7.40 (d,J = 8.8 Hz, 1H), 7.29 (td,J = 8.1, 1.7 Hz, 1H), 7.18 (td,J = 8.0, 1, 5 Hz, 1H), 7.07 (dd,J = 8.1, 1.5 Hz, 1H), 6.94 (d,J = 2.6 Hz, 1H), 6.77 (dd,J = 8.8, 2.6 Hz, 1H), 5.03 (d,J = 14.3 Hz, 1H), 4.92 (d,J = 14.3 Hz, 1H), 4.83 (s, 1H), 3.79 (s, 3H).
[0305] [0305] After 691 mg of 2-chloro-4-fluoroacetophenone and 7.2 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 568 mg of 3-chlorophenol and 665 mg of carbonate of potassium and heated and stirred in an oil bath at 120 °C. After 1.5 hours from the start of the reaction, the mixture was added with water to stop the reaction and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.18 g of the title compound as a brown liquid. 1
[0306] [0306] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 1H), 7.33 (t,J = 8.1 Hz, 1H), 7.20 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.06 (t,J = 2.2 Hz, 1H), 7.02 (d,J = 2.4 Hz, 1H), 6.95 (ddd,J = 8.1, 2.2, 1.0 Hz, 1H), 6.92 (dd,J = 8.7, 2.4 Hz, 1H), 2.66 (s, 3H).
[0307] [0307] After 1.18 g of 1-(2-chloro-4-(3-chlorophenoxy)phenyl)ethan-1-one and 16 mL of DMSO were added to and dissolved in a 100 mL rotary evaporator flask, the mixture was added with 3.25 g of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 h from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.87 g of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 h, the reaction solution was cooled to room temperature and then added with 0.80 mL of methyl iodide, heated in a 35°C water bath and stirred. After 1 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.13 g of crude ketoester product as a brown liquid. Upon purification by column chromatography (45 g of silica gel, hexane:ethyl acetate = 9:1), 427.6 mg of the title compound was obtained as an orange liquid compound. The yield was 32.8%.
[0308] [0308] NMR (400 MHz, CDCl 3 ) δ: 7.83 (d,J = 8.6 Hz, 1H), 7.36 (t,J = 8.1 Hz, 1H), 7.24 (ddd, J = 8.1, 2.0, 0.9 Hz, 1H), 7.11 (t,J = 2.0 Hz, 1H), 7.01-6.95 (m, 3H), 3.96 (s, 3H).
[0309] [0309] After 261 mg of methyl 2-(2-chloro-4-(3-chlorophenoxy)phenyl)-2-oxoacetate and 1.20 mL of DMAc are added to and dissolved in a 50 mL rotary evaporator flask, the The mixture was added with 95.5 mg of sodium triazole and 212.5 mg of trimethylsulfoxonium iodide, and heated and stirred in an oil bath at 50 °C. After 2.5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract substance was washed once with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 331 mg of the crude azole product as an orange liquid. Purification by column chromatography (14 g of silica gel, chloroform:ethyl acetate = 1:1) gave 146.9 mg of the title compound (I-20) as a colorless viscous liquid. . The yield was 44.9%. 1
[0310] [0310] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.89 (s, 1H), 7.43 (d,J = 8.8 Hz, 1H), 7.30 ( t,J = 8.2 Hz, 1H), 7.16 (ddd,J = 8.2, 2.3, 0.9 Hz, 1H), 7.03 (t,J = 2.3 Hz, 1H ), 7.01 (d,J = 2.5 Hz, 1H), 6.91 (ddd,J = 8.2, 2.3, 0.9 Hz, 1H), 6.85 (dd,J = 8.8, 2.5 Hz, 1H), 5.03 (d,J = 14.3 Hz, 1H), 4.93 (d,J = 14.3 Hz, 1H), 4.85 (s, 1H), 3.80 (s, 3H).
[0311] [0311] After 1.20 g of p-iodochlorobenzene, 965 ml of o-chlorophenol and 10.0 ml of DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 3.26 g of carbonate of cesium, 95.7 mg of copper (I) iodide and 210 mg of N,N-dimethyl glycine hydrochloride, and heated and stirred in an oil bath at 90 °C. After 1 hour from the start of the reaction, the oil bath was heated to 135 °C. After 5 hours, the oil bath was returned to room temperature and washed twice with water through a short column. After the mixture was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 674 mg of diaryl ether crude product as a brown liquid. Purification by column chromatography (20 g of silica gel, hexane) gave 392.4 mg of the title compound as a colorless liquid. The yield was 32.7%. 1
[0312] [0312] NMR (400 MHz, CDCl 3 ) δ: 7.47 (dd,J = 8.0, 1.6 Hz, 1H), 7.28 (d,J = 9.0 Hz, 2H), 7, 24 (td,J = 8.0, 1.6 Hz, 1H), 7.12 (td,J = 7.7, 1.5 Hz, 1H), 7.00 (dd,J = 8.1, 1.5 Hz, 1H), 6.89 (d,J = 9.0 Hz, 2H).
[0313] [0313] After 392 mg of 1-chloro-2-(4-chlorophenoxy)benzene and 1.64 ml of dichloromethane were added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 181 µl of methyl chloroglyoxylate and 266 mg of aluminum chloride, and stirred. After 1.5 hours from the start of the reaction, the mixture was added with 2N hydrochloric acid to stop the reaction, and extracted three times with methylene chloride. After the mixture was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 534 mg of crude ketoester product as a colorless liquid. Upon purification by column chromatography (21 g of silica gel, hexane:ethyl acetate = 9:1), 460.8 mg of the title compound was obtained as a colorless liquid. The yield was 86.4%. 1
[0314] [0314] NMR (400 MHz, CDCl 3 ) δ: 8.19 (d,J = 2.1 Hz, 1H), 7.89 (dd,J = 8.7, 2.1 Hz, 1H), 7, 39 (d,J = 9.0 Hz, 2H), 7.02 (d,J = 9.0 Hz, 2H), 6.90 (d,J = 8.7 Hz, 1H), 3.98 ( s, 3H).
[0315] [0315] After 461 mg of methyl 2-(3-chloro-4-(4-chlorophenoxy)phenyl)-2-oxoacetate and 2.1 ml of DMAC were added to and dissolved in a 100 ml rotary evaporator flask, the The mixture was added with 558 mg of cesium carbonate and 295 mg of trimethylsufoxonium bromide, and stirred. After 2 hours, the mixture was heated in an oil bath at 50 °C. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 474.7 mg of crude oxirane product as a yellow liquid. Upon purification by column chromatography (silica gel, hexane:ethyl acetate = 9:1→7:3), 75.2 mg of the title compound was obtained as a colorless liquid. The yield was 15.6%. 1
[0316] [0316] NMR (400 MHz, CDCl 3 ) δ: 7.64 (d,J = 2.2 Hz, 1H), 7.39 (dd,J = 8.5, 2.2 Hz, 1H), 7, 30 (d,J = 9.0 Hz, 2H), 6.95 (d,J = 8.5 Hz, 1H), 6.91 (d,J = 9.0 Hz, 2H), 3.81 ( s, 3H), 3.45 (d,J = 6.3 Hz, 1H), 2.96 (d,J = 6.3 Hz, 1H).
[0317] [0317] After 75.2 mg of methyl 2-(3-chloro-4-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate and 0.70 mL of DMF are added to and dissolved in a 50 ml, the mixture was added with 15.7 mg of triazole and 20.6 mg of triazole sodium, and heated and stirred in an oil bath at 60 °C. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed once with water and then washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 65.8 mg of the crude azole product as a colorless liquid. Purification by column chromatography (3 g of silica gel, chloroform:ethyl acetate = 1:1) gave 55.2 mg of the title compound (I-6) as a colorless viscous liquid. . The yield was 61.0%. 1
[0318] [0318] NMR (400 MHz, CDCl 3 ) δ: 8.17 (s, 1H), 7.92 (s, 1H), 7.80 (d,J = 2.3 Hz, 1H), 7.52 ( dd,J = 8.7, 2.3 Hz, 1H), 7.31 (d,J = 9.0 Hz, 2H), 6.97 (d,J = 8.7 Hz, 1H), 6, 91 (d,J = 9.0 Hz, 2H), 5.01 (d,J = 14.0 Hz, 1H), 4.42 (d,J = 14.0 Hz, 1H), 4.40 ( s, 1H), 3.85 (s, 3H).
[0319] [0319] After 1.05 g of 2-bromo-1-fluorobenzene and 9.0 ml of NMP were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 706 mg of 4-chlorophenol and 829 mg of potassium carbonate, and heated and stirred in an oil bath at 160 °C. After 6.5 hours from the start of the reaction, the mixture was added with water to stop the reaction, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried with anhydrous sodium sulfate, 1.93 g of aryl bromide crude was obtained as a brown liquid. Purification by column chromatography (55 g of silica gel, hexane) gave 903 mg of the title compound as a colorless liquid. The yield was 56.8%. 1
[0320] [0320] NMR (400 MHz, CDCl 3 ) δ: 7.39 (d,J = 8.8 Hz, 1H), 7.33 (d,J = 9.0 Hz, 2H), 7.23 (d, J = 2.8 Hz, 1H), 6.95 (d,J = 9.0 Hz, 2H), 6.89 (dd,J = 8.8, 2.8 Hz, 1H).
[0321] [0321] After 897 mg of 2-bromo-1-chloro-4-(4-chlorophenoxy)benzene, 402 mg of dimethyl oxalate and 14.1 ml of tetrahydrofuran are added to and dissolved in a 25 ml, the mixture was cooled to -78°C in a dry ice and acetone bath, added with 1.16 ml of n-butyl lithium and stirred. After 1 hour of starting the reaction, the mixture was added with 2N hydrochloric acid to stop the reaction, and extracted three times with chloroform. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.11 g of crude ketoester product as a colorless liquid. Upon purification by column chromatography (silica gel, hexane:ethyl acetate = 92:8→71:29), 625 mg of the title compound was obtained as a colorless liquid. The yield was 68.1%. 1
[0322] [0322] NMR (400 MHz, CDCl 3 ) δ: 7.40 (d,J = 8.8 Hz, 1H), 7.35 (d,J = 8.9 Hz, 2H), 7.33 (d, J = 3.0 Hz, 1H), 7.15 (dd,J = 8.8, 3.0 Hz, 1H), 6.98 (d,J = 8.9 Hz, 2H), 3.96 ( s, 3H).
[0323] [0323] After 621 mg of methyl 2-(2-chloro-5-(4-chlorophenoxy)phenyl)-2-oxoacetate and 2.86 ml of dichloromethane were added to and dissolved in a 25 ml rotary evaporator flask, the The mixture was added with 398 mg of trimethylsufoxonium bromide and 100 mg of sodium hydride, and stirred. After 1 hour, the mixture was added with a saturated aqueous solution of ammonium chloride to quench the reaction, and extracted three times with dichloromethane. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 716 mg of crude oxirane product as a yellow liquid. Upon purification by column chromatography (silica gel, hexane:ethyl acetate = 97:3→76:24), 243 mg of the title compound was obtained as a colorless liquid. The yield was 37.5%. 1
[0324] [0324] NMR (400 MHz, CDCl 3 ) δ: 7.33 (d,J = 8.8 Hz, 1H), 7.32 (d,J = 8.9 Hz, 2H), 7.09 (d, J = 2.9 Hz, 1H), 6.97-6.92 (m, 3H), 3.78 (s, 3H), 3.61 (d,J = 6.3 Hz, 1H), 2, 99 (d,J = 6.3 Hz, 1H).
[0325] [0325] After 223 mg of methyl 2-(2-chloro-5-(4-chlorophenoxy)phenyl)oxirane-2-carboxylate and 2.63 ml of DMF are added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 45.7 mg of triazole and 60.3 mg of triazole sodium, and heated and stirred in an oil bath at 60°C. After 2 hours, the mixture was added with a saturated aqueous solution of ammonium chloride, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 267 mg of the crude azole product as a colorless liquid. Upon purification by column chromatography (8 g of silica gel, chloroform:ethyl acetate = 1:1), 205 mg of the title compound (II-1) was obtained as a white solid compound. The yield was 76.3%.
[0326] [0326] NMR (400 MHz, CDCl 3 ) δ: 7.92 (s, 1H), 7.86 (s, 1H), 7.32 (d,J = 8.6 Hz, 1H), 7.30 ( d,J = 8.9 Hz, 2H), 7.07 (d,J = 2.9 Hz, 1H), 6.88 (dd,J = 8.6, 2.9 Hz, 1H), 6, 80 (d,J = 8.9 Hz, 2H), 4.99 (s, 1H), 4.98 (s, 1H), 4.94 (s, 1H), 3.80 (s, 3H).
