6-Aryl-4-aminopicolinates and their use as herbicides

专利摘要:
4-aminopicolinic acid and its amines and acid derivatives comprising aryl or heteroaryl substituents at the 6 position are potent herbicides which broadly inhibit weeds.
公开号:KR20040018532A
申请号:KR10-2004-7001336
申请日:2002-07-30
公开日:2004-03-03
发明作者:발코테리윌리암；바이쎄앤마리；엡제프리브라이언；필즈스티븐크레이그；로어크리스쳔토마스；키스레니죤；리치벅3세죤샌더스；루이즈제임스멜빈；와이머몬티레이；그린레너드안토니오；개스트로져유진；브라이언크리스티；어빈니콜라스마틴；로윌리암치-렁；브루스터윌리암커클랜드；웹스터제프리데일
申请人:다우 아그로사이언시즈 엘엘씨；
IPC主号:

专利说明:

6-aryl-4-aminopicolinate and its use as herbicides {6-Aryl-4-aminopicolinates and their use as herbicides}
[1] Background of the Invention
[2] The present invention relates to certain novel 6-aryl-4-aminopicolinates and their derivatives, and to the use of these compounds as herbicides.
[3] Many picolinic acids and their pesticidal properties have been described in the art. For example, US Pat. No. 3,285,925 describes 4-amino-3,5,6-trichloropicolinic acid derivatives and their use as plant growth inhibitors and herbicides. U.S. Patent 3,325,272 describes 4-amino-3,5-dichloropicolinic acid derivatives and their use to inhibit plant growth. U.S. Patent No. 3,317,549 describes 3,6-dichloropicolinic acid derivatives and their use as plant growth inhibitors. US 3,334,108 describes chlorinated dithiopicolinic acid derivatives and their use as antiparasitic agents. U.S. Patent 3,234,229 describes 4-amino-polychloro-2-trichloromethylpyridine and its use as herbicides. US Pat. No. 3,755,338 describes 4-amino-3,5-dichloro-6-bromopicolinate as a fungicide. Belgian patent 788 756 describes 6-alkyl-4-amino-3,5-dihalopicolinic acid as a herbicide. See Applied and Environmental Microbiology , Vol. 59, No. 7, July 1993, pp. 2251-2256, 4-amino-3,6-dichloropicolinic acid has been identified as an anaerobic degradation product of 4-amino-3,5,6-trichloropicolinic acid and is commercially available as a picolam herbicide. US Pat. No. 6,297,197 B1 describes certain 4-aminopicolinates and their use as herbicides. U. S. Patent 5,783, 522 describes certain 6-phenyl picolinic acids and their use in herbicides, desiccants and defoliants. International Publication No. 9821199 describes 6-pyrazolylpyridine and its use as herbicides. U.S. Patent 5,958,837 describes the synthesis of 6-arylpicolinic acid and its use as herbicides, desiccants and defoliants. U. S. Patent No. 6,077, 650 describes the use of 6-phenylpicolinic acid as a photographic bleach, and EP 0 972 765 Al describes the synthesis of 2-, 3- or 4-arylpyridine. .
[4] Summary of the Invention
[5] It has now been found that certain 6-aryl- or heteroaryl-4-amino-picolinic acids and derivatives thereof are potent herbicides with extensive inhibition of weeds against a wide range of trees, grasses, grasses and hardwoods, and excellent crop selectivity. Turned out. In addition, the compounds of the present invention are excellent in toxicological or environmental properties.
[6] The present invention includes compounds of formula I and derivatives of agriculturally acceptable carboxylic acid groups:
[7]
[8] In Formula I above,
[9] X is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, thio Cyanide or cyano;
[10] Y represents aryl or heteroaryl;
[11] Z is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, thiocyanide Or cyano;
[12] W is -NO ₂ , -N ₃ , -NR ₁ R ₂ , wherein R ₁ and R ₂ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl , Aryl, heteroaryl, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ acyl, C ₁ -C ₆ carboalkoxy, C ₁ -C ₆ alkylcarbamyl, C ₁ -C ₆ alkylsulfonyl , C ₁ -C ₆ trialkylsilyl or C ₁ -C ₆ dialkyl phosphonyl, or R ₁ and R ₂ together with N may be saturated or unsaturated, which may further contain O, S or N heteroatoms. 5 or forms a 6-membered ring), -N = CR ₃ R ₄ or -NHN = CR ₃ R ₄ (wherein, R ₃ and R ₄ are independently H, C _l- C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, aryl or heteroaryl, or R ₃ and R ₄ together with = C form a saturated five or six membered ring.
[13] X represents H or F, Y represents phenyl substituted in the para position in the presence or absence of other substituents, Z represents Cl, W represents NR ₁ R ₂ , wherein R ₁ and R ₂ represent H or C _1, the compound of formula (I) represents a -C ₆ represents an alkyl) are preferred independently. Also, Y Preference is given to compounds which represent a group of wherein A represents O or CH ₂ and at least one A is O. The aryl and heteroaryl groups represented by Y are preferably substituted with one or two groups independently selected from the group consisting of halogen, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl.
[14] The present invention includes herbicide compositions comprising an effective amount of an agriculturally acceptable derivative and a compound of formula (I) and an agriculturally acceptable derivative of a carboxylic acid in admixture with an agriculturally acceptable adjuvant or carrier. The present invention also encompasses the use of the compounds and compositions of the present invention for killing or inhibiting weeds by spraying herbicides comprising the compounds of the present invention into the weeds or their habitats, as well as the soil prior to the growth of the weeds.
[15] Detailed description of the invention
[16] The herbicide compounds of the present invention are derivatives of 4-aminopicolinic acid of formula (II).
[17]
[18] The compound of formula (II) is halogen at 3 position, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C _1- C ₆ haloalkoxy, thiocyanide or cyano substituents, halogen is preferred, and chlorine is particularly preferred; Hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, Thiocyanide or cyano substituents, with hydrogen or fluorine being preferred; Aryl and heteroaryl substituents at the 6 position, with halogen, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl substituted phenyl, pyridinyl, benzofuranyl, benzothienyl, thienyl or thiazoyl It is characterized by.
[19] The amino group at position 4 is unsubstituted or substituted with one or more C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, aryl, heteroaryl, hydroxy, C ₁ -C ₆ alkoxy Or an amino substituent. The amino group may be further derived as amide, carbamate, urea, sulfonamide, silylamine, phosphoramidate, imine or hydrazone. Such derivatives can be broken down into amines. Preference is given to unsubstituted amino groups or amino groups substituted one by one or two alkyl substituents.
[20] Carboxylic acids of formula (I) are generally believed to be the preferred compounds by actually killing or inhibiting weeds. Such compound homologues in which the acid groups of picolinic acid are derived to form an environment for related substituents or acidic groups that can be changed in plants have essentially the same herbicide effect and are included within the scope of the present invention. Thus, when used to describe carboxylic acid functionalities at the 2-position, “agronomically acceptable derivatives” are any salts, esters, acylhydrazides, imidates, thiimidates, amimides well known in the art. Dine, amide, orthoester, acylcyanide, acyl halide, thioester, thionoester, dithioester, nitrile or any other acid derivative, defined as (a) the active ingredient, ie 6-aryl or heteroaryl- The herbicide activity of 4-aminopicolinic acid is substantially not carried out, or (b) can be hydrated, oxidized or metabolized to picolinic acid of formula (I) in a form that is not separated or separated by pH in plants or soil. Preferred agriculturally acceptable derivatives of carboxylic acids include agriculturally acceptable salts, esters and amides. In addition, when used to describe amine functionality at the 4 position, “agriculturally acceptable derivatives” are any salts, silylamines, phosphorylamines, phosphinimimines, phosphoramidates that are well known in the art. , Sulfonamide, sulfilimine, sulfoximine, amineal, hemiamineal, amide, thioamide, carbamate, thiocarbamate, amidine, urea, imine, nitro, nitroso, azide or any other nitrogen Defined as a derivative, wherein (a) substantially does not carry out the herbicide activity of the active ingredient, ie 6-aryl or heteroaryl-4-aminopicolinic acid, or (b) is hydrated with the free amine of formula (II) in plants or soil Can be. Also included in the scope of the invention are N-oxides, which may be separated by the mopyridine of formula II.
[21] Suitable salts include salts derived from alkali or alkaline earth metals, and salts derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and ammonium cations of the formula R ₅ R ₆ R ₇ NH ⁺ , wherein R ₅ , R ₆ and R ₇ are each independently hydrogen or at least one hydroxy, each C ₁ -C ₄ C ₁ -C ₁₂ alkyl, C ₃ -C ₁₂ alkenyl or C ₃ -C ₁₂ alkynyl optionally substituted with alkoxy, C ₁ -C ₄ alkylthio or a phenyl group, provided that R ₅ , R ₆ and R ₇ is steric compatible). In addition, any two of R ₅ , R ₆ and R ₇ may together represent an aliphatic difunctional moiety having 1 to 12 carbon atoms and no more than 2 oxygen atoms or sulfur water. Salts of compounds of formula (I) may be prepared by treating compounds of formula (I) with metal hydroxides (e.g. sodium hydroxide) or amines (e.g. ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethyl Amine, morpholine, cyclododecylamine or benzylamine). Amine salts are often preferred forms of the compounds of formula (I) because they are water soluble and suitable for preparing preferred aqueous herbicide compositions.
[22] Suitable esters are C ₁ -C _l2 alkyl, C ₃ -C _l2 alkenyl or C ₃ -C ₁₂ alkynyl alcohols such as methanol, iso-propanol, butanol, 2-ethylhexanol, butoxyethanol, methoxypropanol , Allyl alcohol, propargyl alcohol or cyclohexanol). The ester is coupled to the alcohol using picolinic acid using a number of suitable activators such as those used for peptide coupling (e.g. dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI)) , By reacting the acid chloride of the corresponding picolinic acid of formula I with a suitable alcohol, or by reacting the corresponding picolinic acid of formula I with a suitable alcohol in the presence of an acid catalyst. Suitable amides include ammonia, or C ₁ -C _l2 alkyl, C ₃ -C _l2 alkenyl or C ₃ -C ₁₂ alkynyl mono or disubstituted amines such as azidine, azetidine, pyrrolidine, pyrrole, imido Dimethylamine, diethanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, cyclo, including but not limited to additional heteroatoms, including but not limited to dazole, tetrazole or morpholine Amides derived from dodecylamine, benzylamine, or cyclic or aromatic amines). Amides can be prepared by reacting the corresponding picolinic acid chlorides, mixed anhydrides or carboxylic esters of formula I with ammonia or a suitable amine.
[23] As used herein, the terms "alkyl", "alkenyl" and "alkynyl", as well as derived terms such as "alkoxy", "acyl", "alkylthio" and alkylsulfonyl ", are straight, branched, and interlinked. Click residues are included within their scope, unless otherwise specified, each is unsubstituted, halogen, hydroxy, alkoxy, alkylthio, C ₁ -C ₆ acyl, formyl, cyano, aryloxy or aryl It may be substituted with one or more substituents selected therefrom, provided that the substituents are sterically compatible and meet the principles of chemical bonding and strain energy.The terms "alkenyl" and "alkynyl" It is considered that the above unsaturated bond is included.
[24] In addition to the term "aryl", derived terms such as "aryloxy" refer to phenyl, indanyl or naphthyl groups, with phenyl being preferred. In addition to the term "heteroaryl", derived terms such as "heteroaryloxy" refer to 5- or 6-membered aromatic rings containing one or more heteroatoms, ie N, O or S, which heteroaromatic rings represent other aromatics. Can be fused into the system. The following heteroaryl groups are preferred.
[25]
[26] Aryl or heteroaryl substituents are unsubstituted, halogen, hydroxy, nitro, cyano, aryloxy, formyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _l- C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, aryl, C ₁ -C ₆ OC (O) alkyl, C ₁ -C ₆ NHC (O) alkyl, C (O) OH, C ₁ -C ₆ C (O) O alkyl, C (O ) NH ₂ , C ₁ -C ₆ C (O) NHalkyl, C ₁ -C ₆ C (O) N (alkyl) ₂ , -OCH ₂ CH _2- , -OCH ₂ CH ₂ CH _2- , -OCH ₂ It may be substituted with one or more substituents selected from the group consisting of O- and -OCH ₂ CH ₂ 0-, provided that the substituents are stericly compatible and meet the principles of chemical bonding and strain energy. Preferred substituents include halogen, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl.
[27] Unless specifically limited otherwise, the term "halogen", including derived terms such as "halo", refers to fluorine, chlorine, bromine and iodine. The terms "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy groups substituted with from 1 to the maximum possible number of halogen atoms.
[28] Compounds of formula (I) can be prepared using well known chemical processes. Necessary starting materials are commercially available or are easily synthesized using standard processes.
[29] The aryl or heteroarylpyridine of the formula (I) substituted at the 6-position is substituted in many ways well known in the art, for example by suitably substituted pyridine with an easy leaving group in the presence of an inert solvent in the presence of a transition metal catalyst. It can be prepared by reacting with organometallic compound of type (IV) within.
[30]
[31] In this case, "L" may be chlorine, bromine, iodine or trifluoromethanesulfonate, where "metal" is Mg-halide, Zn-halide, tri- (C ₁ -C ₄ alkyl) tin, lithium, copper Or B (OR ⁸ ) (OR ⁹ ), where R ⁸ and R ⁹ are independently of each other hydrogen or C ₁ -C ₄ alkyl, or R ⁸ and R ⁹ together form an ethylene or propylene group; "Catalyst" includes transition metal catalysts, in particular palladium catalysts such as palladium diacetate, bis (triphenylphosphine) palladium (II) dichloride] or nickel catalysts such as nickel (II) acetylacetonate, bis (tri Phenylphosphine) nickel (II) chloride].
[32] Alternatively, compounds of formula (I) can be prepared by reacting pyridine (V) with six metals suitably substituted with an aryl or heteroaryl compound of type (IV) in an inert solvent in the presence of a transition metal catalyst.
[33]
[34] In this case, "L" may be chlorine, bromine, iodo or trifluoromethanesulfonate, and "metal" may be Mg-halide, Zn-halide, tri- (C ₁ -C ₄ alkyl) tin, lithium, Copper or B (OR ⁸ ) (OR ⁹ ), where R ⁸ and R ⁹ are independently of each other hydrogen or C ₁ -C ₄ alkyl, or R ⁸ and R ⁹ together form an ethylene or propylene group "Catalysts" are transition metal catalysts, in particular palladium catalysts such as palladium diacetate, bis (triphenylphosphine) palladium (II) dichloride] or nickel catalysts such as nickel (II) acetylacetonate, bis ( Triphenylphosphine) nickel (II) chloride].
[35] The reaction with boronic acid or esters is well known as illustrated by the following references:
[36] (1) W. J. Thompson and J. Gaudino, J. Org. Chem., 49, 5223 (1984);
[37] (2) S. Gronowitz and K. Lawitz, Chem. Scr., 24, 5 (1984);
[38] (3) S. Gronowitz et al., Chem. Scr., 26, 305 (1986);
[39] (4) J. Stavenuiter et al., Heterocycles, 26, 2711 (1987);
[40] (5) V. Snieckus et al., Tetrahedron Letters, 28, 5093 (1987);
[41] (6) V. Snieckus et al., Tetrahedron Letters, 29, 2135 (1988);
[42] (7) M. B. Mitchell et al., Tetrahedron Letters, 32, 2273 (1991); Tetrahedron, 48, 8117 (1992);
[43] (8) JP-A 93/301870.
[44] The reaction with Grignard compounds (metal = Mg-Hal) is well known as exemplified by the following reference:
[45] (9) L. N. Pridgen, J. Heterocyclic Chem., 12, 443 (1975);
[46] (10) M. Kumada et al., Tetrahedron Letters, 21, 845 (1980);
[47] (11) A. Minato et al., J. Chem. Soc. Chem. Commun., 5319 (1984).
[48] The reaction with the organozinc compound (metal = Zn-Hal) is well known as exemplified by the following reference:
[49] (12) A. S. Bell et al., Synthesis, 843 (1987);
[50] (13) A. S. Bell et al., Tetrahedron Letters, 29, 5013 (1988);
[51] (14) J. W. Tilley and S. Zawoiski, J. Org. Chem., 53, 386 (1988); Reference: Document (9).
[52] The reaction with the organotin compound [metal = Sn (C ₁ -C ₄ (alkyl) ₃ ]] is well known as exemplified by the following reference:
[53] (15) T. R. Bailey et al., Tetrahedron Letters, 27, 4407 (1986);
[54] (16) Y. Yamamoto et al., Synthesis, 564 (1986); Reference: Document (6).
[55] Suitably, the coupling of the compound of formula III with the compound of formula IV or the compound of formula V with the compound of formula VI is reacted either in a ring to obtain further derivatives of the compound of formula I Then it can be done.
[56] In addition, compounds of formula (I) can be prepared from compounds such as 3,4,5-trichloropicolinic acid. By using methods well known to those skilled in the art, the carboxylic acid can be converted to a heterocycle, ie a heteroaryl substituent.
[57]
[58] The appropriate 4-halopyridine is reacted suitably, such as by substituting NaN _3, and then the corresponding 4-azide derivative is reduced to yield an amino group at position 4. Carbonylation under standard conditions affords a carboxylic acid at the 2-position.
[59] Suitably substituted pyridine of formula III, wherein L is chloro, bromo, iodo or trifluoromethanesulfonate, can be readily obtained by well known methods. Publication No. WO 0151468]. For example, 6-bromo homologues can be used in several important intermediates, such as the equivalent 6-bromo-4-azido, 6-bromo-4-nitro and 6-bromo-4-nitropyridine N- It can be prepared by reduction of oxide homologues. Such intermediates can in turn be prepared by nucleophilic substitution of the 6-bromo-4-halo homologue with NaN ₃ or electrophilic nitration of the corresponding 6-bromopyridine-N-oxide. Alternatively, such homologues can be prepared by directly amination of the corresponding 4,6-dibromo analogs.
[60] 3- and 5-alkoxy and aryloxy homologues can be prepared by reducing the corresponding 4-azido derivatives, which in turn can be prepared by nucleophilic substitution of the corresponding 4-halopyridine with NaN ₃ . Necessary 3- and 5-alkoxy-4-halopyridine can be prepared according to the method of literature.
[61] 3- and 5-alkylthio homologs can be prepared by calcifying suitable chloropyridine at low temperature and then treating with alkyl disulfide and carbon dioxide. The resulting picolinic acid is reacted with ammonium hydroxide to give the desired product.
[62] 3- and 5-cyano and thiocyanato analogs can be prepared by the action of KCN and KSCN, respectively, in suitable fluoropyridine at high temperature. 3- and 5-fluoro, bromo, iodo and nitro homologues are prepared by electrophilic reactions of unsubstituted precursors with positive halogen or nitro sources such as fluorine gas, bromine, iodine or pyrolytic nitric acid, respectively. It can manufacture.
