Method for preparing isoxazoline derivatives

Abstract

The present invention relates to a compound of formula III [Case 1] JPEG2026505630000027.jpg44160 is reacted with a compound of formula II [Case 2] JPEG2026505630000028.jpg52160 with hydroxylamine or a salt thereof, a base, a chiral catalyst and an organic solvent to prepare a compound of formula III, wherein the base comprises an anion exchange resin and optionally an alkali metal salt, X is hydrogen or a halogen, and R is -COOH, -C(=O)OC. 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R 2 ) and R 1 and R 2 is H and C 1-6 alkyl, and R is —C(═O)OC 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R 2 ), then formula III' [C3] JPEG2026505630000029.jpg41160 is obtained (III'), and then the R group of the compound of formula IIP is hydrolyzed to obtain the compound of formula III.

Description

[Technical Field]

[0001] The present invention relates to a method for preparing isoxazoline derivatives of formula III and also to a method for preparing optically active isoxazoline compounds of formula VI which are useful as pesticides. [Background technology]

[0002] Methods for preparing optically active isoxazoline compounds are described, for example, in WO 2016 / 023787. Optically active isoxazoline compounds bearing cycloserine substituents exhibit two stereocenters, the configuration of which is important for the biological activity of the compounds.

[0003] The reaction described in WO 2016 / 023787 affords cycloserine-substituted isoxazolines with high stereoselectivity and low racemization. However, the presence of some isomers can affect the isolation process and yield of the desired isomer.

[0004] Thus, there remains a need to improve the enantioselectivity of isoxazoline derivatives, more particularly the enantioselectivity of isoxazoline derivatives used to prepare intermediates in the route to optically active isoxazoline compounds, especially isoxazoline compounds bearing a cycloserine substituent. Summary of the Invention [Problem to be solved by the invention]

[0005] The aim of the present invention is to overcome the problems of the prior art by proposing a process for preparing isoxazoline derivatives which improves the yield and / or enantioselectivity of the desired isomer. [Means for solving the problem]

[0006] To this end, the object of the present invention is to provide a compound of formula III [ka] and more particularly compounds of formula IIIa [ka] with a compound of formula II [ka] by reacting the compound of formula (I) with hydroxylamine or a salt thereof, a base, a chiral catalyst and an organic solvent, the base comprises an anion exchange resin and optionally an alkali metal salt; X is hydrogen or halogen, and R is -COOH, -C(=O)OC 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R 2 ) and R 1 and R 2 is H and C 1-6 independently selected from alkyl, R is -C(=O)OC 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R 2 ), then formula III' [ka] is obtained, and then the R group of the compound of formula III' is hydrolyzed to obtain the compound of formula III. DETAILED DESCRIPTION OF THE INVENTION

[0007] In a preferred embodiment, the base comprises an anion exchange resin and an alkali metal salt.

[0008] The method overcomes all of the above problems. More specifically, the present invention provides an increase in the yield and / or enantioselectivity of the desired isomer. It can also be advantageously used in large-scale production.

[0009] In the present invention, X can be hydrogen or a halogen selected from among fluorine (fluoro or F), chlorine (chloro or Cl), bromine (bromo or Br) and iodine (iodo or I), preferably hydrogen and fluorine, and most preferably fluorine.

[0010] R is -C(=O)OC 1-6 Alkyl or -C(O)N(R 1 R 2 )(wherein, R 1 and / or R 2 is C 1-6 alkyl), C 1-6 Alkyl represents a straight-chain or branched hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, and 2-ethylbutyl. Alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, or t-butyl.

[0011] R is -C(=O)OC 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R 2In embodiments selected from the group consisting of: the R group of the compound of formula III' is hydrolyzed by techniques well known in the art using a hydrolysis agent to provide the compound of formula III. The hydrolysis agent can be, for example, an acid such as trifluoroacetic acid or sulfuric acid, or a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium methoxide, or sodium methoxide.

[0012] The anion exchange resin base according to the present invention is more particularly a strong base anion (SBA) exchange resin. Anion exchange resins generally may comprise a positively charged matrix and exchangeable anions.