[0327] [0327] After 0.54 ml of 2-chloro-4-fluoroacetophenone and 7.2 ml of dehydrated DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 0.448 g of p-fluorophenol (1 ) and 0.663 g of potassium carbonate, and heated and stirred in an oil bath at 120 °C. After 1.5 hours from the start of the reaction, the mixture was added with water to stop the reaction and extracted three times with toluene. The extract was washed twice with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain a crude diaryl ether body product. After the crude diaryl ether body product and 16 ml of dehydrated DMSO were added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 3.25 g of iodine and heated and stirred in an oil bath at 100°C. °C After 0.5 h from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.87 g of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 h, the reaction solution was cooled to room temperature and then added with 0.80 mL of methyl iodide, heated in a 35°C water bath and stirred. After 0.5 hour, the mixture was added with a saturated aqueous solution of sodium sulfite to stop the reaction, filtered, added with water and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.14 g of the crude ketoester body product (4) as a brown liquid. Upon purification by column chromatography (50 g of silica gel, hexane:ethyl acetate = 9:1), 0.506 g of the title compound was obtained as a yellow liquid compound. 2 The process yield was 41%. 1
[0328] [0328] NMR (400 MHz, CDCl 3 ) δ: 7.81 (d,J = 8.9 Hz, 1H), 7.16-7.04 (m, 4H), 6.95-6.91 (m , 2H), 3.95 (s, 3H).
[0329] [0329] Under an argon atmosphere, 0.506 g of methyl 2-(2-chloro-4-(4-fluorophenoxy)phenyl)-2-oxoacetate and 3.0 mL of dehydrated DMAc are added to and dissolved in a flask to 50 ml rotary evaporator, the mixture was added with 0.189 g of t-BuONa and 0.302 mg of trimethylsufoxonium bromide, and stirred at room temperature. After 0.5 hour, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 0.239 g of crude product as a yellow liquid. Upon purification by column chromatography (10 g of silica gel, hexane:ethyl acetate = 9:1), 0.054 g of the title compound was obtained as a colorless liquid. The mixture was added to 0.47 ml of dehydrated DMF and dissolved in a 50 ml rotary evaporator flask, and was added with 0.011 g of triazole and 0.015 g of triazole sodium, and heated and stirred in an oil bath at 60° Ç. After 2.0 hours, the mixture was added with a saturated aqueous solution of sodium hydrogen carbonate and extracted three times with toluene. The mixture was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 0.077 g of the crude azole body product as a colorless liquid. Upon purification by column chromatography (10 g of silica gel, chloroform:ethyl acetate = 1:1), 0.022 g of the title compound (I-26) was obtained as a white liquid compound. 1
[0330] [0330] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.38 (d,J = 8.8 Hz, 1H), 7.08 ( t,J = 9.2 Hz, 2H), 7.00 (dd,J = 9.2, 4.5 Hz, 2H), 6.94 (d,J = 2.5 Hz, 1H), 6, 78 (dd,J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.93 (d,J = 14.3 Hz, 1H), 4.87 (s, 1H), 3.78 (s, 3H).
[0331] [0331] After 691 mg of 2-chloro-4-fluoroacetophenone and 7.2 ml of dehydrated DMF were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 767 mg of p-bromophenol and 666 mg of potassium carbonate, and heated and stirred in an oil bath at 120 °C. After 1.5 hours from the start of the reaction, the mixture was added with 10 ml of water to stop the reaction, and extracted with toluene. An organic layer was washed separately with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.330 mg of the title compound as a crude product as a brown liquid. 1
[0332] [0332] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 1H), 7.52 (d,J = 8.9 Hz, 2H), 6.99 (d, J = 2.4 Hz, 1H), 6.95 (d,J = 8.9 Hz, 2H), 6.90 (dd,J = 8.6, 2.4 Hz, 1H), 2.65 ( s, 3H).
[0333] [0333] 1.330 mg of 1-(4-(4-bromophenoxy)-2-chlorophenyl)ethan-1-one and 16 ml of dehydrated DMSO were added to and dissolved in a 100 ml rotary evaporator flask, the mixture was added with 1.657 mg of iodine, and heated and stirred in an oil bath at 100 °C. After 0.5 h from the start of the reaction, the reaction solution was cooled to room temperature and then added with 3.870 mg of potassium carbonate, and again heated and stirred in an oil bath at 100 °C. After 0.5 h, the reaction solution was cooled to room temperature and then added with 0.80 mL of methyl iodide, heated in a 35°C water bath and stirred. After 47 minutes, the reaction solution was added with 10 mL of saturated aqueous sodium sulfite solution to stop the reaction, filtered and then extracted with toluene. An organic layer was washed separately with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. A solvent was distilled off to obtain 1.24 g of crude ketoester product as a brown liquid. Upon purification by column chromatography (50 g of silica gel, hexane:ethyl acetate = 9:1), 700.9 mg of the title compound was obtained as a yellow liquid compound. 2 The process yield was 48.0%. 1
[0334] [0334] NMR (400 MHz, CDCl 3 ) δ: 7.81 (d,J = 8.5 Hz, 1H), 7.55 (d,J = 8.9 Hz, 2H), 7.01-6, 93 (m, 4H), 3.95 (s, 3H).
[0335] [0335] 2.0 mL of dehydrated DMAc solution of 700.9 mg of methyl 2-(4-(4-bromophenoxy)-2-chlorophenyl)-2-oxoacetate was added to a 25 mL rotary evaporator flask and stirred at 0 °C under an argon atmosphere. The mixture was added with 507.6 mg of trimethylsulfoxonium iodide and 218.8 mg of STB, in order, and stirred. After 12 minutes, the mixture was added with
[0336] [0336] NMR (400 MHz, CDCl 3 ) δ: 7.49 (d,J = 9.0 Hz, 2H), 7.40 (d,J = 8.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.94 (d,J = 9.0 Hz, 2H), 6.89 (dd,J = 8.5, 2.4 Hz, 1H), 3.78 ( s, 3H), 3.59 (d,J = 6.3 Hz, 1H), 3.02 (d,J = 6.3 Hz, 1H).
[0337] [0337] NMR (400 MHz, CDCl 3 ) δ: 7.50 (d,J = 9.0 Hz, 2H), 7.39 (d,J = 8.5 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.94 (d,J = 9.0 Hz, 2H), 6.89 (dd,J = 8.5, 2.4 Hz, 1H), 3.52 ( d,J = 6.3 Hz, 1H), 2.95 (d,J = 6.3 Hz, 1H), 1.44 (s, 9H).
[0338] [0338] After 129.4 mg of methyl 2-(4-(4-bromophenoxy)-2-chlorophenyl)oxirane-2-carboxylate and 1.3 ml of dehydrated DMF are added to and dissolved in a 25 ml, the mixture was added with 23.5 mg of triazole and 31.2 mg of triazole sodium salt, and heated and stirred in an oil bath at 60°C. After 2 hours, the mixture was added with 10 ml of saturated aqueous ammonium chloride solution, and extracted with toluene. An organic layer was washed separately with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. A solvent was distilled off to obtain 114.6 mg of crude azole product as a colorless liquid. Purification by column chromatography (5 g of silica gel, chloroform:ethyl acetate = 1:1) gave 82.2 mg of the title compound as a colorless solid. The solid obtained was redissolved in 1.0 ml of toluene at 80°C and recrystallized at room temperature and the crystal obtained was washed with toluene at 0°C. After that, drying was carried out to obtain the title compound (I-25) as 60.1 mg of colorless crystal. 1
[0339] [0339] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.49 (d,J = 8.9 Hz, 2H), 7.41 ( d,J = 8.8 Hz, 1H), 6.98 (d,J = 2.5 Hz, 1H), 6.91 (d,J = 8.9 Hz, 2H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.94 (d,J = 14.3 Hz, 1H), 4.87 ( s, 1H), 3.80 (s, 3H).
[0340] [0340] 1.35 g of 2-chloro-4-fluoroacetophenone was dissolved in 10 ml of DMF, and the mixture was added with 1.13 g of 3,4-difluorophenol and 1.31 g of potassium carbonate, and stirred at 90°C for 6 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.528 g of the title compound as a liquid. colorless viscous. The yield was 69.0%.
[0341] [0341] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.8 Hz, 1H), 7.24-7.16 (m, 1H), 6.99 (d,J = 2 .4 Hz, 1H), 6.94-6.88 (m, 1H), 6.90 (dd,J = 8.8, 2.4 Hz, 1H), 6.83-6.78 (m , 1H), 2.65 (s, 3H).
[0342] [0342] 1.453 g of 1-(2-chloro-4-(3,4-difluorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed into a 100 ml rotary evaporator flask and added to 20 ml DMSO for dissolution. The mixture was added with 4.19 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. Upon completion of the reaction, the mixture was cooled to 60 °C, added with 4.967 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.05 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 10/1), whereby 0.962 g of the title compound was obtained as a colorless liquid. The yield was 57.3%. 1
[0343] [0343] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.8 Hz, 1H), 7.27-7.19 (m, 1H), 6.99-6.93 (m , 3H), 6.87-6.82 (m, 1H), 3.96 (s, 3H).
[0344] [0344] 0.610 g of methyl 2-(2-chloro-4-(3,4-difluorophenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 3.5 ml of DMF, and the mixture was added with 0.355 g of TMSOB and 0.207 g of sodium triazole at -20°C, and stirred for 1 hour while returning to room temperature. The mixture was placed in a 50 °C bath and stirred for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.180 g of the title compound as a white solid. The yield was 24.4%. 1
[0345] [0345] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.88 (s, 1H), 7.43 (d,J = 8.8 Hz, 1H), 7.17 ( dt,J = 9.7, 9.0 Hz, 1H), 6.97 (d,J = 2.5 Hz, 1H), 6.87 (ddd,J = 10.8, 6.6, 2, 9 Hz, 1H), 6.81 (dd,J = 8.8, 2.5 Hz, 1H), 6.74-6.79 (m, 1H), 5.02 (d,J = 14.3 Hz, 1H), 4.94 (d,J = 14.3 Hz, 1H), 4.89 (s, 1H), 3.80 (s, 3H).
[0346] [0346] 1.156 g of 4-bromo-3-chlorophenol was dissolved in 10 ml of DMF, and the solution was added with 0.924 g of p-chlorobenzyl chloride and 0.937 g of potassium carbonate, and stirred at 80°C. for 1 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate.
[0347] [0347] NMR (400 MHz, CDCl 3 ) δ: 7.47 (d,J = 8.9 Hz, 1H), 7.36 (d,J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.06 (d,J = 2.9 Hz, 1H), 6.73 (dd,J = 8.9, 2.4 Hz), 4.98 (s, 2H).
[0348] [0348] 1,000 g of 1-bromo-2-chloro-4-((4-chlorobenzyl)oxy)benzene, synthesized in the previous paragraph, was weighed into a 25 ml four-necked flask and dissolved in 6 .0 mL of THF. The solution was cooled to an internal temperature of -70 °C and dripped with 1.25 mL of 2.67 M/n-butyl lithium/hexane solution for 4 minutes. After the mixture was stirred at the same temperature for 30 minutes, the mixture was dropped with a solution of 0.427 g of dimethyl oxalate for 3 minutes, and stirred for 0.75 hour. Upon completion of the reaction, the mixture was added with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 0.635 g of the title compound as a liquid. colorless viscous. The yield was 62.2%. 1
[0349] [0349] NMR (400 MHz, CDCl 3 ) δ: 7.82 (d,J = 8.8 Hz, 1H), 7.38 (d,J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.02 (d,J = 2.4 Hz, 1H), 6.95 (dd,J = 8.8, 2.4 Hz, 1H), 5.10 ( s, 2H), 3.95 (s, 3H).
[0350] [0350] 0.604 g of methyl 2-(2-chloro-4-((4-chlorobenzyl)oxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 3.5 ml of DMAc, and the The solution was added with 0.336 g of TMSOB and 0.195 g of sodium triazole and stirred at room temperature for 0.5 hour and at 50°C for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/4), thus obtaining 0.192 g of the title compound as a white solid. The yield was 25.5%. 1
[0351] [0351] NMR (400 MHz, CDCl 3 ) δ: 7.97 (s, 1H), 7.86 (s, 1H), 7.38-7.31 (m, 5H), 6.98 (d,J = 2.6 Hz, 1H), 6.77 (dd,J = 8.8, 2.5 Hz, 1H), 4.99 (d,J = 14.2 Hz, 1H), 4.98 (s , 2H), 4.93 (d,J = 14.2 Hz, 1H), 4.85 (s, 1H), 3.78 (s, 3H).
[0352] [0352] 1.23 g of 2-chloro-4-fluoroacetophenone was dissolved in 11 ml of DMF, and the solution was added with 1.12 g of 2-naphthol and 1.18 g of potassium carbonate, and stirred at 90°C for 4 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (40 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 0.968 g of the title compound as a liquid. colorless viscous. The yield was 45.9%. 1
[0353] [0353] NMR (400 MHz, CDCl 3 ) δ: 7.89 (d,J = 8.9 Hz, 1H), 7.86 (d,J = 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.65 (d,J = 8.6 Hz, 1H), 7.54-7.45 (m, 3H), 7.23 (dd,J = 8.9 , 2.4 Hz, 1H), 7.04 (d,J = 2.4 Hz, 1H), 6.95 (dd,J = 8.6, 2.4 Hz, 1H), 2.66 (s , 3H).