[63] 3- and 5-trifluoromethyl homologs are known in the art starting from known compounds 2-fluoro-3-chloro-5-trifluoromethylpyridine and 2,5-dichloro-trifluoromethylpyridine. It can be prepared by standard methods known to those skilled in the art.
[64] 4-N-amide, carbamate, urea, sulfonamide, silylamine and phosphoramidate amino derivatives are free amino compounds, for example, suitable acid halides, chloroformates, carbamyl chloride, sulfonyl chloride, It can be prepared by reacting with silyl chloride or chlorophosphate. Imines or hydrazones can be prepared by reacting the free amine or hydrazine with a suitable aldehyde or ketone.
[65] Substituted 4-amino homologs can be prepared by reacting the corresponding 4-halopyridine-2-carboxylate or any other substitutable four substituents with substituted amines.
[66] Compounds of formula (I) obtained in this way can be recovered by conventional methods. Typically, the reaction mixture is acidified with aqueous acid (eg hydrochloric acid) and extracted with organic solvent (eg ethyl acetate or dichloromethane). Organic solvents and other volatiles can be removed by distillation or evaporation to obtain the desired compound of formula (I) and purified by standard processes such as recrystallization or chromatography.
[67] Compounds of formula (I) have been found to be useful as herbicides before and after germination. The compounds of formula (I) can be sprayed non-selectively (large) in order to control weeds extensively in certain areas, or in small amounts to selectively inhibit undesirable plants. Spreading areas include pastures, pastures, boulevards, roadways, power lines and industrial areas where it is desirable to contain undesirable plants. Another use is to inhibit weeds in crops such as corn, rice and cereals. In addition, compounds of formula I may be used to inhibit weeds in arable crops (eg citrus fruits, apples, gums, palm oil, woodlands, etc.). In general, it is preferable to use post-germination compounds. It is also generally preferred to use the compounds of the present invention to inhibit a wide range of trees, hardwoods, weeds and weeds. Particular preference is given to using the compounds of the invention in order to inhibit undesirable plants in grown crops. While each of the 6-aryl- or heteroaryl-4-aminopicolinate compounds included in formula (I) is within the scope of the present invention, herbicide activity, crop selectivity and the wide range of weed inhibition obtained vary depending on the substituents present. Compounds suitable for particular herbicide utility can be identified using the information and routine testing presented herein.
[68] The term herbicide used in the present invention means an active ingredient that weakens, inhibits or adversely changes plant growth. The herbicidal effective amount or plant inhibitory amount is an active ingredient amount that adversely changes the effect, and includes deviations from natural growth, death, inhibition, drying, retardation and the like. The terms plants and vegetation include germinated seeds, germinated seedlings and grown plants.
[69] Herbicide activity is indicated by the compounds of the present invention when directly sprayed on a plant or its habitat at any stage prior to growth, simmering or germination. The effects observed are not only the plant species to be inhibited, the plant growth stage, the application parameters of the dilution and spray droplet size, the particle size of the solid component, the environmental condition at the point of use, the specific compound used, the specific adjuvant and carrier used, the type of solid, etc. It depends on the amount of chemical applied. Such other factors may be inhibited as is known in the art to promote non-selective or selective herbicide action. In general, it is preferred to spray the compound of formula (I) after germination to relatively immature weeds to maximize weed control.
[70] A spreading rate of about 1 to about 2,000 g / Ha is generally used when carrying out after germination, and a spreading rate of about 1 to about 2,000 g / Ha is generally used even when carried out before germination. Larger spread rates described above generally suppress non-selectively a wide variety of weeds. Typically, smaller spread rates are selectively suppressed and can be used for crop habitats.
[71] Herbicide compounds of the present invention are often sprayed with one or more other herbicides to inhibit a wide variety of weeds. When used with other herbicides, the presently claimed compounds may be combined with other herbicide (s), mixed in a tank with other herbicide (s) or sprayed using other herbicide (s). . Some herbicides that can be used with the compounds of the present invention include sulfonamides (e.g., metosulam, flumetsulam, chloransulammethyl, diclosulam, phenoxsulam, and florasulam), sulfonylureas (e.g., chlorimuron , Tribenuron, sulfomethuron, nicosulfuron, chlorsulfuron, amidosulfuron, triasulfuron, prosulfuron, tritosulfuron, thifensulfuron, sulfosulfuron and metsulfuron), imidazolinone (E.g. imazaquin, imazapic, imazetapyr, imazaphyr, imazamethabenz and imazamox), phenoxyalkanoic acids (e.g. 2,4-D, MCPA, dichloroprop and mecoprop), Pyridinyloxyacetic acid (e.g. astriclopyr and fluoroxypyr), carboxylic acids (e.g. clopyrralid, picloram, 4-amino-3,6-dichloropyridine-2-carboxylic acid and dicamba), dinitro Aniline (e.g. trifluurin, benepine, benfluurin and pendimethalin), chloroacetate Trianilides (e.g. salachlor, acetochlor and metolachlor), semicarbazone (oxine migration inhibitors) (e.g. chlorflurenol and diflufenzopyr), aryloxyphenoxypropionates (e.g. fluazipope , Haloxifop, diclopov, clodinafop and phenoxaprop), and glyphosate, glufosinate, acifluorfen, betazone, clomazone, fumichlorac, fluormethuron, pomesafen, Lactofen, linuron, isoproturon, propizamide, simazine, norflurazon, paraquat, tebutiuuron, diuron, diflufenican, picolinafen, cinidon, cetoxydim, cletodim, traral And other conventional herbicides, including coxidim, quinmerak, isoxaben, bromoxynil and metribuzin. In addition, the herbicide compounds of the present invention may be used with glyphosate and glufosinate in glyphosate resistant or glyphosinate resistant crops. It is also generally preferred to spray other supplemental herbicides simultaneously with the compounds of the invention as a blended formulation or tank mixture.
[72] Compounds of the invention are generally known as herbicide sennas such as cloquintocet, furylazole, dichlormide, benzoxacor, mefenpyr-ethyl, phenchlorazole-ethyl, flurazole, dimuron, dimeth Piperate, thiobencarb, fenchlorim and fluxofenim) to improve their selectivity. The compounds of the present invention can be further used to inhibit weeds in a large number of crops that are resistant to the compounds of the present invention or other herbicides by genetic manipulation or by mutation and selection. For example, corn, wheat, rice, soybeans, sugar beets, cotton, rapeseed, and other crops that are resistant to compounds capable of treating acetolactate synthase inhibitors in sensitive plants. Many glyphosate and glufosinate resistant crops can be treated alone or in combination with these herbicides. Some crops (eg cotton) are resistant to auxin herbicides (eg 2,4-dichlorophenoxyacetic acid). Such herbicides are used to treat these resistant crops or other auxin resistant crops.
[73] Although the 6-aryl or heteroaryl-4-aminopicolinate compounds of formula (I) can be used directly as herbicides, these compounds contain a herbicidally effective amount of the compound together with at least one agriculturally acceptable adjuvant or carrier. It is preferable to use. Suitable adjuvants or carriers should not be toxic to the crops useful at the concentrations used in the application of the selective weed control composition in the presence of the crops and shall not chemically react with the compounds of formula (I) or other composition components. Such mixtures may be designed for direct application to weeds or their habitats, or may be concentrates or combinations which are generally diluted with additional carriers and auxiliaries prior to application. Such compounds include solids such as dust, granules, water dispersible granules, wettable powders or liquids such as emulsifiable concentrates, solutions, emulsions or suspensions.
[74] Suitable agricultural auxiliaries and carriers useful for preparing the herbicide mixtures of the present invention are well known to those skilled in the art.
[75] Liquid carriers that may be used include water, toluene, xylene, petroleum naphtha, crop oils, acetone, methyl ethyl ketone, cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol monomethyl ether And ethylene glycol monomethyl ether, methanol, ethanol, isopropanol, amyl alcohol, ethylene glycol, propylene glycol, glycerin and the like. Water is generally the carrier of choice for diluting the concentrate.
[76] Suitable solid carriers include talc, feldspar clay, silica, attapulgus clay, kaolin clay, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, fuller's earth, cottonseed, flour, soy flour, pumice, wood flour, walnut Shell powder, lignin and the like.
[77] It is generally preferred to incorporate one or more surfactants into the compositions of the present invention. Such surfactants are particularly advantageous for use in solid and liquid compositions which are specifically designed to be diluted with a carrier before sparging. Surfactants can be anionic, cationic or nonionic in nature and can be used as emulsifiers, wetting agents or suspending agents, or for other purposes. Typical surfactants include alkyl sulfate salts such as diethanol ammonium lauryl sulfate; Alkylarylsulfonate salts such as calcium dodecylbenzenesulfonate; Alkylphenol-alkylene oxide adducts such as nonylphenol-C ₁₈ ethoxylate; Alcohol-alkylene oxide addition products such as tridecyl alcohol-C ₁₆ ethoxylate; Soaps such as sodium stearate; Alkylnaphthalenesulfonate salts such as sodium dibutylnaphthalenesulfonate; Dialkyl esters of sulfosuccinate salts such as sodium di (2-ethylhexyl) sulfosuccinate]; Sorbitol esters such as sorbitol oleate; Quaternary amines such as lauryl trimethylammonium chloride; Polyethylene glycol esters of fatty acids such as polyethylene glycol stearate; Block copolymers of ethylene oxide and propylene oxide; And salts of mono and dialkyl phosphate esters.
[78] Other auxiliaries commonly used in agricultural compositions include compatibilizers, antifoams, containment agents, neutralizers, buffers, corrosion inhibitors, dyes, deodorants, electrodeposition agents, penetration aids, tackifiers, dispersants, thickeners, solidifying point depressants, antibacterial agents and the like. In addition, the compositions may contain other miscible components, such as other herbicides, plant growth inhibitors, fungicides, pesticides and the like, and may be combined with liquid fertilizers or solids, in particular fertilizer carriers (eg ammonium nitride, urea, etc.). Can be.
[79] The concentration of active ingredient in the herbicide composition of the present invention is generally from about 0.001 to about 98% by weight. Concentrations of about 0.01 to about 90% by weight are often used. In compositions designed to be used as concentrates, the active ingredient is generally present at a concentration of about 5 to about 98 weight percent, about 10 to about 90 weight percent. Such compositions are usually diluted with an inert carrier (eg water) prior to sparging. Dilution compositions that are generally sprayed on weeds or their habitats generally contain from about 0.0001 to about 1 weight percent of active ingredient, preferably from about 0.001 to about 0.05 weight percent.
[80] The compositions of the present invention can be applied to weeds or their habitats by using typical soil or air cleaners, sprayers and granulators, by adding them to irrigation water, and by other conventional methods known to those skilled in the art. have.
[81] The following examples are present to illustrate various aspects of the invention and are not intended to be limiting of the claims. Many starting materials useful for preparing the compounds of the invention, for example 4-amino-3,6-dichloropyridine-2-carboxylic acid, 4-amino-3,5,6-trifluoro-2-cyano Pyridine, methyl 4-amino-6-bromo-3,5-difluoropyridine-2-carboxylate and methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate are described in US Pat. No. 6,297,197 Described in Bl.
[82] Example
[83] 1. Method for preparing 5,6-dichloropyridine-2-carboxylic acid-N-oxide
[84] 50% hydrogen peroxide (38 g, 0.35 mol) is carefully added to a mechanically stirred compound of trifluoroacetic acid (350 mL) and 5,6-dichloropyridine-2-carboxylic acid (56.4 g, 0.29 mol) at 79 ° C. After 1 hour, the reaction mixture is poured into 1 L of saturated aqueous NaHSO ₃ with vigorous stirring and then cooled in an ice bath. The precipitate is collected and dried to give 5,6-dichloropyridine-2-carboxylic acid-N-oxide (62.9 g, 0.30 mol) at a melting point of 160 ° C.
[85] 2. Method for preparing methyl 5,6-dichloropyridine-2-carboxylate-N-oxide
[86] A suspension of 5,6-dichloropyridine-2-carboxylic acid-N-oxide (5.0 g, 24.0 mmol) in methanol (100 mL) is saturated with HCl gas and the reaction mixture is heated at 40-50 ° C. for 1 h. The solvent is removed and the residue is dissolved in diethyl ether / ethyl acetate. The organic solution is washed with water, saturated sodium bicarbonate and brine, dried and concentrated to give methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (4.0 g, 18.1 mmol).
[87] _{^{l H NMR (DMSO-d 6}} ): δ 7.75 (s, 2H), 3. 88 (s, 3H).
[88] 3. Preparation method of methyl 4,5,6-trichloropyridine-2-carboxylate
[89] A solution of methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (22.0 g, 0.100 mol) and phosphorus oxychloride (15.70 mL, 0.169 mol) is heated at 70 ° C. for 36 hours. The solvent is removed and the residue is carefully dissolved in diethyl ether and water. The organic layer is washed with saturated sodium bicarbonate, water and brine, dried and concentrated to give methyl 4,5,6-trichloropyridine-2-carboxylate (20.0 g, 0.083 mol).
[90] ^l H NMR (CDCl ₃ ): δ 8.16 (s, 1H), 4.02 (s, 3H).
[91] 4. Method for preparing 4,5,6-trichloropyridine-2-carboxylic acid
[92] Methyl 4,5,6-trichloropyridine-2-carboxylate (10.11 g, 42 mmol) is suspended in dioxane (200 mL) and water (200 mL). 1N NaOH (42 mL, 42 mmol) was added to the mixture and the reaction mixture was stirred at 25 ° C. After 72 hours, 2N NaOH (15 mL, 30 mmol) was added to complete the reaction. Dioxane is removed by rotary evaporation and the aqueous residue is acidified with concentrated hydrochloric acid. The precipitate is collected by suction filtration, washed with water and dried to give 4,5,6-trichloropyridine-2-carboxylic acid (8.92 g, 39.6 mmol) at a melting point of 115 to 120 ° C.
[93] 5. Preparation of 4,5 6-trichloropyridine-2-carbonyl chloride
[94] A solution of 4,5,6-trichloropyridine-2-carboxylic acid (5.20 g, 23.1 mmol) and thionyl chloride (3.0 mL) in dichloroethane (30 mL) was refluxed until the off gas stopped. The reaction mixture is concentrated to give 4,5,6-trichloropyridine-2-carbonyl chloride (5.60 g, 23.0 mmol) at a melting point of 60-62 ° C.
[95] 6. Method for preparing (4,5,6-trichloropyridin-2-yl) methanol
[96] Sodium borohydride (173 mg, 4.60 mmol) is added to a mixture of methyl 4,5,6-trichloropyridine-2-carboxylate (1.0 g, 4.16 mmol) in methanol (25 mL) at room temperature. After 40 minutes, the reaction is warmed to 50 ° C. and additional sodium borohydride (307 mg, 8 mmol) is added to the two batches over 3 hours. Methanol is removed by rotary evaporation and the residue is diluted with aqueous 10% citric acid (50 mL) and then vigorously stirred. The precipitate is collected, washed with water and dried to give (4,5,6-trichloropyridin-2-yl) methanol (713 mg, 3.34 mmol) at a melting point of 82 to 83 ° C.
[97] 7. Preparation of 4,5,6-trichloropyridine-2-carbaldehyde
[98] A mixture of (4,5,6-trichloropyridin-2-yl) methanol (3.83 g, 18 mmol) and manganese oxide (IV) (7.8 g, 90 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours Let's do it. More manganese (IV) oxide (4 g, 46 mmol) is added and stirring continued. After an additional 24 hours, the reaction mixture is suction filtered through a silica gel stopper (10 g). After washing the silica gel stopper with additional dichloromethane (2 × 25 mL), manganese oxide (IV) (8 g, 92 mmol) is added to the filtrate and the mixture is stirred at rt for 72 h. The reaction mixture is filtered again and the solvent is removed to give 4,5,6-trichloropyridine-2-carbaldehyde (2.36 g, 11.4 mmol) with a melting point of 84 to 88 ° C.
[99] 8. Method for preparing 2,3,4-trichloro-6- (5-oxazolyl) pyridine
[100] A mixture of 4,5,6-trichloropyridine-2-carbaldehyde (1.66 g, 8 mmol), tosylmethyl isocyanide (1.54 g, 8 mmol) and potassium carbonate (1.09 g, 8 mmol) in methanol (20 mL) was prepared. Heat 30 ° C., then heat 80 ° C. for 5 minutes. The solvent is removed by rotary evaporation and the residue is suspended in water (200 mL) and then vigorously stirred. The precipitate is suction filtered, washed with water and then dried naturally to give 2,3,4-trichloro-6- (5-oxazolyl) pyridine (1.7 g, 6.8 mmol) at a melting point of 128 to 130 ° C.
[101] 9. Method for preparing 4-azido-2,3-dichloro-6- (5-oxazolyl) pyridine
[102] A solution of 2,3,4-trichloro-6- (5-oxazolyl) pyridine (1.47 g, 5.9 mmol) and sodium azide (0.422 g, 6.5 mmol) in DMF (25 mL) was added at 50 ° C. under nitrogen atmosphere. Stir for hours. The reaction mixture is cooled down and diluted with water (100 mL). The solid was filtered off and dried to give 4-azido-2,3-dichloro-6- (5-oxazolyl) pyridine (1.41 g, 5.5 mmol) at a melting point of 154-155 ° C.
[103] 10. Method for preparing 4-amino-2,3-trichloro-6- (5-oxazolyl) pyridine
[104] Sodium borohydride (0.174 g, 4.6 mmol) is added to a stirred suspension of methanol (25 mL) 4-azido-2,3-dichloro-6- (5-oxazolyl) pyridine (1.17 g, 4.6 mmol) at room temperature. . The solvent is removed and water (100 mL) is added to the residue. After stirring for 10 minutes, the formed solid was collected, washed with water and dried to form 4-amino-2,3-dichloro-6- (5oxazolyl) pyridine (1.05 g, 4.55 mmol) at a melting point of 207 to 208 ° C. ).
[105] The following compounds were prepared according to the method of Example 10:
[106] 4-amino-5,6-dichloro-N- (2-hydroxyphenyl) pyridine-2-carboxamide: m.p .: 248 ° C.,
[107] Methyl 4-amino-3-chloro-6- (5-bromo-2-thiazolyl) pyridine-2-carboxylate (Compound 1): ¹ H NMR (CDCl ₃ ): δ7.90 (s, 1H), 7.67 (s, 1 H), 6.52 (wide s, 2 H), 3.97 (s, 3 H).
[108] Methyl 4-amino-3,5-dichloro-6- (5-chloro-2-furanyl) pyridine-2-carboxylate (Compound 2): ¹ H NMR (CDC1 ₃ ): δ 7.27 (d, J = 5.5 Hz, 1H), 6.35 (d, J = 5.5 Hz, 1H), 5.39 (wide s, 2H), 4.01 (s, 3H).