[0013] More preferably, the anion exchange resin may be an OH anion exchange resin. In this case, the exchangeable anion is a hydroxide anion (OH - ) It is also possible to obtain OH anion exchange resin from other types of anion exchange resins. For example, chloride (Cl - ) anion exchange resin can be used to obtain OH anion exchange resin by rinsing the chloride anion exchange resin with aqueous NaOH solution until the active chloride anion sites are exchanged with hydroxide anions. Excess aqueous NaOH solution can be finally removed by rinsing the resin with demineralized water.

[0014] The matrix of the anion exchange resin can be a gel matrix or a microporous matrix, whether crosslinked or not. Matrices of this type can include polystyrene-based matrices or polyacrylic matrices. For example, the matrix can include a styrene-divinylbenzene copolymer.

[0015] The anion exchange resin can be provided in any form, more specifically, any solid form. For example, the anion exchange resin can be provided as beads, more specifically, spherical beads. The beads can have a size ranging from about 0.3 mm to about 1.2 mm, more preferably from about 0.5 mm to about 0.8 mm in their largest dimension (particle size).

[0016] In certain embodiments, the anion exchange resin may contain functional groups such as quaternary ammonium functional groups. More specifically, the anion exchange resin may be aminated with trimethylamine and contain trimethylammonium functional groups. Anion exchange resins typically have an exchange capacity in anionic form, known as the total exchange capacity on a water-wet basis, which may be at least 0.50 equivalents per liter (eq / L), preferably at least 0.80 eq / L. In the method according to the present invention, the amount of exchangeable anions (based on the exchange capacity of the anion exchange resin) may be 0.01 to 10 molar equivalents, preferably 0.05 to 5 molar equivalents, more preferably 0.05 to 1.5 molar equivalents, and most preferably 0.05 to 0.2 molar equivalents.

[0017] In the present invention, the expression "molar equivalent" refers to the number of moles (mol) of the compound of formula II.

[0018] According to the present invention, the anion exchange resin may be, for example, an AmberLite™ resin supplied by DuPont, such as AmberLite™ IRN78 OH ion exchange resin, AmberLite™ HPR4800 OH ion exchange resin (also known as Dowex Marathon™ A OH ion exchange resin) or AmberLite™ A26 OH polymer catalyst.

[0019] The alkali metal salt according to the present invention may be, for example, sodium chloride, sodium bromide, sodium hydroxide, sodium acetate, or sodium carbonate. Other alkali metals, such as lithium or potassium, may be used. More preferably, the alkali metal salt may be an alkali metal hydroxide (Na, Li, K), most preferably sodium hydroxide.

[0020] In the present invention, the amount of alkali metal salt can be 0.01 to 3.00 molar equivalents, preferably 0.04 to 1.40 molar equivalents. More specifically, when R is —C(═O)OC 1-6 Alkyl, -CN, -C(=O)O benzyl and -C(O)N(R 1 R2 ), the amount of alkali metal salt may be 0.01 to 2.00 molar equivalents, preferably 0.04 to 1.00 molar equivalents, and more preferably 0.04 to 0.40 molar equivalents.

[0021] When R is —COOH, the amount of alkali metal salt can be 1.00 to 3.00 molar equivalents, preferably 1.00 to 2.00 molar equivalents, and more preferably 1.00 to 1.40 molar equivalents.

[0022] The organic solvent according to the present invention may include any suitable organic solvent known in the art. For example, the organic solvent may be selected from dichloromethane, 1,2-dichloroethane, toluene, xylene, chlorobenzene, chloroform, tert-butyl methyl ether, isopropanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, 2-methylpropionitrile, butyronitrile, and any combination thereof. Preferred organic solvents may be selected from acetonitrile, isopropanol, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and any combination thereof. Acetonitrile, propionitrile, and tetrahydrofuran are more preferred. Most preferred is acetonitrile.

[0023] In the process according to the present invention, the amount of organic solvent may be 10 to 200 molar equivalents, preferably 20 to 130 molar equivalents, more preferably 50 to 130 molar equivalents, for example 120 molar equivalents.