[0354] [0354] 0.952 g of 1-(2-chloro-4-(naphthalen-2-yloxy)phenyl)ethan-1-one, synthesized in the previous paragraph, was weighed into a 100 ml rotary evaporator flask and added to 10 ml DMSO for dissolution. The mixture was added with 2.60 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 3.11 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.65 mL of iodomethane and stirred at 35 °C for 1.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 10/1), whereby 0.579 g of the title compound was obtained as a colorless liquid. The yield was 53.0%. 1
[0355] [0355] NMR (400 MHz, CDCl 3 ) δ: 7.91 (d,J = 8.9 Hz, 1H), 7.87 (d,J = 8.9 Hz, 1H), 7.81 (dd, J = 8.4, 0.5 Hz, 1H), 7.79 (d,J = 7.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.23 (dd,J = 8.9, 2.4 Hz, 1H), 7.03-6.98 (m, 2H), 3.95 (s, 3H).
[0356] [0356] 0.530 g of methyl 2-(2-chloro-4-(4-naphthalen-2-yloxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 3 ml of DMF, and the solution was added with 0.345 g of TMSOI and 0.157 g of sodium triazole, and stirred at room temperature for 0.5 hour. The mixture was placed in a 50 °C bath and stirred for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (9 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.402 g of the title compound as a white solid. The yield was 28.4%. 1
[0357] [0357] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.89 (s, 1H), 7.89-7.84 (m, 2H), 7.76 (d,J = 8.0 Hz, 1H), 7.53-7.40 (m, 4H), 7.21 (dd,J = 8.9, 2.4 Hz, 1H), 7.03 (d,J = 2.5 Hz, 1H), 6.88 (dd,J = 8.7, 2.5 Hz, 1H), 5.04 (d,J = 14.3 Hz, 1H), 4.95 (d, J = 14.3 Hz, 1H), 4.90 (s, 1H), 3.80 (s, 3H).
[0358] [0358] 1.21 g of 2-chloro-4-fluoroacetophenone was dissolved in 15 ml of N-methyl-2-pyrrolidone (NMP), and the solution was added with 1.26 g of 4-cyanophenol and 3, 89 g of cesium carbonate, and stirred at 130°C for 1 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (75 g of silica gel, hexane/ethyl acetate = 10/1), thereby obtaining 1.466 g of the title compound as a liquid. colorless viscous. The yield was 73.9%. 1
[0359] [0359] NMR (400 MHz, CDCl 3 ) δ: 7.70-7.67 (m, 3H), 7.12-7.09 (m, 3H), 6.99 (dd,J = 8.5, 2.4 Hz, 1H), 2.67 (s, 3H).
[0360] [0360] 1.43 g of 1-(2-chloro-4-(4-cyanophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed into a 100 ml rotary evaporator flask and added to 20 ml DMSO for dissolution. The mixture was added with 3.894 g of iodine and stirred for 0.5 hour in an oil bath at 100 °C. After completion of the reaction, the mixture was cooled to 60 °C, added with 4.66 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.0 mL of iodomethane and stirred at 35 °C for 2.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. After the residue was purified by column chromatography (35 g of silica gel, toluene/ethyl acetate = 5/1), recrystallization was carried out from hexane/ethyl acetate to obtain 0.643 g of the title compound as of a colorless solid. The yield was 38.8%. 1
[0361] [0361] NMR (400 MHz, CDCl 3 ) δ: 7.85 (d,J = 8.6 Hz, 1H), 7.48 (d,J = 8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.08 (d,J = 2.3 Hz, 1H), 7.03 (dd,J = 8.6, 2.3 Hz, 1H), 3.97 ( s, 3H).
[0362] [0362] 0.620 g of methyl 2-(2-chloro-4-(4-cyanophenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 4.5 ml of DMF, and the solution was added with 0.374 g of TMSOB and 0.216 g of sodium triazole and stirred at room temperature for 0.5 hour and at 50°C for 1.5 hour. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (15 g of silica gel, hexane/ethyl acetate = 1/4), thus obtaining 0.202 g of the title compound as a white solid. The yield was 25.8%. 1
[0363] [0363] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.88 (s, 1H), 7.66 (d,J = 8.9 Hz, 2H), 7.48 ( d,J = 8.7 Hz, 1H), 7.08 (d,J = 2.5 Hz, 1H), 7.05 (d,J = 8.9 Hz, 2H), 6.90 (dd, J = 8.7, 2.5 Hz, 1H), 5.03 (d,J = 14.3 Hz, 1H), 5.00 (s, 1H), 4.96 (d,J = 14.3 Hz, 1H), 3.81 (s, 3H).
[0364] [0364] 1.43 g of 2-chloro-4-fluoroacetophenone was dissolved in 15 ml of DMF, and the mixture was added with 1.50 g of 4-chloro-3-fluorophenol and 1.62 g of carbonate of potassium, and stirred at 100°C for 3 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (60 g of silica gel, hexane/ethyl acetate = 10/1),
[0365] [0365] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 1H), 7.41 (t,J = 8.7 Hz, 1H), 7.02 (d, J=2.4Hz, 1H), 6.93 (dd,J=8.6, 2.4Hz, 1H), 6.88 (dd,J=9.6, 2.7Hz, 1H), 6.83 (ddd,J = 8.7, 2.7, 1.3 Hz), 2.66 (s, 3H).
[0366] [0366] 1.508 g of 1-(2-chloro-4-(4-chloro-3-fluorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotary evaporator flask, and added with 20 mL of DMSO for dissolution. The mixture was added with 4.09 g of iodine and stirred in an oil bath at 100 °C for 0.5 hour. After completion of the reaction, the mixture was cooled to 60 °C, added with 4.85 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.0 mL of iodomethane and stirred at 35 °C for 3.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (33 g of silica gel, hexane/ethyl acetate = 6/1), thereby obtaining 1.064 g of the title compound as a pale yellow liquid. The yield was 61.5%. 1
[0367] [0367] NMR (400 MHz, CDCl 3 ) δ: 7.83 (d,J = 8.6 Hz, 1H), 7.45 (t,J = 8.7 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.98 (dd,J = 8.6, 2.4 Hz, 1H), 6.92 (dd,J = 9.4, 2.7 Hz, 1H), 6.86 (ddd,J = 8.7, 2.7, 1.3 Hz), 3.96 (s, 3H).
[0368] [0368] 1.05 g of methyl 2-(2-chloro-4-(4-chloro-3-fluorophenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 6 ml of DMF, and the mixture was added with 0.579 g of TMSOB and 0.335 g of sodium triazole at 0°C, and stirred for 30 minutes while returning to room temperature. The mixture was stirred in a 50 °C bath for 2.5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (20 g of silica gel, hexane/ethyl acetate = 1/4), thus obtaining 0.380 g of the title compound as a pale yellow solid. The yield was 29.3%. 1HRMN (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.87 (s, 1H), 7.43 (d,J = 8.8 Hz, 1H), 7.38 (t,J = 8.7 Hz, 1H), 7.02 (d,J = 2.5 Hz, 1H), 6.87-6.82 (m, 2H), 6.76 (ddd,J = 8.7, 2.7, 1.3 Hz), 5.02 (d,J = 14.3 Hz, 1H), 5.01 (s, 1H), 4.94 (d,J = 14.3 Hz, 1H) , 3.80 (s, 3H).
[0369] [0369] 1.24 g of 2-fluoroacetophenone was dissolved in 15 ml of DMF, and the solution was added with 1.269 g of 4-chlorophenol and 3.82 g of cesium carbonate, and stirred at 100 °C for 5 ,5 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.30 g of the title compound as a a colorless viscous liquid. The yield was 58.7%. 1
[0370] [0370] NMR (400 MHz, CDCl 3 ) δ: 7.83 (dd,J = 7.8, 1.8 Hz, 1H), 7.45 (ddd,J = 8.3, 7.3, 1, 8 Hz, 1H), 7.32 (d,J = 9.0 Hz, 2H), 7.20 (ddd,J = 7.8, 7.3, 1.1 Hz, 1H), 6.95 ( d,J = 9.0 Hz, 2H), 6.90 (dd,J = 8.3, 1.1 Hz, 1H), 2.61 (s, 3H).
[0371] [0371] 1.28 g of 1-(2-(4-chlorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, were weighed in a 100 ml rotaevaporator flask, and added with 20 ml of DMSO for dissolution. The mixture was added with 4.20 g of iodine and stirred in an oil bath at 100 °C for 0.5 hour. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.00 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.05 ml of iodomethane and stirred at 35 °C for 2 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (32 g of silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.011 g of the title compound as a pale yellow liquid. The yield was 67.2%. 1
[0372] [0372] NMR (400 MHz, CDCl 3 ) δ: 7.96 (dd,J = 7.8, 1.8 Hz, 1H), 7.55 (ddd,J = 8.5, 7.3, 1, 8 Hz, 1H), 7.35 (d,J = 8.9 Hz, 2H), 7.26-7.22 (m, 1H), 7.00 (d,J = 8.9 Hz, 2H) , 6.86 (d,J = 8.3 Hz, 1H), 3.72 (s, 3H).
[0373] [0373] 1.01 g of methyl 2-(2-(4-chloro-phenoxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, was dissolved in 7 ml of DMF, and the mixture was added with 0.660 g of TMSOB and 0.381 g of triazole sodium at 0°C, and stirred for 30 minutes while returning to room temperature. The mixture was stirred in a 50 °C bath for 2.5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (20 g of silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.273 g of the title compound as a white solid. The yield was 21.0%. 1
[0374] [0374] NMR (400 MHz, CDCl 3 ) δ: 8.05 (s, 1H), 7.85 (s, 1H), 7.44 (dd,J = 7.8, 1.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.30 (d,J = 9.0 Hz, 2H), 7.20 (ddd,J = 8.6, 7.3, 1.1 Hz, 1H), 6.90 (d,J = 9.0 Hz, 2H), 6.86 (dd,J = 8.1, 1.0 Hz, 1H), 5.03 (d,J = 14.1 Hz, 1H), 4.87 (d,J = 14.1 Hz, 1H), 4.59 (s, 1H), 3.55 (s, 3H).
[0375] [0375] After 741.3 mg of 2,5-dichloropyridine and 9.0 ml of N-methyl pyrrolidone were added to and dissolved in a 25 ml rotary evaporator flask, the mixture was added with 1.14 g of 4-bromo -3-chlorophenol and 1.96 g of potassium carbonate, and heated and stirred in an oil bath at 160 °C. After 5 hours, the mixture was added with aqueous ammonium chloride solution, and extracted three times with toluene. The extract was washed three times with water and then washed once with a saturated saline solution. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 1.91 g of diaryl ether crude product as a brown liquid. Purification by column chromatography (silica gel, hexane:ethyl acetate = 100:0→95:5) gave 1.53 g of 2-(4-bromo-3-chlorophenoxy)-5-chloropyridine, which is the title compound as a colorless liquid compound. The yield was 95.9%. 1
[0376] [0376] NMR (400 MHz, CDCl 3 ) δ: 8.12 (dd,J = 2.7, 0.6 Hz, 1H), 7.68 (dd,J = 8.7, 2.7 Hz, 1H ), 7.62 (d,J = 8.7 Hz, 1H), 7.27 (d,J = 2.7 Hz, 1H), 6.94 (dd,J = 8.7, 2.7 Hz , 1H), 6.93 (dd,J = 8.7, 0.6 Hz, 1H).
[0377] [0377] After 640 mg of 2-(4-bromo-3-chlorophenoxy)-5-chloropyridine, 284 mg of dimethyl oxalate and 5.0 ml of tetrahydrofuran are added to and dissolved in a 25 ml rotary evaporator flask , the mixture was cooled to -78 °C in a dry ice and acetone bath, added with 0.82 mL (2.67 M) of n-butyl lithium and stirred. After 1.5 hours from the start of the reaction, the mixture was added with 2N hydrochloric acid to stop the reaction, and extracted three times with chloroform. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 748 mg of crude ketoester product as an orange liquid. Purification by column chromatography (silica gel, hexane:ethyl acetate = 88:12 to 67:33) gave 338 mg of methyl 2-(2-chloro-4-((5-chloropyridin-2- yl)oxy)phenyl)-2-oxoacetate, which is the title compound, as a colorless liquid compound. The yield was 51.6%. 1
[0378] [0378] NMR (400 MHz, CDCl 3 ) δ: 8.17 (dd,J = 2.7, 0.6 Hz, 1H), 7.87 (d,J = 8.6 Hz, 1H), 7, 74 (dd,J = 8.7, 2.7 Hz, 1H), 7.25 (d,J = 2.2 Hz, 1H), 7.17 (dd,J = 8.6, 2.2 Hz , 1H), 7.00 (dd,J = 8.7, 0.6 Hz, 1H), 3.96 (s, 3H).
[0379] [0379] After 313 mg of methyl 2-(2-chloro-4-(5-chloropyridin-2-yl)oxy)phenyl)-2-oxoacetate, obtained in the previous paragraph, and 1.44 ml of N,N - dimethylacetamide were added to and dissolved in a 50 ml rotary evaporator flask, the mixture was added with 114 mg of sodium triazole and 200 mg of TMSOB, and heated and stirred in an oil bath at 50 °C. After 3 hours from the start of the reaction, the mixture was added with an aqueous solution of ammonium chloride and extracted three times with toluene. The extract was washed once with water and was washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 338 mg of the crude azole product as a yellow liquid. Purification by column chromatography (silica gel, chloroform:ethyl acetate = 47:53→0:100) gave 166 mg of 2-(2-chloro-4-((5-chloropyridin-2-yl) oxy)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate, which is the title compound, in the form of a colorless viscous substance. The yield was 42.3%. 1
[0380] [0380] NMR (400 MHz, CDCl 3 ) δ: 8.14 (d,J = 2.7 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.69 ( dd,J = 8.6, 2.7 Hz, 1H), 7.50 (d,J = 8.7 Hz, 1H), 7.20 (d,J = 2.4 Hz, 1H), 7, 02 (dd,J = 8.7, 2.4 Hz, 1H), 6.92 (d,J = 8.6 Hz, 1H), 5.06 (d,J = 14.2 Hz, 1H), 4.91 (d,J = 14.2 Hz, 1H), 4.89 (s, 1H), 3.79 (s, 3H).