[109] Methyl 4-amino-3-chloro-6- (1-methyl-1H-pyrazol-3-yl) pyridine-2-carboxylate (Compound 3): 1 H NMR (CDCl ₃ ): δ 7.39 (d, J = 2.3 Hz, 1H), 7.38 (s, 1H), 6.86 (d, J = 2.3 Hz, 1H), 4.90 (wide s, 2H), 4.01 (s, 3H), 3.97 (s, 3H).
[110] Methyl 4-amino-3-chloro-6- (1-methyl-1H-pyrazol-5-yl) pyridine-2-carboxylate (Compound 4): ¹ H NMR (CDCl ₃ ): δ 7.46 (d, J = 2.1 Hz, 1H), 6.96 (s, 1H), 6.49 (d, J = 2.1 Hz, 1H), 4.90 (wide s, 2H), 4.17 (s, 3H), 3.99 (s, 3H).
[111] Methyl 4-amino-3-chloro-6- (3-pyrazolyl) pyridine-2-carboxylate (Compound 5): ¹ H NMR (CDC1 ₃ ): δ7.62 (wide s, 1H), 7.24 (s, 1H), 6.75 (wide s, 1H), 4.98 (wide s, 2H), 4.01 (s, 3H).
[112] Methyl 4-amino-3-chloro-6- (4-triazolyl) pyridine-2-carboxylate (Compound 6): ¹ H NMR (CDC1 ₃ ): δ 11.90 (wide s, 1H), 8.27 (s, 1H ), 7.45 (s, 1H), 4.90 (wide s, 2H), 4.04 (s, 3H).
[113] 11.Method for preparing methyl 4-amino-3-chloro-6- (5-oxazolyl) pyridine-2-carboxylate (Compound 7)
[114] 4-amino-2,3-dichloro-6- (5-oxazolyl) pyridine (800 mg, 3.48 mmol), sodium acetate (571 mg, 6.96 mmol), palladium acetate (16 mg, 0.07 mmol) and 4 in methanol (25 mL) The bis (diphenylphosphino) butane (30 mg, 0.07 mmol) solution is pressurized with carbon monoxide at 100 psi. After 12 hours at 100 ° C., the reaction mixture is cooled and concentrated. The residue is dissolved in ethyl acetate and washed twice with water. The organic layer is dried (MgSO ₄ ) and concentrated to afford methyl 4-amino-3-chloro-6- (5oxazolyl) pyridine-2-carboxylate (788 mg, 3.10 mmol) at a melting point of 166 to 170 ° C.
[115] The following compounds were prepared according to the method of Example 11:
[116] Methyl 4-amino-3-chloro-6- (2-5-methyl-1,3,4-thiadiazolyl) pyridine-2-carboxylate (Compound 8); Melting point: 237-238 ° C.,
[117] Methyl 4-amino-3-chloro-6- (2-benzthiazolyl) pyridine-2-carboxylate (Compound 9); Melting point: 224 ℃,
[118] Methyl 4-amino-3-chloro-6- (1-methyl-1H-tetrazol-5-yl) pyridine-2-carboxylate (Compound 10); Melting point: 239 to 241 ° C.
[119] Methyl 4-amino-3-chloro-6- (2-methyl-2H-tetrazol-5-yl) pyridine-2-carboxylate (Compound 11); Melting point: 250-252 ° C.
[120] 12.Method for preparing 4,5,6-trichloropyridine-2-dimethyliminochloride
[121] N, N-dimethyl 4,5,6-trichloropyridine-2-carboxamide (2.5 g, 0.01 mol) and dimethylformamide (3 drops) in oxalyl chloride (10 mL) were heated to reflux for 1 hour. . The reaction mixture is concentrated and the residual oil is triturated with diethyl ether to give a pale yellow hygroscopic solid which is used without further purification.
[122] 13. Method for preparing 4,5,6-trichloro-6- (2-benzthiazolyl) pyridine
[123] 2-aminobenzeneethanol (1.40 mL, 0.013 mol) in dichloromethane (100 mL) was added to 4,5,6- (trichloro) pyridine-2-dimethyliminochloride (3.2 g, 0.013 mol) in dichloromethane (100 mL). ) And triethylamine (2.0 mL) drop wise. After addition, the reaction mixture is warmed to room temperature over 2 hours. The solvent is then removed in vacuo and the crude product is column chromatography (0.1% diethyl ether in hexanes) to give 2,3,4-trichloro-6- (2-benzthiazolyl) pyridine (1.58 g, 0.005 mol) is obtained.
[124] ¹ H NMR δ 8.44 (s, 1 H) 8.10 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 7.3,1H), 7.51 (m, 2H).
[125] 14. Method for preparing 4,5,6-trichloropyridine-2-carboxamide
[126] Methyl 4,5,6-trichloropyridine-2-carboxylate (15 g, 62.4 mmol) is suspended in concentrated aqueous ammonium hydroxide (80 mL) and methanol (150 mL). After 4 hours at 25 ° C., methanol is removed and the aqueous suspension is filtered. The filter cake is washed with water and dried to give 4,5,6-trichloropyridine-2-carboxamide (13 g, 56.9 mmol) at a melting point of 169 to 170 ° C.
[127] 15. Preparation of 4,5,6-trichloropyridine-2-carbonitrile
[128] 4,5,6-trichloropyridine-2-carboxamide (8.0 g, 35.0 mmol) is dissolved in acetonitrile (150 mL). The mixture is heated to reflux with phosphorus oxychloride (6.6 mL, 70.0 mmol) and the reaction mixture. After 16 hours, the volatiles are removed and the residue is partitioned between saturated aqueous NaHCO ₃ (200 mL) and ethyl acetate (200 mL). The organic layer is washed with brine (100 mL), dried (Na2S04) and filtered through silica gel (10 g). The filtrate is evaporated and dried to 4,5,6-trichloropyridine-2-carbonitrile (6.9 g, 33.3 mmol) at a melting point of 87-88 ° C.
[129] 16.Method of preparing 2,3,4-trichloro-6- (1H-tetrazol-5-yl) pyridine
[130] 4,5,6-trichloropyridine-2-carbonitrile (4.77 g, 23.0 mmol), azidotrimethylsilane (6.1 mL, 46.0 mmol) and dibutyltin oxide (0.57 g, 2.3 mmol) in toluene (75 mL) Is heated to 90 ° C. After 3 hours, the reaction mixture is heated to reflux. After 7 hours, azidotrimethylsilane (0.5 mL, 3.8 mmol) and dibutyltin oxide (100 mg, 0.4 mmol) were added to complete the reaction. After a short time, the volatiles are removed and the residue is dissolved in methanol (50 mL) and then briefly stirred at 25 ° C. The volatiles are removed and the residue is partitioned between saturated aqueous NaHCO ₃ (200 mL), ethyl acetate (200 mL) and diethyl ether (100 mL), the layers are carefully separated to maintain insoluble white matter in the aqueous fraction. . The aqueous fraction is then acidified to pH 2 with concentrated HCl with vigorous stirring. The white precipitate was collected, washed with water and dried to give 2,3,4-trichloro-6- (lH-tetrazol-5-yl) pyridine (5.4 g, 21.6 mmol) at a melting point of 197 to 198 ° C. do.
[131] 17. 2,3,4-trichloro-6- (1-methyl-lH-tetrazol-5-yl) pyridine and 2,3,4-trichloro-6- (2-methyl-1H-tetrazol- 5-yl) pyridine
[132] 2,3,4-trichloro-6- (lH-tetrazol-5-yl) pyridine (3.25 g, 13 mmol), iodomethane (1.84 g, 13 mmol) and potassium carbonate (1.79) in dimethylformamide (100 mL) g, 13 mmol) is stirred at 25 ° C. for 22 hours. The volatiles were removed and the residue was column chromatographed (15% ethyl acetate in hexane) to give 2,3,4-trichloro-6- (1-methyl-1H-tetrazol-5yl at melting points 138-141 ° C. ) Pyridine (1.66 g, 6.3 mmol) and 2,3,4-trichloro-6- (2-methylH-tetrazol-5-yl) pyridine (1.05 g, 4.0 mmol) at a melting point of 156-157 ° C. were obtained. do.
[133] 18. Preparation of 4,5,6-trichloro- (N'-2-acetyl) pyridine-2-carbohydrazide
[134] A mixture of 4,5,6-trichloropyridine-2-carbonyl chloride (9.0 g, 37 mmol) in pyridine (100 mL) is cooled to 0 ° C. and hydrazide acetate (3.0 g, 40 mmol) is added. The ice bath was removed and after 2.5 h at 25 ° C., methanol (50 mL) was added and then the reaction mixture was briefly stirred. The volatiles are removed and the residue is suspended in water (100 mL) and stirred vigorously. The precipitate was collected, washed with water and dried to give 4,5,6-trichloro- (N'-2-acetyl) pyridine-2-carbohydrazide (8 g, 28 mmol) at a melting point of 185-188 ° C. do.
[135] 19.Method for preparing 2,3,4-trichloro-6- (5-methyl-1,3,4-thiadiazol-2-yl) pyridine
[136] 4,5,6-trichloro- (N'-2-acetyl) pyridine-2-carbohydrazide (4.0 g, 14 mmol) and 2,4-bis (4-methoxyphenyl)-in toluene (50 mL) The mixture of 1,3-dithia-2,4-diphosphetane-2,4-disulfite (Lawson's reagent, 5.73 g, 14 mmol) is stirred at 90 ° C. overnight. After cooling to room temperature, the insoluble precipitate is suction filtered and the filtrate is concentrated. The residue is partitioned between ethyl acetate (100 mL) and water (100 mL) and the organic fractions are dried (Na ₂ SO ₄ ), then filtered and rotary evaporated to afford impure product (4 g). The precipitated material from the aqueous washings was collected by suction filtration, combined with the impure product, and purified by column chromatography (0-100% ethyl acetate in hexane) to give 2,3,4-trichloro at a melting point of 148 to 150 ° C. Obtain -6- (5-methyl-1,3,4-thiadiazol-2-yl) pyridine (1.59 g, 5.7 mmol).
[137] 20.Method for preparing N- (2-hydroxyphenyl) -4-amino-5,6-dichloropyridine-2-carboxamide
[138] A solution of 4,5,6-trichloropyridine-2-carbonyl chloride (1.0 g, 4.1 mmol) in dichloromethane (10 mL) was diluted to 2-aminophenol (0.45 g, 4.1 mmol) in dichloromethane (30 mL) at 0 ° C. And triethylamine (0.6 mL) dropwise. The reaction mixture is warmed to room temperature and further stirred for 30 minutes. The solvent is removed and the residue is partitioned between 20% tetrahydrofuran / ethyl acetate and 1M hydrochloric acid. The organic layer was separated, washed with saturated sodium bicarbonate and brine, then dried (MgSO ₄ ) and concentrated to a N- (2hydroxyphenyl) -4,5,6-trichloropyridine with a melting point of 240 ° C. (decomposition). 2-carboxamide (1.26 g, 4.0 mmol) is obtained.
[139] 21.Method for preparing 4-amino-2,3-dichloro-6- (2-benzoxazolyl) -pyridine
[140] N- [obtained from N-(2-hydroxyphenyl) -2- (4,5,6-trichloro) pyridinecarboxamide via azide formation followed by sodium borohydride reduction in toluene (50 mL) A solution of (2-hydroxyphenyl) -4-amino-5,6-dichloropyridine2-carboxamide (1.80 g, 5.7 mmol) and p-toluenesulfonic acid (0.2 g) was added to a Dean-Stark tube. reflux under nitrogen overnight using traps). After cooling, the reaction mixture is diluted with ethyl acetate and THF and the organic mixture is washed with saturated aqueous sodium bicarbonate. The organic layer was dried, concentrated and the residue triturated with petroleum ether / diethyl ether to afford 4-amino-2,3-dichloro-6- (2-benzoxazolyl) pyridine (1.30 g, 4.6 mmol). To obtain.
[141] _{^{l H NMR (DMSO-d 6}} ): δ7. 82 (d, 2 H), 7.66 (s, 1 H), 7.55-7. 38 (m, 2 H), 7.18 (wide s, 2 H).
[142] 22. Preparation of 4,5,6-trichloropyridine-2-carbothioamide
[143] 4,5,6-trichloropyridine-2-carboxamide (10.4 g, 46 mmol) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4 in toluene (150 mL) The mixture with diphosphetane-2,4-disulfite (Lawson's reagent, 22.0 g, 54 mmol) is heated under reflux for 2 hours. The reaction mixture is cooled, diluted with water (250 mL) and then extracted with ethyl acetate (2 x 150 mL). The organic phase is dried (Na ₂ SO ₄ ) and concentrated. The residue is purified by column chromatography (20% ethyl acetate in hexane) to give 4,5,6-trichloropyridine-2-carbothioamide (6.5 g, 27 mmol) at a melting point of 168-169 ° C.
[144] 23. 2,3,4-trichloro-6- [5- (trifluoromethyl) -1,3-thiazol-2-yl] pyridine and 2,3,4-trichloro-6- (4- Method for preparing trifluoromethyl) -1,3-thiazol-2-yl) pyridine
[145] 4,5,6-trichloropyridine-2-carbothioamide (2.85 g, 11.8 mmol) and 1-chloro-3,3,3-trifluoroacetone (2.59 g, 17.7 mmol) in glacial acetic acid (25 mL); Is heated under reflux for 4 h. Upon cooling, the solid formed is filtered and washed with water (3 x 100 mL) and sodium bicarbonate (3 x 50 mL). The solid is then dissolved in dichloromethane and the organic phase is washed with brine (150 mL) and dried (MgSO ₄ ). The solvent is removed and the residue is purified by preparative liquid chromatography (90% acetonitrile in water) to give 2,3,4-trichloro-6- [5- (trifluoromethyl) -1,3-thiazole -2-yl] pyridine (0.70 g, 2.1 mmol) [ ¹ H NMR (CDCl ₃ ) δ 7.91 (s, 1H); 8.29 (s, 1H)] and 2,3,4-trichloro-6- [4- (trifluoromethyl) -1,3-thiazol-2-yl] pyridine (0.20 g, 0.6 mmol) [ ¹ H NMR (CDC1 ₃ ) 8.24 (1H, s), 8.39 (1H, s)].
[146] 24. Method for preparing methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate
[147] 4-amino-3,6-dichloropyridine-2-carboxylic acid (1100 g, 5.31 mol) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane in water (6000 mL) The bis (tetrafluoroborate) (2100 g, 5.93 mol) solution is raised to 65 ° C. for 6 hours. After cooling to ambient temperature, the reaction mixture is further stirred for 8 hours. The solution was concentrated and the residual solid washed with 6N hydrochloric acid (5 × 1000 mL) and then dried to 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylic acid (757 g, 3.53 mol, purity: 58 %) Is obtained. The crude is added to methanol (3000 mL) saturated with anhydrous hydrogen chloride and the reaction mixture is heated to 45 ° C. for 2 hours. The solution is added to ice water (4000 mL) with vigorous stirring and the resulting solids are collected. The crude ester is dissolved in ethyl acetate (1000 mL), washed with saturated sodium bicarbonate (2 × 1000 mL), dried and concentrated. The resulting solid is recrystallized from ethyl acetate / hexanes to give methyl 4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylate (402.5 g, 1.67 mol) at a melting point of 128 to 131 ° C.
[148] 25. Preparation of Methyl 4-amino-3-chloro-6- (3,4-dimethylphenyl) pyridine-2-carboxylate (Compound 12)
[149] 3,4-dimethylphenylboric acid (2.1 g, 14.0 mmol) in acetonitrile (100 mL), cesium fluoride (6.3 g, 41.5 mmol), 1,4-bis (diphenylphosphino) butane (0.5 g, 1.2 mmol) The solution of methyl 4-amino-3,6-dichloropyridine-2-carboxylate (2.5 g, 10.0 mmol) and triethylamine (5 mL) was sparged with nitrogen for 30 minutes. Palladium acetate (0.3 g, 1.2 mmol) is added and the reaction mixture is heated at reflux for 3 hours. After cooling, water (200 mL) is added and the mixture is extracted with ethyl acetate (2 x 100 mL). The organic layer is washed with brine (100 mL), dried (NaSO ₄ ) and then concentrated. The residue was purified by column chromatography (33% ethyl acetate in hexane) to give methyl 4-amino-3-chloro-6- (3,4-dimethylphenyl) pyridine-2-carboxylate (1.4 at melting point 154-156 ° C.). g, 5.0 mmol) is obtained.
[150] The following 4-amino-6- (aryl or heteroaryl) picolinate was prepared according to the method of Example 25:
[151] Methyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 13); Melting point: 130-131 ° C,
[152] Methyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 14); Melting point: 233 to 236 ° C,
[153] Methyl 4-amino-3,5-dichloro-6- (4-methoxyphenyl) pyridine-2-carboxylate (Compound 15); Melting point: 107-109 ° C,
[154] Methyl 4-amino-3-chloro-6-phenylpyridine-2-carboxylate (Compound 16); _{^{l H NMR (CDCl 3):}} δ7.9 (d, 2H), 7.5 (m, 3H), 7.1 (s, 1H), 4.8 ( broad s, 2H), 4.0 (s , 3H),
[155] Methyl 4-amino-3-chloro-6- (4-methoxyphenyl) pyridine-2-carboxylate (Compound 17); Melting point: 148-149 ° C,
[156] Methyl 4-amino-6- (4-methylphenyl) -3- (trifluoromethyl) pyridine-2-carboxylate (Compound 18); ^l H NMR (CDC1 ₃ ): δ 7.85 (d, 2H), 7.25 (d, 2H), 7.00 (s, 1H), 4.90 (wide s, 2H), 3.95 (s, 3H), 2.40 (s, 3H),
[157] Methyl 4-amino-3-chloro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 19); Melting point: 132 ℃,
[158] Methyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 20); Melting point: 111-113 ° C,
[159] Methyl 4-amino-3-chloro-6- (3-methylphenyl) pyridine-2-carboxylate (Compound 21); Melting point: 98 ℃,
[160] Methyl 4-amino-3-chloro-6- (4-thiomethoxyphenyl) pyridine-2-carboxylate (Compound 22); Melting point: 185 ° C,
[161] Methyl 4-amino-3-chloro-6- (2-methoxyphenyl) pyridine-2-carboxylate (Compound 23); _{^{l H NMR (CDCl 3):}} δ 7.80 (m, 1H), 7.30 (m, 1H), 7.20 (s, 1H) 6.95 (m, 2H), 4.80 ( broad s, 1H), 4.00 (s , 3H) , 3.80 (s, 3 H),
[162] Methyl 4-amino-3-chloro-6- (3-methoxyphenyl) pyridine-2-carboxylate (Compound 24); Melting point: 122-123 ° C,
[163] Methyl 4-amino-3-chloro-6- (2-methylphenyl) pyridine-2-carboxylate (Compound 25): ¹ H NMR (CDCl ₃ ): δ7.30 (m, 4H), 6.70 (s, 1H) , 4.90 (wide s, 2H), 4.00 (s, 3H), 2.35 (s, 3H),
[164] Methyl 4-amino-3-chloro-6- (2-chlorophenyl) pyridine-2-carboxylate (Compound 26); Melting point: 115-117 ° C,
[165] Methyl 4-amino-3-chloro-6- (3-chlorophenyl) pyridine-2-carboxylate (Compound 27); Melting point: 141 ℃,
[166] Methyl 4-amino-3-chloro-6- [4- (trifluoromethyl) phenyl] pyridine-2-carboxylate (Compound 28); Melting point: 149 ℃,
[167] Methyl 4-amino-3-chloro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 29); Melting point: 184 ℃,
[168] Methyl 4-amino-3-chloro-6- (4-ethylphenyl) pyridine-2-carboxylate (Compound 30); Melting point: 119 ℃,
[169] Methyl 4-amino-3-chloro-6- (4-acetylphenyl) pyridine-2-carboxylate (Compound 31); Melting point: 146-148 ° C.,
[170] Methyl 4-amino-3-chloro-6- (5-bromo-2-methoxyphenyl) pyridine-2-carboxylate (Compound 32); Melting point: 191 to 120 ° C,
[171] Methyl 4-amino-3-chloro-6- (2-fluorophenyl) pyridine-2-carboxylate (Compound 33); Melting point: 121-122 ° C.,
[172] Methyl 4-amino3-chloro-6- (3,5-difluorophenyl) pyridine-2-carboxylate (Compound 34); Melting point: 118-119 ° C,
[173] Methyl 4-amino-3-chloro-6- (4-isopropylphenyl) pyridine-2-carboxylate (Compound 35); Melting point: 92-93 ° C,
[174] Methyl 4-amino3-chloro-6- (4-biphenyl) pyridine-2-carboxylate (Compound 36); Melting point: 185 to 186 ° C,
[175] Methyl 4-amino-3-chloro-6- (2-fluorophenyl) pyridine-2-carboxylate (Compound 37); Melting point: 121-122 ° C.,
[176] Methyl 4-amino-3-chloro-6- (4-chloro-3-methylphenyl) pyridine-2-carboxylate (Compound 38); Melting point: 155 to 156 ° C,
[177] Methyl 4-amino3-chloro-6- (3-chloro-4-fluorophenyl) pyridine-2-carboxylate (Compound 39); Melting point: 169-170 ° C.,
[178] Methyl 4-amino-3-chloro-6- (3,4-dichlorophenyl) pyridine-2-carboxylate (Compound 40); Melting point: 170 ℃,
[179] Methyl 4-amino-3-chloro-6- (4-formylphenyl) pyridine-2-carboxylate (Compound 41); Melting point: 106 to 108 ° C,
[180] Methyl 4-amino-3-chloro-6- (3-cyanophenyl) pyridine-2-carboxylate (Compound 42); Melting point: 139 to 140 ° C,
[181] Methyl 4-amino-3-chloro-6- (3-cyanophenyl) pyridine-2-carboxylate (Compound 43); Melting point: 125 ℃,
[182] Methyl 4-amino-3,5-dichloro-6- [4- (trifluoromethyl) phenyl] pyridine-2-carboxylate (Compound 44); Melting point: 110-111 ° C,
[183] Methyl 4-amino-3-chloro-6- (4-chloro-2-methylphenyl) pyridine-2-carboxylate (Compound 45); Melting point: 114-115 ° C.,
[184] Methyl 4-amino-3-chloro-6- (3, 5-bis- (trifluoromethyl) phenyl) pyridine-2-carboxylate (Compound 46); Melting point: 139 to 140 ° C,
[185] Methyl 4-amino-3-chloro-6- (2-naphthyl) pyridine-2-carboxylate (Compound 47); Melting point: 108-109 ° C,
[186] Methyl 4-amino-3-chloro-5-fluoro-6- (4-methylphenyl) -pyridine-2-carboxylate (Compound 48): ¹ H NMR (CDC1 ₃ ): δ 7.80 (d, 2H), 7.25 (d, 2H), 4.90 (wide s, 2H), 4.00 (s, 3H), 2.40 (s, 3H),
[187] Methyl 4-acetamido-3-chloro-5-fluoro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 49); Melting point: 178-179 ° C.,
[188] Methyl 4-amino-3-chloro-6- (3,4-difluoromethylenedioxyphenyl) pyridine-2-carboxylate (Compound 50); Melting point: 130-132 ° C.,
[189] Methyl 4-amino-3-chloro-6- (3,5-difluorophenyl) pyridine-2-carboxylate (Compound 51); Melting point: 155 ℃,
[190] Methyl 4-acetamido-3-chloro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylate (Compound 52); Melting point: 134-135 ° C.,
[191] Methyl 4-acetamido-3-chloro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 53); Melting point: 151 to 152 ° C,
[192] Methyl 4-acetamido-3-chloro-6- (2-chloro-4-fluorophenyl) pyridine-2-carboxylate (Compound 54); Melting point: 162 to 163 ° C,
[193] Methyl 4-acetamido-3-chloro-6- (2,6-difluorophenyl) pyridine-2-carboxylate (Compound 55); Melting point: 156-157 ° C,
[194] Methyl 4-amino-3-chloro-6- [4- (trifluoromethoxy) phenyl] pyridine-2-carboxylate (Compound 56); Melting point: 119-120 ° C.,
