Process for making isoxazoline compound and intermediate thereof

Abstract

To provide a process for making an isoxazoline compound, specifically lotilaner.SOLUTION: Provided is a process for making enantiomerically pure isoxazoline compounds of a formula (1). Also provided is a process for making enantiomerically pure isoxazoline compounds of the formula (1), characterized by improving the enantiomeric purity of 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid by crystallization.SELECTED DRAWING: None

Description

[Background technology]

[0001] Lotilaner, i.e., 5-[(5S)-4,5-dihydro-5-(3,4,5-trimethylsilyl]-2,4-dihydro- ... 3-methyl-5-(trifluoromethyl)-3-isoxazolyl N-[2-oxo-2-[(2,2,2-trifluoroethyl)-trifluoroethyl]a (S)-5-[5-(3,4, 5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazo [(2,2,2-trifluoromethyl-3-yl)-3-methyl-thiophene-2-carboxylic acid] The compound (1a) shown below is a compound of formula (1a): [ka] It is useful for pest control, particularly for the control of ectoparasites. It inhibits two types of gamma-aminobutyric acid (GABA)-gated chloride ion channels. blocks the movement of chloride ions across cell membranes, resulting in the death of insects and mites In particular, lotilaner has been shown to be effective in animals (humans, livestock including fish, and domestic animals, particularly dogs). ) including the treatment of ectoparasites (e.g., flea infestations) and the treatment of mite infestations and It is useful for extermination.

[0002] Lotilaner is a well-known isoxazoline derivative with insecticidal and acaricidal activity. It belongs to the class of insecticides and is used in agriculture, forestry, lawn care, home and wood products, seedling protection, and veterinary medicine. For example, such isoxazolines can be used as the compounds described in WO2010 / 0700 68 and WO2013 / 079407.

[0003] The production of pure enantiomers is expensive and time-consuming. The method is described in WO2014 / 090918, in which (S)-ena The enantiomers are the following carboxylic acids: [ka] are resolved by crystallization of the diastereomeric salts, followed by repeated cycles of racemization. and then further resolving the diastereomeric salts. The process of undergoing cycles of racemization and resolution is laborious and expensive. It is advantageous to form the antipodes directly. The direct formation of the enantiomers of isomethyl-4,5-dihydro-isoxazoles is known in the art. Known in the art, including US2014 / 0206633; US2014 / 0350 261;WO2013 / 116236;WO2014 / 081800;Angew,Ch em.Int.Ed.2010,49,5762-7566; and WO2017 / 176 This includes those described in 948. Summary of the Invention

[0004] The present invention provides a method for making an isoxazoline compound, particularly lotilaner, comprising the steps of: Cinchona alkaloid-directed asymmetric hydroxylamine / enone cascade reaction The present invention provides a method that avoids the costly and laborious cycle of resolution, racemization, and further resolution. Provide.

[0005] In one embodiment, the present invention provides an enantiomerically pure isoxazolidinyl compound of formula (1) compounds [ka] wherein R5 is a C1-C4 aliphatic chain optionally containing a double or triple bond, The chain may optionally be substituted with halogen, cyano, nitro, hydroxyl, oxo, C3-C6 cycloalkyl, or alkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C1-C4 alkyl -C(O)C(alkyl), -SC(O)C(alkyl), -S(O)C(alkyl), and -SO(C) Substituted with 1 to 5 substituents independently selected from the group consisting of 1 to C4 alkyl ) 1. A method for preparing (i) reacting a compound of formula (2) with hydroxylamine [ka] (wherein X is halogen and —C(O)OR4, where R4 is C1-C4 alkyl) ), a suitable base, and a compound of formula (3) [ka] (In the formula, Y - is an anion, R1 is selected from the group consisting of hydrogen and methoxy; R2 is selected from the group consisting of ethyl and vinyl; R3 is aryl, optionally nitro, halogen, amino, trifluoromethyl , C1-C4 alkyl, C1-C4 alkoxy, and benzyloxy, aryl substituted with 1 to 5 substituents selected from the group consisting of aryl, heteroaryl, and Optionally, halogen, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy and heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy ... (selected from the group consisting of to obtain a compound of formula (4), [ka] (ii) converting X in the compound of formula (4) to a carboxylic acid to obtain a compound of formula (5); P, [ka] (iii) optionally reacting a compound of formula (5) with C 1~5 Alcohol, C 2~5 Alkyl Anid, C 3~9 Alkyl ketone, C 2~8 Alkyl ethers, and C 2~8 Alkyria acetate, and optionally water and C 5~8 From hydrocarbons and an anti-solvent selected from the group consisting of: and (iv) coupling a compound of formula 5 with an appropriate amine The present invention relates to a method, including:

[0006] In another aspect, the present invention provides enantiomerically pure lotilaner of formula (1a) [ka] 1. A method for preparing (i) reacting a compound of formula (2) with hydroxylamine [ka] (wherein X is halogen and —C(O)OR4, where R4 is C1-C4 alkyl) ), a suitable base, and a compound of formula (3) [ka] (In the formula, Y - is an anion, R1 is selected from the group consisting of hydrogen and methoxy; R2 is selected from the group consisting of ethyl and vinyl; R3 is aryl, optionally nitro, halogen, amino, trifluoromethyl , C1-C4 alkyl, C1-C4 alkoxy, and benzyloxy, aryl substituted with 1 to 5 substituents selected from the group consisting of aryl, heteroaryl, and Optionally, halogen, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy and heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy ... (selected from the group consisting of to obtain a compound of formula (4), [ka] (ii) converting X in the compound of formula (4) to a carboxylic acid to obtain a compound of formula (5); P, [ka] (iii) optionally reacting a compound of formula (5) with C 1~5 Alcohol, C 2~5 Alkyl Anid, C 3~9 Alkyl ketone, C 2~8 Alkyl ethers, and C 2~8 Alkyria acetate, and optionally water and C 5~8 From hydrocarbons and an anti-solvent selected from the group consisting of: and (iv) reacting a compound of formula 5 with 2-amino-2',2',2'-trifluoroethyl-acetonitrile It can be coupled with an amide or optionally a carboxyl-protected glycine. If necessary, the compound was deprotected and coupled with 2,2,2-trifluoroethylamine. The method further relates to a method comprising coupling a sequential reactant.

[0007] In one embodiment, the present invention provides an enantiomerically pure isoxazolidinyl compound of formula (1) wherein R5 is a C1-C4 aliphatic chain optionally containing a double or triple bond. The chain may optionally be a halogen, cyano, nitro, hydroxyl, oxo, C3- C6 cycloalkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C1 -C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, and - substituted with 1 to 5 substituents independently selected from the group consisting of SO2C1-C4 alkyl; a process for preparing an enantiomerically pure compound of formula (4) [ka] (wherein X is halogen and —C(O)OR4, where R4 is C1-C4 alkyl) ), wherein (i) reacting a compound of formula (2) with hydroxylamine [ka] (wherein X is halogen and —C(O)OR4, where R4 is C1-C4 alkyl) ), a suitable base, and a compound of formula (3) [ka] (In the formula, Y - is an anion, R1 is selected from the group consisting of hydrogen and methoxy; R2 is selected from the group consisting of ethyl and vinyl; R3 is aryl, optionally nitro, halogen, amino, trifluoromethyl , C1-C4 alkyl, C1-C4 alkoxy, and benzyloxy, aryl substituted with 1 to 5 substituents selected from the group consisting of aryl, heteroaryl, and Optionally, halogen, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy and heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy ... (selected from the group consisting of The method includes reacting

[0008] The present invention is further illustrated by Scheme 1. In Scheme 1, all products The method can be carried out by techniques well known in the art (e.g., extraction, evaporation, trituration, chromatographic separation). The compound can be isolated and purified by various techniques (microcrystalline cellulose, chromatography, and recrystallization). [ka]

[0009] Step 1 of Scheme 1 is the preparation of a compound of formula (2) where X is a halogen and —C(O) OR4 (wherein R4 is C1-C4 alkyl) with the formula ( 3) in the presence of hydroxylamine and a suitable base to form the enantiomer Cinchona alkaloid-directed asymmetric hydroxylation affords the merically pure compound of formula (4) 1 is a diagram of the amine / enone cascade reaction.

[0010] Those skilled in the art will appreciate that compounds of formula (2) exist as geometric isomers. In the compound of formula (2), the bond from the double bond to the CF3 group does not allow such a geometric isomerism. The present invention relates to isomers (including E-isomers, Z-isomers, and mixtures thereof) in any ratio. The use of E-isomers, Z-isomers, and mixtures thereof is particularly preferred. Compound 2) is a compound in which X is chloro or bromo, more preferably bromo. Other particularly preferred compounds of formula (2) are those in which X is —C(O)OR4 and R4 is The compound is selected from the group consisting of methyl and ethyl, more preferably methyl. Preferred compounds of formula (3) are those in which R1 is methoxy.

[0011] The compound of formula (3) is typically 0.0 based on the compound of formula (2). A molar ratio of 0.01 to 10, more typically a molar ratio of 0.01 to 1, and even more typically 0. It is used in a molar ratio of 0.5 to 0.5.

[0012] Examples of suitable bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, hydroxide Barium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxy Examples of suitable amines include potassium hydroxide, potassium t-butoxide, and the like. Suitable bases are lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, etc. , cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxide, hydroxide The base is selected from the group consisting of potassium t-butoxide, potassium t-butoxide, and mixtures thereof. Typically, the base is present in a molar ratio of 1 to 10, more typically based on the compound of formula (2). are used in a molar ratio of 1 to 5, and even more typically in a molar ratio of 2 to 4. The manufacturer advises that if hydroxylamine is used as the salt, an additional base may be used. You will understand what you will get.

[0013] The reaction illustrated in Step 1 of Scheme 1 can be carried out in a solvent (e.g., a lower alcohol, e.g., chlorinated solvents (e.g., methyl chloride, solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, etc.), ether solvents (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, etc.), dihydrofuran, diisopropyl ether, and methyl t-butyl ether, t-amino methyl ether, ethyl t-butyl ether), aromatic solvents (e.g., toluene, chlorobenzene, and benzotrifluoride), or alkane solvents (e.g., hexane, heptane, methylcyclohexane, and cyclohexane), as well as mixtures of such solvents The reaction is typically carried out in a temperature range of -50°C to 50°C. At temperatures of, more typically, -40°C to 0°C, more typically, -40°C to -10°C, More typically, it is carried out at a temperature of -30°C to -20°C and generally takes 1 to 48 hours.