[0381] [0381] After 890.8 mg of 4-fluorophenyl sulfur pentafluoride and 7.2 mL of DMF were added to and dissolved in a 30 mL centrifuge tube, the mixture was added with 914.8 mg of 4-bromo-3 -chlorophenol and 1.5680 g of cesium carbonate, and heated and stirred in an oil bath at 120 °C. After 4 hours from the start of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with benzene. The extract was washed once with water and then washed twice with a saturated saline solution. After the extract was dried with anhydrous sodium sulfate, 1.5400 g of aryl bromide crude product was obtained as a brown liquid. Purification by column chromatography (silica gel, hexane) gave 1.3452 g of (4-(4-bromo-3-chlorophenoxy)phenyl)pentafluoro-λ6-sulfan, which is the title compound, under the form of a colorless liquid compound. The yield was 81.9%. 1
[0382] [0382] NMR (400 MHz, CDCl 3 ) δ: 7.74 (d,J = 9.1 Hz, 2H), 7.62 (d,J = 8.8 Hz, 1H), 7.18 (d, J = 2.8 Hz, 1H), 7.03 (d,J = 9.1 Hz, 2H), 6.85 (dd,J = 8.8, 2.8 Hz, 1H).
[0383] [0383] The 409.9 mg of (4-(4-bromo-3-chlorophenoxy)phenyl)pentafluoro-λ6-sulfan obtained in the previous paragraph and 1.5 ml of tetrahydrofuran were added to and dissolved in a flask to 25 mL rotary evaporator and then cooled with water, and the mixture was added with 1.18 mL (1.27 M) of isopropyl magnesium chloride · lithium chloride complex and stirred. After 30 minutes, the mixture was added with 0.15 ml of methyl chloroglyoxylate and stirred continuously. After 1 hour, the mixture was added with 2N hydrochloric acid to stop the reaction and extracted three times with chloroform. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 524.6 mg of crude product as an orange liquid. Purification by column chromatography (silica gel, hexane/ethyl acetate = 91/9 → 70/30) gave 59.2 mg of 2-(2-chloro-4-(4-
[0384] [0384] NMR (400 MHz, CDCl 3 ) δ: 7.85 (d,J = 8.6 Hz, 1H), 7.82 (d,J = 9.1 Hz, 2H), 7.14 (d, J = 9.1 Hz, 2H), 7.07 (d,J = 2.3 Hz, 1H), 7.03 (dd,J = 8.6, 2.3 Hz, 1H), 3.97 ( s, 3H).
[0385] [0385] After 59.2 mg of 2-(2-chloro-4-(4-pentafluoro-λ6-sulfanyl)phenoxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, and 0.2 ml of DMAc are added to and dissolved in a 50 ml rotary evaporator flask, the mixture was added with 16.9 mg of sodium triazole and 29.5 mg of TMSOB, and heated and stirred in an oil bath at 50 °C. After 3 hours, the mixture was added with aqueous ammonium chloride solution, and extracted three times with toluene. The extract was washed once with water and was washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 59.1 mg of crude product as a yellow liquid. Purification by column chromatography (silica gel, chloroform/ethyl acetate = 1/1) gave 25.1 mg of 2-(2-chloro-4-(4-(pentafluoro-λ6-sulfanyl)phenoxy) )phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propionate, which is the title compound, as a colorless liquid compound. The yield was 35.3%. 1
[0386] [0386] NMR (400 MHz, CDCl 3 ) δ: 8.00 (s, 1H), 7.89 (s, 1H), 7.76 (d,J = 9.1 Hz, 2H), 7.48 ( d,J = 8.8 Hz, 1H), 7.07 (d,J = 2.5 Hz, 1H), 7.03 (d,J = 9.1 Hz, 2H), 6.90 (dd, J = 8.8, 2.5 Hz, 1H), 5.03 (d,J = 14.3 Hz, 1H), 4.96 (d,J = 14.3 Hz, 1H), 4.87 ( s, 1H), 3.81 (s, 3H).
[0387] [0387] 1.31 g of 2-chloro-4-fluoroacetophenone was dissolved in 14 ml of NMP, and the solution was added with 1.02 g of 2,4-difluorophenol and 1.27 g of potassium carbonate, and stirred at 100°C for 5.5 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 9/1), thus obtaining 1.65 g of the title compound as a viscous liquid. colorless. The yield was 77.3%. 1
[0388] [0388] NMR (400 MHz, CDCl 3 ) δ: 7.64 (d,J = 8.7 Hz, 1H), 7.16 (td,J = 8.9, 5.5 Hz, 1H), 7, 02-6.90 (m, 3H), 7.01 (dd,J=8.7, 2.5Hz, 1H), 2.64 (s, 3H).
[0389] [0389] 1.652 g of 1-(2-chloro-4-(2,4-difluorophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, and 20 mL of DMSO were added to and dissolved in a flask for a rotary evaporator. 100ml. The mixture was added with 5.70 g of iodine and stirred in an oil bath at 100 °C for 0.5 hour. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.76 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.2 mL of iodomethane and stirred at 35 °C for 2.5 hours. After completion of the reaction, excess iodine was quenched with a saturated aqueous solution of sodium sulfite, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (30 g of silica gel, hexane/ethyl acetate = 5/1), thereby obtaining 1.20 g of the title compound as a colorless liquid. The yield was 62.7%. 1
[0390] [0390] NMR (400 MHz, CDCl 3 ) δ: 7.81 (d,J = 8.7 Hz, 1H), 7.17 (td,J = 8.9, 5.4 Hz, 1H), 7, 04-6.90 (m, 4H), 3.95 (s, 3H).
[0391] [0391] 1.20 g of 2-(2-chloro-4-(2,4-difluorophenoxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, was dissolved in 5.5 ml of DMAc, and the The solution was added with 0.757 g of TMSOB and 0.434 g of sodium triazole, and stirred at room temperature for 0.5 hour. The mixture was placed in a 50 °C bath and stirred for 4 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.402 g of the title compound as a white solid. The yield was 24.0%. 1
[0392] [0392] NMR (400 MHz, CDCl 3 ) δ: 7.99 (1H, s), 7.88 (1H, s), 7.39 (d,J = 8.8 Hz, 1H), 7.11 ( td,J = 8.9, 5.5 Hz, 1H), 7.00-6.90 (m, 3H), 6.76 (dd,J = 8.8, 2.6 Hz, 1H), 5 .02 (d,J = 14.3 Hz, 1H), 4.90 (d,J = 14.3 Hz, 1H), 4.83 (s, 1H), 3.79 (s, 3H).
[0393] [0393] 1.26 g of 2-bromo-4-fluoroacetophenone was dissolved in 10 ml of DMF, and the solution was added with 1.11 g of 4-bromophenol and 2.46 g of cesium carbonate, and stirred at 100°C for 1 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 9/1), thus obtaining 1.93 g of the title compound as a viscous liquid. colorless. The yield was 89.2%. 1
[0394] [0394] NMR (400 MHz, CDCl 3 ) δ: 7.57-7.49 (m, 3H), 7.20 (d,J = 2.4 Hz, 1H), 7.10-6.93 (m , 3H), 2.64 (s, 3H).
[0395] [0395] The 1.91 g of 1-(2-bromo-4-(4-bromophenoxy)phenyl)ethan-1-one, synthesized in the previous paragraph, and 20 mL of DMSO were added to and dissolved in a rotary evaporator flask of 100 ml. The mixture was added with 4.20 g of iodine and stirred in an oil bath at 100 °C for 0.5 hour. After completion of the reaction, the mixture was cooled to 60 °C, added with 5.00 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.05 mL of iodomethane and stirred at 35 °C for 3.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.38 g of the title compound as a pale yellow liquid. The yield was 64.7%. 1
[0396] [0396] NMR (400 MHz, CDCl 3 ) δ: 7.73 (d,J = 8.7 Hz, 1H), 7.54 (d,J = 8.9 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.01-6.96 (m, 3H), 3.95 (s, 3H).
[0397] [0397] 1.38 g of 2-(2-bromo-4-(4-bromophenoxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, was dissolved in 5 ml of DMF, and the mixture was added with 0.696 g of TMSOB and 0.397 g of sodium triazole, and stirred for 30 hours while returning to room temperature. The mixture was stirred in a 50 °C bath for 3 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.335 g of the title compound as a yellow solid. The yield was 20.2%. 1
[0398] [0398] NMR (400 MHz, CDCl 3 ) δ: 7.97 (s, 1H), 7.87 (s, 1H), 7.48 (d,J = 8.9 Hz, 2H), 7.39 ( d,J = 8.8 Hz, 1H), 7.18 (d,J = 2.5 Hz, 1H), 6.91 (d,J = 8.9 Hz, 2H), 6.85 (dd, J = 8.8, 2.5 Hz, 1H), 5.02 (s, 2H), 4.98 (s, 1H), 3.80 (s, 3H).
[0399] [0399] 1.61 g of 2-trifluoromethyl-4-fluoroacetophenone was dissolved in 10 ml of DMF, and the mixture was added with 1.48 g of 4-bromophenol and 3.27 g of potassium carbonate, and stirred. at 100°C for 1 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off, and 2.50 g of the title compound was obtained as a colorless viscous liquid by vacuum drying. The yield was 89.3%. 1
[0400] [0400] NMR (400 MHz, CDCl 3 ) δ: 7.55-7.49 (m, 3H), 7.31 (d,J = 2.4 Hz, 1H), 7.12 (dd,J = 8 .5, 2.4 Hz, 1H), 6.95 (d,J = 8.9 Hz, 2H), 2.58 (s, 3H).
[0401] [0401] 2.48 g of 1-(4-(4-bromophenoxy)-2-(trifluoromethyl)phenyl)ethan-1-one and 15 ml of DMSO were added to and dissolved in a 100 ml rotary evaporator flask. The mixture was added with 5.61 g of iodine and stirred in an oil bath at 100 °C for 0.5 hour. After completion of the reaction, the mixture was cooled to 60 °C, added with 6.70 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.05 mL of iodomethane and stirred at 35 °C for 3.5 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.38 g of the title compound as a pale yellow liquid. The yield was 49.5%. 1
[0402] [0402] NMR (400 MHz, CDCl 3 ) δ: 7.66 (d,J = 8.6 Hz, 1H), 7.55 (d,J = 8.9 Hz, 2H), 7.34 (d, J = 2.4 Hz, 1H), 7.14 (dd,J = 8.6, 2.4 Hz, 1H), 6.99 (d,J = 8.9 Hz, 2H), 3.94 ( s, 3H).
[0403] [0403] 1.38 g of 2-(4-(4-bromophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, was dissolved in 5 ml of DMF, and the mixture was added with 0.707 g of TMSOB and 0.406 g of sodium triazole, and stirred for 30 minutes while returning to room temperature. The mixture was stirred in a 50 °C bath for 5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.147 g of the title compound as a yellow solid. The yield was 4.3%. 1
[0404] [0404] NMR (400 MHz, CDCl 3 ) δ: 8.11 (s, 1H), 7.89 (s, 1H), 7.62 (d,J = 8.9 Hz, 1H), 7.50 ( d,J = 8.8 Hz, 2H), 7.39 (d,J = 2.7 Hz, 1H), 7.06 (dd,J = 8.9, 2.8 Hz), 6.93 ( d,J = 8.8 Hz), 5.08 (d,J = 14.1 Hz, 1H), 4.72 (d,J = 14.1 Hz, 1H), 4.68 (s, 1H) , 3.80 (s, 3H).
[0405] [0405] 1.24 g of 2-bromo-4-fluoroacetophenone was dissolved in 10 ml of NMP, and the mixture was added with 1.10 g of 4-trifluorophenol and 2.46 g of potassium carbonate, and stirred. at 100°C for 0.5 hour, 120°C for 1 hour and 140°C for 1.5 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate = 9/1), thereby obtaining 1.04 g of the title compound as a viscous liquid. colorless. The yield was 50.9%. 1
[0406] [0406] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 2H), 7.58 (d,J = 8.5 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.12 (d,J = 8.6 Hz, 2H), 7.01 (dd,J = 8.5, 2.4 Hz, 1H), 2.65 ( s, 3H).
[0407] [0407] The 1.02 g of 1-(2-bromo-4-(4-trifluoromethyl)phenoxy)phenyl)ethan-1-one, obtained in the previous paragraph, and 11.5 ml of DMSO were added to and dissolved in a 100 ml rotary evaporator flask. The mixture was added with 2.33 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. Upon completion of the reaction, the mixture was cooled to 60 °C, added with 2.76 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.60 mL of iodomethane and stirred at 35 °C for 3 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 0.677 g of the title compound as a pale yellow liquid. The yield was 58.9%. 1
[0408] [0408] NMR (400 MHz, CDCl 3 ) δ: 7.76 (d,J = 8.6 Hz, 1H), 7.69 (d,J = 8.9 Hz, 2H), 7.25 (dJ = 2.4 Hz, 1H), 7.18 (d,J = 8.9 Hz, 2H), 7.05 (dd,J = 8.6, 2.4 Hz, 1H), 3.96 (s, 3H).