[0024] The reaction may be carried out in the presence of water; in other words, the process solvent may further comprise water. The weight ratio of organic solvent to water may be from 200:1 to 1:1, preferably from 100:1 to 5:1, and more preferably from 50:1 to 8:1. The amount of water in the above weight ratio refers to the total amount of water in the process, which may result, for example, from an aqueous hydroxylamine solution, from a wet resin, from a solution of an alkali metal salt, from adding water directly during the process, and / or from neutralizing the alkali metal salt with a carboxylic acid functional group when R is —COOH.

[0025] The method according to the present invention includes hydroxylamine or a salt thereof, preferably hydroxylamine. The term "hydroxylamine" means free hydroxylamine of formula HNOH, and the hydroxylamine salt may be, for example, hydroxylammonium chloride. In the method according to the present invention, the amount of hydroxylamine or a salt thereof may be 0.5 to 10 molar equivalents, preferably 0.7 to 5 molar equivalents, more preferably 1.0 to 1.5 molar equivalents, and most preferably 1.1 to 1.2 molar equivalents.

[0026] A chiral catalyst according to the invention is more particularly a catalyst comprising at least one chiral moiety, preferably at least two chiral moieties.

[0027] The chiral catalyst may include any suitable chiral catalyst known in the art.

[0028] In a first example, the chiral catalyst may be a compound of formula III as described on page 2 of WO 2016 / 023787 (incorporated by reference), preferably a dimeric chiral catalyst of formula III as described on page 4 of WO 2016 / 023787, more preferably the compound R-(6-methoxy-4-quinolyl)-[(2S)-1-[[2,3,5,6-tetrafluoro-4-[[(2S)-2-[(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-1-ium-1-yl]methyl]phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]methanol dihalide, wherein the halide may be bromine or chlorine. The bromide-based catalyst (TFBBQ) having the following CAS number 1879067-61-4 is described as a compound of formula XVII on page 8 of WO 2016 / 023787. On pages 7-8 of WO 2016 / 023787, the compound of formula XVII can be prepared by reacting a compound of formula XV with a suitable halogenating agent such as SOBr, POBr, PBr, HBr, NaBr / HSO, or any combination thereof in a suitable solvent such as acetic acid, toluene, xylene, chlorobenzene, dichlorobenzene, heptane, ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, water, or any combination thereof to obtain a compound of formula XVI. The compound of formula XVI can then be reacted with a compound of formula X as described on page 7 of WO 2016 / 023787 in the presence of a suitable organic solvent such as toluene, acetonitrile, acetone, methanol, ethanol, 1-pentanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethylformamide, N-methylpyrrolidone, anisole, water or any combination thereof to provide a compound of formula XVII.

[0029] In a second example, the chiral catalyst can be a compound of Formula 2-5 or a compound of Formula 7-12, as described in U.S. Patent Application Publication No. 2014350261 (incorporated by reference) as a chiral phase transfer catalyst.

[0030] In a third example, the chiral catalyst can be a compound of formula III described in WO 2020 / 094434 (incorporated by reference) or described in WO 2021 / 197880 (incorporated by reference).

[0031] In a fourth example, the chiral catalyst may further be a quinine derivative, such as (R)-(6-methoxy-4-quinolyl)-[(1S,2S,4S,5R)-1-[[2,3,5,6-tetrafluoro-4-[[(1S,2S,4S,5R)-2-[(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-1-ium-1-yl]methyl]phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]methanol dibromide.

[0032] In the process according to the present invention, the amount of chiral catalyst may be 0.001 to 1.0 molar equivalent, preferably 0.01 to 0.5 molar equivalent, more preferably 0.03 to 0.2 molar equivalent.

[0033] The process according to the present invention may be carried out at a temperature ranging from -78°C to 80°C, preferably from -20°C to +20°C, more preferably from -20°C to 0°C.

[0034] The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 4 hours.

