IL322407A - Process for the preparation of isoxazoline derivatives - Google Patents

Description

Process for the preparation of isoxazoline derivatives The present invention relates to a process for the preparation of isoxazoline derivatives of formula III, and also for the preparation of optically active isoxazoline compounds of formula VI, the isoxazoline compounds of formula VI being useful as pesticide.

Processes for the preparation of optically active isoxazoline compounds are described, for example, in WO2016/023787. Optically active isoxazoline compounds with cycloserine substituent show two stereocentres which configuration is important for the biological activity of the compounds.The reaction describes in WO2016/023787 gives cycloserine substituted isoxazolines with high stereoselectivity and low racemization. However, the presence of several isomers can affect the isolation process and the yield of the desired isomer.Therefore, there is still a need to improve the enantioselectivity of isoxazoline derivatives, more particularly used to prepared optically active isoxazoline compounds especially intermediates in the routes to isoxazoline compounds with cycloserine substituent.

The aim of the present invention is to overcome the problems of the prior art techniques by proposing a process for the preparation of isoxazoline derivatives which improves the yield and/or the enantioselectivity of the desired isomer.To this end, an object of the present invention is to provide a process for the preparation a compound of formula III COOH(III), and more particularly a compound of formula Illa by reacting a compound of formula II with hydroxylamine or its salt, a base, a chiral catalyst, and an organic solvent,wherein said base comprises an anion exchange resin and optionally alkali metal salt, wherein X is hydrogen or halogen, and R is selected among -COOH, -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl, and -C(O)N(R1R2) wherein R1 and R2 are independently selected from H and C1-6alkyl, andwherein when R is selected among -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl, and -C(O)N(R1R2), a compound of formula III’ is obtained being then hydrolysed to obtain the compound of formula III.In a preferred embodiment, said base comprises the anion exchange resin and the alkali metal salt.

Thanks to said process, all the above problems have been overcome. More particularly, the present invention provides an increased yield and/or the enantioselectivity of the desired isomer. It can also be advantageously used for large scale production.

In the present invention, X can be hydrogen or halogen selected among fluorine (fluoro or F), chlorine (chloro or Cl), bromine (bromo or Br) and iodine (iodo or I), preferably hydrogen and fluorine. Most preferably fluorine.When R is -C(=O)OC1-ealkyl or -C(O)N(R1R2) wherein R1 and/or R2 are Cue alkyl, Ci-ealkyl represents straight-chain or branched hydrocarbons, with 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, l- 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 with 1 to 4 carbon atoms are preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.

In the embodiment wherein R is selected among -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl and -C(O)N(R1R2), the R group of the compound of formula IIF is hydrolysed to obtain the compound of formula III via techniques well-known in the art, in using a hydrolysing agent. The hydrolysing 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.

The anion exchange resin base according to the present invention is more particularly a strong base anion (SBA) exchange resin. An anion exchange resin can generally comprise a positively charged matrix and exchangeable anions.More preferably, the anion exchange resin can be an OH anion exchange resin. In this case, the exchangeable anions are hydroxide anions (OH). It is also possible to obtain an OH anion exchange resin from other types of anion exchange resins. For example, a chloride (CF) anion exchange resin can be used to obtain an OH anion exchange resin by rinsing said chloride anion exchange resin with an aqueous solution of NaOH until the active chloride anion sites are exchanged by hydroxide anions. Excess of aqueous solution of NaOH can be finally removed by rinsing the resin with demineralized water.

The matrix of the anion exchange resin can be a gel matrix or a microporous matrix, crosslinked or not. This type of matrix can comprise a polystyrenic matrix or a polyacrylic matrix. For example, the matrix can comprise a copolymer of styrene-divinylbenzene.The anion exchange resin may be provided in any form, more particularly in any solid form. For example, the anion exchange resin may be provided as beads, and more particularly as spherical beads. The beads may have a size across their largest dimension (particle diameter) of from about 0.3 mm to about 1.2 mm, and more preferably from about 0.5 mm to about 0.8 mm.In a particular embodiment, the anion exchange resin can comprise a functional group, such as quaternary ammonium functional group. More particularly, the anion exchange resin can be aminated with trimethylamine, and can comprise the trimethyl ammonium functional group. The anion exchange resin has typically an exchange capacity, well-known as Total Exchange Capacity on a water-wet basis, of the anion form, which can be of at least 0.50 equivalent per liter (eq/L), and preferably of at least 0.80 eq/L. In the process according to the present invention, the amount of exchangeable anions (based on the exchange capacity of the anion exchange resin) can be from 0.01 to 10 molar equivalents, preferably from 0.05 to 5 molar equivalents, more preferably from 0.05 to 1.5 molar equivalents, and most preferably from 0.to 0.2 molar equivalents.In the present invention, the expression "molar equivalents" is based on the number of moles (mol) of the compound of formula II.According to the present invention, the anion exchange resin can be, for example, the AmberLite™ resin supplied by Dupont, such as AmberLite™ IRN78 OH Ion Exchange Resin, AmberLite™ HPR4800 OH Ion Exchange Resin (also well-known as Dowex Marathon™ A OH Ion Exchange Resin), or AmberLite™ A26 OH Polymeric Catalyst.