[0014] Exemplary compounds of formula (3) include (R)-[(2S)-1-[(3,5-bis- (trifluoromethylphenyl)methyl]-5-vinyl-quinuclidin-1-ium-2- (R)-[(2S)-1- [(3,5-bis-trifluoromethylphenyl)methyl]-5-vinyl-quinuclidine -1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol chloride, (R )-[(2S)-1-[(3,5-bis-trifluoromethylphenyl)methyl]-5- Vinyl-quinuclidin-1-ium-2-yl]-(4-quinolyl)methanol bromide , (R)-[(2S)-1-[(2,3,5-trifluorophenyl)methyl]-5-biphenyl Nyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinolyl)methano Bromide, (R)-[(2S)-1-[(3,5-di-t-butylphenyl)methyl ]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinol (R)-[(2S)-1-[(anthracen-9-yl) Methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4- quinolyl)methanol bromide.

[0015] Step 2 of Scheme 1 involves converting X of a compound of formula (4) to a carboxylic acid of a compound of formula (5). The compound of formula (4) where X is a halogen atom is converted into The residue is metallated by halogen-metal exchange with a Grignard reagent or alkyllithium, and the metal The carboxylic acid can be produced by reacting the carboxylic acid species with carbon dioxide or with a reagent that can generate the carboxylic acid. This reaction can be easily carried out to give the compound of formula (5). It is well known. See WO2014 / 090918. The compound of formula (4) is easily converted to the compound of formula (5) by hydrolysis. The reaction is easy to perform and well known.

[0016] Step 3 of Scheme 1 involves coupling a compound of formula (5) with an appropriate amine to give a compound of formula To obtain an isoxazoline compound of formula (1) (e.g., Lotilaner, a compound of formula (1a)), 1 illustrates the steps of the reaction of the present invention. Depending on the appropriate amine, this coupling step can yield isoxazolines other than lotilaner. The phosphorus compound can be obtained. Suitable amines refer to compounds of formula (6). [ka] wherein R5 is a C1-C4 aliphatic chain optionally containing a double or triple bond, The chain may optionally be substituted with halogen, cyano, nitro, hydroxyl, oxo, C3-C6 cycloalkyl, or alkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C1-C4 alkyl -C(O)C(alkyl), -SC(O)C(alkyl), -S(O)C(alkyl), and -SO(C) Substituted with 1 to 5 substituents independently selected from the group consisting of 1 to C4 alkyl ) In one embodiment, R5 is optionally halogen, cyano, nitro, hydroxyl, and C1-C2 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of oxo and In another embodiment, R5 is optionally substituted with 1 to 3 halogen substituents. In another embodiment, R5 is a C1-C2 alkyl optionally containing 1 to 3 fluorines. In another embodiment, R5 is a C1-C2 alkyl substituted with an fluoro substituent. In another embodiment, R5 is ethyl optionally substituted with 1 to 3 halogen substituents. and ethyl optionally substituted with 1 to 3 fluoro substituents. R5 is ethyl substituted with 1 to 3 fluoro substituents. is an ethyl substituted with three fluoro substituents.

[0017] An exemplary suitable amine is 2-amino-2',2',2'-toluidine, a compound of formula (7): Trifluoroethyl-acetamide [ka] Alternatively, optionally carboxyl-protected glycine can be reacted with 2,2,2-trifluoroethyl The reaction product is coupled with an amine. Carboxylic acid or activated carboxylic acid Acid derivatives (e.g., acid halides) can be coupled with amines in this manner to give amines. The steps for producing carboxyl-protected glycines are well known in the art. The use of amines, deprotection, and amide coupling with 2,2,2-trifluoroethylamine were also reported. This can be easily achieved in the same manner. reference.

[0018] In another aspect, the present invention provides an enantiomerically pure compound of formula (5) [ka] 1. A method for preparing (i) reacting a compound of formula (2) with hydroxylamine [ka] (wherein X is halogen and —C(O)OR4, where R4 is C1-C4 alkyl) ), a suitable base, and a compound of formula (3) [ka] (In the formula, Y - is an anion, R1 is selected from the group consisting of hydrogen and methoxy; R2 is selected from the group consisting of ethyl and vinyl; R3 is aryl, optionally nitro, halogen, amino, trifluoromethyl , C1-C4 alkyl, C1-C4 alkoxy, and benzyloxy, aryl substituted with 1 to 5 substituents selected from the group consisting of aryl, heteroaryl, and Optionally, halogen, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy and heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy ... (selected from the group consisting of to obtain a compound of formula (4), [ka] (ii) converting X in the compound of formula (4) to a carboxylic acid to obtain a compound of formula (5); pu, and (iii) optionally reacting a compound of formula (5) with C 1~5 Alcohol, C 2~5 Alkyl Anid, C 3~9 Alkyl ketone, C 2~8 Alkyl ethers, and C 2~8 Alkyria acetate, and optionally water and C 5~8 From hydrocarbons and an anti-solvent selected from the group consisting of The present invention relates to a method, including:

[0019] In another embodiment, in a process for preparing an enantiomerically pure compound of formula (5), In another embodiment, the crystallization step (iii) is carried out using a poorly soluble There is a medium.

[0020] The present disclosure also provides a compound of formula (5): 3-methyl-5-[(5S)-5-(3,4,5 -trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole-3- A method for improving the enantiomeric purity of a thiophene-2-ylcarboxylic acid, , C 1~5 Alcohol, C 2~5 Alkyl cyanide, C 3~9 Alkyl ketone, C 2~8 Alkyl ethers, and C 2~8 a solvent selected from the group consisting of alkyl acetates; Optionally, water and C 5~8 and a poor solvent selected from the group consisting of hydrocarbons. Also provided is a method, including:

[0021] 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trimethylphenyl) Fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid The enantiomeric purity of a compound can be determined under controlled conditions by crystallization from a solvent or solvent mixture. This can be improved by crystallization under the conditions 1~5 Alcohol, C2 ~5 Alkyl cyanide, C 3~9 Alkyl ketone, C 2~8 Alkyl ether, C 2~8 Alkyl acetate, preferably C 1~5 Alcohol, C 2~5 Alkyl cyanides, and and C 3~9 Alkyl ketones have been found to be useful solvents for such purification.

[0022] Accordingly, the present disclosure provides enantiomerically pure isoxazoline compounds of formula (1) 1. A method for making 3-methyl-5-[(5S)-5-(3,4,5-trimethyl-2-methyl-4- ...2-methyl chlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl] C is characterized by improving the enantiomeric purity of thiophene-2-carboxylic acid. 2~5 In a preferred embodiment, the method comprises crystallizing C from an alkyl cyanide. 2~5 The alkyl cyanide is acetonitrile.

[0023] The present disclosure relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid (compound of formula (5)), comprising the steps of: 1~5 In a preferred embodiment, the method comprises crystallizing the compound from alcohol. 1~5 The alcohol is isopropanol.

[0024] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 3~9 Alkyl ketone In a preferred embodiment, the method comprises crystallizing from C 3~9 Alkylke ton is acetone.

[0025] As used herein, the term "enantiomerically pure" means greater than 90% (or i.e., present in enantiomeric excess (i.e., ee) of 80% or greater (S) In one embodiment, "enantiomerically pure" refers to an enantiomer. The term refers to the (S)-enantiomer present in greater than 92% (i.e., 84% or greater ee). In one embodiment, the term "enantiomerically pure" refers to a 9-mer. Refers to the (S)-enantiomer present in greater than 4% (i.e., 88% or greater ee). In one embodiment, the term "enantiomerically pure" refers to an enantiomer that is greater than 95% (i.e., i.e., the (S)-enantiomer present in greater than 90% ee. In this context, the term "enantiomerically pure" refers to a compound that is greater than 96% (i.e., 92% In one embodiment, the term "(S)-enantiomer" refers to the (S)-enantiomer, which is present in an amount of 100 or more (ee). The term "enantiomerically pure" refers to an enantiomer that is greater than 97% (i.e., 94% or greater ee In one embodiment, "enantiomer" refers to the (S)-enantiomer present in the (S)-form. The term "merically pure" refers to a compound present in greater than 98% (i.e., 96% or greater ee). In one embodiment, "enantiomerically pure" refers to the (S)-enantiomer. The term "free" refers to (S)-enantiomers present in greater than 99% (i.e., 98% or greater ee). In one embodiment, the term "enantiomerically pure" refers to an antipodal or anti-antibody. The term refers to (S)-enanthates present in greater than 99.8% (i.e., 99.6% or greater ee). Refers to a thiomer.

[0026] The use of an anti-solvent may be advantageous. As used in this context, an "anti-solvent" is a solvent represented by formula (5): A solvent in which the solubility of the compound is significantly lower than that of the selective solvent. Preferably, the anti-solvent is miscible with the selective solvent.

[0027] Also provided is a method for improving the enantiomeric purity of a compound of formula (5) above, comprising the steps of: C 1~5 Alcohol, C 2~5 Alkyl cyanide, C 3~9 Alkyl ketone, C 2~8 a alkyl ether, and C 2~8 alkyl acetates. Also provided is a method comprising crystallizing from a solvent comprising an anti-solvent.

[0028] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid (compound of formula (5)), comprising the steps of: 1~5 In a preferred embodiment, the method comprises crystallization from alcohol / water. , C 1~5 The alcohol:water ratio is about 9:1 (v / v). , C 1~5 The alcohol is isopropanol. 1~5 The alcohol was isopropanol, and the ratio of isopropanol to water was 9:1 (v / v). v).

[0029] Thus, the present invention provides an enantiomerically pure isoxazoline compound of formula (1) 1. A method for making 3-methyl-5-[(5S)-5-(3,4,5-trimethyl-2-methyl-4- ...2-methyl chlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl] C is characterized by improving the enantiomeric purity of thiophene-2-carboxylic acid. 1~5 In a preferred embodiment, C1 ~5 The alcohol:water ratio is about 9:1 (v / v). ~5 The alcohol is isopropanol. 1~5 The alcohol was isopropanol, and the ratio of isopropanol to water was 9:1 (v / v). be.

[0030] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 3~9 Alkyl ketone In a preferred embodiment, the method comprises crystallizing the compound from water. 3~9 Archi The ratio of ketone to water is about 9:1 (v / v). 3~9 a In a further preferred embodiment, the alkyl ketone is acetone. 3~9 Alkylke The solvent is acetone, and the ratio of acetone:water is 9:1 (v / v).