[0409] [0409] 0.663 g of 2-(2-bromo-4-(4-trifluoromethyl)phenoxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, was dissolved in 4.5 ml of DMF, and the mixture was added with 0.344 g of TMSOB and 0.195 g of sodium triazole, and stirred for 30 hours while returning to room temperature. The mixture was stirred in a 50 °C bath for 4 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.142 g of the title compound as a yellow solid. The yield was 17.8%. 1
[0410] [0410] NMR (400 MHz, CDCl 3 ) δ: 7.98 (s, 1H), 7.88 (s, 1H), 7.63 (d,J = 8.6 Hz, 2H), 7.45 ( d,J = 8.8 Hz, 1H), 7.25 (d,J = 2.5 Hz, 1H), 7.07 (d,J = 8.6 Hz, 2H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H), 5.04 (s, 2H), 5.00 (s, 1H), 3.81 (s, 3H).
[0411] [0411] 1.20 g of 2-trifluoromethyl-4-fluoroacetophenone was dissolved in 10 ml of NMP, and the mixture was added with 1.16 g of 4-tribromophenol and 2.48 g of potassium carbonate, and stirred. at 120°C for 1.5 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.31 g of the title compound as a viscous liquid. colorless. The yield was 64.5%. 1
[0412] [0412] NMR (400 MHz, CDCl 3 ) δ: 7.66 (d,J = 8.7 Hz, 2H), 7.53 (d,J = 8.5 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.20 (dd,J = 8.5, 2.4 Hz, 1H), 7.13 (d,J = 8.7 Hz, 2H), 2.59 ( s, 3H).
[0413] [0413] The 1.30 g of 1-(2-trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)ethan-1-one, obtained in the previous paragraph, and 15 ml of DMSO were added to and dissolved in a 100 ml rotary evaporator flask. The mixture was added with 3.03 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 3.61 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.75 mL of iodomethane and stirred at 35 °C for 2 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 0.755 g of the title compound as a pale yellow liquid. The yield was 51.6%. 1
[0414] [0414] NMR (400 MHz, CDCl 3 ) δ: 7.70 (d,J = 8.9 Hz, 2H), 7.69 (d,J = 8.7 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.23-7.17 (m, 3H), 3.95 (s, 3H). Synthesis of 2-hydroxy-2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)methyl propionate
[0415] [0415] After 0.386 g of 2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, be dissolved in 4 ml of dichloroethane and cooled to -15°C, the mixture was dripped with 1.4 mL (1.4 M) of a trimethylaluminum-hexane solution over 10 minutes. After the mixture was stirred at the same temperature for 30 minutes, the mixture was added with an aqueous hydrochloric acid solution and extracted with chloroform. After the organic layer was washed with hydrochloric acid, water and a saturated saline solution, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. 0.392 g of the title compound was obtained as a colorless liquid by vacuum drying. Synthesis of 2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)methyl acrylate
[0416] [0416] 0.392 g of 2-hydroxy-2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)methyl propionate obtained in the previous paragraph was dissolved in 5 ml of toluene, and the mixture was added with 94.8 mg of p-toluenesulfonic acid monohydrate and refluxed for 1 hour. The mixture was added with 91.8 mg of p-toluenesulfonic acid monohydrate over 1 hour, 0.5 g of 4A molecular sieves over 30 minutes, and 109 mg of p-
[0417] [0417] NMR (400 MHz, CDCl 3 ) δ: 7.64 (d,J = 8.8 Hz, 2H), 7.35 (d,J = 2.5 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.17 (dd,J = 8.4, 2.5 Hz, 1H), 7.12 (d,J = 8.8 Hz, 2H), 6.62 ( s, 1H), 5.79 (s, 1H), 3.77 (s, 1H). Synthesis of 2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)oxirane-2-methyl carboxylate
[0418] [0418] After 0.250 g of 2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)methyl methyl acrylate, synthesized in the previous paragraph, be dissolved in 1.6 ml of acetonitrile and 1, 6 ml of methanol and being cooled in an ice bath, the mixture was added with 184 mg of urea-hydrogen peroxide adduct and 89.2 mg of potassium carbonate, and stirred at room temperature for 6.5 hours. After completion of the reaction, the mixture was added with 2N hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and a saturated saline solution, the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 0.239 g of the title compound as a colorless liquid. The yield was 91.7%. 1
[0419] [0419] NMR (400 MHz, CDCl 3 ) δ: 7.64 (d,J = 8.6 Hz, 2H), 7.63 (d,J = 8.6 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.20 (dd,J = 8.6, 2.5 Hz, 1H), 7.12 (d,J = 8.6 Hz, 2H), 3.76 ( s, 3H), 3.66 (d,J = 6.2 Hz, 1H), 3.06 (d,J = 6.2 Hz, 1H).
[0420] [0420] 0.230 g of 2-(2-(trifluoromethyl)-4-(4-(trifluoromethyl)phenoxy)phenyl)oxirane-2-methyl carboxylate obtained in the previous paragraph was dissolved in 2 ml of DMF, and the mixture was added with 51.7 mg of triazole and 39.4 mg of triazole sodium, and stirred at 50°C for 3 hours and at 60°C for 3 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thereby obtaining 0.187 g of the title compound as a white solid. The yield was 69.5%. 1
[0421] [0421] NMR (400 MHz, CDCl 3 ) δ: 8.12 (s, 1H), 7.89 (s, 1H), 7.70-7.64 (m, 3H), 7.45 (d,J = 2.7 Hz, 1H), 7.13 (dd,J = 9.0, 2.7 Hz, 1H), 7.10 (d,J = 9.0 Hz, 2H), 5.09 (d ,J = 14.1 Hz, 1H), 4.74 (s, 1H), 4.73 (d,J = 14.1 Hz, 1H), 3.81 (s, 3H). <Synthesis Example 40. Synthesis of Compound I-40> Synthesis of 1-(4-(4-bromo-3-fluorophenoxy)-2-chlorophenyl)ethan-1-one
[0422] [0422] 1.30 g of 2-chloro-4-fluoroacetophenone was dissolved in 10 ml of DMF, and the mixture was added with 1.60 g of 4-bromo-3-fluorophenol and 3.17 g of carbonate of potassium, and stirred at 80°C for 3 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue is purified by column chromatography (silica gel, hexane/ethyl acetate = 9/1), thereby obtaining 2.03 g of the title compound as a viscous liquid. colorless. The yield was 78.3%.
[0423] [0423] NMR (400 MHz, CDCl 3 ) δ: 7.65 (d,J = 8.6 Hz, 1H), 7.56 (dd,J = 8.8, 8.0 Hz, 1H), 7, 03 (d,J = 2.4 Hz, 1H), 6.94 (dd,J = 8.6, 2.4 Hz, 1H), 6.84 (dd,J = 9.2, 2.7 Hz , 1H), 6.77 (ddd,J = 8.8, 2.7, 0.9 Hz, 1H), 2.66 (s, 3H). Synthesis of 2-(4-(4-bromo-3-fluorophenoxy)-2-chlorophenyl)-2-methyl oxoacetate
[0424] [0424] The 2.01 g of 1-4-(4-bromo-3-fluorophenoxy)-2-chlorophenyl)ethan-1-one obtained in the previous paragraph was added to and dissolved in 11.5 ml of DMSO. The mixture was added with 4.74 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 56.8 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.2 mL of iodomethane and stirred at 35 °C for 2.5 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.36 g of the title compound as a pale yellow liquid. The yield was 59.8%. 1
[0425] [0425] NMR (400 MHz, CDCl 3 ) δ: 7.83 (d,J = 8.6 Hz, 1H), 7.59 (dd,J = 8.7, 7.8 Hz, 1H), 7, 02 (d,J = 2.3 Hz, 1H), 6.99 (dd,J = 8.6, 2.3 Hz, 1H), 6.90 (dd,J = 9.0, 2.7 Hz , 1H), 6.80 (ddd,J = 8.7, 2.7, 1.2 Hz, 1H), 3.96 (s, 3H). Synthesis of 2-(4-(4-bromo-3-fluorophenoxy)-2-(chlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propionate (compound I -40)
[0426] [0426] 1.11 g of 2-(4-(4-bromo-3-fluorophenoxy)-2-chlorophenyl)-2-methyl oxoacetate obtained in the previous paragraph was dissolved in 6 ml of DMAc, and the mixture was added with 0.603 g of TMSOB and 0.345 g of sodium triazole and stirred at room temperature for 30 minutes. The mixture was stirred in a 50 °C bath for 2 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.365 g of the title compound as a light yellow solid. The yield was 27.2%. 1
[0427] [0427] NMR (400 MHz, CDCl 3 ) δ: 8.01 (s, 1H), 7.88 (s, 1H), 7.52 (dd,J = 8.7, 7.9 Hz, 1H), 7.45 (d,J = 8.8 Hz, 1H), 7.02 (d,J = 2.5 Hz, 1H), 6.86 (dd,J = 8.8, 2.5 Hz, 1H ), 6.81 (dd,J = 9.3, 2.7 Hz, 1H), 6.72 (ddd,J = 8.7, 2.7, 1.1 Hz, 1H), 5.03 ( d,J = 14.3 Hz, 1H), 4.94 (d,J = 14.3 Hz, 1H), 4.88 (s, 3H), 3.80 (s, 3H). <Synthesis example 41. Synthesis of compound I-133> Synthesis of 1-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)ethan-1-one
[0428] [0428] 1.85 g of 2-trifluoromethyl-4-fluoroacetophenone was dissolved in 15 ml of DMAc, and the mixture was added with 1.40 g of 3,4-difluorophenol and 3.81 g of potassium carbonate, and stirred at 90°C for 1 hour. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off, and 2.75 g of the title compound were obtained as a colorless viscous liquid. The yield was 96.6%. 1
[0429] [0429] NMR (400 MHz, CDCl 3 ) δ: 7.51 (d,J = 8.5 Hz, 1H), 7.31 (d,J = 2.5 Hz, 1H), 7.25-7, 15 (m, 1H), 7.13 (dd,J = 8.5, 2.5 Hz, 1H), 6.92 (ddd,J = 10.7, 6.6, 2.9 Hz, 1H) , 6.83-6.77 (m, 1H), 2.58 (s, 3H).