[0035] The method can be carried out by dosing at least one reactant selected from hydroxylamine or a salt thereof, an anion exchange resin, a chiral catalyst, a compound of formula II, and any combination thereof. Dosing a reactant is well known in the art and refers to adding a compound in several aliquots or in a continuous stream over a predetermined period of time.

[0036] In certain embodiments, the method according to the present invention may further comprise a separation step to remove the anion exchange resin after obtaining the compound of formula III. If there is a hydrolysis step before the formation of the compound of formula III, the separation step may be carried out after obtaining the compound of formula III'.

[0037] This separation step can be carried out by techniques well known in the art, such as decantation, centrifugation, or filtration (e.g., using a centrifuge, Nutsche filter, candle filter, or pocket filter). Before and / or after separation of the resin, the pH of the reaction mixture can be adjusted, and if necessary, the reaction mixture can be heated to dissolve the compound of formula III. The reaction mixture can be adjusted to a pH of 4 to 8, preferably 5 to 6, using an acid such as hydrochloric acid (HCl). The reaction mixture can be heated to a temperature of 15 to 50°C to dissolve the compound of formula III.

[0038] The preparation of compounds of formula II is based on an aldol reaction followed by a dehydration step, said reaction being well known in the art.

[0039] More specifically, compounds of formula II can be prepared by reacting compounds of formula Ia in the presence of a base, preferably an anhydrous base such as triethylamine. [ka] Compounds of formula Ib [ka] to form the aldol product, followed by dehydration in the presence of a dehydrating agent such as thionyl chloride, acetic anhydride or acetyl chloride and a catalyst such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine.

[0040] The process according to the invention involves reacting a compound of formula III with a chlorinating agent such as thionyl chloride or phosgene to give a compound of formula IV [ka] Preferably, the compound of formula IVa [ka] The method may further comprise the step of preparing a compound of formula:

[0041] The method according to the present invention comprises reacting a compound of formula IV with a compound of formula V [ka] Compounds of formula Va [ka] to form a compound of formula VI [ka] Compounds of formula VIa [ka] The method may further comprise the step of preparing a compound of formula:

[0042] This step is well known in the art and can be carried out in the presence of an organic solvent and a base, more preferably an aqueous base. For organic solvents exhibiting low water immiscibility, for example, aromatic solvents such as chlorobenzene or toluene, esters such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane or dichloroethane, ethers such as 2-methyl-tetrahydrofuran, dipropyl ether or dibutyl ether, or nitrile solvents such as butyronitrile or benzonitrile, can be used together with an aqueous solution of an alkali metal base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or potassium carbonate or sodium carbonate. When it is desirable to use a solvent with much greater water miscibility, such as acetonitrile, propionitrile, methyl acetate, tetrahydrofuran, or diethyl ether, a tertiary amine base such as triethylamine, N,N-dimethylaniline, pyridine, or diisopropylethylamine can be used. More preferably, a water-immiscible solvent and an aqueous base can be used.

[0043] More specifically, the step of reacting a compound of formula IV with a compound of formula V is [ka] or a concentrate composition comprising a compound of formula VIb.

[0044] The concentrated composition can include the compound of formula VIb (5S,4R) and at least one isomer of the compound of formula VI selected from the isomer (5S,4S), the isomer (5R,4R), the isomer (5R,4S), and any combination thereof.

[0045] In a preferred embodiment, the concentrate composition may comprise the compound of formula VIb (5S,4R) and the isomer of the compound of formula VI (5R,4R).

[0046] The concentrated composition may comprise a molar proportion of the isomer (5S,4R) of greater than 50%, for example at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, based on the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S).