[0031] Thus, the present invention provides an enantiomerically pure isoxazoline compound of formula (1) 1. A method for making 3-methyl-5-[(5S)-5-(3,4,5-trimethyl-2-methyl-4- ...2-methyl chlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl] C is characterized by improving the enantiomeric purity of thiophene-2-carboxylic acid. 3~9 In a preferred embodiment, a method is provided, comprising crystallizing from alkyl ketone / water. C 3~9 The ratio of alkyl ketone to water is about 9:1 (v / v). C 3~9 The alkyl ketone is acetone. ~9 The alkyl ketone is acetone and the ratio of acetone:water is 9:1 (v / v).

[0032] A preferred antisolvent is C 5~8 Particularly preferred anti-solvents are: Consists of water, pentane, hexane, heptane, cyclohexane, and methylcyclohexane A particularly preferred poor solvent is methylcyclohexane. The ratio of solvents is not critical and typically ranges from 2:1 to 1:6 (v / v).

[0033] Therefore, the present invention provides 3-methyl-5-[(5S)-5-(3,4,5-trichloro (phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene A method for improving the enantiomeric purity of phenyl-2-carboxylic acid, comprising the steps of: 1~5 a Alcohol and C 5~8 The present invention provides a method for producing a hydroxybenzoate comprising crystallizing the hydroxybenzoate from a hydrocarbon. In C 1~5 The alcohol is selected from the group consisting of ethanol and isopropanol. will be done.

[0034] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 2~8 Alkyl ether Ru and C 5~8 In a preferred embodiment, a method is provided for crystallizing the hydroxyl group from a hydrocarbon. C 2~8 The alkyl ethers are tetrahydrofuran and 2-methyltetrahydrofuran. The compound is selected from the group consisting of:

[0035] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 2~8 Alkyl acetate Route and C 5~8In a preferred embodiment, a method is provided for crystallizing the hydroxyl group from a hydrocarbon. C 2~8 The alkyl acetate may be selected from the group consisting of ethyl acetate and isopropyl acetate. be selected.

[0036] The present invention relates to 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 3~9 Alkyl ketone and C 5~8 In a preferred embodiment, the method comprises crystallizing the hydroxyl group from a hydrocarbon. , C 3~9 The alkyl ketone is selected from the group consisting of acetone and methyl ethyl ketone. do.

[0037] As used herein, the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or Specifically, the term "halogen" refers to fluorine, chlorine, and iodine atoms. More specifically, the term "halogen" refers to chlorine and bromine atoms. and bromine atoms.

[0038] Y - The term "anion" in relation to refers to a negatively charged organic or inorganic group. For example, Y - are tosylate, brosylate, mesylate, nosylate, triflate, acetate, etc., or may be a halide, sulfate, phosphate, hydroxide, tetrafluoride, etc. In one embodiment, Y - is a halide. 1 In one embodiment, Y - is chloride or bromide.

[0039] The term "aryl" refers to phenyl, naphthyl, anthracenyl, and the like. In one embodiment, "aryl" is phenyl. "Anthracen-9-yl" is anthracen-9-yl.

[0040] The term "heteroaryl" refers to a heteroaryl selected from the group consisting of nitrogen, oxygen, and sulfur. fully unsaturated rings containing at least one heteroatom, including pyridyl, pyrimidyl, These include pyrazinyl, indolyl, quinolinyl, acridinyl and the like.

[0041] "C1-C4 alkyl" means a straight or branched chain alkyl group having 1 to 4 carbon atoms. refers to the alkyl group.

[0042] The term "C1-C4 alkoxy" refers to a C1-C4 alkyl group bonded through an oxygen atom. It refers to the aryl group.

[0043] The term "about," when used in connection with a measurable, numerical variable, means an indication of the variable, and all variables within experimental error of the indicated value or within ±10% of the indicated value, whichever is greater. Points to a value.

[0044] The term "C1-C4 aliphatic chain, which may optionally contain a double or triple bond" means straight-chain, branched, or branched chains having 1 to 4 carbon atoms and optionally containing double or triple bonds; or non-aromatic cyclic alkyl groups, such as methyl, ethyl, ethynyl, propyl, Examples include propenyl and butynyl.

[0045] "C 1~5 The term "alcohol" refers to a linear or branched alcohol having 1 to 5 carbon atoms. refers to alkanols in the form of alcohols, such as methanol, ethanol, n-propanol, iso- Examples include propanol, 1-butanol, and 1,3-propanediol.

[0046] "C 2~5 The term "alkyl cyanide" refers to a straight-chain alkyl group having a total of 2 to 5 carbon atoms. or branched alkyl cyanides, such as acetonitrile, propionitrile ( proprionitrile, and butyronitrile.

[0047] "C 3~9 The term "alkyl ketone" refers to a ketone having an oxo group and a total of 3 to 9 carbon atoms. refers to a linear, branched, or cyclic alkyl group having the formula: chirketone, and cyclohexanone.

[0048] "C 2~8 The term "alkyl ether" refers to a straight chain alkyl group having a total of 2 to 8 carbon atoms. refers to alkyl ethers, branched or cyclic, such as diethyl ether, methyl t -butyl ether, t-amyl methyl ether, ethyl t-butyl ether, tetrahydrofuran Examples include tetrahydrofuran (THF), 2-methylTHF, and dioxane.

[0049] "C 3~8 The term "alkyl acetate" refers to acetic acids having a total of 3 to 8 carbon atoms. refers to linear or branched alkyl esters of, for example, methyl acetate, ethyl acetate, acetic acid Examples include isopropyl acetate, butyl acetate, and isobutyl acetate.

[0050] "C 5~8 The term "hydrocarbon" refers to any saturated alkyl hydrocarbon, whether linear, branched, or cyclic. refers to hydrogen, e.g., pentane, hexane, heptane, octane, cyclopentane, cyclopentane Examples include cyclohexane and methylcyclohexane.

[0051] The terms "crystallize," "crystallizing," and "crystallization" refer to the process following complete dissolution. This should be understood to refer to precipitation and slurry processes without complete dissolution. Processes include those involving complete dissolution followed by precipitation with continued stirring.

[0052] The present invention is further illustrated by the following examples, which are intended to be illustrative. It is merely illustrative and is not intended to limit the invention in any way. [Example]

[0053] Example 1 (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- (chlorophenyl)-5-(trifluoromethyl)-4H-isoxazole [ka] (Z / E)-1-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoromethyl Oro-3-(3,4,5-trichlorophenyl)but-2-en-1-one (1.0 g, 2.1mmol) and (R)-[(2S)-1-[[3,5-bis(trifluoromethyl )phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methyl (4-quinolyl)methanol bromide (135 mg, 0.2138 mmol, 0. 1 equivalent) in dichloromethane (100 mL) under nitrogen. The solution was heated to -15°C. Cool to 0 °C and add a solution of hydroxylamine in water (386 μL, 6.25 mmol, 16.2 mol / L, 3.0 equiv.) and sodium hydroxide (0.70 mL, 7.0 mmol 1, 10M, 3.3 equiv.) was slowly added to the reaction mixture while maintaining the internal temperature at -10°C. After stirring at -10°C for 7 hours, the cooling was turned off and the reaction was stirred at room temperature overnight. The reaction mixture was transferred to a round-bottom flask and concentrated under reduced pressure at room temperature to give a solid. The solid was dissolved in ethyl acetate (3 mL) and purified by automated flash chromatography on silica gel. The crude product was purified by column chromatography eluting with EtOAc:hexane (1:1). The solvent was removed from the fractions containing the product under reduced pressure at 40°C to give a pale yellow solid (0.83 3g, 81%).

[0054] Example 2 (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- (chlorophenyl)-5-(trifluoromethyl)-4H-isoxazole [ka] (Z / E) 1-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoro 10.0 g of bromo-3-(3,4,5-trichlorophenyl)but-2-en-1-one ( 20.9 mmol) and (R)-[(2S)-1-[[3,5-bis(trifluoromethyl) phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6- (Methoxy-4-quinolyl)methanol bromide (2.14 mmol, 0.1 equiv.) The solution was cooled to between -10°C and -15°C. A solution of hydroxylamine in water (3.9 mL, 63.2 mmol, 16.2 mol / L, 3.0 equiv.) and sodium hydroxide (7.0 mL, 70 mmol, 10 M, 3.3 (equivalent) was added slowly while maintaining the internal temperature between -10°C and -15°C. After stirring at −10° C. for 18 hours, the reaction mixture was transferred to a round-bottom flask and heated at room temperature under reduced pressure. The solid was then dissolved in ethanol (90 mL) at 50° C. and stirred at 50° C. ( Stir for 30 minutes in a water bath, then add water (300 mL) dropwise slowly with stirring to form a suspension. A suspension was obtained. The suspension was filtered, and the above evaporation and recrystallization were repeated three times. The solid was collected in 25-3 ml portions. Drying in a vacuum oven at 0°C for 4 days yielded 10.34g (97.4%). The isomers were characterized by chiral HPLC and were found to be 91.34% S-isomer and 8.67% R-isomer. Sexual bodies shown.

[0055] Example 3a (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- (chlorophenyl)-5-(trifluoromethyl)-4H-isoxazole [ka] (Z / E) 1-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoro 50.0 g of bro-3-(3,4,5-trichlorophenyl)but-2-en-1-one 104.5mmol) and (R)-[(2S)-1-[[3,5-bis(tert-butyl) phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6- Methoxy-4-quinolyl)methanol bromide (0.11 equivalents) in dichloromethane (10 The reaction mixture was combined in 30 mL of ethyl acetate (200 mL) and ethyl t-butyl ether (400 mL). The mixture was stirred at 20°C for 30 minutes, then cooled to the range of -20°C and added to a solution of hydroxylamine in water ( 50%, 40 mL, 313 mmol, 3.0 equiv) and sodium hydroxide (34.5 mL , 345 mmol, 10 M, 3.3 equiv.) while maintaining the internal temperature between -15°C and -20°C. After stirring at -15°C to -20°C for 18 hours, an aqueous solution of hydrochloric acid (1N, 500 mL) was added, and the reaction mixture was stirred at 15-20°C. Then, stirring was stopped and the mixture was stirred for 30 minutes. After 1 minute the phases were separated. The organic layer was extracted with aqueous hydrochloric acid (1N, 75 mL), the layers were separated, and the The organic layer was extracted again with aqueous hydrochloric acid (1N, 100 mL). The organic layer was separated and washed with saturated sodium bicarbonate. Extract with aqueous sodium bicarbonate (75 mL), separate the layers, and reconstitute the organic layer with saturated sodium bicarbonate. The layers were separated and the organic layer was dried over sodium sulfate (10 g). The organic layer was filtered and the cake was washed with ethyl t-butyl ether (50 mL), Montmorillonite clay (50 g) was then added and the mixture was stirred at 10°C to 20°C. After a period of time, the reaction mixture was filtered and the cake was rinsed with ethyl t-butyl ether (50 mL). The filtrate was concentrated to about 100 mL, THF was added twice, and the filtrate was concentrated again to about 100 mL, and then T HF (150 mL) was added to give the title compound as a solution in THF. Evaluation by LC showed 96.5% S-isomer and 3.5% R-isomer.