[195] Methyl 4-acetamido-3-chloro-6- (2,5-dichlorophenyl) pyridine-2-carboxylate (Compound 57); Melting point: 143 ℃,
[196] Methyl 4-amino-3-chloro-6- (2-chloro-4-fluorophenyl) pyridine-2-carboxylate (Compound 58); Melting point: 155 to 157 ° C,
[197] Methyl 4-amino-3-chloro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylate (Compound 59); Melting point: 107-109 ° C,
[198] Methyl 4-acetamido-3-chloro-6- (4-chloro-3-fluorophenyl) pyridine-2-carboxylate (Compound 60); Melting point: 156-157 ° C,
[199] Methyl 4-amino-3-chloro-6- (4-chloro-3-fluorophenyl) pyridine-2-carboxylate (Compound 61); Melting point: 149-151 ° C.,
[200] Methyl 4-amino-3-chloro-6- [2-chloro-4- (trifluoromethyl) phenyl] pyridine-2-carboxylate (Compound 62); ¹ H NMR (CDCl ₃ ): δ7.70 (m, 2H), 7. 60 (m, 1H), 7.05 (s, 1H), 4.90 (bs, 2H), 4.00 (s, 3H),
[201] Methyl 4-acetamido-3-chloro-6- (3,4-dimethoxyphenyl) pyridine-2-carboxylate (Compound 63); Melting point: 153 to 154 ° C,
[202] Methyl 4-amino-3-chloro-6- (3,4-dimethoxyphenyl) pyridine-2-carboxylate (Compound 64); Melting point: 126-127 ° C,
[203] Methyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 65); Melting point: 233 to 236 ° C,
[204] Methyl 4-acetamido-3-chloro-6- (4-chloro-2-methoxyphenyl) pyridine-2-carboxylate (Compound 66); Melting point: 176 to 178 ° C,
[205] Methyl 4-amino-3-chloro-6- (3,4-ethylenedioxyphenyl) pyridine-2-carboxylate (Compound 67): ¹ H NMR (CDC1 ₃ ): δ7.50 (d, 1H), 6.40 (m, 1H), 7.05 (s, 1H), 6.90 (d, 1H) 4.80 (wide s, 2H), 4.30 (s, 4H), 4.00 (s, 3H),
[206] Methyl 4-amino-3-chloro-6- (4-chloro-2-methoxyphenyl) pyridine-2-carboxylate (Compound 68); Melting point: 152 to 154 ° C,
[207] Methyl 4-acetamido-3-chloro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 69); ¹ H NMR (DMSO-d ₆ ): δ 7.40 (m, 2H), 7.20 (s, 1H), 7.10 (m, 1H), 6.70 (wide s, 2H), 6.10 (s, 2H), 3.90 ( s, 3H),
[208] Methyl 4-acetamido-3-chloro-6- (4-chloro-3-methoxymethylphenyl) pyridine-2-carboxylate (Compound 70); Melting point: 120-122 DEG C,
[209] Methyl 4-amino-3-chloro-6- (4-chloro-3-methoxymethylphenyl) pyridine-2-carboxylate (Compound 71); Melting point: 173 to 174 ° C,
[210] Methyl 4-acetamido-3-chloro-6- (2-chloro-3, 4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 72); Melting point: 195-196 ° C,
[211] Methyl 4-amino-3-chloro-6- (2-chloro-3,4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 73); Melting point 155 to 156 캜,
[212] Methyl 4-acetamido-3-chloro-6- (5-indanyl) pyridine-2-carboxylate (Compound 74); Melting point: 132-134 ° C,
[213] Methyl 4-amino-3-chloro-6- (5-indanyl) pyridine-2-carboxylate (Compound 75); Melting point: 165 to 166 ° C,
[214] Methyl 4-acetamido-3-chloro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylate (Compound 76); ¹ H NMR (CDC1 ₃ ): δ 8. 90 (s, 1H), 8.45 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 6.85 (d, 1H), 4. 65 (t, 2H), 4.00 (s, 3H) , 3.25 (t, 3H), 2.30 (s, 3H),
[215] Methyl 4-amino-3-chloro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylate (Compound 77); Melting point: 143 ℃,
[216] Methyl 4-acetamido-3-chloro-6- (5-chloro-2-fluoro-4-methylphenyl) pyridine-2-carboxylate (Compound 78); Melting point: 185 to 187 ° C,
[217] Methyl 4-amino-3-chloro-6- (5-chloro-2-fluoro-4-methylphenyl) pyridine-2-carboxylate (Compound 79); Melting point: 108-110 ° C,
[218] Methyl 4-amino-3-chloro-6- (4-methoxy-3-methylphenyl) pyridine-2-carboxylate (Compound 80); Melting point: 158 ° C,
[219] Methyl 4-acetamido-3-chloro-6- (2,5-dimethoxyphenyl) pyridine-2-carboxylate (Compound 81); Melting point: 124 to 125 ° C,
[220] Methyl 4-amino-3-chloro-6- (2,5-dimethoxyphenyl) pyridine-2-carboxylate (Compound 82); ¹ NMR (CDCl ₃ ): δ 7.40 (d, 1H). 7.30 (s, 1H), 6.95 (m, 1H), 4.80 (wide s, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H),
[221] Methyl 4-acetamido-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 83); Melting point: 156 ° C,
[222] Methyl 4-amino-3-chloro-5-fluoro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 84); Melting point: 160 ℃,
[223] Methyl 4-amino-3-chloro-5-fluoro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylate (Compound 85); Melting point: 120 ℃,
[224] Methyl 4-amino-3,5-dichloro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 86); Melting point: 160-162 캜,
[225] Methyl 4-acetamido-3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridine-2-carboxylate (Compound 87); Melting point: 177-178 ° C.,
[226] Methyl 4-amino-3-chloro-5-fluoro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 88); Melting point: 122 ℃,
[227] Methyl 4-N-pyrrolyl-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 89); Melting point: 118-119 ° C,
[228] Methyl 4-amino-3,5-difluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 90); Melting point: 165 to 166 ° C,
[229] Methyl 4-amino-3,5-difluoro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 91); Melting point: 145 to 146 ° C,
[230] Methyl 4-amino-3,5-difluoro-6- (2-chloro-4-methylphenyl) pyridine-2-carboxylate (Compound 92); _{^{l H NMR (CDCl 3):}} δ7.30 (m, 2H), 7.15 (m, 1H), 4.60 (bs, 2H), 4.00 (s, 3H), 2.40 (s, 3H),
[231] Methyl 4-amino-3,5-difluoro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylate (Compound 93); Melting point: 182-183 ° C,
[232] Methyl 4-amino-3,5-difluoro-6- [4- (trifluoromethyl) phenyl] pyridine-2-carboxylate (Compound 94); Melting point: 177-178 ° C.,
[233] Methyl 4-amino-3,5-difluoro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylate (Compound 95); Melting point: 189 to 190 ° C,
[234] Methyl 4-amino-3-chloro-6- (2-benzofuranyl) pyridine-2-carboxylate (Compound 96); Melting point: 182-183 ° C,
[235] Methyl 4-acetamido-3-chloro-6- (2-benzothienyl) pyridine-2-carboxylate (Compound 97); Melting point: 184 to 185 ° C,
[236] Methyl 4-amino-3-chloro-6- (5-chloro-2-thienyl) pyridine-2-carboxylate (Compound 98); ¹ H NMR (CDC1 ₃ ): δ 7.40 (d, 1H), 7.20 (m, 2H), 6.80 (wide s, 2H), 3.90 (s, 3H),
[237] Methyl 4-acetamido-6- (2-benzofuranyl) -3-chloropyridine-2-carboxylate (Compound 99); ¹ H NMR (DMSO-d ₆ ): δ10.00 (Wide s, 1H), 8.80 (s, 1H), 8.25 (s, 3H), 7.70 (m, 1H), 7.60 (s, 1H) 7.40 (m , 2H), 7.60 (s, 1H), 4.00 (s, 3H) 2.25 (s, 3H).
[238] Methyl 4-amino-3-chloro-6- (3,5-dimethyl-4-isoxazolyl) pyridine-2-carboxylate (Compound 100); Melting point: 143 ℃,
[239] Methyl 4-acetamido-3-chloro-6- (3-thienyl) pyridine-2-carboxylate (Compound 101); Melting point: 133 ℃ and
[240] Methyl 4-amino-3-chloro-6- (3-pyridyl) pyridine-2-carboxylate (Compound 102); Melting point: 144 to 146 ° C.
[241] 26. Preparation of Methyl 4-acetamido-3-chloro-6- (2-thiazolyl) pyridine-2-carboxylate (Compound 103)
[242] Methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (1.0 g, 4.05 mmol), 2- (trimethylstannyl) thiazole (2.9 g, 17.3 mmol) in tetrahydrofuran (75 mL) and The dichlorobis (triphenylphosphine) palladium (II) (0.4 g, 0.6 mmol) solution is heated under reflux for 4 hours. The reaction is diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer is dried (MgSO ₄ ) and concentrated. Crude product was purified by column chromatography (50% ethyl acetate in hexane) to yield methyl 4-acetamido-3-chloro-6- (2-thiazolyl) pyridine-2-carboxylate (0.38) at a melting point of 187-188 ° C. g, 1.2 mmol).
[243] The following 4-amino-6- (aryl or heteroaryl) picolinate was prepared according to the method of Example 26:
[244] Methyl 4-amino-3,5-dichloro-6- (2-furanyl) pyridine-2-carboxylate (Compound 104); Melting point: 116 to 117 ° C,
[245] Methyl 4-amino-3,5-dichloro-6- (2-thienyl) pyridine-2-carboxylate (Compound 105); Melting point: 132 ℃,
[246] Methyl 4-amino-3-chloro-6- (2-thienyl) pyridine-2-carboxylate (Compound 106); Melting point: 138-139 ° C.,
[247] Methyl 4-amino-3-chloro-6- (6-methoxy-4-pyridinyl) pyridine-2-carboxylate (Compound 107); Melting point: 185 to 187 ° C,
[248] Methyl 4-amino-3-chloro-6- (6-hydroxy-3-pyridinyl) pyridine-2-carboxylate (Compound 108); Melting point: 251 to 252 ° C,
[249] Methyl 4-amino-3-chloro-6- (2-pyridinyl) pyridine-2-carboxylate (Compound 109); Melting point: 142-145 ° C.,
[250] Methyl 4-amino-3-chloro-6- (2-furanyl) pyridine-2-carboxylate (Compound 110); Melting point: 117 ℃,
[251] Methyl 4-amino-3-chloro-6- (5-chloro-2-pyridyl) pyridine-2-carboxylate (Compound 111); Melting point: 145 ~ 150 ° C,
[252] Methyl 4-acetamido-3-chloro-6- (3- (6-methyl) pyridazyl) pyridine-2-carboxylate (Compound 112); Melting point: 205-206 ° C,
[253] Methyl 4-amino-3-chloro-5-fluoro-6- (2-thiazolyl) pyridine-2-carboxylate (Compound 113); Melting point: 185 to 187 ° C,
[254] Methyl 4-amino-3-chloro-6- (2- (5-methylthiazolyl)) pyridine-2-carboxylate (Compound 114); Melting point: 186-188 ° C. and
[255] Methyl 4-amino-3,5-dichloro-6- (5-thiazolyl) pyridine-2-carboxylate (Compound 115); Melting point: 168-170 degreeC.
[256] 27.Method for preparing methyl 4-acetamido-3-chloro-6- (trimethylstannyl) pyridine-2-carboxylate
[257] Methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (5.00 g, 19.0 mmol), 1,4-bis (diphenylphosphino) butane (0.81 g, 1.9 mmol) in dioxane (150 mL) ) And hexamethylditin (6.22 g, 19.0 mmol) solution is sparged with nitrogen for 15 minutes. Palladium acetate (0.43 g, 1.9 mmol) is then added and the mixture is refluxed for 3 hours. After filtration through celite, the reaction mixture is concentrated. The residue is dissolved in ethyl acetate and washed three times with water. The organic layer is dried, concentrated and dissolved in an ethyl acetate / hexanes (1: 1) mixture. The solid impurities were filtered off and the solvent was removed to give methyl 4-acetamido-3-chloro-6- (trimethylstannyl) pyridine-2-carboxylate (4.25 g, 10.9 mmol) at a melting point of 113 to 115 ° C. do.
[258] 28. Preparation of Methyl 4-acetamido-3-chloro-6- (5- (2-chloro) pyrimidinyl) pyridine-2-carboxylate (Compound 116)
[259] Methyl 4-acetamido-3-chloro-6- (trimethylstannyl) -pyridine-2-carboxylate (1.00 g, 2.60 mmol), 1,4-bis (diphenylphosphino) in dioxane (30 mL) Butane (0.12 g, 0.29 mmol) and 5-bromo-2-chloropyrimidine (0.25 g, 1.30 mmol) solutions are sparged with nitrogen for 15 minutes. Palladium acetate (0.07 g, 0.29 mmol) is then added and the mixture is refluxed for 3 hours. After filtration through celite, the reaction mixture is concentrated. The residue is dissolved in ethyl acetate and washed three times with water. The organic layer was dried, concentrated and then column chromatography (50% ethyl acetate in hexanes) to methyl 4-acetamido-3-chloro-6- (5- (2-chloro) pyrimidinyl) pyridine-2 -Carboxylate (0.120 g, 0.35 mmol) is obtained.
[260] _{^{l H NMR (CDC1 3) δ9.22}} (s, 2H), 9.08 (s, 1H), 8.03 ( broad s, 1H), 4.05 (s , 3H), 2.37 (s, 3H).
[261] The following compounds were prepared according to the method of Example 28:
[262] Methyl 4-acetamido-3-chloro-6- (5-pyrimidinyl) pyridine-2-carboxylate (Compound 117); Melting point: 178-185 ° C.,
[263] Methyl 4-acetamido-3-chloro-6- (3- (6-methyl) pyridazinyl) pyridine-2-carboxylate (Compound 118); Melting point: 205-206 ° C,
[264] 29. Method for preparing methyl 6-acetylene-3,4-dichloropyridine-2-carboxylate
[265] Copper iodide (I) (0.16 g, 0.84 mmol) is stirred in triethylamine for 10 minutes at 75 ° C. and cooled to room temperature. Trimethylsilylacetylene (0.40 mL, 2.8 mmol) is then added, the mixture is stirred for 10 minutes and then dichlorobis (triphenyl-phosphine) palladium (II) (0.30 g, 0.43 mmol) is added. After another 10 minutes, methyl 3,4,6-trichloropyridine-2-carboxylate (2.00 g, 8.30 mmol) in triethylamine (10 mL) is added. A second fraction of trimethylsilylacetylene (1.40 mL, 10 mmol) is further added and the mixture is heated to 90 ° C. in an oil bath. After 15 minutes, the reaction mixture is cooled, filtered through diatomaceous earth, and then concentrated. The crude reaction product is then eluted through a silica gel short column (25% ethyl acetate in hexanes) to yield 2.20 g (7.30 mmol) of crude methyl 3,4-dichloro-6-trimethylsilylacetylenepyridine-2-carboxylate. . The material is dissolved in tetrahydrofuran (50 mL), cooled to −20 ° C. and treated with 1M tetrabutylammonium fluoride in THF (8.0 mL; 8.0 mmol). In a few minutes, the crude mixture is poured into ice, extracted with diethyl ether, dried (MgSO ₄ ), filtered and evaporated to give a black solid. Purification by column chromatography (25% ethyl acetate in hexanes) yields methyl 6-acetylene-3,4-dichloropyridine-2-carboxylate (1.22 g, 5.30 mmol).
[266] ¹ H NMR (CDC1 ₃ ): δ7.70 (s, 1H), 4.02 (s, 3H), 3.31 (s, 1H).
[267] The following compounds were prepared according to the method of Example 29:
[268] Methyl 4-acetamido-6-acetylene-3-chloropyridine-2-carboxylate; ¹ H NMR (CDCl ₃ ) δ 8.78 (s, 1H), 7.97 (wide s, 1H), 4.00 (s, 3H), 3.22 (s, 1H), 2.36 (s, 3H).
[269] 30. Preparation of Methyl 3,4-dichloro-6- (4-triazolyl) pyridine-2-carboxylate and Methyl 3-azido-4-chloro-6- (4-triazolyl) pyridine-2-carboxylate Way
[270] Methyl 6-acetylene-3,4-dichloropyridine-2-carboxylate (1.50 g, 6.50 mmol) is stirred with sodium azide (1.30 g, 19.50 mmol) in DMF (50 mL) at 50 ° C. After 16 hours, the reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water (acidified with IN hydrochloric acid). The organic layer is separated, dried (MgSO ₄ ), filtered and concentrated. Crude product was purified by reverse phase preparative liquid chromatography (40-70% acetonitrile in water) to give methyl 3,4-dichloro-6- (4-triazoyl) -pyridine-2-carboxylate (0.35 g, 1.29 mmol). [ ¹ H NMR (CDC1 ₃ ) δ8.35 (s, 1H), 8. 28 (s, 1H), 4.07 (s, 3H)] and methyl 3-azido-4-chloro-6- (4-tria Crude) pyridine-2-carboxylate (0.30 g, 1.10 mmol) [ ¹ H NMR (CDC1 ₃ ) δ8.37 (s, 1H), 7.97 (s, 1H), 4.06 (s, 3H)].
[271] 31.Methyl 4-acetamido-3-chloro-6- (3-bromo-5-isoxazoyl) pyridine-2-carboxylate (Compound 119) and methyl 4-acetamido-3-chloro-6 (3-Bromo-4-isoxazoyl) pyridine-2-carboxylate (Compound 120)
[272] A solution of dibromoformaloxime (0.38 g, 1.87 mmol) in ethyl acetate (3 mL) was diluted with methyl acetamido-6-acetylene-3-chloropyridine-2 in ethyl acetate and water (0.4 mL) over 4 hours. Add slowly to carboxylate (0.70 g, 2.80 mmol) and potassium bicarbonate (0.37 g, 3.70 mmol). After further stirring at ambient temperature for 16 hours, the crude reaction mixture is partitioned between ethyl acetate and water. The organic layer is separated, dried (MgSO ₄ ), filtered and concentrated. The product was purified by reverse phase preparative liquid chromatography (60% acetonitrile in water with 0.5% phosphoric acid) to give the starting material methyl 4-acetamido-6-acetylene-3-chloropyridine-2-carboxylate (0.15 g, 0.06 mmol), methyl 4-acetamido-3-chloro-6- (3-bromo-5-isoxazoyl) pyridine-2-carboxylate (0.51 g, 1.37 mmol) [ ¹ H NMR (CDC1 ₃ ) δ9.14 (s, 1H), 8.00 (wide s, 1H), 7.05 (s, lH), 4.05 (s, 3H), 2.37 (s, 3H)] and methyl 4-acetamido-3-chloro- 6- (3-bromo-4-isoxazoyl) pyridine-2-carboxylate (0.03 g, 0.08 mmol) [ ¹ H NMR (CDC1 ₃ ) δ9.22 (s, 1H), 8.92 (wide s, 1H ), 8.00 (s, lH), 4.02 (s, 3H), 2.34 (s, 3H)].
[273] 32. Methyl 3,4-dichloro-6- (2-methyl-3-pyrazoyl) pyridine-2-carboxylate, methyl 3,4-dichloro-6- (3-pyrazoyl) pyridine-2-carboxylate and Method for preparing methyl 3,4-dichloro-6- (1-methyl-3-pyrazoyl) pyridine-2-carboxylate
[274] Trimethylsilyldiazomethane (2.0 M in hexanes, 10 mL, 20.0 mmol) was added to methyl 6-acetylene-3, 4-dichloropyridine-2-carboxylate (1.70 g, 7.0 in ethyl acetate and methanol (1: 1, 50 mL). mmol) is added to the solution. After 4 hours, the reaction mixture is concentrated and the residue is purified by column chromatography (25-50% ethyl acetate in petroleum ether) to give methyl 3,4-dichloro-6- (2-methyl-3-pyrazoyl) pyridine. -2-carboxylate (0.33 g, 1.15 mmol) [ ¹ H NMR (CDC1 ₃ ) δ 7.80 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 4.25 (s, 3H), 4.05 (s, 3H); Methyl 3,4-dichloro-6- (3-piazoyl) pyridine-2-carboxylate (0.50 g, 1.84 mmol) [ ¹ H NMR (CDC1 ₃ ) δ10.90 (wide s, 1H), 8.09 (s, 1H) 7.68 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 4.05 (s, 3H)] and methyl 3,4-dichloro-6- (1-methyl-3- Pyrazoyl) pyridine-2-carboxylate (0.08 g, 0.28 mmol) [ ¹ H NMR (CDC1 ₃ ) δ8.14 (s, 1H), 7.40 (d, J = 2.3 Hz, 1H), 6. 89 (d , J = 2.3 Hz, 1H), 4. 25 (s, 3H), 3.96 (s, 3H)].
[275] 33.Method for preparing methyl 4-amino-3-chloro-6- (3- (6-methyl) pyridazinyl) pyridine-2-carboxylate
[276] Methyl 4-acetamido-3-chloro-6- (3- (6-methyl) pyridazinyl) pyridine-2-carboxylate (100 mg, 0.31 mmol) and sodium methoxide (17 mg, 0) in methanol (4 mL) 31 mmol) is heated under reflux under nitrogen atmosphere for 1 hour. Heat is removed and the reaction mixture is stirred overnight at room temperature. After removal of the solvent, the residue is dissolved in ethyl acetate, washed with water and brine and then dried (MgSO ₄ ). Column chromatography (10% methanol in dichloromethane) gave methyl 4-amino-3-chloro-6- (3- (6-methyl) pyridazinyl) pyridine-2-carboxylate (47 mg, 0.17 mmol).
[277] The following compounds were prepared according to the method of Example 33:
[278] Methyl 4-amino-3-chloro-6- (3-thienyl) pyridine-2-carboxylate (Compound 122); Melting point: 129 ℃,
[279] Methyl 4-amino-3-chloro-6- (2-thiazolyl) pyridine-2-carboxylate (Compound 123); Melting point: 195-197 ° C,
[280] Methyl 4-amino-3-chloro-6- (1-methyl-1H-pyrazol-4-yl) pyridine-2-carboxylate (Compound 124); Melting point: 174-176 ° C.,
[281] Methyl 4-amino-3-chloro-6- (2-benzothienyl) pyridine-2-carboxylate (Compound 125); Melting point: 177-178 ° C.,
[282] Methyl 4-amino-3-chloro-6- (5-pyrimidinyl) pyridine-2-carboxylate (Compound 126); Melting point: 195 ℃,
[283] 34. Preparation of Methyl 4-amino-3-chloro-6- (6-hydroxy-3-pyridinyl) pyridine-2-carboxylate (Compound 127)
[284] Methyl 4-amino-3-chloro-6- (6-t-butoxy-3-pyridinyl) pyridine-2-carboxylate (0.50 g, 1.49 mmol) was diluted with THF and trifluoroacetic acid (1: 1) ( 5 mL) dissolved in the mixture and heated at reflux for 30 minutes. The volatiles were removed in vacuo and the crude was purified by HPLC (linear gradient, 100% acetonitrile in 100% water) to methyl 4-amino-3-chloro-6- (6-hydroxy) at melting point 251 to 252 ° C. 3-pyridinyl) pyridine-2-carboxylate (0.35 g, 1.25 mmol) is obtained.
[285] 35. Preparation of Methyl 4-amino-3-chloro-6- (6-chloro-3-pyridinyl) pyridine-2-carboxylate (Compound 128)
[286] Methyl 4-amino-3-chloro-6- (6-hydroxy-3-pyridinyl) pyridine-2-carboxylate (0.30 g, 1.07 mmol) is suspended in pure dichlorophenylphosphine (2.5 mL, 1.84 mmol). And the mixture is heated to 50 ° C. for 1 hour. The volatiles were removed in vacuo and the residue was purified by column chromatography (1: 1, hexanes / EtOAc) to give methyl 4-amino-3-chloro-6- (6-chloro-pyridinyl) pyridine-2-carboxyl Yield (0.11 g, 0.37 mmol) is obtained.
[287] 36. Preparation of Methyl 4-amino-3-chloro-6- (4- (2-methylthiazolyl))-pyridine-2-carboxylate (Compound 129)