[0047] In certain embodiments, the concentrate composition comprises: - the isomer (5S,4S) of the compound of formula VI in a molar proportion of less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1%, more preferably 0%, relative to the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S), and / or - a molar proportion of less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.1%, more preferably 0% of the isomer (5R,4S) of the compound of formula VI relative to the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S); may include:

[0048] When X is F, the isomer (5S,4R) of the compound of formula VI (i.e., the compound of formula VIb) is 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide. The method according to the present invention may also relate to the preparation of a concentrated composition comprising the compound of formula VI (5S,4R) and at least one isomer of the compound of formula VI selected from isomer (5S,4S), isomer (5R,4R), isomer (5R,4S), and any combination thereof. The isomer (5S,4S) is 4-[(5S)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide and the isomer (5R,4R) is 4-[(5R)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide. oxazol-3-yl]-N-[(4R)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide, and the isomer (5R,4S) is 4-[(5R)-5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(4S)-2-ethyl-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide.

[0049] Compounds of formula V may be of the following type: [ka] , preferably [ka] under basic conditions as described, for example, in WO2015166094 (incorporated by reference).

[0050] Another object of the present invention relates to the use of an anion exchange resin as defined in the present invention in a process for preparing a compound of formula III. [Example]

[0051] The following non-limiting examples demonstrate the improved performance associated with the method according to the present invention, with Examples (Ex.) 1, 3a, 3b, 4a, 4b, 5 and 6 being examples according to the present invention and Example 2 being a comparative example.

[0052] The ingredients used in the examples below are detailed as follows: the resin is an anion exchange resin (solid form) commercialized by DuPont under the name AmberLite™ IRN78 OH ion exchange resin; - Hydroxylamine is a 50% aqueous solution of hydroxylamine, the chiral catalyst is TFBBQ (CAS number 1879067-61-4) (rac-(R)-(6-methoxy-4-quinolyl)-[rac-(2S,5R)-1-[[2,3,5,6-tetrafluoro-4-[[rac-(2S,5R)-2-[rac-(R)-hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-1-ium-1-yl]methyl]phenyl]methyl]-5-vinyl-quinuclidin-1-ium-2-yl]methanol dibromide), and The organic solvent is acetonitrile or tetrahydrofuran (THF).

[0053] Example 1: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid To a solution of 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid (20.0 g, 47.5 mmol) in acetonitrile (230 g) was added a 25% aqueous solution of sodium hydroxide (7.6 g, 47.5 mmol), and the resulting mixture was cooled to -15°C. Once the mixture reached -15°C, AmberLite™ IRN78 OH resin (3.8 g, 20% w / w of the compound of Formula II as defined in Table 1) and TFBBQ (5.6 g, 5.7 mmol) were added. A 50% aqueous solution of hydroxylamine (3.64 g, 55.2 mmol) was charged to the reaction mixture over 1 hour. The reaction was then stirred at -15°C for 6 hours. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (13.3 g, 114 mmol) was added to obtain a pH of 3.5. The mixture was heated to 40° C. and filtered to remove the resin. The filtrate was then concentrated under vacuum to remove the solvent. The residue was then dissolved in 2-methyltetrahydrofuran (181.9 g), and the pH was adjusted to pH 4 with 32% aqueous hydrochloric acid. The organic solution was then extracted with water (182 g). The organic layer was then concentrated under vacuum to obtain the crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (19.4 g, 39.9 mmol, 78.8% yield, two stereoisomers, the S isomer was obtained with an enantiomeric excess (ee) of 81%) without further purification.

[0054] Comparative Example 2: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid using only NaOH To a solution of 4-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-2-methylbenzoic acid (20.0 g, 47.5 mmol) in acetonitrile (230 g) was added a 25% aqueous solution of sodium hydroxide (7.6 g, 47.5 mmol), and the resulting mixture was cooled to -15 °C. Once the mixture reached -15 °C, a second equivalent of a 25% aqueous solution of sodium hydroxide (7.6 g, 47.5 mmol) and TFBBQ (5.6 g, 5.7 mmol) were added to the mixture. A 50% aqueous solution of hydroxylamine (3.64 g, 55.2 mmol) was charged to the reaction mixture over 1 hour. The reaction was then stirred at -15 °C for 1 hour. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (12.2 g, 107 mmol) was added to obtain a pH of 5.5. The mixture was then concentrated under vacuum to remove the solvent. The residue was then dissolved in 2-methyltetrahydrofuran (181.9 g) and the pH was adjusted to pH 4 with 32% aqueous hydrochloric acid. The organic solution was then extracted with water (179.5 g). The organic layer was concentrated under vacuum to obtain the crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (19.8 g, 39.9 mmol, 84.0% yield, two isomers, 16% ee for the S isomer) without further purification.