[0056] Example 3b 3-Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) (fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid [ka] (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- 2-chlorophenyl-5-(trifluoromethyl)-4H-isoxazole in THF A 2% solution (185.0 g, 374.8 mmol) was cooled to 0-5°C. A solution of sodium chloride in THF (2 M, 300 mL, 1.6 equiv.) was added to the flask at an internal temperature of 10°C. The reaction mixture was stirred at 15-20°C for 2-4 hours. After passing concentrated sulfuric acid (50 mL) through the mixture, carbon dioxide gas (58 g, 3.5 equivalents) was added at 0°C to 5°C. The reaction mixture was stirred at 0-5°C for 2 hours and then added with 8% aqueous sodium chloride. The solution (601 g) was added dropwise at less than 10°C, followed by 37% aqueous hydrochloric acid (92.5 g) at 0°C. Less than 100 ml was added to give the title compound.

[0057] Example 3c 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl] ]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl (4H-isoxazol-3-yl)thiophene-2-carboxamide [ka] 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trimethylphenyl) fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid ( Dissolve 101.5 g (221.3 mmol) in dichloromethane (DCM) (1000 mL) The mixture was heated to 40°C. Thionyl chloride (50 g, 1.9 equivalents) was added dropwise and the reaction mixture was refluxed. The reaction mixture was stirred at flow rate for 2-4 hours. The reaction mixture was concentrated to 100-200 mL and diluted with DCM (50 Two more cycles of concentration followed by addition of DCM were performed. In a vessel, add 2-aminotrifluoroethyl-acetamide HCl (50.26 g, 1.2 equiv. A suspension of 70.1% CI 67.29 in DCM (500 mL) was cooled to 0-5°C and triethylamine (70.1%) was added. 5g, 3.1 equivalents) was added and the reaction mixture was stirred at 0-5°C for 30 minutes. A solution of the compound in DCM was added to 2-amino-trifluoroethylene while maintaining the internal temperature below 5°C. The reaction mixture was stirred at 0°C to 5°C for 2 to 4 hours. 1N HCl (500 mL) was added dropwise and the reaction mixture was stirred at 15-25°C for 30 minutes. Stirring was stopped and after 30 minutes the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution ( 1N, 1000 mL), the layers were separated and the organic layer was extracted with water (1000 mL). The layers were separated and the organic layer was concentrated under vacuum to 200-300 mL. Ethyl acetate (500 mL) ) was added twice and the batch was concentrated to 200 mL. The reaction mixture was heated to 55°C and n-heptane was added. After 1 hour, n-heptane (1000 mL) was added dropwise. The mixture was stirred at 55° C. for 3 hours. The batch was gradually cooled to 35° C. over 3 hours. It was then cooled to 20° C. over 3 hours. The batch was filtered and the cake was diluted with n-heptane (200 After drying under vacuum at 50° C. for 12 hours, 113 g of the title compound was obtained.

[0058] Example 4a (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- (chlorophenyl)-5-(trifluoromethyl)-4H-isoxazole [ka] Butenone bromothiophene (658 g), (R)-[(2S )-1-[(3,5-di-t-butylphenyl)methyl]-5-vinyl-quinuclidine- 1-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide (57g ), dichloromethane (1120 g), and methyl tert-butyl ether (MTBE) (2586g) of hydroxylamine hydrochloride (261g) of water (333g, 0 The solution was added at -30°C, followed by an aqueous solution of sodium hydroxide (32%, 548g ) was added, also at -30°C. The reaction mixture was stirred at -30°C for several hours until the conversion was complete. The reaction mixture was heated to 0-5°C, and hydrochloric acid (37%, 286 g), ethanol (468 The mixture was warmed to 40°C and transferred to a quench solution consisting of 1000 ml of ethanol (2000 g) and water (600 g). After confirming that H=5-6, the phases were separated. The organic layer was concentrated under reduced pressure, and the distillate was collected by fresh distillation. The mixture was then replaced with pure methyl tert-butyl ether (2 cycles, 1777 g each). The mixture was briefly heated to reflux and then cooled to -10°C to induce precipitation of the catalyst. The turbid liquid is filtered and optionally added with hydrochloric acid (37%, 240 g), sodium chloride (240 g), and water (1080 g), and optionally filtered through a filter bed of bleaching earth. The filtrate was washed with saturated bicarbonate solution (1200 g) and the organic layer was extracted with the product (S)-isoxazoline. The product was stored as a MTBE solution containing dibromothiophene.

[0059] Example 4b 3-Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) (fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid [ka] Example 4a ((5S)-3-(5-bromo-4-methyl-2-thienyl in MTBE) -5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-iso The reaction mixture formed from the oxazole was added to the reactor and concentrated. The distillate was added to fresh T HF (2 cycles, 2136 g each). Ethyl magnesium chloride (tetrahydrofuran) About 25% in toluene, 933 g) was added after cooling it to -10°C. After the PLC is complete, add carbon dioxide gas (236 g) as quickly as possible at an internal temperature of -1°C. The reaction mixture was stirred at an internal temperature of 0° C. After completion of the reaction (HPLC) The reaction mixture was diluted with sodium chloride (110 g), water (2235 g), and 37% hydrochloric acid (2 The mixture was quenched by slowly adding the solution of 1,000 mg of 1,000 sucrose to a mixture containing 83 g of 1,000 sucrose at ambient temperature. After settling, the phases were separated. The organic layer was concentrated and the distillate was replaced with fresh acetonitrile (2 The reaction mixture was briefly warmed to obtain a clear solution, which was then After cooling to 10°C, the product was isolated by centrifugation and dissolved in pre-chilled acetonitrile (46 The wet (S)-isoxazolethiophenecarboxylic acid was dried in a vacuum oven. The dry yield was 82% of the theoretical yield. : 100%, Chiral purity: 99.8a%.

[0060] Example 4c 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl] ]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl (4H-isoxazol-3-yl)thiophene-2-carboxamide [ka] Dried S-isoxazolethiophenecarboxylic acid (from Example 4b, 20 g) and toluene (250 g) are charged to the reactor and the mixture is heated to 110° C. After the reaction was completed, toluene was evaporated under vacuum with N The mixture was evaporated at MT 50°C and the residue was diluted with fresh dichloromethane (165g).

[0061] In a separate reactor, 2-aminotrifluoroethyl-acetamide HCl (8.8 g) was added to The mixture was suspended in 200 g of dichloromethane and triethylamine (13.7 g) was added at ambient temperature. The resulting mixture was cooled to 0°C, and the acyl chloride reaction mixture in dichloromethane was stirred at 0°C. The combined reaction mixture was stirred at 0°C for an additional 1-8 hours and then measured by IPC. I checked the conversion.

[0062] Upon sufficient conversion (IPC), the mixture was diluted with 1M hydrochloric acid (37% HCl (9.6 g) and water (77.4 g) of the mixture), followed by a saturated sodium bicarbonate solution ( The mixture was extracted with sodium (8.4 g, water (96.1 g) and finally with water (105 g).

[0063] The organic layer was concentrated in vacuo (up to 300 mbar) at 40°C and ethyl acetate (46.9 g) was added. The reaction mixture was heated to 55°C and heptane (93.2 g) was added slowly. The mixture was sprayed with 1.0 w / w% Lotilaner (0.26 g) and the cloudy reaction mixture was stirred for 2 hours. Additional heptane (142.5 g) was added slowly and the resulting white suspension was stirred for 4 The thick suspension was allowed to warm to 35°C within 6 hours and then slowly warm to 20°C within 1 hour. After stirring for 2 hours, the product was isolated by centrifugation and washed with ethyl acetate (8. The product was heated at 50°C, 300 mbar, and washed with a mixture of hexane (41.4 g) and heptane (41.4 g). The dry yield was 87.6% of the theoretical yield. Purity: 99.9%. OD: 99.78%.

[0064] Example 5 3-Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) (fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid [ka] (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trimethyl- 2-chlorophenyl-5-(trifluoromethyl)-4H-isoxazole in THF A 2% solution (185.0 g, 374.8 mmol) was cooled to 0-5°C. A solution of sodium chloride in THF (2 M, 300 mL, 1.6 equiv.) was added to the flask at an internal temperature of 10°C. The reaction mixture was stirred at 15-20°C for 2-4 hours. After passing concentrated sulfuric acid (50 mL) through the mixture, carbon dioxide gas (58 g, 3.5 equivalents) was added at 0°C to 5°C. The reaction mixture was stirred at 0-5°C for 2 hours and then added with 8% aqueous sodium chloride. The solution (601 g) was added dropwise at less than 10°C, followed by 37% aqueous hydrochloric acid (92.5 g) at 0°C. Added in less than.

[0065] The reaction mixture was stirred at 10-15°C for 30 minutes, then the stirring was stopped and the phases were separated after 30 minutes. The organic layer was concentrated under vacuum to approximately 370 mL, followed by the addition of THF (1850 mL). The reaction mixture was concentrated to about 370 mL to 555 mL by repeating the heating and concentration under vacuum three times. After confirming that the material is dry, add acetonitrile (925 mL) followed by approximately 555 mL. The reaction mixture was heated to 75° C. and concentrated under vacuum to 740 mL. The reaction mixture was cooled slowly to 50°C over a period of 1 hour. Product seeds (1.85 g) were added at 50°C and the reaction mixture was The mixture was stirred at 50° C. for 30 minutes. The batch was gradually cooled to −10° C. over 3 hours and The batch was maintained at 0° C. for 2 hours. The batch was filtered and the cake was diluted with cold acetonitrile (93-185 mL). The wet cake was dried under vacuum at 50°C for 12 hours, and then 110 g of the title compound was obtained. The product was characterized by chiral HPLC, which showed >99.9% S-isomer. It was.