[288] HCl gas is bubbled through a solution of methyl 4-acetamido-3- chloro-6- (4- (2-methylthiazolyl))-pyridine-2-carboxylate (100 mg, 0.31 mmol) for 2 minutes. The mixture is refluxed for 2 hours, cooled and then concentrated. The residue is partitioned between methylene chloride and 1M ammonium hydroxide. The organic layer was separated off, dried (MgS0 ₄ ) and concentrated to methyl 4-amino-3-chloro-6- (4- (2-methylthiazolyl))-pyridine-2-carboxylate (74 mg, 0.26 mmol) is provided:
[289] ¹ H NMR (CDC1 ₃ ) δ7.94 (s, 1H), 7.58 (s, lH), 4.97 (wide s, 2H), 4.02 (s, 3H), 2.77 (s, 3H).
[290] The following compounds were prepared according to the method of Example 36;
[291] Methyl 4-amino-3-chloro-6- (3-bromo-5-isoxazoyl) -pyridine-2-carboxylate (Compound 130); ¹ H NMR (CDC1 ₃ ) δ 7.29 (s, 1H), 6.98 (s, 1H), 5.00 (wide s, 1H), 4.00 (s, 3H),
[292] Methyl 4-amino-3-chloro-6- (3-bromo-4-isoxazoyl))-pyridine-2-carboxylate (Compound 131); ¹ H NMR (CDCl ₃ ) δ 8.88 (s, 1H), 7.28 (s, 1H), 4.90 (wide s, 1H), 4.00 (s, 3H).
[293] 37.Method for preparing 4-amino-3-chloro-6- (3,4-dimethylphenyl) pyridine-2-carboxylic acid (compound 132):
[294] Methyl 4-amino-3-chloro-6- (3,4-dimethylphenyl) pyridine-2-carboxylate (0.9 g, 0.003 mol) was added under reflux in methanol (50 mL) and 1N sodium hydroxide (75 mL) for 2 hours. Heat. The reaction mixture is partially concentrated and then acidified with concentrated hydrochloric acid. The solid is collected and dried to give 4-amino-3-chloro-6- (3,4-dimethylphenyl) pyridine-2-carboxylic acid (0.85 g, 0.003 mol) having a melting point of 192 to 194 ° C.
[295] The following acids were prepared according to the method of Example 37:
[296] 4-amino-3,5-dichloro-6- (phenyl) pyridine-2-carboxylic acid (compound 133); Melting point: 135 ℃,
[297] 4-amino-3,5-dichloro-6- (4-methoxyphenyl) pyridine-2-carboxylic acid (compound 134); Melting point: 139-140 ° C., decomposition,
[298] 4-Amino-3-chloro-6- (phenyl) pyridine-2-carboxylic acid (compound 135); Melting point: 180-181 ° C., decomposition,
[299] 4-Amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylic acid (compound 136); Melting point: 166 to 167 ° C,
[300] 4-Amino-3-chloro-6- (4-thiomethylphenyl) pyridine-2-carboxylic acid (compound 137); Melting point: 173 to 175 ° C,
[301] 4-Amino-3-chloro-6- (3-methylphenyl) pyridine-2-carboxylic acid (compound 138); Melting point: 173 to 175 ° C,
[302] 4-amino-3-chloro-6- (2-methoxyphenyl) pyridine-2-carboxylic acid (compound 139); Melting point: 177-179 ° C.,
[303] 4-Amino-3-chloro-6- (2-chlorophenyl) pyridine-2-carboxylic acid (compound 140); Melting point: 196-197 ° C,
[304] 4-amino-3-chloro-6- (4-methoxyphenyl) pyridine-2-carboxylic acid (compound 141); ¹ H NMR (DMSO-d ₆ ): δ 7.82 (d, J = 8.8 Hz, 2H), 7.20 (s, 1 H), 7.00 (d, J = 8.8 Hz, 2H), 6.64 (s, 2H), 6.52 (s, 1 H), 3.78 (s, 3 H),
[305] 4-Amino-3-chloro-6- (2-fluorophenyl) pyridine-2-carboxylic acid (compound 142); Melting point: 192 ℃,
[306] 4-Amino-3-chloro-6- (3-chlorophenyl) pyridine-2-carboxylic acid (compound 143); Melting point: 171 ° C,
[307] 4-Amino-3-chloro-6- (4-acetylphenyl) pyridine-2-carboxylic acid (compound 144); Melting point: 177-178 ° C.,
[308] 4-amino-3-chloro-6- (2,4-difluorophenyl) pyridine-2-carboxylic acid (compound 145); Melting point: 206 ℃, decomposition,
[309] 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylic acid (compound 146); Melting point: 176 to 177 ° C,
[310] 4-amino-3-chloro-6- (4-isopropylphenyl) pyridine-2-carboxylic acid (compound 147); Melting point: 142-143 ° C.,
[311] 4-Amino-3-chloro-6- (4-biphenyl) pyridine-2-carboxylic acid (compound 148); Melting point: 300-305 ° C,
[312] 4-Amino-3-chloro-6- (4-chloro-3-methylphenyl) pyridine-2-carboxylic acid (compound 149); Melting point: 190-191 ° C,
[313] 4-amino-3-chloro-6- (3,4-dichlorophenyl) pyridine-2-carboxylic acid (compound 150); Melting point: 185 to 186 ° C,
[314] 4-Amino-3-chloro-6- (3-chloro-4-fluorophenyl) pyridine-2-carboxylic acid (compound 151): Melting point: 183-184 캜,
[315] 4-Amino-3-chloro-6- [4- (trifluoromethyl) phenyl] pyridine-2-carboxylic acid (compound 152): Melting point: 175 to 176 캜,
[316] 4-amino-3-chloro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylic acid (compound 153); Melting point: 182 ℃,
[317] 4-Amino-3-chloro-6- (4-chlorophenyl) pyridine-2-carboxylic acid (compound 154); Melting point: 165 ℃,
[318] 4-Amino-3-chloro-6- (4-chloro-2-methylphenyl) pyridine-2-carboxylic acid (compound 155); Melting point: 153 to 154 ° C,
[319] 4-amino-3-chloro-6- (4-fluorophenyl) pyridine-2-carboxylic acid (compound 156); Melting point: 170-171 ° C.,
[320] 4-amino-3-chloro-6- [3- (trifluoromethyl) phenyl] pyridine-2-carboxylic acid (compound 157); Melting point: 175-176 ° C.,
[321] 4-Amino-3-chloro-6- (2-fluoro-4-methylphenyl) pyridine-2-carboxylic acid (compound 158); Melting point: 187-189 ° C.,
[322] 4-Amino-3-chloro-6- (4-hydroxymethylphenyl) pyridine-2-carboxylic acid (compound 159); Melting point: 181 to 182 ° C,
[323] 4-Amino-3-chloro-6- [4- (fluoromethyl) phenyl] pyridine-2-carboxylic acid (compound 160): Melting point: 156 to 157 캜,
[324] 4-amino-3-chloro-6- [bis-3,5- (trifluoromethyl) phenyl] pyridine-2-carboxylic acid (compound 161); Melting point: 184 ℃,
[325] 4-amino-3-chloro-6- (2-naphthyl) pyridine-2-carboxylic acid (compound 162); Melting point: 168-169 ° C.,
[326] 4-Amino-3-chloro-5-fluoro-6- (4-methylphenyl) pyridine-2-carboxylic acid (compound 163): Melting point: 145-148 캜, decomposition,
[327] 4-Amino-3-chloro-6- (3-chloro-4-methylphenyl) pyridine-2-carboxylic acid (compound 164); Melting point: 188 ℃,
[328] 4-Amino-3-chloro-6- (2-methylphenyl) pyridine-2-carboxylic acid (compound 165); Melting point: 188-189 ° C.,
[329] 4-amino-3-chloro-6- (3,4-difluoromethylenedioxyphenyl) pyridine-2-carboxylic acid (compound 166); Melting point: 170 ℃,
[330] 4-amino-3-chloro-6- (3,5-difluorophenyl) pyridine-2-carboxylic acid (compound 167); Melting point: 182-183 ° C,
[331] 4-amino-3-chloro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylic acid (compound 168); Melting point: 162 to 163 ° C,
[332] 4-amino-3-chloro-6- (2,6-difluorophenyl) pyridine-2-carboxylic acid (compound 169); Melting point: 165 to 166 ° C,
[333] 4-Amino-3-chloro-6- (3-chloro-4-fluorophenyl) pyridine-2-carboxylic acid (compound 170); Melting point: 156-157 ° C,
[334] 4-amino-3,5-dichloro-6- [4- (trifluoromethyl) phenyl] pyridine-2-carboxylic acid (compound 171); Melting point: 158-160 ° C,
[335] 4-Amino-3-chloro-5-fluoro-6- (4-trifluorophenyl) pyridine-2-carboxylic acid (compound 172); Melting point: 137-138 ° C.,
[336] 4-Amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylic acid (compound 173); Melting point: 164 to 165 ° C,
[337] 4-amino-3-chloro-6- [4- (trifluoromethoxy) phenyl] pyridine-2-carboxylic acid (Compound 174); Melting point: 164 to 165 ° C,
[338] 4-Amino-3-chloro-6- (4-ethylphenyl) pyridine-2-carboxylic acid (compound 175); Melting point: 152 ℃,
[339] 4-amino-3-chloro-6- (2-fluorophenyl) pyridine-2-carboxylic acid (compound 176); Melting point: 121-122 ° C.,
[340] 4-amino-3-chloro-6- (2,5-dichlorophenyl) pyridine-2-carboxylic acid (compound 177); Melting point: 213-215 ° C.,
[341] 4-amino-3-chloro-6- (2,4-dimethylphenyl) pyridine-2-carboxylic acid (compound 178); ¹ H NMR (DMSO-d ₆ ): δ7.25 (m, 1H), 7.15 (m, 2H), 6.8 (s, 1H), 6.70 (bs, 2H), 2.30 (s, 3H), 2.25 (s , 3H),
[342] 4-amino-3-chloro-6- (4-chloro-3- (trifluoromethyl) phenyl) pyridine-2-carboxylic acid (compound 179); Melting point: 176 ℃,
[343] 3-Chloro-6- (4-methylphenyl) -4- (N-pyrrolyl) pyridine-2-carboxylic acid (compound 180); Melting point: 136-137 ° C.,
[344] 4-amino-3-chloro-6- (4-chloro-3-fluorophenyl) pyridine-2-carboxylic acid (compound 181); Melting point: 156-157 ° C,
[345] 4-Amino-3-chloro-6- (4-chloro-2- (trifluoromethyl) phenyl) pyridine-2-carboxylic acid (compound 182); Melting point: 178-180 ° C,
[346] 4-Amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylic acid (compound 183); Melting point: 169-170 ° C.,
[347] 4-amino-3-chloro-6- (2-chloro-4- (trifluoromethyl) phenyl) pyridine-2-carboxylic acid (compound 184); ¹ H NMR (DMSO-d ₆ ): δ8.00 (s, 1H), 7.80 (m, 2H), 7.00 (s, 1H), 6.85 (wide s, 2H),
[348] 4-Amino-3-chloro-6- (3,4-dimethoxyphenyl) pyridine-2-carboxylic acid (compound 185): Melting point: 182-183 ° C.,
[349] 4-amino-3-chloro-6- (4-chloro-2-methoxyphenyl) pyridine-2-carboxylic acid (compound 186); Melting point: 182-183 ° C,
[350] 4-Amino-3-chloro-6- (2-chloro-3,4-methylenedioxyphenyl) pyridine-2-carboxylic acid (compound 187); Melting point: 226 to 227 ° C,
[351] 4-amino-3-chloro-6- (5-indanyl) pyridine-2-carboxylic acid (compound 188); Melting point: 204 to 205 캜,
[352] 4-Amino-3-chloro-5-fluoro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylic acid (compound 189); Melting point: 154 to 155 ° C,
[353] 4-Amino-3-chloro-6- (2-chloro-4-methylphenyl) pyridine-2-carboxylic acid (compound 190); Melting point: 71-72 ° C.,
[354] 4-Amino-3-chloro-6- (4-methyl-3-thiomethylphenyl) pyridine-2-carboxylic acid (compound 191); Melting point: 188 to 190 ° C,
[355] 4-Amino-3-chloro-6- (5-chloro-2-fluoro-4-methylphenyl) pyridine-2-carboxylic acid (compound 192); Melting point: 173 to 175 ° C,
[356] 4-Amino-3-chloro-6- (4-methoxy-3-methylphenyl) pyridine-2-carboxylic acid (compound 193); Melting point: 131 ℃,
[357] 4-amino-3-chloro-6- (2,5-dimethoxyphenyl) pyridine-2-carboxylic acid (compound 194); Melting point: 185 to 186 ° C,
[358] 4-Amino-3-chloro-6- (4-chloro-3-methoxymethylphenyl) pyridine-2-carboxylic acid (compound 195); Melting point: 162 ℃,
[359] 4-Amino-3-chloro-5-fluoro-6- (3,4-methylenedioxyphenyl) pyridine-2-dicarboxylic acid (compound 196); Melting point: 169 ℃,
[360] 4-Amino-3-chloro-5-fluoro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylic acid (compound 197); Melting point: 171 ° C,
[361] 4-amino-3,5-dichloro-6- (4-chlorophenyl) pyridine-2-carboxylic acid (compound 198); Melting point: 164 to 165 ° C,
[362] 4-Amino-3-chloro-5-fluoro-6- (2,4-dichlorophenyl) pyridine-2-carboxylic acid (compound 199); Melting point: 152 ℃,
[363] 4-Amino-3,5-fluoro-6- (4- (trifluoromethyl) phenyl) pyridine-2-carboxylic acid (compound 200); Melting point: 169-170 ° C.,
[364] 4-Amino-3-chloro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylic acid (compound 201); _{^{l H NMR (DMSO-d 6}} ): δ7.80 (s, 1H), 7.70 (d, 1H), 6.85 (d, 3H), 6.60 ( broad s, 2H), 4.60 (t , 2H), 3. 30 (t, 3H),
[365] 4-amino-3,5-difluoro-6- (6-chlorophenyl) pyridine-2-carboxylic acid (compound 202); Melting point: 166-167 ° C., decomposition,
[366] 4-amino-3,5-difluoro-6- (4-methylphenyl) pyridine-2-carboxylic acid (compound 203); Melting point: 144-145 ° C,
[367] 4-Amino-3,5-difluoro-6- (2-chloro-4-methylphenyl) pyridine-2-carboxylic acid (compound 204); ¹ H NMR (DMSO-d ₆ ): δ 7.42 (s, 1H), 7.30 (m, 2H), 6.80 (wide s, 2H), 2.40 (s, 3H),
[368] 4-amino-3,5-difluoro-6- (2,4-dichlorophenyl) pyridine-2-carboxylic acid (compound 205); _{^{l H NMR (CD 3 0D)}} : δ7.4 (m, 2H), 7.58 (m, 1H),
[369] 4-amino-3,5-difluoro-6- (4-chloro-2-fluorophenyl) pyridine-2-carboxylic acid (compound 206); Melting point: 155 to 156 ° C,
[370] 4-amino-3,5-difluoro-6- (3,4-methylenedioxyphenyl) pyridine-2-carboxylic acid (compound 207); Melting point: 174-175 ° C.,
[371] 4-amino-3,5-dichloro-6- (2-thienyl) pyridine-2-carboxylic acid (compound 208); Melting point: 144 ℃,
[372] 4-amino-3-chloro-6- (4-pyridinyl) pyridine-2-carboxylic acid (compound 209); Melting point: 155 ℃, decomposition,
[373] 4-amino-3,5-dichloro-6- (2-furfuryl) pyridine-2-carboxylic acid (compound 210); Melting point: 152 ℃,
[374] 4-amino-3-chloro-6- (2-thienyl) pyridine-2-carboxylic acid (compound 211); ¹ H NMR (DMSO-d ₆ ): δ 7.46 (m, 2H), 7.07 (m, 1H), 6.93 (s, 1H), 6.09 (m, 2H)
[375] 4-Amino-3-chloro-6- (2-furfuryl) pyridine-2-carboxylic acid (compound 212); ¹ H NMR (DMSO-d ₆ ): δ7.71 (m, 1H), 6.89 (s, 1H), 6.82 (m, 1H), 5.56 (m, 1H), 6.17 (m, 2H),
[376] 4-amino-3-chloro-6- (6-methoxy-3-pyridinyl) pyridine-2-carboxylic acid (compound 213); Melting point: 110 ℃, decomposition,
[377] 4-amino-3-chloro-6- (2-pyridinyl) pyridine-2-carboxylic acid (compound 214); Melting point: 185 ℃, decomposition,
[378] 4-amino-3-chloro-6- (5-chloro-2-thienyl) pyridine-2-carboxylic acid (compound 215); Melting point: 178-179 ° C.,
[379] 4-amino-3-chloro-6- (3-thienyl) pyridine-2-carboxylic acid (compound 216); Melting point: 184 ℃,
[380] 4-amino-3-chloro-6- (2,3-dihydro-5-benzofuranyl) pyridine-2-carboxylic acid (compound 217); Melting point: 218-220 ° C,
[381] 4-amino-3-chloro-6- (5-methyl-2-thienyl) pyridine-2-carboxylic acid (compound 218); Melting point: 175-176 ° C.,
[382] 4-amino-6- (2-benzofuranyl) -3-chloropyridine-2-carboxylic acid (compound 219); Melting point: 151 ℃,
[383] 4-amino-3-chloro-6- (2-pyrazinyl) pyridine-2-carboxylic acid (compound 220); Melting point: 172-173 ° C,
[384] 4-Amino-3-chloro-5-fluoro-6- (6-chloro-3-pyridinyl) pyridine-2-carboxylic acid (compound 221); Melting point: 125 ℃, decomposition,
[385] 4-amino-3-chloro-6- (2-thiazolyl) pyridine-2-carboxylic acid (compound 222); Melting point: 184 to 185 ° C,
[386] 4-Amino-3-chloro-6- (1-methyl-1 H-pyrazol-5-yl) pyridine-2-carboxylic acid (compound 223); Melting point: 230-232 캜,
[387] 4-amino-3-chloro-6- (2-benzothienyl) pyridine-2-carboxylic acid (compound 224); Melting Point: 176 ℃
[388] 4-amino-3-chloro-6- (6-chloro-3-pyridinyl) pyridine-2-carboxylic acid (compound 225); Melting point: 110-144 ° C.,
[389] 4-Amino-3-chloro-6- (2-benzoxazolyl) pyridine-2-carboxylic acid (compound 226): Melting point: 262 DEG C, decomposition,
[390] 4-amino-3-chloro-6- (2- (5-methyl-1,3,4-oxadiazolyl)) pyridine-2-carboxylic acid (compound 227); Melting point: 210 ℃,
[391] 4-amino-3-chloro-6- (5-pyrimidinyl) pyridine-2-carboxylic acid (compound 228); Melting point: 180 ℃,
[392] 4-amino-3-chloro-6- (2- (5-methyl-1,3,4-thiadiazolyl)) pyridine-2-carboxylic acid (compound 229); Melting point: 200-201 캜,
[393] 4-amino-3-chloro-6- (2-benzothiazolyl) pyridine-2-carboxylic acid (compound 230); Melting point: 283 ℃,
[394] 4-amino-3-chloro-6- (5-oxazolyl) pyridine-2-carboxylic acid (compound 231); Melting point: 166 to 170 ° C,
[395] 4-amino-3-chloro-6- (2-benzoxazolyl) pyridine-2-carboxylic acid (compound 232); Melting point: 262 ° C (decomposition),
[396] 4-Amino-3-chloro-6- (3- (6-methyl) pyridazinyl) pyridine-2-carboxylic acid (compound 233); Melting point: 212-213 ° C,
[397] 4-amino-3-chloro-6- (3- (6-methyl) pyridazyl) pyridine-2-carboxylic acid (compound 234); melting point: 212 to 213 ° C,
[398] 4-amino-3-chloro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylic acid (compound 235); ¹ H NMR (DMSO-d ₆ ): δ 8. 01 (s, lH), 7.53 (s, lH), 6.76 (wide s, 2H), 2.71 (s, 3H),
[399] 4-amino-3,5-dichloro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylic acid (compound 236); ¹ H NMR (DMSO-d ₆ ): δ 7.88 (s, lH), 6.98 (wide s, 2H), 2.71 (s, 3H),
[400] 4-amino-3,5-dichloro-6- (5-chloro-2-furanyl) pyridine-2-carboxylic acid (compound 237); _{^{l H NMR (DMSO-d 6}} ): δ7.33 (d, J = 3.6Hz, 1H), 7.05 ( broad s, 2H), 6.72 (d , J = 3. 6Hz, 1H).
[401] 4-Amino-3-chloro-5-fluoro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylic acid (compound 238): ^l H NMR (DMSO-d ₆ ): δ7.73 ( s, lH), 6.90 (wide s, 2H), 2.43 (s, 3H),
[402] 4-Amino-3-chloro-6- (2-methoxy-5-pyrimidinyl) -2-carboxylic acid (compound 239); Melting point: 153 ℃,
[403] 4-amino-3-chloro-6- (2- (5-methylthiazolyl)) pyridine-2-carboxylic acid (compound 240); Melting point: 166-167 ° C and
[404] 4-amino-3,5-dichloro-6- (5-thiazolyl) pyridine-2-carboxylic acid (compound 241); Melting point: 175 to 177 ° C.
[405] 38. Method of Preparation of Methyl 4-amino-3-chloro-6- (4-hydroxymethylphenyl) pyridine-2-carboxylate (Compound 242):
[406] Sodium borohydride (112 mg, 3 mmol) in methyl 4-amino-3-chloro-6- (4-formylphenyl) pyridine-2-carboxyl in methanol / dichloromethane (1: 1, 100 mL) cooled using an ice bath. Slowly add to the rate (2.87 g, 9.87 mmol) solution. After the addition is complete, the ice bath is removed and the reaction mixture is stirred for 15 minutes and then concentrated. The residue is dissolved in ethyl acetate / water and the organic phase is washed with brine, then dried (MgSO ₄ ) and concentrated. The residue was column chromatographed on silica gel (40% ethyl acetate / hexane) to give methyl 4-amino-3-chloro-6- (4-hydroxymethylphenyl) pyridine-2-carboxylate having a melting point of 138-139 ° C. 2.5 g, 8.54 mmol) is obtained.
[407] 39. Preparation of Methyl 4-amino-3-chloro-6- [4- (fluoromethyl) phenyl] pyridine-2-carboxylate (Compound 243) :
[408] (Diethylamino) sulfur trifluoride (0.73 mL, 5.5 mmol) in methyl 4-amino-3-chloro-6- (4-hydroxymethyl-phenyl) pyridine-2-carboxyl in dichloromethane (35 mL) at 0 ° C. Add dropwise to the rate (1.46 g, 5.0 mmol) solution. The reaction mixture is stirred for 15 minutes, quenched with ice and then quenched with water. The product is extracted with ethyl acetate and the organic phase is washed with brine and then concentrated. The residue was purified by column chromatography (dichloromethane / hexane) to give methyl 4-amino-3chloro-6- (4-fluoromethylphenyl) pyridine-2-carboxylate (480 mg, 1.6) with a melting point of 95-97 ° C. mmol) is obtained.
[409] 40. Method for preparing decyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 244):
[410] Methyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (0.545 g, 1.73 mmol) is suspended in decanol (20 mL) and titanium methoxide (0.029 g, 1.73 mmol), and then the mixture is heated to reflux for 5 hours. The reaction mixture is concentrated and the residue is dissolved in ethyl acetate (100 mL) and then washed with water (100 mL) and saturated sodium bicarbonate (100 mL). The organic phase is dried (MgSO ₄ ) and concentrated to decyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (0.67 g, 1.5 mmol) is obtained.
[411] The following esters were prepared in a similar manner:
[412] 2-butoxyethyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 245); Melting point: 103-104 캜,
[413] 2-ethylhexyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 246); ¹ H NMR (CDCl ₃ ): δ 7.89 (d, 2H), 7.41 (d, 2H), 4. 32 (d, 2H), 1.94 (m, 6H), 1.75 (m, 1H), 1.40 (m, 8H).
[414] 2-methylheptyl-4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 247); ¹ H NMR (CDC1 ₃ ): δ7.91 (d, 2H), 7.44 (d, 2H), 5.23 (m, 1H), 4.85 (s, 2H), 1.89 (t, 3H), 1.70 (m, 1H ), 1.38 (d, 2H), 1.26 (m, 8H),
[415] 2-butoxyethyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 248); ¹ H NMR (CDC1 ₃ ): δ7.75 (d, 2H), 7.19 (d, 2H), 7.04 (s, 1H), 4.83 (s, 2H), 4.55 (t, 2H), 3.78 (t, 2H ), 3.53 (t, 2H), 2.37 (s, 3H), 1.91 (t, 3H), 1.58 (m, 2H), 1.38 (m, 2H),
[416] Butyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 249); Melting point: 60-62 ° C,
[417] Ethoxybutyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 250); ¹ H NMR (CDC1 ₃ ): δ 7.81 (d, 2H), 7.22 (d, 2H), 7.08 (s, 1H), 4.79 (s, 2H), 4.53 (t, 2H), 3.63 (t, 2H ), 3.52 (q, 2H), 2.41 (s, 3H), 2.10 (m, 2H), 1.22 (t, 3H),