[0055] Example 3: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid using methyl ester type starting materials 3a) Preparation of methyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (compound of formula III′ with R=COOCH3): To a solution of methyl 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoate (2.0 g, 4.6 mmol) in acetonitrile (22.3 g) was added a 25% aqueous solution of sodium hydroxide (0.7 g, 4 mmol), and the resulting reaction mixture was cooled to −15° C. Once the mixture reached −15° C., AmberLite™ IRN78 OH resin (0.4 g, 20% w / w of the compound of Formula II as defined in Table 1) and TFBBQ (0.6 g, 0.6 mmol) were added to the mixture. A 50% aqueous solution of hydroxylamine (0.4 g, 6.0 mmol) was charged to the reaction mixture over 1 hour. The reaction mixture was then stirred at −15° C. for 6 hours. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (1.0 g, 8.8 mmol) was added to obtain a pH of 4.0. The mixture was heated to 40° C. and filtered to remove the resin. The filtrate was then concentrated under vacuum to remove the solvent. The resulting residue was dissolved in 2-methyltetrahydrofuran (16.1 g), and the organic solution was extracted with water (16.1 g). The organic layer was then concentrated under vacuum to obtain the crude product methyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (1.8 g, 3.3 mmol, 71.7% yield, 76% ee of two stereoisomers with the S-isomer) without further purification.

[0056] 3b) Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid by base hydrolysis of the methyl ester prepared in example 3a): To a solution of methyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]2-methylbenzoate (100.2 mg, 0.22 mmol) in tetrahydrofuran (310.5 mg) was added a 25% aqueous solution of sodium hydroxide (157.2 mg, 0.98 mmol). The reaction mixture was stirred at 25° C. for 24 hours. After completion of the reaction (99.8% conversion), a 32% aqueous solution of hydrochloric acid (112.4 mg, 0.99 mmol) and water (112.7 mg) were added to the reaction mixture. The mixture was stirred at 25° C., and the organic layer was separated and concentrated under vacuum to give the crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid without further purification (75.5 mg, 0.173 mmol, 77.6% yield, two isomers with 77.6% ee of the S-isomer).

[0057] Example 4: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid using t-butyl ester starting material 4a) Preparation of tert-butyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (compound of formula III′ where R=COOC(CH3)3): To a solution of tert-butyl 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoate (2.0 g, 4.2 mmol) in acetonitrile (20.3 g) was added a 25% aqueous solution of sodium hydroxide (0.7 g, 4 mmol), and the resulting reaction mixture was cooled to −15° C. Once the mixture reached −15° C., AmberLite™ IRN78 OH resin (0.4 g, 20% w / w of the compound of Formula II as defined in Table 1) and TFBBQ (0.5 g, 0.5 mmol) were added to the mixture. A 50% aqueous solution of hydroxylamine (0.3 g, 5.0 mmol) was charged to the reaction mixture over 1 hour. The reaction mixture was then stirred at −15° C. for 6 hours. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (1.0 g, 8.8 mmol) was added to adjust the pH to 4.0, and the mixture was heated to 40 ° C. and filtered to remove the resin. The filtrate was then concentrated under vacuum to remove the solvent. The resulting residue was then dissolved in 2-methyltetrahydrofuran (16.1 g). The organic solution was then extracted with water (16.1 g). The organic layer was then concentrated under vacuum to give the crude product tert-butyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (2.1 g, 3.7 mmol, 88% yield, 57.6% ee of two stereoisomers with the S-isomer) without further purification.