[0430] [0430] 2.73 g of 1-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)ethan-1-one synthesized in the previous paragraph were weighed and added with 35 ml of DMSO to dissolution. The mixture was added with 6.91 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 8.35 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 1.7 mL of iodomethane and stirred at 35 °C for 2 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 7/1), thereby obtaining 1.60 g of the title compound as a pale yellow liquid. The yield was 51.3%. 1
[0431] [0431] NMR (400 MHz, CDCl 3 ) δ: 7.67 (d,J = 8.6 Hz, 1H), 7.34 (d,J = 2.5 Hz, 1H), 7.28-7, 20 (m, 1H), 7.15 (dd,J = 8.6, 2.5 Hz), 6.96 (ddd,J = 10.5, 6.6, 2.9 Hz, 1H), 6 .87-6.82 (m,1H), 3.95 (s, 3H). Synthesis of 2-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)methyl acrylate
[0432] [0432] After 1.59 g of 2-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, be dissolved in 17.6 ml of dichloro ethane and cooled to -15 °C, the mixture was dripped with 6.3 mL (1.4 M) of a trimethylaluminum-hexane solution over 6 minutes. After the mixture was stirred at the same temperature for 30 minutes, the mixture was added with an aqueous hydrochloric acid solution and extracted with chloroform. After the organic layer was washed with hydrochloric acid, water and a saturated saline solution, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. This solution was dissolved in 15 ml of toluene, added with 426 mg of 98% sulfuric acid and refluxed for 0.5 hour. Upon completion of the reaction, this solution was dropped into a saturated aqueous solution of sodium bicarbonate and washed with water and a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 10/1), thus obtaining 0.757 g of the title compound as a colorless liquid. The yield was 77.9%. 1
[0433] [0433] NMR (400 MHz, CDCl 3 ) δ: 7.28 (d,J = 2.5 Hz, 1H), 7.23 (d,J = 8.4 Hz, 1H), 7.22-7, 14 (m, 1H), 7.10 (dd,J = 8.4, 2.5 Hz, 1H), 6.91 (ddd,J = 10.9, 6.6, 2.9 Hz, 1H) , 6.83-6.77 (m, 1H), 6.60 (d,J = 1.0 Hz, 1H), 5.77 (d,J = 1.0 Hz, 1H), 3.76 ( s, 3H). Synthesis of 2-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propanoate (compound I -133)
[0434] [0434] After 0.726 g of 2-(4-(3,4-difluorophenoxy)-2-(trifluoromethyl)phenyl)methyl acrylate, synthesized in the previous paragraph, is dissolved in 4.6 ml of acetonitrile and 4.6 ml of of methanol and cooled in an ice bath, the mixture was added with 532 mg of urea-hydrogen peroxide adduct and 258 mg of potassium carbonate, and stirred at room temperature for 7 hours. After completion of the reaction, the mixture was added with 2N hydrochloric acid, and extracted with ethyl acetate. After the organic layer was washed with water and a saturated saline solution, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. This solution was dissolved in 5 ml of DMF, added with 130 mg of triazole and 170 mg of triazole sodium, and stirred at 60°C for 5 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thereby obtaining 0.187 g of the title compound as a white solid. The yield was 79.4%. 1
[0435] [0435] NMR (400 MHz, CDCl 3 ) δ: 8.11 (s, 1H), 7.88 (s, 1H), 7.64 (d,J = 8.9 Hz, 1H), 7.38 ( d,J = 2.7 Hz, 1H), 7.22-7.15 (m, 1H), 7.06 (dd,J = 8.9, 2.7 Hz, 1H), 6.89 (ddd ,J = 10.7, 6.6, 2.9 Hz, 1H), 5.08 (d,J = 14.1 Hz, 1H), 4.76 (s, 1H), 4.72 (d, J = 14.1 Hz, 1H), 3.79 (s, 3H). <Synthesis example 42. Synthesis of compound IIIc-4> Synthesis of 1-(2-chloro-4-(quinolin-6-yloxy)phenyl)ethan-1-one
[0436] [0436] 1.01 g of 2-chloro-4-fluoroacetophenone was dissolved in 10 ml of NMP, and the mixture was added with 1.02 g of 6-quinolinol and 2.46 g of potassium carbonate, and stirred. at 80°C for 3.5 hours. After completion of the reaction, the mixture was added with toluene, and the organic layer was washed with a 2N aqueous solution of sodium hydroxide, water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 2/3), thus obtaining 1.19 g of the title compound as a viscous liquid. colorless. The yield was 68.1%. 1
[0437] [0437] NMR (400 MHz, CDCl 3 ) δ: 8.91 (dd,J = 4.2, 1.7 Hz, 1H), 8.16 (d,J = 9.1 Hz, 1H), 8, 09 (dd,J = 8.4, 1.7 Hz, 1H), 7.68 (d,J = 8.6 Hz, 1H), 7.48 (dd,J = 9.1, 2.7 Hz , 1H), 7.43 (dd,J = 8.4, 4.2 Hz, 1H), 7.39 (d,J = 2.7 Hz, 1H), 7.08 (d,J = 2, 4 Hz, 1H), 6.99 (dd,J = 8.6, 2.4 Hz, 1H), 2.67 (s, 3H). Synthesis of 2-(2-Chloro-4-(quinolin-6-yloxy)phenyl)-2-methyl oxoacetate
[0438] [0438] 1.18 g of 1-(2-chloro-4-(quinolin-6-yloxy)phenyl)ethan-1-one, obtained in the previous paragraph, was added to and dissolved in 15 ml of DMSO. The mixture was added with 3.24 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 3.84 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.8 mL of iodomethane and stirred at 35 °C for 3 hours. After completion of the reaction, excess iodine was quenched with saturated aqueous sodium sulfite solution, toluene was added and the precipitated solution was filtered through celite. The filtered solid was decanted with toluene and added to the above solution. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thereby obtaining 242 mg of the title compound as a pale orange liquid. The yield was 17.8%. Synthesis of 2-(2-Chloro-4-(quinolin-6-yloxy)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propionate (compound IIIc-4 )
[0439] [0439] 239 mg of 2-(2-chloro-4-(quinolin-6-yloxy)phenyl)-2-methyl oxoacetate obtained in the above process was dissolved in 2.1 mL of DMAc, and the mixture was added with 148 mg of TMSOB and 83.1 mg of sodium triazole, and stirred at room temperature for 30 hours. The mixture was stirred in a 50 °C bath for 6 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off, the residue was purified by column chromatography (silica gel, chloroform/methanol = 20/1) and then recrystallized from ethyl acetate , thus obtaining 37.4 mg of the title compound as a white solid. The yield was 12.6%. 1
[0440] [0440] NMR (400 MHz, CDCl 3 ) δ: 8.89 (dd,J = 4.2, 1.7 Hz, 1H), 8.13(d,J = 9.1 Hz, 1H), 8, 08 (d,J = 8.3 Hz, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.46 (dd,J = 9.1, 2.7 Hz, 1H ), 7.45 (d,J = 8.8 Hz, 1H), 7.42 (dd,J = 8.3, 4.2 Hz, 1H), 7.33 (d,J = 2.7
[0441] [0441] 1.20 g of 2-trifluoromethyl-4-fluoroacetophenone was dissolved in 10 ml of NMP, and the mixture was added with 1.21 g of 1-naphthol and 2.96 g of cesium carbonate, and stirred. at 100°C for 4 hours. Upon completion of the reaction, the mixture was added with toluene and the organic layer was washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off, and 1.37 g of the title compound was obtained as a pale orange solid. The yield was 58.7%. 1
[0442] [0442] NMR (400 MHz, CDCl 3 ) δ: 7.99 (d,J = 8.3 Hz, 1H), 7.92 (d,J = 8.2 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.63 (d,J = 8.7 Hz, 1H), 7.57-7.44 (m, 3H), 7.14 (dd,J = 7.5 , 0.8 Hz, 1H), 7.01 (d,J = 2.4 Hz), 6.89 (dd,J = 8.7, 2.4 Hz), 2.64 (s, 3H). Synthesis of 2-(2-Chloro-4-(naphthalen-1-yloxy)phenyl)-2-methyl oxoacetate
[0443] [0443] 1.36 g of 1-(2-chloro-4-(naphthalen-1-yloxy)phenyl)ethan-1-one, obtained in the previous paragraph, was weighed and added with 15 ml of DMSO to dissolution. The mixture was added with 3.48 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 4.09 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.95 mL of iodomethane and stirred at 35 °C for 3 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel,
[0444] [0444] NMR (400 MHz, CDCl 3 ) δ: 7.92 (d,J = 8.3 Hz, 2H), 7.80 (d,J = 8.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.58-7.47 (m, 3H), 7.18 (d,J = 7.5 Hz, 1H), 6.99 (d,J = 2.4 Hz, 1H), 6.95 (dd,J = 8.7, 2.4 Hz, 1H), 3.94 (s, 3H). Synthesis of 2-(2-Chloro-4-(naphthalen-1-yloxy)phenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propionate (compound IIId-1 )
[0445] [0445] 2-(2-Chloro-4-(naphthalen-1-yloxy)phenyl)-2-methyl oxoacetate, obtained in the previous paragraph, was dissolved in 6 mL of DMAc, and the mixture was added with 0.641 g of TMSOB and 0.368 g of sodium triazole and stirred at room temperature for 30 minutes. The mixture was stirred in a 50 °C bath for 3 hours. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed three times with water and then washed with a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/3), thus obtaining 0.368 g of the title compound as a white solid. The yield was 27.9%. 1
[0446] [0446] NMR (400 mHz, CDCl 3 ) δ: 8.02 (brd,J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.99 (brd,J = 9.3 Hz, 1H), 7.88 (s, 1H), 7.70 (d,J = 8.3 Hz, 1H), 7.57-7.47 (m, 2H), 7.44 (dd,J = 8 .1, 7.7 Hz, 1H), 7.39 (d,J = 8.8 Hz, 1H), 7.01 (d,J = 2.5 Hz, 1H), 6.86 (dd,J = 8.8, 2.5 Hz, 1H), 5.02 (d,J = 14.2 Hz, 1H), 4.92 (d,J = 14.2 Hz, 1H), 4.86 (s , 1H), 3.79 (s, 3H). <Synthesis example 44. Synthesis of compound IIIf-2> Synthesis of 1-(6-(4-chlorophenoxy)pyridin-3-yl)ethan-1-one
[0447] [0447] 0.998 g of commercially available 2-chloro-5-acetyl pyridine was dissolved in 13 ml of DMF, and the mixture was added with 0.908 g of 4-chlorophenol and 2.51 g of potassium carbonate, and stirred in an 80 °C oil bath for 1.5 h. After completion of the reaction, the mixture was added with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium hydroxide, water and a saturated saline solution, and dried with anhydrous sodium sulfate. A solvent is distilled off and the residue is purified by column chromatography (silica gel, chloroform/ethyl acetate = 50/1), thereby obtaining 1.33 g of the title compound as a colorless liquid. . The yield was 83.9%. 1
[0448] [0448] NMR (400 MHz, CDCl 3 ) δ: 8.74 (d,J = 2.3 Hz, 1H), 8.29 (dd,J = 8.7, 2.3 Hz, 1H), 7, 40 (d,J = 8.8 Hz, 2H), 7.10 (d,J = 8.8 Hz, 2H), 7.00 (d,J = 8.7 Hz, 1H), 2.57 ( s, 3H). Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)-2-methyl oxoacetate
[0449] [0449] 1.00 g of 1-(6-(4-chlorophenoxy)pyridin-3-yl)ethan-1-one, synthesized in the previous paragraph, was weighed and added with 6 ml of DMSO for dissolution. The mixture was added with 3.26 g of iodine and stirred at 100 °C for 0.5 hour in an oil bath. After completion of the reaction, the mixture was cooled to 60 °C, added with 3.93 g of potassium carbonate and stirred at 100 °C for 0.5 hour. The mixture was cooled to 35 °C, added with 0.303 mL of iodomethane and stirred at 35 °C for 2.5 hours. Upon completion of the reaction, toluene and a saturated aqueous solution of sodium sulfite were added to the mixture, and the precipitated solution was filtered through celite. The organic layer of the solution was separated and the aqueous layer was extracted with toluene. The organic layers were combined and washed with water and a saturated saline solution. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5/1), thereby obtaining 0.156 g of the title compound as a pale yellow solid. The yield was 51.3%.
[0450] [0450] NMR (400 MHz, CDCl 3 ) δ: 8.88 (dd,J = 2.4, 0.7 Hz, 1H), 8.38 (dd,J = 8.7, 2.4 Hz, 1H ), 7.39 (d,J = 8.9 Hz, 2H), 7.11 (d,J = 8.9 Hz), 7.04 (dd,J = 8.7, 0.7 Hz, 1H ), 3.97 (s, 3H). Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)methyl acrylate
[0451] [0451] 24.7 mg of sodium hydride was weighed into a 20 ml rotary evaporator flask, decanted with hexane and suspended in 1 ml of DMSO. After the mixture was added with 0.270 mg of methyltriphenylphosphine iodide and stirred at room temperature for 30 minutes, 0.148 g of methyl 2-(6-(4-chlorophenoxy)pyridin-3-yl)-2-oxoacetate was dissolved, synthesized in the previous paragraph, in 1.5 ml of DMSO, was dropped for 2 minutes, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was added with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and dried over anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5/1), thereby obtaining 55.1 mg of the title compound as a colorless liquid. . The yield was 37.6%. 1
[0452] [0452] NMR (400 MHz, CDCl 3 ) δ: 8.20 (d,J = 2.5 Hz, 1H), 7.79 (dd,J = 8.6, 2.5 Hz, 1H), 7, 36 (d,J = 8.7 Hz, 2H), 7.09 (d,J = 8.7 Hz, 2H), 6.92 (d,J = 8.6 Hz, 1H), 6.43 ( d,J = 0.6 Hz, 1H), 5.92 (d,J = 0.6 Hz, 1H), 3.83 (s, 3H). Synthesis of 2-(6-(4-chlorophenoxy)pyridin-3-yl)oxirane-2-methyl carboxylate
[0453] [0453] 55.1 mg of 2-(6-(4-chlorophenoxy)pyridin-3-yl)methyl acrylate, synthesized in the previous paragraph, was dissolved in 0.5 ml of acetonitrile and 0.5 ml of methanol , and the mixture was added with 56.7 mg of urea-hydrogen peroxide (UHP) adduct and 25.9 mg of potassium carbonate under ice bath cooling, and stirred at room temperature for 3 hours. After completion of the reaction, the mixture was added with an aqueous ammonium chloride solution and then extracted with ethyl acetate. After the organic layer was washed with water and a saturated saline solution, the organic layer was dried with anhydrous sodium sulfate, and the solvent was distilled off. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 3/1), thus obtaining 28.7 mg of the title compound as a colorless liquid. . The yield was 49.4%. 1
[0454] [0454] NMR (400 MHz, CDCl 3 ) δ: 8.31 (d,J = 2.5, 0.7 Hz, 1H), 7.85 (dd,J = 8.6, 2.5 Hz, 1H ), 7.36 (d,J = 8.9 Hz, 2H), 7.09 (d,J = 8.9 Hz, 2H), 6.93 (dd,J = 8.6, 0.7 Hz , 1H), 3.80 (s, 3H), 3.46 (d,J = 6.3 Hz, 1H), 2.97 (d,J = 6.3 Hz, 1H). Synthesis of 2-(6-(4-Chlorophenoxy)pyridin-3-yl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)methyl propionate (compound IIIf-2)
[0455] [0455] 28.7 mg of 2-(6-(4-chlorophenoxy)pyridin-3-yl)oxirane-2-carboxylate, synthesized in the previous paragraph, was dissolved in 0.5 ml of DMF, and the mixture was added with 7.4 mg of triazole and 9.6 mg of triazole sodium, and stirred at 50°C for 40 minutes. After completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and then dried over anhydrous sodium sulfate. A solvent is distilled off and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 1/5), thereby obtaining 23.7 mg of the title compound as a white solid. . The yield was 67.4%. 1
[0456] [0456] NMR (400 MHz, CDCl 3 ) δ: 8.47 (d,J = 2.5, 0.6 Hz, 1H), 8.18 (s, 1H), 8.01 (dd,J = 8 .7, 2.5 Hz, 1H), 7.91 (s, 1H), 7.37 (d,J = 8.9 Hz, 2H), 7.08 (d,J = 8.9 Hz, 2H ), 6.96 (dd,J = 8.7, 0.6 Hz, 1H), 4.99 (d,J = 14.0 Hz, 1H), 4.45 (s,1H), 4.40 (d,J = 14.0 Hz, 1H), 3.84 (s, 3H).