[418] 2-ethylbutyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 251); ¹ H NMR (CDC1 ₃ ): δ 7.82 (d, 2H), 7.22 (d, 2H), 4.75 (s, 2H), 4.75 (s, 2H), 2.39 (s, 2H), 2.39 (s, 2H ), 1.91 (m, 6H), 1.42 (m, 8H),
[419] Ethyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 252); Melting point: 88-89 ° C.,
[420] Butoxyethyl 4-amino-3-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate, (compound 253); Melting point: 103-104 캜,
[421] 2-ethylhexyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 254); ¹ H NMR (CDCl ₃ ): δ7.91 (d, 2H), 7.41 (d, 2H), 4.86 (s, 2H), 4.32 (d, 2H), 1.94 (m, 6H), 1.75 (m, 1H ), 1.40 (m, 8H),
[422] Ethyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 255); ¹ H NMR (DMSO-d ₆ ): δ7.75 (d, 1H), 7.50 (m, 2H), 7.05 (s, 1H), 4.50 (q, 2H), 5.0 (wide s, 2H), 1.30 ( t, 3H),
[423] Propyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 256); ¹ H NMR (CDC1 ₃ ): δ7.60 (d, 1H), 7.50 (m, 1H), 7. 35 (m, lH), 7.05 (s, lH), 5.00 (wide s, 2H), 4.40 (t, 2H), 1.95 (m, 2H), 1.05 (t, 3H),
[424] Butyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 257); ¹ H NMR (CDCl ₃ ): δ7.60 (d, 1H), 7.50 (m, 1H), 7.35 (m, lH), 7.05 (s, 1H), 5.00 (wide s, 2H), 4.50 (t, 2H), 1.90 (m, 2H), 1.50 (m, 2H), 1.00 (t, 3H),
[425] Pentyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 258); ¹ H NMR (CDC1 ₃ ): δ7.60 (d, 1H), 7.50 (m, 1H), 7. 35 (m, 1H), 7.05 (s, 1H), 5.00 (wide s, 2H), 4.5 (t, 2H), 1.95 (m, 2H), 1.4 (m, 4H), 0.90 (t, 3H),
[426] 2-ethylhexyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 259); ¹ H NMR (CDC1 ₃ ): δ7.60 (d, 1H), 7.50 (m, 1H), 7.35 (m, 1H), 7.30 (s, 1H), 5.50 (wide s, 2H), 4.35 (d, 2H), 1.90 (m, 1H), 1.50 (m, 8H), 0.90 (m, 6H),
[427] Decyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 260); _{^{l H NMR (CDC1 3):}} δ7.60 (d, 1H), 7.45 ( broad s, 1H), 7.35 (d , 1H), 7.25 (s, 1H), 4.90 ( broad s, 2H), 4.40 (t , 2H), 1.80 (m, 2H), 1. 30 (m, 17 H),
[428] 2-methylethyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 261); ¹ H NMR (DMSO-d ₆ ): δ7.75 (d, 1H), 7.50 (m, 2H), 7.05 (s, 1H), 5.20 (m, 1H), 3.80 (wide s, 2H), 1.40 ( d, 6H),
[429] Hexyl 4-amino-3-chloro-6- (2,4-dichlorophenyl) pyridine-2-carboxylate (Compound 262); ¹ H NMR (CDCl ₃ ): δ 7.69 (d, 1H), 7.50 (m, lH), 7.30 (d, 1H), 7.05 (s, 1H), 4.95 (wide s, 2H), 4.50 (t, 2H), 1.80 (m, 2H), 1.80 (m, 4H), 1.00 (t, 2H),
[430] Ethyl 4-amino-3-chloro-6- (4-methylphenyl) pyridine-2-carboxylate (Compound 263); melting point: 129-130 ° C.,
[431] 41.Method for preparing 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) -2- (N-benzyl) picolinamide (Compound 264):
[432] 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (80 mg, 0.415 mmol) was added to 4-amino-3-chloro-5-fluoro-6- (in tetrahydrofuran (8 mL) at room temperature. 4-chlorophenyl) pyridine-2-carboxylic acid (100 mg, 0.332 mmol), benzyl amine (43 mg, 0.398 mmol), N-methylmorpholine (74 mg, 0.731 mmol), 1-hydroxybenzotriazole (91.5 mg, 0.598 mmol). After 16 hours, the reaction mixture is concentrated and the residue is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is saturated with saturated aqueous sodium bicarbonate and brine and dried (MgSO ₄ ). Purification by column chromatography yields 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) -2- (N-benzyl) picolinamide (112 mg, 0.287 mmol).
[433] ¹ H NMR (CDC1 ₃ ): δ8.13 (m, 1H), 7.83 (m, 2H), 7.48-7. 29 (m, 6H), 5.03 (wide s, 2H), 4.67 (d, J = 6.0 Hz, 2H).
[434] 42. Preparation of Methyl 4-N-methylamino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (Compound 265):
[435] Methyl 4-amino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (1.0 g, 3.2 mmol) in tetrahydrofuran (12 mL), iodomethane (0.3 mL, 4.8 mmol) and sodium hydroxide (0.16 g, 3.9 mmol) solutions are refluxed under nitrogen atmosphere for 4 hours. After cooling, the solvent is evaporated off and the residue is dissolved in ethyl acetate (50 mL). The organic layer is washed with sodium bicarbonate (3 × 50 mL), dried (Na ₂ SO ₄ ) and then concentrated. The product was purified by column chromatography (dichloromethane) to give methyl 4-N-methylamino-3-chloro-5-fluoro-6- (4-chlorophenyl) pyridine-2-carboxylate (0.154 g, 0.47 mmol) To obtain:
[436] ¹ H NMR (CDC1 ₃ ): δ 7.83 (d, 2H) 7.44 (d, 2H) 4.88 (s, 1H) 3.97 (s, 1H) 3.29 (d, 3H).
[437] 43.Method for preparing methyl 4-acetamido-3-chloro-6- (1-ethoxyvinyl) pyridine-2-carboxylate:
[438] Methyl 4-acetamido-3,6-dichloropyridine-2-carboxylate (0.988 g, 4.0 mmol), ethoxyvinylbutyltin (2.70 mL, 8.0 mmol) and cesium fluoride (1.34 g) in dioxane (20 mL) , 8.8 mmol) sparged with nitrogen for 15 minutes. Dichlorobis (turaphenylphosphine) palladium (II) (0.140 g, 0.2 mmol) is added and then the mixture is heated at 100 ° C. for 5 hours. After cooling, ether is added and the reaction mixture is filtered through a silica plug. The solvent was removed and the crude product was purified by chromatography [ethyl acetate: hexane (1: 2)] to yield methyl4-acetamido-3-chloro-6- (1-ethoxyvinyl) pyridine-2-carboxylate. (0.780 g, 2.6 mmol) is obtained.
[439] ¹ H NMR (CDCl ₃ ): δ 8.85 (s, 1H), 7.90 (wide s, 1H), 5.47 (d, J = 2.0 Hz, 1H), 4.44 (d, J = 2.0 Hz, 1H), 4.01 (s, 3H), 3.98 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H).
[440] 44.Method for preparing methyl 4-acetamido-3-chloro-6- (bromoacetyl) pyridine-2-carboxylate:
[441] N-bromosuccinimide (0.377 g, 2.13 mmol) was added to methyl 4-acetamido-3-chloro-6- (l-ethoxyvinyl) pyridine-2 in THF (40 mL) and water (2 mL) at room temperature. Add one total of carboxylate (0.636 g, 2.13 mmol) solution. After 15 minutes, the reaction mixture is concentrated and the residue is partitioned between dichloromethane and water. The organic layer is separated, dried (MgSO ₄ ) and then concentrated to give methyl 4-acetamido-chloro-6- (bromoacetyl) pyridine-2-carboxylate (0.714 g, 2.04 mmol).
[442] ¹ H NMR (CDC1 ₃ ): δ9.12 (s, 1H), 7.99 (wide s, 1H), 4.82 (s, 2H), 4.06 (s, 3H), 2.36 (s, 3H).
[443] 45.Method for preparing methyl 4-acetamido-3-chloro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylate (Compound 266):
[444] Methyl 4-acetamido-3-chloro-6- (bromoacetyl) pyridine-2-carboxylate (0.10 g, 0.286 mmol) and thioacetamide (21.5 mg, 0.286 mmol) were combined in methanol (5 mL), The temperature is raised to 60 ° C. for 15 minutes. After cooling, the reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate: hexane, 2: 1) to methyl acetamido-3-chloro-6- (4- (2-methylthiazolyl) Obtain pyridine-2-carboxylate (25 mg, 0.078 mmol).
[445] ¹ H NMR (CDC1 ₃ ): δ 9.24 (s, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 4.03 (s, 3H), 2.79 (s, 3H), 2.34 (s, 3H ).
[446] The following compounds were prepared in a similar manner:
[447] Methyl 4-amino-3, 5-dichloro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylate (Compound 267); ¹ H NMR (CDC1 ₃ ): δ 7. 14 (s, 1H), 5.40 (wide s, 2H), 3.98 (s, 3H), 2.81 (s, 3H),
[448] Methyl 4-amino-3-chloro-5-fluoro-6- (4- (2-methylthiazolyl)) pyridine-2-carboxylate (Compound 268); ¹ H NMR (CDC1 ₃ ): δ 7.81 (s, 1H), 4.96 (wide s, 2H), 3.97 (s, 3H), 2.80 (s, 3H).
[449] Methyl 4-amino-3-chloro-6- (4- (2,2,2-trifluoromethylthiazolyl)) pyridine-2-carboxylate (Compound 269); ¹ H NMR (CDC1 ₃ ): δ 8.35 (s, 1H), 7.65 (s, 1H), 4.92 (wide s, 2H), 4.04 (s, 3H), (with trifluorothioacetamide).
[450] Methyl 4-amino-3-chloro-5-fluoro-6- (4- (2,2,2-trifluoromethyl thiazolyl)) pyridine2-carboxylate (Compound 270); ¹ H NMR (CDC1 ₃ ): δ 8.28 (s, 1H), 5.03 (wide s, 2H), 4.02 (s, 3H), (with trifluorothioacetamide).
[451] 46. Method for preparing methyl 3,4,5-trichloro-6- (5-chloro-2-furyl) pyridine-2-carboxylate:
[452] Benzyltrimethylammonium tetrachloroiodate (292 mg, 0.70 mmol) was added to methyl-3,4,5-trichloro-6- (2-furyl) pyridine-2-carboxylate (101 mg, 0.33 mmol) in acetic acid (5 mL). To the solution. After 1 hour, the suspension is diluted with diethyl ether and the organic mixture is washed with 0.1N sodium thiosulfate and 0.1N sodium bicarbonate and dried (MgSO ₄ ). The residue was purified by column chromatography (diethyl ether: hexane, 5:95) to give methyl 3,4,5-trichloro-6- (5-chloro-2-furyl) pyridine-2-carboxylate (58 mg, 0.17 mmol) is obtained.
[453] ¹ H NMR (CDC1 ₃ ): δ 7.41 (d, J = 3.6 Hz, 1 H), 6.40 (d, J = 3. 6 Hz, 1H), 4.05 (s, 3H).
[454] 47. Methyl 6- (5-bromo-2-thiazolyl) -3,4-dichloropyridine-2-carboxylate and methyl 4-bromo-6- (5-bromo-2-thiazolyl) -3 Method for preparing chloropyridine-2-carboxylate:
[455] Bromine (0.188 mL, 3.67 mmol) is added to a solution of methyl 3,4-dichloro-6- (2-thiazolyl) pyridine-2-carboxylate (1.01 g, 3.5 mmol) in acetic acid (15 mL). The mixture is heated at 75 ° C. overnight. After cooling, saturated sodium bicarbonate is added and the mixture is extracted with diethyl ether. The organic layer is washed with saturated metabisulfate and brine and dried (MgSO ₄ ). The residue was purified by column chromatography (ethyl acetate: hexane, 1: 4) to give methyl 6 (5-bromo-2-thiazolyl) -3,4 dichloropyridine-2-carboxylate and methyl 4, which were not isolated. -Bromo-6- (5-bromo-2-thiazolyl) -3-chloropyridine-2-carboxylate (0.277 mg) mixture [ ^l H NMR (CDC1 ₃ ): δ8.51 (s, 0.33H) , 8.34 (s, 0.66H), 7.84 (s, 1H), 4.07 (s, 3H)] and unreacted methyl 3,4-dichloro-6- (2-thiazolyl) pyridine-2-carboxylate (185 mg) To obtain.
[456] 48. Method of Preparation of Herbicide Composition
[457] In the following exemplary compositions, parts and percentages are based on weight.
[458] Emulsifiable concentrate
[459] Compound (A)
[460] weight% Compound (18)26.2 Nonionic emulsifier- (di-tert-butyl) -phenyl-poly (oxypropylene) block polymer with polyglycol 26-3 (oxyethylene) The polyoxyethylene content is about 12 mol.5.2 Witconate P12-20 (anionic emulsifier-calcium dodecylbenzene sulfonate 60% by weight active)5.2 Aromatic 100 (aromatic solvent in the xylene region)63.4
[461] Compound (B)
[462] weight% Compound (22)3.5 Sunspray 11N (paraffin oil)40.0 Polyglycol 26-319.0 Oleic acid1.0 Aromatic solvents in the xylene region36.5
[463] Compound (C)
[464] weight% Compound (22)13.2 Stepon C-6525.7 Ethomeen T / 257.7 Etomin T / 1518.0 Aromatic solvents in the xylene region35.4
[465] Compound (D)
[466] weight% Compound (128)30.0 Agrimer Al-10LC (Emulsifier)3.0 N-methyl-2-pyrrolidone67.0
[467] Compound (E)
[468] weight% Compound (128)10.0 Agrimul 70-A (dispersant)2.0 Amsul DMAP 60 (Thickener)2.0 Emulsogen M (emulsifier)8.0 Attagel 50 (dispersion aid)2.0 Cereals76.0
[469] This concentrate is diluted with water to provide an emulsion of a suitable concentration to inhibit weeds.
[470] Wettable powder
[471] Compound (F)
[472] weight% Compound (65)26.2 Polyglycol 26-32.0 Polyfon H4.0 Zeosyl 100 (precipitated hydrated SiO ₂ )17.0 Barden Clay + Inert51.0
[473] Compound (G)
[474] weight% Compound (39)62.4 Polyphon H (sodium salt of lignin sulfonate)6.0 Sellogen HR (Sodium Naphthalene Sulfonate)4.0 Zeoroom 10027.6
[475] Compound (H)
[476] weight% Compound (128)1.4 Kunigel VI (carrier)30.0 Stepanol ME anhydride (wetting agent)2.0 Tosnanon GR 31A (Binder)2.0 Kaolin NK-300 Clay (filler)64.6
[477] The active ingredient is added to the corresponding carrier, mixed and ground to obtain a wettable powder that is wettable and has excellent susceptibility. By diluting such wettable powders with water, suspensions of suitable concentrations for inhibiting weeds can be obtained.
[478] Water Dispersible Granule
[479] Formulation (I)
[480] weight% Compound (165)26.0 Cellogen HR4.0 Polyphone H5.0 Zeoroom 10017.0 Kaolinite Clay48.0
[481] The active ingredient is added to the hydrated silica, mixed with the other ingredients and then ground to a powder. The powder is agglomerated with water and sieved to provide granules of -10 to +60 mesh. By dispersing these granules with water, a suspension suitable for inhibiting weeds can be obtained.
[482] Granules
[483] Compound (J)
[484] weight% Compound (65)5.0 Celetom MP-8895.0
[485] The active ingredient is added to the Celetom MP 88 carrier or other suitable carrier in a polar solvent such as N-methyl-pyrrolidinone, cyclohexanone, γ-butyrolactone, and the like. The resulting granules can be sprayed using hands, granulator applicators, airplanes, and the like, to suppress weeds.
[486] Compound (K)
[487] weight% Compound (225)1.0 Polyphone H8.0 Nekal BA 772.0 Zinc stearate2.0 Vaden clay87.0
[488] All materials are blended, ground to a powder, then water is added and the clay mixture is stirred until a paste is formed. The mixture is extracted through a die to obtain granules of the appropriate size.
[489] Water soluble liquid
[490] Compound (L)
[491] weight% Compound (165)3.67 Monoethanolamine pH Buffer0.5 water95.83
[492] The active ingredient is dissolved in an appropriate amount of water and additional monoethanolamine is added as a buffer. A water soluble surfactant can be added. Other auxiliaries may be added to improve the physical, chemical and / or formulation properties.
[493] 49. Assessment of herbicide activity after germination
[494] Seeds of the desired test plant species are sown in plastic pots with a surface area of 64 cm ² with a Grace-Sierra MetroMix 306 sowing mixture, typically having a pH of 6.0-6.8 and an organic content of about 30%. If it is necessary to improve germination and keep the plant healthy, it is treated with fungicides and / or other chemical or physical treatments. Plants are grown for 7 to 21 days in a greenhouse with a photoperiod of about 15 hours and maintained at about 23 to 29 ° C. during the day and 22 to 28 ° C. at night. Nutrient and water are supplied on a regular basis, and supplementary light is provided in an overhead metal halide 1000 W lamp as needed. Plants are used for testing when the first or second bony leaves are reached.
[495] The highest determined weight to be tested for each test compound is placed in a 20 mL glass vial and dissolved in 4 mL of a 97: 3 v / v (vol / vol) acetone and dimethyl sulfoxide (DMSO) mixture to give a thick stock. . If the test compound does not readily dissolve, the mixture is warmed and / or sonicated. The resulting thick stocks were acetone, water, isopropyl alcohol, DMSO, Atplus 411F Crop Oil Concentrate and Triton X-155 Surfactant (48.5: 39: 10: 1.5: 1.0: 0.02 v / v Dilute with an aqueous mixture containing b). The highest concentration solution to be tested was prepared by diluting 2 mL aliquots of the stock solution to 13 mL of the mixture, and the lower concentration by making serial dilutions of the stock solution. About 1.5 mL of each solution aliquot of known concentration was sprayed uniformly to each test plant pot using a Devilbiss atomizer operated at 2 to 4 psi (140 to 280 kP) compressed air pressure to each plant. Apply evenly. Control plants are sprayed in the same way using an aqueous mixture. In this test, about 1 g per hectare is sparged with a spray rate of 1 ppm.
[496] The treated and control plants are placed in a greenhouse as described above and water is supplied to the sewer to prevent the removal of moisture from the test compound. After two weeks, the condition of the test plant compared to the untreated plant is measured visually and evaluated on a 0 to 100% scale, where 0 corresponds to intact and 100 corresponds to complete death.
[497] J. Berkson. Journal of the American Statistical Society, 48, 565 (1953); D. Finney, "Probit Assay" Cambridge University Press (1952)], by using generally accepted probit assays, the data can be used to calculate GR ₅₀ and GR ₈₀ values. It is defined as a growth reduction factor corresponding to the effective amount of herbicide required to kill each target plant or inhibit 50 to 80%, respectively.
[498] Some compounds tested, spray rates used, plant species tested and results are shown in Tables 1A, 1B and 2. Selectivity to wheat and corn is shown in Tables 3 and 4.
[499]
[500]
[501] XANST = Dog Snout (Taxium Strummarium)
[502] CHEAL = Ming Joo Joo (Chenopodium album)
[503] ECHCG = weeds (Icainoclus cluster-Gali)
[504] CYPES = Yellow Nutserce (Cypercerus Cool Renters)
[505]
[506] XANST = Dogtail (xanthium strumarium)
[507] CHEAL = Ming Joo Joo (Chenopodium album)
[508] ECHCG = weeds (Icainoclus cluster-Gali)
[509] CYPES = Yellow Nutserce (Cypercerus Cool Renters)
[510]
[511] CHEAL = Ming Joo Joo (Chenopodium album)
[512] AMARE = White Mist (Red Root) (Amaranth Retroplexus)
[513] TRZAS = Wheat (B. Merika)
[514]
[515] XANST = Dog Snout (Taxium Strummarium)
[516] CHEAL = Ming Joo Joo (Chenopodium album)
[517] AMARE = White Magnolia (Red Root) (Amaranthus Retroplexus)
[518] ZEAMX = Corn (# 14 3377) (G Mace)
[519] 50. Assessment of herbicide activity before germination
[520] Soil matrix by mixing seeds of the desired test plant species in a ratio of 70:30 loam (43% silt, 19% clay and 38% sand; pH: about 8.1; organic content: about 1.5%) to sand Sowing on. The soil matrix is contained in plastic flowerpots with a surface area of 113 cm ² . If it is necessary to improve germination and keep the plant healthy, it is treated with fungicides and / or other chemical or physical treatments.
[521] The highest determined weight to be tested for each test compound is placed in 20 mL glass vials and dissolved in 4 mL of 97: 3 v / v (vol / vol) of acetone and dimethyl sulfoxide mixture to give a thick stock. If the test compound does not readily dissolve, the mixture is warmed and / or sonicated. The thick stock obtained is diluted with a mixture of water and Tween ^R 155 surfactant (99.9: 0.1) to give a sparging solution of known concentration. The highest concentration solution to be tested is prepared by diluting 2 mL aliquots of the stock solution to 15 mL of the mixture, and the lower concentration is prepared by serial dilution of the stock solution. About 2.5 mL of each known aliquot of the solution was sprayed uniformly onto the soil surface (113 cm ² ) using a 5.0 mL Cornwall glass syringe equipped with a TeeJet TN-3 hollow cone nozzle. The pollen is evenly sprayed on the soil. Spray to the control pot in the same manner using the aqueous mixture.
[522] Treatment pots and control pots are placed in a greenhouse with a photoperiod of about 15 hours and maintained at about 23 to 29 ° C. during the day and at 22 to 28 ° C. at night. Nutrient and water are supplied on a regular basis, and the auxiliary light is provided in an overhead metal halide 1000 W lamp as needed. Water is fed to a constant temperature. After 3 weeks, the condition of the germinated and grown treated plants compared to the condition of untreated plants grown by germination was visually measured and scaled from 0 to 100% (where 0 corresponds to intact and 100 completely killed or germinated). Is equivalent to not).
[523] Some compounds tested, spray rates used, plant species tested and results are shown in Tables 5A and 5B.
[524]
[525]
[526] CHEAL = Ming Joo Joo (Chenopodium album)
[527] AMARE = White Magnolia (Red Root) (Amaranthus Retroplexus)
[528] DIGSA = Winter (Large) (Digitaria guinealis)
[529] SETFA = Foxtail (Setaria Favery)