[0058] 4b) Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid by acid hydrolysis of the t-butyl ester prepared in example 4a): To a solution of tert-butyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (101.4 mg, 0.21 mmol) in tetrahydrofuran (312.2 mg) and water (130.8 mg), trifluoroacetic acid (TFAA) (144.4 mg, 1.266 mmol) was added at 25° C. The reaction mixture was then heated at 60° C. for 18 hours. After completion of the reaction (98.0% conversion), the mixture was concentrated under vacuum. To the residue, dichloromethane (227 mg) and water (257 mg) were added. The mixture was stirred at 25° C. for 5 minutes. The organic layer was separated and concentrated under vacuum to give the crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (54.3 mg, 0.124 mmol, 60.4% yield, 56.6% ee of two stereoisomers with the S-isomer) without further purification.

[0059] Example 5: Preparation of Compound of Formula IV by Phosgenation of Compound of Formula III Prepared in Example 1 To a solution of 4-[3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-2-methylbenzoic acid (81.1 g, 187 mmol) in chlorobenzene (190.4 g) was added N-methyl-2-pyrrolidone (0.23 g, 2.3 mmol). The reaction mixture was then stirred at 85°C, and phosgene (37.0 g, 374 mmol) was added over 1.5 hours. The mixture was then stirred at 85°C for 4 hours. After completion of the reaction, chlorobenzene was removed by distillation under high vacuum (800-16 mbar) at Tj = 90°C. After distillation, the oily brown crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoyl chloride was collected in a flask (79.6 g, 158 mmol, 84.7% yield), which was then dissolved in butyronitrile (116 g) and used in the next step without further purification.

[0060] Example 6: Preparation of compound of formula VI by coupling with compound of formula V prepared in Example 5 To a solution of (4R)-N-ethyl-N-hydroxy-2-oxo-oxazolidine-4-carboxamide (22.2 g, 127 mmol) in water (122 g) at 25°C and pH 4.9, 25% aqueous NaOH (21.2 g, 133 mmol) was added to adjust the pH to 9.0. Once the pH was set to 9.0, the solution was heated to 45°C. The pH was maintained at 9.0 by adding 25% aqueous NaOH at 45°C, and butyronitrile (127.5 g) was added. Then, a solution of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoyl chloride in butyronitrile (192.5 g, Example 7) was added over 1 hour. The pH was maintained at 6.0 by adding a 25% aqueous solution of NaOH (4.9 g, 31.2 mmol). The reaction mixture was then stirred at 45° C. and pH 6.0 for 30 minutes. The stirring was then stopped, the reaction mixture was settled, separated, and the organic layer was concentrated under vacuum. The brown oily crude product was dried in an oven at 50° C. for 10 hours to give a beige powder corresponding to 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (87.6 g, 160 mmol, 81% yield, 75% ee of two diastereoisomers with the 5S,4R-isomer).

[0061] Comparative Example 7: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid using LiOH only Compound II (21 mg, 0.045 mmol) and catalyst (0.1 molar equivalents) were weighed into a glass shell vial in a 96-position reaction block. The block was then transferred to a glove box (O2 < 1%). Acetonitrile (0.225 ml, to obtain a 0.2 M solution of compound II) was added, followed by cooling to -15 °C. Base (16% w / v, LiOH 4.75% w / v, 2 equivalents) was added, followed by hydroxylamine (3.5 μL of 50% w / v hydroxylamine in water, 1.3 molar equivalents). The reaction block was sealed and stirred for 20 h. The vessel was warmed to -10 °C, and then HCl (100 g / L, 40 μL, 2.5 molar equivalents) was added.

[0062] Example 8: Preparation of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid Compound II (21 mg, 0.045 mmol) and catalyst (0.1 molar equivalents) were weighed into a glass shell vial in a 96-position reaction block. The block was then transferred to a glove box (O2 < 1%), and AmberLite™ RN78 OH resin (0.005 g, 20% w / w of compound II as defined in Table 1) was added to the vessel. Acetonitrile (0.225 ml, to obtain a 0.2 M solution of compound II) was added, followed by cooling to -15 °C. Base (16% w / v, 4.75% w / v LiOH, 1.2 molar equivalents) was added, followed by hydroxylamine (3.5 μL of 50% w / v hydroxylamine in water, 1.3 molar equivalents). The reaction block was sealed and stirred for 20 h. The vessel was warmed to -10°C and then HCl (100g / L, 40uL, 2.5 molar equivalents) was added.