[0066] The above product seeds were prepared as follows: (5S)-3-(5-bromo-4-methyl -2-thienyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl A solution of (48.93 g, 99.1 m)-4H-isoxazole in 300 mL of THF mol) was cooled to 0-5°C. A solution of ethylmagnesium chloride in THF (2M, 80 mL) was added dropwise while maintaining the internal temperature below 10°C. The reaction mixture was heated to 15°C. The mixture was stirred at 0°C for 2 to 4 hours. Then, concentrated sulfuric acid (50 mL) was passed through the mixture, followed by carbon dioxide gas ( The reaction mixture was stirred at 0°C to 5°C for 6 hours. The mixture was stirred for 1 hour, and 5% aqueous sodium chloride solution (157 g) was added dropwise at a temperature below 10°C, followed by 37% Aqueous hydrochloric acid (25 g) was added dropwise at a temperature below 0°C. The reaction mixture was stirred at 10-15°C for 30 minutes. The mixture was stirred for 30 minutes, then the stirring was stopped and the phases were separated. The organic layer was concentrated to remove the solvent. 50 ml of heptane was added to the mixture, and then the solvent was removed. The crude product was dissolved in 50 ml of E A was dissolved in 100 mL of heptane at 40° C. An additional 1000 mL of heptane was added dropwise. The mixture was then stirred at 40°C for 15 hours. The mixture was filtered to obtain a wet cake, which was then slurried with acetone at 20°C. The mixture was filtered and the wet cake was dried under vacuum at 50°C for 3 hours to give 9.7 g of The product was evaluated by chiral HPLC and showed more than 99.9% S-isomer. was done.

[0067] Example 6 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl] ]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl (4H-isoxazol-3-yl)thiophene-2-carboxamide [ka] 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trimethylphenyl) fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid ( A solution of 101.5 g (221.3 mmol) of HCl in 1000 mL of DCM was heated to 40 °C. Thionyl chloride (50 g, 1.9 eq.) was added dropwise and the reaction mixture was refluxed for 2-4 hours. The reaction mixture was concentrated to 100-200 mL, and DCM (500 mL) was added. Two more cycles of concentration followed by addition of DCM were carried out. Trifluoroethyl-acetamide HCl (50.26 g, 1.2 eq.) in DCM (500 The suspension was cooled to 0-5°C and triethylamine (70.15 g, 3.1 equiv.) was added. The reaction mixture was stirred at 0°C to 5°C for 30 minutes. Then, a solution of the acid chloride in DCM was added. , 2-amino-trifluoroethyl-acetamide, while maintaining an internal temperature below 5°C. The reaction mixture was stirred at 0°C to 5°C for 2 to 4 hours. 1 (500 mL) was added dropwise and the reaction mixture was stirred at 15-25°C for 30 minutes. Stirring was stopped. After 30 minutes the phases were separated. The organic layer was washed with saturated sodium bicarbonate solution (1N, 1000 mL The layers were separated and the organic layer was extracted with water (1000 mL). The mixture was concentrated under vacuum to 200-300 mL. Ethyl acetate (500 mL) was added twice and the The mixture was concentrated to 200 mL. The reaction mixture was heated to 55° C. and added n-heptane (700 mL). was added dropwise at 55° C. Product seeds (1.0 g) were added and the reaction mixture was stirred at 55° C. for 1 hour. N-heptane (1000 mL) was added dropwise and the mixture was stirred at 55°C for 3 hours. The batch was gradually cooled to 35°C over 3 hours, then cooled to 20°C over 3 hours. The mixture was filtered, and the cake was washed with n-heptane (200 mL). It was then dried under vacuum at 50°C for 12 hours. After drying, 113 g of the title compound was obtained.

[0068] The above product seed was prepared as follows: The crude product was dissolved in 7.9 parts by weight of cumene. A solution was obtained at less than 150°C. 2.3 parts by weight of heptane was then added to the hot solution with a small amount of Addition was continued until turbidity was observed. Heating was stopped and the mixture was allowed to cool to ambient temperature and stirred overnight. After filtration and drying under vacuum, the desired polymorph G was obtained as a powder, which was used as a seed. was used to induce crystallization of polymorph G in subsequent batches.

[0069] Example 7 3-Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) (fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid [ka] 2-Bromo-3-methyl-5-acetylthiophene (20g), p-toluenesulfone Acid monohydrate (2.3 g) and ethylene glycol (11.3 g) were dissolved in toluene (120 ml) L) and heated at 115°C for 12 hours with stirring while adding Dean-St The reaction mixture was then cooled and saturated aqueous sodium bicarbonate was added. The organic layer was separated, washed twice with water (40 mL), and concentrated under vacuum. Concentration at 60°C gave 2-(5-bromo-4-methyl-2-thienyl)-2-methyl-1, 3-Dioxolane was obtained.

[0070] 2-(5-bromo-4-methyl-2-thienyl)-2-methyl-1,3-dioxane ( 25.2 g) and THF (50 mL) were combined and cooled in an ice / water bath. Ethyl magnesium chloride in HF (2.0 M, 75 mL) was added while the temperature was cooled to ice / The temperature was maintained at 10°C to 30°C in a water bath. The reaction mixture was then warmed to ambient temperature. After 90 minutes, The reaction mixture was cooled to 0-5°C in an ice / water bath and carbon dioxide gas was added at 5-14°C for 30 min. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to 0°C to 10°C, and 75 mL of saturated aqueous brine was added at 10°C to 35°C. The pH was then adjusted to approximately 1 with 37% aqueous HCl. Water (25 mL) was added and the reaction mixture was stirred. The aqueous layer was separated and the organic layer was washed with saturated brine. The washed organic layer was concentrated under vacuum at 40° C. to give 3-methyl-2-propanol. 5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2-carvone The acid (19.2 g) was obtained as a red oily product that solidified on storage at ambient temperature. MS:E SI+228.96;ESI-:226.98.

[0071] 3-methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2- Carboxylic acid (19.2 g), potassium carbonate (24.9 g), and 60 mL of dimethylformamide The reaction mixture was cooled to 0-5°C in an ice / water bath and then iodine was added. Methyl chloride (13.1 mL) was added dropwise while maintaining the temperature at 0-5°C. After stirring at ambient temperature for 1 hour, the mixture was cooled to 0-10°C and added with water (180 mL) and ethyl acetate ( The aqueous layer was separated and the organic layer was washed with water (2×60 mL) and brine. The organic layer was then evaporated under vacuum at 40° C. to give methyl 3- Methyl-5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2-carbohydrate The xylate (21.3 g) was obtained as a red oil. MS: ESI+243.00 .

[0072] p-Toluenesulfonic acid monohydrate (1.7g), methyl 3-methyl-5-(2-methyl -1,3-dioxolan-2-yl)thiophene-2-carboxylate (21.3g) acetone (140 mL), and water (14 mL) were combined and stirred at 35°C for 2 hours, and then The mixture was cooled to 20°C by heating. Sodium bicarbonate (1.5 g) was then added and the reaction mixture was heated to 20°C. The mixture was stirred at rt for 10 min. The mixture was then concentrated under vacuum at 40° C. to give a residue. The mixture was dissolved in 20 mL of ethyl acetate and washed with water (50 mL). The layers were separated and the organic layer was washed with water (2 The organic layer was concentrated under vacuum at 40° C. to give a residue which was then purified by the addition of n-heptane. By flash chromatography using a mixture of MTBE (0-15% v / v) in ethanol, and purified to obtain methyl 5-acetyl-3-methylthiophene-2-carboxylate (4 0.9g) was obtained. 1 H NMR(500MHz,CDCl3)δ ppm 2.51(d ,J=5.87Hz,6H)3.85(s,3H)7.43(s,1H). 13 CNM R(126MHz,CDCl3)δ ppm 15.85(s,1C)26.80(s, 1C)52.06(s,1C)76.74(s,1C)77.00(s,1C)77.2 6(s,1C)132.65(s,1C)135.25(s,1C)145.37(s, 1C)146.02(s,1C)162.57(s,1C)190.78(s,1C).

[0073] Methyl 5-acetyl-3-methyl-thiophene-2-carboxylate (4.1 g), 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (5.7 4 g), triethylamine (8.4 mL), and MTBE (41 mL) were combined and added to the reaction mixture. The mixture was heated to about 57° C. After 3 hours, the reaction mixture was cooled to ambient temperature and stirred for 12 hours. The reaction mixture was then cooled to 0-5°C, and thionyl chloride (2.3 mL) was added. The mixture was added dropwise, maintaining the temperature at 10° C. The reaction mixture was then allowed to warm to ambient temperature and stirred overnight. The mixture was then diluted with MTBE (45 mL) and cooled to 0-5°C. A mixture of aqueous ammonium chloride (45 mL) and water (45 mL) was added dropwise. The reaction mixture was then soaked in acetic acid. The aqueous layer was extracted with ethyl acetate (41 mL). The organic layers were combined and washed with aqueous brine (2 x 40 mL). The residue was suspended in ethanol (50 mL) and evaporated at 30-40°C. The mixture was stirred for 1 hour, then cooled to 0-5°C. Water (50 mL) was added to the mixture at 0-5°C while stirring. The mixture was added dropwise and stirred for 3 hours to give a solid. The solid was collected by filtration and pre-cooled. Wash with a 1:3 ethanol / water mixture (2 × 10 mL) and dry under vacuum at 35°C to 40°C. methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4 ,5-trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate( 8.43 g) was obtained as a brown solid. E / Z ratio: 77:23 ( 1 by H NMR).

[0074] Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(trifluoromethyl)phenyl ]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4 (-quinolyl)methanol bromide (69 mg) and DCM (50 mL) were combined and The mixture was cooled to 0 to -15°C. A pre-cooled aqueous solution of sodium hydroxide (10N, 0.33 mL) was added. A mixture of hydroxylamine (50%, 0.223 mL) and hydroxylamine (50%, 0.223 mL) was cooled to -10 The solution was added dropwise via syringe while maintaining the temperature at -15°C. After 5 hours, an aqueous solution of hydrochloric acid (2N, 2 5 mL) was slowly added, and the reaction mixture was then warmed to 10-15°C. The layers were then separated. The organic layer was washed with water (2 times 25 mL) and evaporated under vacuum at 50° C. to give methyl 3- Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) 4H-isoxazol-3-yl]thiophene-2-carboxylate ( 640 mg) was obtained, which was used in the next step without further purification.