权利要求:
Claims (10)
[1" claim-type="Currently amended] Compounds of formula (I) and derivatives of agriculturally acceptable carboxylic acid groups.
Formula I

In Formula I above,
X is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, thio Cyanide or cyano;
Y is an aryl group selected from the group consisting of a heteroaryl group selected from the group consisting of phenyl, indanyl, naphthyl, and other five or six membered heteroaromatic rings containing one or more heteroatoms which may be fused to other aromatic systems , Aryl or heteroaryl group is unsubstituted, halogen, hydroxy, nitro, cyano, aryloxy, formyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkoxy, C ₁ -C ₆ acyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl, C _1- C ₆ alkylsulfonyl, aryl, C ₁ -C ₆ OC (O) alkyl, C ₁ -C ₆ NHC (O) alkyl, C (O) OH, C ₁ -C ₆ C (O) Oalkyl, C ( O) NH ₂ , C ₁ -C ₆ C (O) NHalkyl, C ₁ -C ₆ C (O) N (alkyl) ₂ , -OCH ₂ CH _2- , -OCH ₂ CH ₂ CH ₂ -,-OCH ₂ O- and -OCH ₂ CH ₂ 0- may be substituted with one or more substituents selected from the group consisting of ;
Z is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, aryloxy, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, thiocyanide Or cyano;
W is -NO ₂ , -N ₃ , -NR ₁ R ₂ , wherein R ₁ and R ₂ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl , Aryl, heteroaryl, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ acyl, C ₁ -C ₆ carboalkoxy, C ₁ -C ₆ alkylcarbamyl, C ₁ -C ₆ alkylsulfonyl , C ₁ -C ₆ trialkylsilyl or C ₁ -C ₆ dialkyl phosphonyl, or R ₁ and R ₂ together with N may be saturated or unsaturated, which may further contain O, S or N heteroatoms. 5 or forms a 6-membered ring), -N = CR ₃ R ₄ or -NHN = CR ₃ R ₄ (wherein, R ₃ and R ₄ are independently H, C _l- C ₆ alkyl, C ₃ -C ₆ alkenyl, C ₃ -C ₆ alkynyl, aryl or heteroaryl, or R ₃ and R ₄ together with = C form a saturated five or six membered ring.
[2" claim-type="Currently amended] The compound of claim 1, wherein X represents H or F. 7.
[3" claim-type="Currently amended] The compound of claim 1 or 2, wherein Y is A heteroaryl group selected from the group consisting of: wherein the heteroaryl group is unsubstituted or substituted with one or more halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl groups.
[4" claim-type="Currently amended] The compound of claim 1 or 2, wherein Y represents a phenyl group unsubstituted or substituted with one or more halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl groups.
[5" claim-type="Currently amended] The compound of claim 4, wherein Y represents a phenyl group substituted in the para position.
[6" claim-type="Currently amended] The compound of any one of claims 1-5, wherein Z represents Cl.
[7" claim-type="Currently amended] 7. The compound of claim 1, wherein W represents NR ₁ R ₂ , wherein R ₁ and R ₂ independently represent H or C ₁ -C ₆ alkyl.
[8" claim-type="Currently amended] The compound of claim 1, wherein X represents H or F, Y represents unsubstituted or phenyl substituted with one or more halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl groups, and Z represents Cl And W represents NR ₁ R ₂ , wherein R ₁ and R ₂ independently represent H or C ₁ -C ₆ alkyl.
[9" claim-type="Currently amended] A herbicidal composition comprising a herbicidally effective amount of the compound of formula (I) according to any one of claims 1 to 8 in admixture with an agriculturally acceptable adjuvant or carrier.
[10" claim-type="Currently amended] A method of controlling weeds, comprising contacting the weeds or their habitats with the herbicidal effective amount of the compound of formula I according to any one of claims 1 to 8 or spraying the soil to prevent weed germination.