[0063] [Table 1]

[0064] The results are summarized in Table 2 below, and the compounds of formula IIIa and IIIb are as follows: [ka] The X and R groups in compounds III, III', IIIa and IIIb are defined in Table 1.

[0065] [Table 2]

[0066] The results in Table 2 clearly demonstrate that the present invention provides increased enantioselectivity and / or increased chemical yield of the desired isomer IIIa.

Claims

1. Formula III 【Chemistry 1】 with a compound of formula II 【Chemistry 2】 with hydroxylamine or a salt thereof, a base, a chiral catalyst and an organic solvent, the base comprises an anion exchange resin and optionally an alkali metal salt; X is hydrogen or halogen, and R is —COOH, —C(═O)OC 1-6 Alkyl, —CN, —C(═O)O benzyl and —C(O)N(R 1 R 2 ), and R 1 and R 2 is H and C 1-6 independently selected from alkyl, R is -C(=O)OC 1-6 Alkyl, —CN, —C(═O)O benzyl and —C(O)N(R 1 R 2 ), then formula III' 【Transformation 3】 and then hydrolyzing the R group of said compound of formula III' to obtain said compound of formula III.

2. 2. The method of claim 1, wherein the resin is an OH anion exchange resin.

3. 3. The method of claim 1, wherein the anion exchange resin comprises quaternary ammonium functional groups.

4. The method according to any one of claims 1 to 3, characterized in that the matrix of the anion exchange resin comprises a styrene-divinylbenzene copolymer.

5. 5. The method according to any one of claims 1 to 4, characterized in that the amount of exchangeable anion is 0.01 to 10 molar equivalents, preferably 0.05 to 5 molar equivalents, preferably 0.05 to 1.5 molar equivalents, more preferably 0.05 to 0.2 molar equivalents, based on the number of moles of the compound of formula II.

6. 6. The method according to any one of claims 1 to 5, characterized in that the amount of the alkali metal salt is 0.01 to 3.00 molar equivalents, preferably 0.04 to 1.40 molar equivalents, based on the number of moles of the compound of formula II.

7. 7. The method according to any one of claims 1 to 6, characterized in that the amount of organic solvent is 10 to 200 molar equivalents, preferably 20 to 130 molar equivalents, based on the number of moles of the compound of formula II.

8. The method according to any one of claims 1 to 7, further comprising the addition of water.

9. The method according to any one of claims 1 to 8, characterized in that the amount of hydroxylamine or a salt thereof can be 0.5 to 10 molar equivalents, preferably 0.7 to 5 molar equivalents, more preferably 1.0 to 1.5 molar equivalents, based on the number of moles of the compound of formula II.

10. 10. The method according to any one of claims 1 to 9, characterized in that the amount of the chiral catalyst is 0.001 to 1.0 molar equivalent, preferably 0.01 to 0.5 molar equivalent, based on the number of moles of the compound of formula II.

11. The compound of formula III is reacted with a chlorinating agent to form a compound of formula IV 【Chemistry 4】 11. The method according to any one of claims 1 to 10, further comprising the step of preparing a compound of formula:

12. The compound of formula IV is reacted with a compound of formula V 【Transformation 5】 to form a compound of formula VI 【Transformation 6】 12. The method of claim 11, further comprising preparing a compound of formula:

13. The step of reacting the compound of formula IV with the compound of formula V is 【Transformation 7】 13. The method according to claim 12, characterized in that it is for preparing a concentrated composition comprising a compound of formula VIb or a compound of formula VIb.

14. 14. The method of claim 13, wherein the concentrated composition comprises the compound of formula VIb (5S,4R) and at least one isomer of the compound of formula VI selected from isomer (5S,4S), isomer (5R,4R), isomer (5R,4S), and any combination thereof.

15. Use of an anion exchange resin, preferably an OH anion exchange resin, in the process for preparing a compound of formula III.

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