[0075] Methyl 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5- (Trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carbo The xylate (640 mg) was combined twice successively with THF (5 mL) and evaporated to a residue This was dissolved in THF (4.2 mL), water (1.6 mL), and an aqueous solution of sodium hydroxide (1 0N, 0.22 mL) The reaction mixture was then heated to 60° C. with stirring. After 4 hours, the reaction mixture was evaporated to near dryness to give a residue which was diluted with ethyl acetate (50 The mixture was partitioned between aqueous hydrochloric acid (0.5N HCl, 25 mL) and aqueous hydrochloric acid (0.5N HCl, 25 mL). The layers were separated and the organic layer The residue was washed with water (2 x 25 mL) and evaporated under vacuum at 50 °C to give a residue. (5 mL) and then evaporated under vacuum at 60° C. to give the title compound as a foamy solid. (450 mg). S / R ratio: 89:11. 1 H NMR (500 MHz, CDCl3) δ ppm 2.53-2.60(m,3H)3.63-3.73(m,1H)4.03 -4.12(m,1H)7.12-7.14(m,1H)7.60-7.65(m,2H ).

[0076] Example 8 Methyl 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-( (trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide Silate [ka] 3-Methyl-2-thiophenecarboxylic acid (2.5 g) and THF (5 mL) were heated at ambient temperature and then 2,2,6,6-tetramethylpiperidinyl magnesium chloride salt Lithium chloride complex (50 mL, 0.94 M in THF) was added while controlling the temperature below 45 °C. The reaction mixture was stirred at 25° C. for 1 hour and then N- Methoxy-N-methylacetamide (5.0 mL) was added while controlling the temperature below 40°C. After stirring at ambient temperature for approximately 90 minutes, the reaction mixture was cooled to 0-5°C. The mixture was cooled and aqueous hydrochloric acid (2M, 100 mL) was added, controlling the temperature below 45°C. TBE (100 mL) was added, the layers were separated, and the aqueous layer was extracted with MTBE (50 mL). The combined organic layers were washed with aqueous brine (2×25 mL) and evaporated under vacuum at 45° C. 5-Acetyl-3-methyl-thiophene-2-carboxylic acid (4.8 g) was obtained as a yellow solid. I got it.

[0077] 5-acetyl-3-methyl-thiophene-2-carboxylic acid (4.8 g) in potassium carbonate (3.0 equiv.) and DMF (30 mL), followed by methyl iodide (2.5 equiv.) After 45 minutes, water (90 mL) and MTBE (120 mL) were added with stirring. The layers were then separated and the aqueous layer was extracted with MTBE (60 mL). The combined organic layers were washed with water (2× 30 mL), and then evaporated under vacuum at 55° C. to give methyl 5-acetyl-3-methyl Thiophene-2-carboxylate (4.5 g) was obtained.

[0078] Methyl 5-acetyl-3-methyl-thiophene-2-carboxylate (4.5 g), 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl)ethanone (3.6 6 g), triethylamine (2.9 mL), and MTBE (30 mL) were combined and added to the reaction mixture. The mixture was heated to about 60° C. After 6.5 hours, additional triethylamine (2.0 mL) was added. The reaction mixture was cooled to 0-5°C and the temperature was increased to 12°C. Thionyl chloride (1.7 mL) was added dropwise while maintaining the temperature below ambient. After stirring for 1 hour, the mixture was diluted with MTBE (30 mL) and cooled to 10°C. Then, a mixture of saturated aqueous sodium bicarbonate (30 mL) and water (30 mL) was slowly added. The layers were then separated and the aqueous layer was extracted with MTBE (30 mL). Wash with aqueous brine solution (2 x 30 mL) and evaporate under vacuum at 30-40 °C to give a residue The residue was twice suspended in ethanol (30 mL) and evaporated to near dryness. The residue was suspended in ethanol (30 mL) and stirred at 0 to 5°C for 1 hour to obtain a solid. The tissue was collected by filtration and diluted with a pre-chilled 1:3 ethanol / water mixture (2 × 10 mL). Washing and drying under vacuum at 40°C yields methyl 3-methyl-5-[(E / Z)-4,4,4- Trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl]thiophene Benzene-2-carboxylate (2.54 g) (almost pure E isomer ( 1 (by H NMR) ) was obtained.

[0079] Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(trifluoromethyl)phenyl ]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4 (-quinolyl)methanol bromide (69 mg) and DCM (50 mL) were combined and The mixture was cooled to 0 to -15°C. A pre-cooled aqueous solution of sodium hydroxide (10N, 0.33 mL) was added. A mixture of hydroxylamine (50%, 0.223 mL) and hydroxylamine (50%, 0.223 mL) was cooled to -10 While maintaining the temperature at -10°C to -15°C, the solution was added dropwise via syringe with stirring. After 5 hours at °C, the mixture was analyzed. S / R ratio: 89:11.

[0080] Example 9 Methyl 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-( (trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide Silate Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(trifluoromethyl)phenyl ]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4 -quinolyl)methanol bromide (69 mg), and toluene / methylcyclohexane ( The mixture was cooled to -10 to -15°C. Aqueous sodium chloride solution (10N, 0.33 mL) and aqueous hydroxylamine solution (50%, The mixture (0.223 mL) was added via syringe while maintaining the temperature at -10°C to -15°C. The mixture was analyzed after 46 hours at -10°C to -15°C. Ratio: 92:8.

[0081] Example 10 Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5- Trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate [ka] Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(t-butyl)phenyl]methyl ]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinol Add methanol bromide (69 mg) and DCM (50 mL) and heat at -10 to -15°C. The mixture was cooled to °C. A pre-cooled aqueous solution of sodium hydroxide (10 N, 0.33 mL) and A mixture of 2,000 ml of methylpropanol and 2,000 ml of methylpropanol in water (50%, 0.223 mL) was heated to a temperature of -10°C to -15°C. While maintaining the temperature at -10°C to -15°C, the solution was added dropwise via syringe with stirring. After a period of time, the mixture was analyzed. S / R ratio: 81:19.

[0082] Example 11 Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5- Trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(t-butyl)phenyl]methyl ]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinol (I)methanol bromide (69 mg) and DIPE (50 mL) were combined and Cool to 15° C. Add pre-cooled aqueous sodium hydroxide (10 N, 0.33 mL) and A mixture of hydroxylamine aqueous solution (50%, 0.223 mL) was added at a temperature of -10°C to - The solution was added dropwise via syringe while stirring, while maintaining the temperature at 15°C. After 8 hours the mixture was analyzed. S / R ratio: 88:12.

[0083] Example 12 Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5- Trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate Methyl 3-methyl-5-[(E / Z)-4,4,4-trifluoro-3-(3,4,5 -trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (50 0mg), (R)-[(2S)-1-[[3,5-bis(t-butyl)phenyl]methyl ]-5-vinyl-quinuclidin-1-ium-2-yl]-(6-methoxy-4-quinol (I)methanol bromide (69 mg), and diisopropyl ether (40 mL), and DCM (10 mL) was added and cooled to -10 to -15°C. Aqueous hydroxylamine solution (10N, 0.33 mL) and aqueous hydroxylamine solution (50%, 0.22 mL) were added. The mixture (3 mL) was stirred via syringe while maintaining the temperature at -10°C to -15°C. After 18 hours at -10°C to -15°C, the mixture was analyzed. S / R ratio: 91 :9.

[0084] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses.

[0085] Clause 1. Enantiomerically pure isoxazoline compounds of formula (1) (wherein R5 is a C1-C4 aliphatic chain optionally containing a double or triple bond, said chain optionally , halogen, cyano, nitro, hydroxyl, oxo, C3-C6 cycloalkyl, C1 ~C4 alkoxy, C1-C7 aminocarbonyl, -N(C1-C4 alkyl)2, -S C1-C4 alkyl, -S(O)C1-C4 alkyl, and -SO2C1-C4 alkyl substituted with 1 to 5 substituents independently selected from the group consisting of The method of (i) Compounds of formula (2) (wherein X is a halogen and —C(O)OR4 (wherein R4 is C hydroxylamine and a suitable and a compound of formula (3) - is an anion, and R1 is hydrogen and methoxy. R2 is selected from the group consisting of ethyl and vinyl; and R3 is selected from the group consisting of aryl. optionally nitro, halogen, amino, trifluoromethyl, C1-C4 Independently selected from the group consisting of alkyl, C1-C4 alkoxy, and benzyloxy aryl substituted with 1 to 5 substituents, and heteroaryl, optionally substituted with halo; The group consisting of phenyl, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy. and heteroaryl substituted with 1 to 3 independently selected substituents, selected) to obtain a compound of formula (4), (ii) converting X of the compound of formula (4) to a carboxylic acid of the compound of formula (5); (iii) optionally reacting a compound of formula (5) with C1~5 Alcohol, C 2~5 Alkyl Anid, C 3~9 Alkyl ketone, C 2~8 Alkyl ether, C 2~8 Alkyl acetate a solvent selected from the group consisting of acetone, and optionally water and C 5~8 A group consisting of hydrocarbons and an anti-solvent selected from the group consisting of: and (iv) coupling the compound of formula 5 with an appropriate amine A method comprising:

[0086] Clause 2. The suitable amine is a compound of formula (6) (wherein R5 is optionally double or A C1-C4 aliphatic chain containing a triple bond, said chain optionally containing halogen, cyano, Nitro, hydroxyl, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, C 1-C7 aminocarbonyl, -N(C1-C4 alkyl)2, -SC1-C4 alkyl, Independently selected from the group consisting of -S(O)C1-C4 alkyl and -SO2C1-C4 alkyl 2. The method of claim 1, wherein the alkyl group is substituted with 1 to 5 substituents selected from the group consisting of:

[0087] Clause 3. R5 is optionally halogen, cyano, nitro, hydroxyl, oxo, C3 ~C6 cycloalkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C -C(O)C(1-C4 alkyl), -SC(O)C(1-C4 alkyl), and -SO2Substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4 alkyl The method of clause 2, wherein the alkyl is a C3 alkyl.

[0088] Clause 4. R5 is optionally halogen, cyano, nitro, hydroxyl, oxo, C3 ~C6 cycloalkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C -C(O)C(1-C4 alkyl), -SC(O)C(1-C4 alkyl), and -SO2Substituted with 1 to 5 substituents independently selected from the group consisting of C1-C4 alkyl 3. The method of claim 2, wherein the compound is ethyl.