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同族专利:

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公开号 | 公开日

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EP1414814B1|2005-02-02|

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WO2003011853A1|2003-02-13|

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US20030114311A1|2003-06-19|

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CA2453623A1|2003-02-13|

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DE60202876D1|2005-03-10|

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CN1245401C|2006-03-15|

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BR0211532B1|2013-05-21|

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AU2002322777B2|2007-08-02|

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JP4528524B2|2010-08-18|

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CA2453623C|2010-11-09|

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WO2003011853A8|2004-07-15|

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KR100904155B1|2009-06-22|

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BR0211532A|2004-09-14|

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CN1551876A|2004-12-01|

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DE60202876T2|2006-03-23|

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EP1414814A1|2004-05-06|

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JP2005505523A|2005-02-24|

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US6784137B2|2004-08-31|

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AR037228A1|2004-11-03|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-07-30|Priority to US30861701P

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2001-07-30|Priority to US60/308,617

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2002-07-30|Application filed by 다우 아그로사이언시즈 엘엘씨

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2002-07-30|Priority to PCT/US2002/024120

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2004-03-03|Publication of KR20040018532A

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2009-06-22|Application granted

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2009-06-22|Publication of KR100904155B1

优先权:

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申请号 | 申请日 | 专利标题

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US30861701P| true| 2001-07-30|2001-07-30|

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US60/308,617|2001-07-30|

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PCT/US2002/024120|WO2003011853A1|2001-07-30|2002-07-30|6-aryl-4-aminopicolinates and their use as herbicides|