[0457] [0457] After 2-(2-chloro-4-(4-chlorophenoxy)phenyl)2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate, synthesized in Synthesis Example 11 , be dissolved in 1 ml of DMF, the mixture was added with cesium carbonate and iodomethane, and stirred. After 3 hours, the mixture was added with saturated aqueous ammonium chloride solution, and extracted with chloroform. The extract was washed with water and then washed with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain the crude azole product as a brown liquid. Upon purification by column chromatography (silica gel, hexane/ethyl acetate = 9/1→0/1), the title compound was obtained. 1
[0458] [0458] NMR (400 MHz, CDCl 3 ) δ: 7.71 (s, 1H), 7.67 (s, 1H), 7.33 (d,J = 9.2 Hz, 2H), 7.10 ( d,J = 8.8 Hz, 1H), 6.99-6.94 (m, 3H), 6.71 (dd,J = 8.8, 2.8 Hz, 1H), 5.03 (d ,J = 15.2 Hz, 1H), 4.99 (d,J = 14.8 Hz, 1H), 3.85 (s, 3H), 3.53 (s, 3H). <Synthesis Example 46. Synthesis of Compound I-440> Synthesis of N-Benzyl-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-2-hydroxy-3-(1H-1,2,4 - triazol-1-yl)propanamide (I-440)
[0459] [0459] After dissolving 91 mg of Compound (I-1) synthesized in Synthesis Example 5 in 1 ml of DMF, the mixture was added with 30 mg of benzylamine, 77 mg of 4-(4 ,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium (DMT-MM) and left at room temperature for 12 hours and then stirred for 12 hours and again left for 12 hours. After the solvent was distilled off, the mixture was added with water and extracted with chloroform, dried over anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent was purified by column chromatography (silica gel, chloroform :methanol = 39:1) to obtain 12.2 mg of the title compound as a colorless solid. The yield was 12%.
[0460] [0460] NMR (400 MHz, CDCl 3 ) δ: 8.24 (s, 1H), 7.95 (t,J = 6 Hz, 1H), 7.73 (s, 1H), 7.48 (d, J = 2.2 Hz, 2H), 7.44 (d,J = 8.8 Hz, 1H), 7.28 (t,J = 7.0 Hz, 2H), 7.22 (d,J = 7.4 Hz, 2H), 7.21 (t,J = 9.3 Hz, 1H), 7.08 (d,J = 2.5 Hz, 1H), 7.04 (d,J = 8, 9 Hz, 2H), 6.86 (dd,J = 8.8, 2.5 Hz, 1H), 6.80 (s, 1H), 5 (d,J = 14.3 Hz, 1H), 4 .91 (d,J = 14.4 Hz, 1H), 4.28 (dd,J = 14.9, 6.3 Hz, 1H), 4.20 (dd,J = 15, 5.9 Hz, 1H). <Synthesis Example 47. Synthesis of Compound I-64> Synthesis of 2-acetoxy-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-3-(1H-1,2,4-triazol-1 - yl) methyl propanoate (I-1)
[0461] [0461] 83.0 mg of Compound (I-1), synthesized in Synthesis Example 5, and 0.2 ml of pyridine were added to and dissolved in a 10 ml rotary evaporator flask, and 28 µl of acetyl chloride was added. added and stirred. After 6 hours, the mixture was added with 2.8 mg of N,N-dimethylaminopyridine and stirred continuously. After 5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract was washed once with water and was washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 107 mg of crude product as a brown liquid. Upon purification by column chromatography (silica gel, chloroform:ethyl acetate = 72:28→21:79), 7.7 mg of the title compound was obtained as a white solid. The yield was 5.6%. 1
[0462] [0462] NMR (400 MHz, CDCl 3 ) δ: 7.81 (s, 1H), 7.54 (s, 1H), 7.34 (d,J = 8.9 Hz, 2H), 7.28 ( d,J = 9.0 Hz, 1H), 7.00-6.94 (m, 3H), 6.77 (dd,J = 9.0, 2.6 Hz, 1H), 5.38 (d ,J = 15.1 Hz, 1H), 5.28 (d,J = 15.1 Hz, 1H), 3.84 (s, 3H), 2.24 (s, 3H).
[0463] [0463] After 82.2 mg of Compound (I-1), synthesized in Synthesis Example 5, and 0.2 ml of N,N-dimethylformamide were added to and dissolved in a 10 ml rotary evaporator flask, the mixture was added with 26 µl of phenyl isocyanate and stirred at room temperature. After 7.5 hours, the mixture was added with a saturated aqueous solution of ammonium chloride to stop the reaction, and extracted three times with toluene. The extract was washed once with water and was washed once with saturated saline. After the extract was dried over anhydrous sodium sulfate, a solvent was distilled off to obtain 114 mg of crude product as a white solid. Upon purification by column chromatography (chloroform:ethyl acetate = 100:0→70:30), 16.1 mg of the title compound was obtained as a white solid. The yield was 15%. 1
[0464] [0464] NMR (400 MHz, CDCl 3 ) δ: 7.79 (s, 1H), 7.77 (s, 1H), 7.44-7.31 (m, 7H), 7.16-7.10 (m, 2H), 7.00-6.94 (m, 3H), 6.78 (br, 1H), 5.50 (d,J = 15.1 Hz, 1H), 5.42 (d, J = 15.1 Hz, 1H), 3.87 (s, 3H). <Synthesis Example 49. Synthesis of Compound I-442> Synthesis of 2-((tert-butoxycarbonyl)oxy)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-3-(1H-1, Methyl 2,4-triazol-1-yl)propanoate (compound I-442)
[0465] [0465] 81.6 mg of Compound (I-1), synthesized in Synthesis Example 5, was dissolved in 0.2 ml of N,N-dimethylformamide, and the mixture was added with 11.0 mg of sodium hydride. sodium, 92 µl of di-tert-butyl dicarbonate and 5.6 mg of dimethylaminopyridine and stirred at room temperature for 0.5 hour. Upon completion of the reaction, the mixture was added with a saturated aqueous solution of ammonium chloride, extracted with toluene and washed with water and a saturated saline solution. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain 105 mg of the title compound under form of a colorless viscous liquid. The yield was 100%. 1
[0466] [0466] NMR (400 MHz, CDCl 3 ) δ: 7.77 (s, 1H), 7.69 (s, 1H), 7.35 (d,J = 9.0 Hz, 1H), 7.33 ( d,J = 8.9 Hz, 2H), 6.98-6.94 (m, 1H), 6.96 (d,J = 8.9 Hz, 2H), 6.77 (dd,J = 9 .0, 2.6 Hz, 1H), 5.39 (d,J = 15.1 Hz, 1H), 5.34 (d,J = 15.1 Hz, 1H), 3.84 (s, 3H ), 1.54 (s, 9H). <Synthesis Example 50. Synthesis of Compound I-54> Synthesis of 2-((tert-butoxycarbonyl)oxy)-2-(2-chloro-4-(4-chlorophenoxy)phenyl)-3-(1H-1, Methyl 2,4-triazol-1-yl)propanoate (compound I-54)
[0467] [0467] 75.0 mg of Compound (I-1), synthesized in Synthesis Example 5, were weighed into a pressure resistant reaction tube and 4 mL of 2 mol/L methylamine was added, and the mixture was was reacted at 80°C for 21 hours and at room temperature for 8 days. Upon completion of the reaction, the solvent and excess amine were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/ethanol = 15/1) to obtain 9.0 mg of the title compound as a colorless viscous liquid. The yield was 12%. 1
[0468] [0468] NMR (400 MHz, CDCl 3 ) δ: 8.10 (s, 1H), 7.93 (s, 1H), 7.49 (d,J = 8.8 Hz, 1H), 7.34 ( d,J = 8.9 Hz, 2H), 7.00 (d,J = 2.6 Hz, 1H), 6.96 (d,J = 8.9 Hz, 2H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 6.56 (brq,J = 5.0 Hz, 1H), 5.38 (s, 1H), 5.12 (d,J = 14.1 Hz, 1H), 5.04 (d,J = 14.1 Hz, 1H), 2.78 (d,J = 5.0 Hz, 3H). <Preparation example>
[0469] [0469] Hydrates and emulsions were formulated as set out below, using any synthesized azole derivative described herein. Preparation example 1 (wettable agent) 21.4 parts of azole derivative
[0470] [0470] By means of the petri dish test, the antimicrobial properties of the compounds according to the present invention were tested against various plant pathogenic microorganisms. A control compound A and a control compound B, synthesized in the production example above, were used as a control compound. Control compound A is a compound described in Patent Literature 1, and is represented by the chemical formula (A), given below. In addition, control compound B is a compound described in Patent Literature 2, and is represented by the chemical formula (B), given below.
[0471] [0471] After autoclaving, the compounds of the present invention were dissolved in dimethyl sulfoxide so as to have a predetermined concentration of agent in a PDA medium (potato-dextrose-agar medium) that was cooled to about 60°C. °C, and 1% (V/V) was added to the PDA medium. The compounds were mixed well so that the agent concentration was uniform in the PDA medium, and the medium was poured into the petri dish to prepare a plating medium containing the compounds according to the present invention.
[0472] [0472] On the other hand, the efflorescence of various plant pathogenic microorganisms previously cultivated in the PDA medium was pierced with a cork-punch having a diameter of 4 mm and inoculated into the aforementioned agent-containing plating medium. After culturing for a predetermined period of time and at a temperature according to Table 2, the diameter of the efflorescence on the agent treated plate was measured. Compared to the diameter of efflorescence on an untreated flat plate that does not contain any agent, a rate (%) of inhibition of mycelium elongation was calculated using the Equation presented below.
[0473] [0473] (In the above Equation, R = rate (%) of inhibition of mycelium elongation, dc = diameter of efflorescence in untreated plate, dt = diameter of efflorescence in agent treated plate)
[0474] [0474] The results obtained were evaluated in 5 stages, according to the criteria shown in Table 9. The higher the antimicrobial index, the better the antimicrobial property.
[0475] [0475] An antimicrobial test was performed using Fusarium graminearum by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-20, I-21, I-23, I-25, I-24, I - 47, I-48, I-7, I-29, I-236, I-130, I-234, I-128, I-40, I-133 and IIId-1 had an antimicrobial index of 5. In In contrast, control compound B had an antimicrobial index of 3. Furthermore, at 1.25 mg/L, control compound A had an antimicrobial index of 4, while compounds I-1, I-25, I- 122 and I-130 had an antimicrobial index of 5. Test Example B: Pyrenophora teres
[0476] [0476] An antimicrobial test was performed using Pyrenophora teres by the method described above. At the 5 mg/L test substance, control compound A had an antimicrobial index of 2, while compounds I-1, I-228, I-3, I-27, I-29, I-236 and I- 130 had an antimicrobial index of 5. At this time, control compound B had an antimicrobial index of 2. Test example C: Pyricularia oryzae
[0477] [0477] An antimicrobial test was performed using Pyricularia oryzae by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-20, I-21, I-23, I-25, I-26, I -52, I-27, I-28, I-47, I-48, I-7, I-29, I-31, I-236, I-130, II-1 and IIIc-1 had an antimicrobial index of 5. At this time, control compound B had an antimicrobial index of 2. In addition, at 0.63 mg/L, control compound A had an antimicrobial index of 3, while compounds I-1, I- 122 and I-228 had an antimicrobial index of 5. Test example D: Gaeumannomyces graminis
[0478] [0478] An antimicrobial test was performed using Gaeumannomyces graminis by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-2, I-5, I-18, I-19, I-20, I -21, I-23, I-24, I-25, I-26, I-52, I-27, I-28, I-47, I-48, I-7, I-29, I-35 , I-33, I-31, I-236, I-130, II-1, IIIb-9 and IIIc-1 had an antimicrobial index of 5. In addition, at 0.08 mg/L, the control compound A had an antimicrobial index of 3 and control compound B had an antimicrobial index of 1, while compounds I-1, I-23, I-25, I-1222, I-128, I-27, I-29 , I-236 and I-130 had an antimicrobial index of 5.
[0479] [0479] An antimicrobial test was performed using Ustilago nuda by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-19, I-20, I-21, I-25, I-27, I -7, I-29, I-236 and I-130 had an antimicrobial index of 5. At this time, control compound B had an antimicrobial index of 1. In addition, at 1.25 mg/L, control compound B had an antimicrobial index of 1. control A had an antimicrobial index of 3, while compounds I-1, I-122, I-228, I-334, I-236 and I-130 had an antimicrobial index of 5. Test example F: Rhizoctonia solani
[0480] [0480] An antimicrobial test was performed using Rhizoctonia solani by the method described above. In the 5 mg/L test substance, any one of compounds I-5, I-6, I-22, I-334, I-27, I-236 and I-130 had an antimicrobial index of
[0481] [0481] An antimicrobial test was performed using Sclerotinia sclerotiorum by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-18, I-20, I-21, I-23, I-25, I -26, I-27, I-47, I-48, I-7, I-29, I-33, I-31, I-236, I-130 and IIIc-1 had an antimicrobial index of 5. At that time, control compound B had an antimicrobial index of 2.