[0089] Clause 5. R5 is optionally halogen, cyano, nitro, hydroxyl, oxo, C3 ~C6 cycloalkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C -C(O)C(1-C4 alkyl), -SC(O)C(1-C4 alkyl), and -SO2Substituted with 1 to 3 substituents independently selected from the group consisting of C1-C4 alkyl 3. The method of clause 2, wherein the methyl group is methyl.

[0090] Clause 6. R5 is optionally halogen, cyano, nitro, hydroxyl, oxo, C3 ~C6 cycloalkyl, C1-C4 alkoxy, C1-C7 aminocarbonyl, -N(C -C(O)C(1-C4 alkyl), -SC(O)C(1-C4 alkyl), and -SO2C1-C4 alkyl, 1, 2, or 3 substituents independently selected from the group consisting of 5. The method according to clause 2 or 4, wherein the methyl group is ethyl substituted with a substituent.

[0091] Clause 7. R5 is ethyl substituted with 1, 2, or 3 halogen substituents. 7. The method of any one of 2, 4, and 6.

[0092] Clause 8. Clauses 2, 4, 6, and 7, wherein R5 is ethyl substituted with one halogen substituent. 7. The method according to any one of claims 1 to 6.

[0093] Clause 9. Clauses 2, 4, 6, and 7, wherein R5 is ethyl substituted with two halogen substituents. 7. The method according to any one of claims 1 to 6.

[0094] Clause 10. Clauses 2, 4, 6, wherein R5 is ethyl substituted with three halogen substituents. and 7. The method according to any one of claims 1 to 7.

[0095] Clause 11. Clauses 2, 4, and 5, wherein R5 is ethyl substituted with one fluoro substituent. 9. The method according to any one of 6 to 8.

[0096] Clause 12. Clauses 2, 4, 6, wherein R5 is ethyl substituted with two fluoro substituents. 7 and 9. The method according to any one of claims 7 and 9.

[0097] Clause 13. Clauses 2, 4, 6, wherein R5 is ethyl substituted with three fluoro substituents. 7 and 10. The method according to any one of claims 7 and 10.

[0098] Clause 14. The suitable amine is 2-amino-2',2',2'-trifluoroethyl- 14. The compound according to any one of clauses 1, 2, 4, 6, 7, 10 and 13, which is acetamide. method.

[0099] Clause 15. The suitable amine may optionally be carboxyl-protected glycine, if necessary. In this case, the amine was deprotected and then coupled with 2,2,2-trifluoroethylamine. 2. The method of clause 1, wherein the reactant

[0100] Clause 16. A process for preparing an enantiomerically pure compound of formula (5), comprising: (i) Compounds of formula (2) (wherein X is a halogen and —C(O)OR4 (wherein R4 is C hydroxylamine and a suitable and a compound of formula (3) - is an anion, and R1 is hydrogen and methoxy. R2 is selected from the group consisting of ethyl and vinyl; and R3 is selected from the group consisting of aryl. optionally nitro, halogen, amino, trifluoromethyl, C1-C4 Independently selected from the group consisting of alkyl, C1-C4 alkoxy, and benzyloxy aryl substituted with 1 to 5 substituents, and heteroaryl, optionally substituted with halo; The group consisting of phenyl, trifluoromethyl, C1-C4 alkyl, and C1-C4 alkoxy. and heteroaryl substituted with 1 to 3 independently selected substituents, selected) to obtain a compound of formula (4), (ii) converting X of the compound of formula (4) to a carboxylic acid of the compound of formula (5); (iii) optionally reacting the compound of formula (5) with C 1~5 Alcohol, C 2~5 Archi Lucianide, C 3~9 Alkyl ketone, C 2~8 Alkyl ether, C 2~8 Alkyria acetate, and optionally water and C 5~8 From hydrocarbons and an anti-solvent selected from the group consisting of A method comprising:

[0101] Clause 17. The method of any one of clauses 1 to 16, wherein X is a halogen.

[0102] Clause 18. The method of clause 17, wherein X is bromo.

[0103] Clause 19. The method of clause 18, wherein X is chloro.

[0104] Clause 20. X is -C(O)OR4 (wherein R4 is C1-C4 alkyl), Item 17. The method according to any one of Items 1 to 16.

[0105] Clause 21. The method of clause 20, wherein R4 is methyl.

[0106] Clause 22. The method of clause 20, wherein R4 is ethyl.

[0107] Clause 23. The method of any one of clauses 1 to 22, wherein R1 is methoxy.

[0108] Clause 24. Any of clauses 1 to 23, wherein step (i) is carried out at a temperature of -40°C to -10°C. 1. The method according to claim 1.

[0109] Clause 25. Any of clauses 1 to 23, wherein step (i) is carried out at a temperature of -30°C to -20°C. 1. The method according to claim 1.

[0110] Clause 26. Any one of clauses 1 to 23, wherein step (i) is carried out at a temperature of about -30°C. The method described below.

[0111] Clause 27. The compound of formula (2), hydroxylamine, the appropriate base, and the compound of formula The reaction with compound (3) is carried out in the presence of a solvent system containing dichloromethane and an ether. 27. The method according to any one of clauses 1 to 26.

[0112] Article 28. The ether is methyl t-butyl ether, ethyl t-butyl ether, dibutyl ether, 28. The method according to claim 27, wherein the compound is methyl ether, isopropyl ether, or t-amyl methyl ether. .

[0113] Article 29. The ether is methyl t-butyl ether or ethyl t-butyl ether 28. The method according to clause 27, wherein

[0114] Clause 30: The compound of formula (4) has an enantiomeric excess of 80% or more, 29. The method of any one of claims 28 to 29.

[0115] Clause 31. The compound of formula (4) has an enantiomeric excess of 93% or more, 29. The method of any one of claims 28 to 29.

[0116] Clause 32. The method of any one of clauses 1 to 31, wherein step (iii) is performed.

[0117] 33. The method of claim 32, wherein the anti-solvent is present in (iii).

[0118] The solvent in question in clause 34.(iii) is C 1~5 Alcohol, Article 32 or 3 The method described in 3.

[0119] The solvent in question in clause 35.(iii) is C 2~5 Alkyl cyanide, Article 32 or or the method described in 33.

[0120] The solvent in question in clause 36.(iii) is C 3~9 Alkyl ketones, Article 32 or is the method described in 33.

[0121] The solvent in question in clause 37.(iii) is C 2~8 Alkyl ethers, Article 32 or the method described in 33.

[0122] The solvent in question in clause 38.(iii) is C 2~8 Alkyl acetate, Clause 32 Or the method described in 33.

[0123] The C in Article 39.(iii) 1~5 the alcohol is isopropanol, 34. The method according to claim 34.

[0124] The C in Article 40.(iii) 1~5 The alcohol is ethanol, Article 34 The method described.

[0125] The C in Article 41.(iii) 2~5 The alkyl cyanide is acetonitrile; The method described in clause 35.

[0126] The C in Article 42.(iii) 3~9 Clause 36, wherein the alkyl ketone is acetone. The method described below.

[0127] The C in Article 43.(iii) 3~9 The alkyl ketone is methyl ethyl ketone , the method described in clause 36.

[0128] The C in Article 44.(iii) 2~8 The alkyl ether is tetrahydrofuran. 37. The method according to claim 37.

[0129] The C in Article 45.(iii) 2~8 Alkyl ether is 2-methyltetrahydro 37. The method according to claim 37, wherein the furan is

[0130] The C in Article 46.(iii) 2~8 The alkyl acetate is ethyl acetate. Item 39. The method according to item 38.

[0131] The C in Article 47.(iii) 2~8 The alkyl acetate is isopropyl acetate. 38. The method according to claim 38.

[0132] In any one of Clauses 32 to 47, the anti-solvent in Clause 48.(iii) is water. The method described.

[0133] The anti-solvent in clause 49.(iii) is C 5~8 Articles 32 to 47, which are hydrocarbons 10. The method according to any one of claims 1 to 9.

[0134] Article 50. The C 5~8 49. The method of claim 48, wherein the hydrocarbon is pentane.

[0135] Article 51. The C 5~8 49. The method of claim 48, wherein the hydrocarbon is hexane.

[0136] Article 52. The C 5~8 49. The method of claim 48, wherein the hydrocarbon is heptane.

[0137] Article 53. The C 5~8 49. The method of claim 48, wherein the hydrocarbon is cyclohexane.

[0138] Article 54. The C 5~8 49. The method of claim 48, wherein the hydrocarbon is methylcyclohexane. .

[0139] Clause 55. The compound of formula (5) has an enantiomeric excess of 90% or more, 54. The method of any one of claims 1 to 54.

[0140] Clause 56. The compound of formula (5) has an enantiomeric excess of 96% or more, 54. The method of any one of claims 1 to 54.

[0141] Clause 57. The compound of formula (5) has an enantiomeric excess of 98% or more, 54. The method of any one of claims 1 to 54.

[0142] Clause 58. The compound of formula (5) has an enantiomeric excess of 99% or more, 54. The method of any one of claims 1 to 54.

[0143] Clause 59. The enantiomeric excess of the compound of formula (5) is 99.6% or more. 55. The method according to any one of claims 1 to 54.

[0144] Article 60. 3-Methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5 -(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carbohydrate 1. A method for improving the enantiomeric purity of a carboxylic acid, comprising: 1~5 Alcohol, C2 ~5 Alkyl cyanide, C 3~9 Alkyl ketone, C 2~8 Alkyl ether, C 2~8 a solvent selected from the group consisting of alkyl acetates, and optionally water and C 5~8 carbonization and an anti-solvent selected from the group consisting of hydrogen.

[0145] Clause 61. The method of clause 60, wherein the anti-solvent is present.

[0146] Article 62. The solvent is C 1~5 62. The method according to clause 60 or 61, wherein the alcohol is alcohol.

[0147] Article 63. The solvent is C 2~5 The compound according to clause 60 or 61, which is an alkyl cyanide Law.

[0148] Article 64. The solvent is C 3~9 62. The method according to claim 60 or 61, wherein the alkyl ketone is .

[0149] Article 65. The solvent is C 2~8 The method according to clause 60 or 61, which is an alkyl ether Law.

[0150] Article 66. The solvent is C 2~8 62. The compound according to claim 60 or 61, which is an alkyl acetate. method.

[0151] Article 67. The C 1~5 63. The method of clause 62, wherein the alcohol is isopropanol.

[0152] Article 68. The C 1~5 63. The method of clause 62, wherein the alcohol is ethanol.

[0153] Article 69. The C 2~5 The method according to clause 63, wherein the alkyl cyanide is acetonitrile Law.