[0482] [0482] An antimicrobial test was performed using Microdochium nivale by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-21, I-25, I-52, I-27, I-47, I-48, I -29, I-236 and I-130 had an antimicrobial index of 5. At this time, control compound B had an antimicrobial index of 1.
[0483] [0483] An antimicrobial test was performed using Gibberella fujikuroi by the method described above.
[0484] [0484] In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-19, I-20, I-21, I-23, I- 25, I-26, I-27, I-47, I-48, I-7, I-29, I-31, I-236, I-130 and IIIc-1 had an antimicrobial index of 5. At this time , control compound B had an antimicrobial index of 2.
[0485] [0485] An antimicrobial test was performed using Zymoseptoria tritici by the method described above. In the 5 mg/L test substance, any of compounds I-1, I-122, I-228, I-334, I-20, I-21, I-52, I-47, I-7, I -29, I-236, I-130 and IIIc-1 had an antimicrobial index of 5. At this time, Control Compound A had an antimicrobial index of 4 and Control Compound B had an antimicrobial index of 1.
[0486] [0486] The compounds of the present invention were dissolved in acetone so as to have a predetermined agent concentration, and 5% (v/v) was added to ion exchange water containing Gramin S (60 ppm final concentration of Gramin S) . The prepared liquid medicine was sprayed onto a second-leaf stage wheat (variety: agriculture no. 61) grown in a rectangular plastic pot (6 cm × 6 cm) at a rate of 1000 L/ha (agent treated area). In addition, the untreated area was prepared, in which ion-exchanged water (final concentration of 60 ppm Gramin S) containing 5% acetone, which did not contain the compound, was sprinkled over the wheat. After spraying, the spray solution on a wheat leaf was air-dried, and a spore fluid (set to 200 spores/field of view, 60 ppm Gramin S) of Puccinia recondite-causing microorganisms was inoculated with spray and maintained for 48 hours under high humidity conditions at 25 °C. After that, the wheat leaf was kept in a greenhouse. 14 days after inoculation, Puccinia recondite morbidity was examined, and a control value was calculated using the following equation.
[0487] [0487] In addition, morbidity was determined based on Table 11 below.
[0488] [0488] In the above tests, for example, at a concentration of 100 g/ha, any one of compounds I-1, I-122, I-228, I-334, I-2, I-5, I-20 , I-22, I-23, I-25, I-26, I-19, I-52, I-27, I-28, I-47, I-48, I-29, I-31, II -1 and IIIb-9 had a control value of 70% or more.
[0489] [0489] In addition, at 3.13 g/ha, the control value of compound I-1 was 73% and the control value of I-20 was 80%, while that of control compound A was 20%.
[0490] [0490] The compounds of the present invention were adjusted to a predetermined concentration (100 g/l), according to Test Example 2, in a cotyledon of cucumber (variety: cucumber Sagami Hanjiro) cultivated using a plastic pot rectangular (6 cm × 6 cm), and sprinkled at a rate of
[0491] [0491] In addition, morbidity was determined based on Table 12 below.
[0492] [0492] In the above tests, for example, at a concentration of 100 g/ha, control compound B had a control value of 0%, while any of compounds I-1, I-122, I-228, I-334, I-20 and I-25 had a control value of 90% or more.
[0493] [0493] The influence on wheat growth by seed treatment and the controlling effect on Puccinia recondite were evaluated. After a compound dissolved in DMSO was rubbed onto wheat seed (variety: agriculture #61) in a plastic tube, so that the yield was 200 g ai/100 kg of seed, 20 g ai/100 kg of seed, or 2 g ai/100 kg of seeds, the 8-grain wheat seeds were sown in an 80 cm2 pot. Lower irrigation was managed in the greenhouse, a wheat plant height was examined 16 days after sowing, a growth rate (%) against wheat was examined by the Equation presented below, and the growth degree was calculated by Equation presented below.
[0494] [0494] The results of the degree of growth are shown in Table 13, below.
[0495] [0495] Spore fluid of the microorganisms causing Puccinia recondite (adjusted to 200 spores/field of view, Gramin S of 60 ppm) was inoculated by spray and kept for 48 hours under high humidity conditions at 25°C. After that, he was kept in a greenhouse. 11 days after inoculation, Puccinia recondite morbidity was examined and the control value was calculated using the Equation below. Morbidity was examined on the same scale as Test Example 2.
[0496] [0496] Control value results are shown in Table 14 below.
[0497] [0497] As described above, Compound I-1 was superior in disease control effect compared to Control Compound A by seed treatment. It was also found that the influence of growth on wheat was weak, and that phytotoxicity was weak.
[0498] [0498] The control effect test on Septoria tritici was tested in the UK test field using the emulsion (prepared according to Preparation Example 2) containing Compound (I-1) and Control compound A as the active ingredients. The amount of agent contained in each emulsion was adjusted to the amount shown in Table 15, and sprayed twice with growth stages BBCH 31-32 and 37-39 (200 L/ha). The severity of the flag leaf and the second leaf was evaluated 50 days after the second spraying. The control value was calculated from the average gravity of the flag leaf and the second leaf.
[0499] [0499] The above results are shown in Table 15 below.
[0500] [0500] As described above, it was revealed that the emulsion containing compound I-1 as the active ingredient had a higher control value for Septoria tritici than the emulsion containing control compound A as the active ingredient.
[0501] [0501] The azole derivative according to the present invention may suitably be used as an active ingredient of an agricultural or horticultural germicide, a plant growth regulator and a protective agent for industrial materials.

权利要求:
Claims (14)
[1]
[1] A compound, characterized in that it is represented by the following general formula (I), or an N-oxide or agrochemically acceptable salt thereof: [Chemical formula 1] in the general formula (I), A is N or CH; D is a hydrogen, a halogen group or SRD; where RD is hydrogen, a cyano group, a C1-C6-alkyl group, a C1-C6-haloalkyl group, a C2-C6-alkenyl group, a C2-C6-haloalkenyl group, a C2-C6-alkynyl group, or a C2-C6-haloalkynyl group; R1 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group , a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, a phenyl-C2-C4-alkynyl group, or COXR5; wherein R5 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4 group -alkyl, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, or a phenyl-C2-C4-alkynyl group; X is a single bond, -O-, or -NR6-; R6 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group , a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, or a phenyl-C2-C4-alkynyl group; and R5 and R6 may form a ring; R2 is -OR7 or -NR8R9; wherein each of R7, R8 and R9 is independently a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C3-C8-cycloalkyl-C1-C4-alkyl group, a phenyl group, a phenyl-C1-C4-alkyl group, a phenyl-C2-C4-alkenyl group, or a phenyl-C2-C4-alkynyl group, and R8 and R9 may form a ring, wherein the aliphatic groups in R1, R2, R5, R6, R7, R8 and R9 may have 1, 2, 3 or the maximum possible number of one or more of the same or different Ra groups, and Ra is independently selected from a halogen group, a cyano group, a nitro group, a C1-C4-alkoxy group, and a C1-C4-haloalkoxy group; R4 is a halogen group, a cyano group, a nitro group, an amino group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamine group, a C1-C4-dialkylamine group, a C1-C4-alkylacylamine group, -SOR10 or -SF5; the cycloalkyl group or phenyl group moieties in R1, R2, R5, R6, R7, R8 and R9, or the phenyl group moiety in R4, may have 1, 2, 3, 4, 5, or the maximum possible number of the same or different Rb groups, and Rb is independently selected from a halogen group, a cyano group, a nitro group, a C1-C4-alkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkyl group and a C1-C4-haloalkoxy group; R3 is a halogen group, a cyano group, a nitro group, a phenyl group, a phenyloxy group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1- C4-haloalkoxy, -SOR10 or -SF5;
wherein R10 is a C1-C4-alkyl group or a C1-C4-haloalkyl group; E is a phenyl group or a 6-membered heteroaromatic ring containing 1 or 2 N atoms; n R3 are linked to any substitution sites; when E is a phenyl group, then n is 0, 1, 2, 3 or 4, and when E is a 6-membered heteroaromatic ring containing 1 or 2 N atoms, then n is 0, 1 or 2; Y is an oxygen atom, -CH2O-, -OCH2-, -NH-, -N(-C1-C4-alkyl)-, -N(-C3-C6-cycloalkyl)-, or -S(O)p -, which binds to any E sites; wherein p is 0, 1 or 2; Z is an aromatic hydrocarbon group which is a phenyl group or a naphthyl group, or a 5-membered or 6-membered heteroaromatic ring, or a 9-membered or 10-membered heteroaromatic ring formed by 2 rings, containing from 1 to 4 heteroatoms selected from O, N and S; and m R4 are linked to any substitution sites; when Z is an aromatic hydrocarbon group, then m is 1, 2, 3, 4 or 5 and when Z is a heteroaromatic ring, then m is 0, 1, 2, 3 or 4.
[2]
[2] Compound or the salt thereof, according to claim 1, characterized in that in the general formula (I), R1 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, a C2 group -C6-alkynyl, or COXR5; R2 is -OR7; R5 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, or a C2-C6-alkynyl group; R6 is a hydrogen, a C1-C6-alkyl group, a C2-C6-alkenyl group, or a C2-C6-alkynyl group; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR10, or -SF5; and
R4 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group, a C1-C4-alkylamine group, a C1-C4-dialkylamine group, a C1-C4-alkylacylamine group, -SOR10, or -SF5.
[3]
[3] A compound or salt thereof, according to claim 1 or 2, characterized in that in the general Formula (I), R1 is a hydrogen, a C1-C6-alkyl group, or COXR5; R5 is a hydrogen, or a C1-C6-alkyl group; R6 is a hydrogen; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, -SOR10, or -SF5; and R4 is a halogen group, a nitro group, a cyano group, an amino group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, a C1-C4-haloalkoxy group , a C1-C4-alkylamine group, a C1-C4-dialkylamine group, a C1-C4-alkylacylamine group, -SOR10, or -SF5.
[4]
[4] A compound or salt thereof, according to any one of claims 1 to 3, characterized in that, in the general Formula (I), R1 is a hydrogen, or a C1-C6-alkyl group; R7 is a C1-C6-alkyl group; R3 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, or a C1-C4-alkoxy group; and R4 is a halogen group, a cyano group, a C1-C4-alkyl group, a C1-C4-haloalkyl group, a C1-C4-alkoxy group, or a C1-C4-haloalkoxy group.
[5]
[5] A compound or salt thereof, according to any one of claims 1 to 4, characterized in that, in the general formula (I), E is a phenyl group.
[6]
[6] Compound or salt thereof, according to any one of claims 1 to 5, characterized in that, in the general formula (I), Z is a phenyl group, a naphthyl group, or a 5-membered or 6-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N and S.
[7]
[7] The compound or salt thereof, according to any one of claims 1 to 6, characterized in that, in the general formula (I), Z is a phenyl group.
[8]
[8] A compound or salt thereof, according to any one of claims 1 to 7, characterized in that, in the general formula (I), Y is an oxygen atom.
[9]
[9] A compound or salt thereof, according to any one of claims 1 to 8, characterized in that, in the general formula (I), A is N, and D is a hydrogen.
[10]
[10] Compound or the salt thereof, according to any one of claims 1 to 9, characterized in that it is represented by the following general formula (II): [Chemical formula 2] [11]
[11] Method for producing a compound as defined in any one of claims 1 to 10, represented by the general formula (I) described above, characterized in that it comprises a step of converting a compound represented by the following general formula (V) into a compound represented by the following general formula (VI) by using a dialkyl sulfate represented by the following general formula (VII) or R7-LG, in which LG is a nucleophilically substitutable leaving group, iodine and a carbonate in dimethyl sulfoxide.
[Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [12]
[12] Production method according to claim 11, characterized in that LG in R7-LG is a halogen group.
[13]
[13] Method of producing the compound represented by the general formula (VI) described above, as defined in claim 11, characterized in that it comprises a step of converting the compound represented by the general formula (V) into the compound represented by the general formula (VI) using R7-LG, in which LG is a nucleophilically substitutable leaving group, iodine, and a carbonate in dimethyl sulfoxide.
[14]
[14] Agricultural or horticultural chemical agent, or a protective agent for industrial material, characterized in that it comprises as an active ingredient, a compound as defined in any one of claims 1 to 10, represented by the general formula (I) described above.

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法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2022-02-22| B11A| Dismissal acc. art.33 of ipl - examination not requested within 36 months of filing|

优先权:

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申请号 | 申请日 | 专利标题

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JP2017218655|2017-11-13|

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JPJP2017-218655|2017-11-13|

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PCT/JP2018/041971|WO2019093522A1|2017-11-13|2018-11-13|Azole derivative, intermediate compound, method for producing azole derivative, agent for agricultural and horticultural use, and material protection agent for industrial use|

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