[0154] Article 70. The C 3~9 65. The method of clause 64, wherein the alkyl ketone is acetone.

[0155] Article 71. The C 3~9 65. The compound according to claim 64, wherein the alkyl ketone is methyl ethyl ketone. method.

[0156] Article 72. The C 2~8 The alkyl ether is tetrahydrofuran, as described in Clause 65 How to do it.

[0157] Article 73. The C 2~8 the alkyl ether is 2-methyltetrahydrofuran, 65. The method described in claim 65.

[0158] Article 74. The C 2~8 67. The method of claim 66, wherein the alkyl acetate is ethyl acetate. .

[0159] Article 75. The C 2~8 The alkyl acetate is isopropyl acetate, as described in Clause 66. How to do it.

[0160] Clause 76. The method of any one of clauses 60 to 75, wherein the anti-solvent is water.

[0161] Article 77. The antisolvent is C 5~8 hydrocarbons, as described in any one of clauses 60 to 75 How to do it.

[0162] Article 78. The C 5~8 78. The method of claim 77, wherein the hydrocarbon is pentane.

[0163] Article 79. The C 5~8 78. The method of clause 77, wherein the hydrocarbon is hexane.

[0164] Article 80. The C 5~8 78. The method of clause 77, wherein the hydrocarbon is heptane.

[0165] Article 81. The C 5~8 78. The method of clause 77, wherein the hydrocarbon is cyclohexane.

[0166] Article 82. The C 5~8 78. The method of claim 77, wherein the hydrocarbon is methylcyclohexane. .

[0167] Article 83. The crystallized 3-methyl-5-[(5S)-5-(3,4,5-trichloro- (trifluorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thio The enantiomeric purity of phen-2-carboxylic acid is 98% or more, Articles 60 to 82 10. The method according to any one of claims 1 to 9.

[0168] Article 88. The crystallized 3-methyl-5-[(5S)-5-(3,4,5-trichloro- (trifluorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thio The enantiomeric purity of phen-2-carboxylic acid is 99% or more, Articles 60 to 82 10. The method according to any one of claims 1 to 9.

[0169] Article 89. The crystallized 3-methyl-5-[(5S)-5-(3,4,5-trichloro- (trifluorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thio The enantiomeric purity of phen-2-carboxylic acid is 99.8% or more. 82. The method of any one of claims 82 to 82.

[0170] Clause 90. Contains an isoxazoline compound of formula (1) with an enantiomeric purity of 98% or more , composition.

[0171] Clause 91. Contains an isoxazoline compound of formula (1) with an enantiomeric purity of 99% or more , composition.

[0172] Clause 92. Isoxazoline compounds of formula (1) with an enantiomeric purity of 99.8% or more A composition comprising:

[0173] Article 93. A method for treating or preventing flea infestations, comprising administering to a patient in need thereof: 90. A method comprising administering a therapeutically effective amount of the composition described in 90.

[0174] Article 94. A method for treating or preventing flea infestations, comprising administering to a patient in need thereof: 91. A method comprising administering a therapeutically effective amount of the composition described in 91.

[0175] Article 95. A method for treating or preventing flea infestations, which comprises administering to a patient in need thereof: 92. A method comprising administering a therapeutically effective amount of the composition of claim 92.

[0176] Clause 96. The method of any one of clauses 93 to 95, wherein the patient is a dog.

[0177] Clause 97. The method of any one of clauses 93 to 95, wherein the patient is a cat.

[0178] Clause 98. The isoxazoline compound of formula (1) is lotilaner. Clauses 90 to 92 The composition according to any one of the preceding claims.

[0179] Article 99. The isoxazoline compound of formula (1) is lotilaner. Articles 93 to 97 10. The method according to any one of claims 1 to 9.

[0180] Article 100. The suitable base is lithium hydroxide, sodium hydroxide, potassium hydroxide, Barium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxide from the group consisting of potassium hydroxide, potassium t-butoxide, and mixtures thereof 60. The method of any one of clauses 1 to 59, selected.

[0181] Article 101.Y - However, tosylate, brosylate, mesylate, nosylate, triflate consisting of nitrates, acetates, halides, sulfates, phosphates, hydroxides, and boron tetrafluoride 60. The method of any one of clauses 1 to 59, selected from the group:

[0182] Article 102.Y - is a halide, as described in any one of clauses 1 to 59 and 101 How to do it.

[0183] Article 103.Y - is a chloride, The method described.

[0184] Article 104.Y - is a bromide, The method described.

Claims

1. Enantiomerically pure isoxazoline compounds of formula (1) 【Chemical 1】 (In the formula, R ５ is C optionally containing a double or triple bond １ ~C ４ an aliphatic chain, The chain may optionally be selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ３ ~C ６ Shik Roalkyl, C １ ~C ４ Alkoxy, C １ ~C ７ Aminocarbonyl, —N(C １ ~C ４ a Rukill) ２ , -SC １ ~C ４ Alkyl, —S(O)C １ ~C ４ Alkyl, and —SO ２ C １ ~C ４ substituted with 1 to 5 substituents independently selected from the group consisting of alkyl ） 1. A method for making a (i) reacting a compound of formula (2) with hydroxylamine 【Chemistry 2】 (wherein X is a halogen and —C(O)OR ４ (In the formula, R ４ is C １ ~C ４ is alkyl ), a suitable base, and a compound of formula (3) 【Chemistry 3】 (In the formula, Y － is an anion, R １ is selected from the group consisting of hydrogen and methoxy; R ２ is selected from the group consisting of ethyl and vinyl; R ３ is aryl, optionally nitro, halogen, amino, trifluoromethyl , C １ ~C ４ Alkyl, C １ ~C ４ Independently from the group consisting of alkoxy and benzyloxy aryl substituted with 1 to 5 substituents selected from the following: Optionally, halogen, trifluoromethyl, C １ ~C ４ Alkyl, and C １ ~C ４ Arco heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy, arylsulfonyl ... selected from the group consisting of to obtain a compound of formula (4), 【Chemistry 4】 (ii) replacing X of the compound of formula (4) with a compound of formula (5) 【Chemistry 5】 converting the compound of formula (I) to a carboxylic acid of formula (II), (iii) optionally reacting the compound of formula (5) with C １～５ Alcohol, C ２～５ Archi Lucianide, C ３～９ Alkyl ketone, C ２～８ Alkyl ether, C ２～８ Alkyria acetate, and optionally water and C ５～８ From hydrocarbons and an anti-solvent selected from the group consisting of: and (iv) coupling the compound of formula 5 with a suitable amine A method comprising:

2. 10. The method of claim 1, wherein X is bromo.

3. X is -C(O)OR ４ (In the formula, R ４ is methyl.

4. R １ The method of any one of claims 1 to 3, wherein is methoxy.

5. The suitable amine is a compound of formula (6): 【Chemistry 6】 (In the formula, R ５ is C optionally containing a double or triple bond １ ~C ４ an aliphatic chain, The chain may optionally be selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C ３ ~C ６ Shik Roalkyl, C １ ~C ４ Alkoxy, C １ ~C ７ Aminocarbonyl, —N(C １ ~C ４ a Rukill) ２ , -SC １ ~C ４ Alkyl, —S(O)C １ ~C ４ Alkyl, and —SO ２ C １ ~C ４ substituted with 1 to 5 substituents independently selected from the group consisting of alkyl 10. The method according to claim 1, wherein the hydroxyl group is hydroxypropyl methylcellulose.

6. The suitable amine may be 2-amino-2',2',2'-trifluoroethyl-acetate The method of claim 5, wherein the hydroxybenzoate is hydroxybenzoate.

7. The compound of formula (2), hydroxylamine, the appropriate base, and the compound of formula (3) wherein the reaction with the compound is carried out in the presence of a solvent system comprising dichloromethane and an ether; The method according to any one of claims 1 to 6.

8. Any one of claims 1 to 7, wherein the enantiomeric excess of the compound of formula (5) is 90% or more. The method according to any one of claims 1 to 4.

9. The method according to any one of claims 1 to 8, wherein (iii) crystallization is carried out.

10. (iii) was crystallized, and the enantiomeric purity of the compound of formula (5) was 98%.

9. The method according to claim 1, wherein the content of the hydroxybenzoates is 0.05% or more.

11. (iii) is crystallized, and the solvent is acetonitrile, and the compound of formula (5) The compound of any one of claims 1 to 8, wherein the enantiomeric purity of the compound is 98% or more. How to post.

12. 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trimethylphenyl) fluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid 1. A method for improving enantiomeric purity, comprising: １～５ Alcohol, C ２～５ Al Kircyanide, and C ３～９ The method includes crystallizing from a solvent selected from alkyl ketones. Law.

13. The crystallized 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenoxy) 4H-isoxazol-3-yl)thiophene- 13. The method of claim 12, wherein the enantiomeric purity of the 2-carboxylic acid is 98% or greater. 。

14. Enantiomerically pure compounds of formula (5) 【Chemistry 7】 1. A method for making a (i) reacting a compound of formula (2) with hydroxylamine 【Chemistry 8】 (wherein X is a halogen and —C(O)OR ４ (In the formula, R ４ is C １ ~C ４ is alkyl ), a suitable base, and a compound of formula (3) 【Chemistry 9】 (In the formula, Y － is an anion, R １ is selected from the group consisting of hydrogen and methoxy; R ２ is selected from the group consisting of ethyl and vinyl; R ３ is aryl, optionally nitro, halogen, amino, trifluoromethyl , C １ ~C ４ Alkyl, C １ ~C ４ Independently from the group consisting of alkoxy and benzyloxy aryl substituted with 1 to 5 substituents selected from the following: Optionally, halogen, trifluoromethyl, C １ ~C ４ Alkyl, and C １ ~C ４ Arco heteroaryl substituted with 1 to 3 substituents independently selected from the group consisting of aryl, aryloxy, arylsulfonyl ... selected from the group consisting of to obtain a compound of formula (4), 【Chemistry 10】 (ii) replacing X of the compound of formula (4) with a compound of formula (5) 【Chemistry 11】 and converting the compound into a carboxylic acid of (iii) optionally reacting the compound of formula (5) with C １～５ Alcohol, C ２～５ Archi Lucianide, C ３～９ Alkyl ketone, C ２～８ Alkyl ether, C ２～８ Alkyria acetate, and optionally water and C ５～８ From hydrocarbons and an anti-solvent selected from the group consisting of A method comprising:

15. 15. The method of claim 14, wherein the crystallization of (iii) is carried out.

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