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

In the present invention, the amount of the alkali metal salt can be from 0.01 to 3.00 molar equivalents, and preferably from 0.04 to 1.40 molar equivalents. More particularly, when R is selected among -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl, and -C(O)N(R1R2), the amount of the alkali metal salt can be from 0.01 to 2.00 molar equivalents, preferably from 0.04 to 1.00 molar equivalents, and more preferably from 0.04 to 0.40 molar equivalents.

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

The organic solvent according to the present invention can comprise any suitable organic solvent well-known in the art. For example, the organic solvent can be selected among di chloromethane, 1,2-di chloroethane, toluene, xylenes, chlorobenzene, chloroform, tert-butyl methyl ether, iso-propanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, 2-methylpropionitrile, butyronitrile, and any combinations thereof. The preferred organic solvent can be selected among acetonitrile, iso-propanol, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran and any combinations thereof. More preferred are acetonitrile, propionitrile and tetrahydrofuran. Most preferred is acetonitrile.

In the process according to the present invention, the amount of the organic solvent can be from to 200 molar equivalents, preferably from 20 to 130 molar equivalents, and more preferably from 50 to 130 molar equivalents, and by example 120 molar equivalents.

The reaction may be carried out in the presence of water, or in other words the process solvent can further comprise water. The weight ratio of organic solvent: water can 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 said weight ratio refers to the total amount of water in the process, which can for example come from an aqueous hydroxylamine solution, from a wet resin, from a solution of alkali metal salt, from adding water directly in the process, and/or from the neutralisation of alkali metal salt with the carboxylic acid function when R is -COOH.

The process according to the present invention comprises hydroxylamine or its salt, and preferably hydroxylamine. The term "hydroxylamine" means the free hydroxylamine of formula H2NOH, and the hydroxylamine salts can be for example hydroxylammonium chloride. In the process according to the present invention, the amount of hydroxylamine or its salts can be from 0.5 to 10 molar equivalents, preferably from 0.7 to 5 molar equivalents, more preferably from 1.0 to 1.5 molar equivalents, and most preferably from 1.1 to 1.2 molar equivalents.

The chiral catalyst according to the present invention is more particularly a catalyst comprising at least one chiral moiety, and preferably at least two chiral moieties.The chiral catalyst can comprise any suitable chiral catalyst well-known in the art.

In a first example, the chiral catalyst can be the compounds of formula III described on page in WO2016/023787 (incorporated by reference), preferably the dimeric chiral catalyst of formula III described on page 4 in WO2016/023787, and more preferably the compound R-(6- methoxy-4-quinolyl)-[(2S)-l-[[2,3,5,6-tetrafluoro-4-[[(2S)-2-[(R)-hydroxy-(6-methoxy-4- quinolyl)methyl]-5-vinyl-quinuclidin-l-ium-l-yl]methyl]phenyl]methyl]-5-vinyl-quinuclidin- l-ium-2-yl]methanol dihalide, where the halide can be bromine or chlorine. The bromide based catalyst (TFBBQ) with the following CAS number: 1879067-61-4 described as compound of formula XVII on page 8 in WO2016/023787. In WO2016/023787 pages 7-8, said compound of formula XVII can be prepared from the compound of formula XV with a suitable halogenating reagent such as SOBr2, POBr3, PBr3, HBr, NaBr/H2SO4, or any combinations thereof; in a suitable solvent such as acetic acid, toluene, xylene, chlorobenzene, dichlorobenzene, heptane, ethyl acetate, dichloromethane, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4-di oxane, dimethylformamide, N-methyl pyrrolidone, water, or any combinations thereof; to yield the compound of formula XVI. Then the compound of formula XVI can react with the compound of formula X described on page 7 of WO2016/023787, in the presence of a suitable organic solvent such as toluene, acetonitrile, acetone, methanol, ethanol, 1-pentanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, dimethyl formamide, N-methyl pyrrolidone, anisole, water, or any combinations thereof, to yield the compound of formula XVII.In a second example, the chiral catalyst can be the compounds of formula 2 to 5 or compounds of formula 7 to 12 as chiral phase transfer catalysts, described in US2014350261A(incorporated by reference).In a third example, the chiral catalyst can be the compounds of formula III described in WO2020/094434 (incorporated by reference) or described in WO2021/197880 (incorporated by reference).In a fourth example, the chiral catalyst can be further quinine derivatives, such as (R)-(6- methoxy-4-quinolyl)-[(lS,2S,4S,5R)-l-[[2,3,5,6-tetrafluoro-4-[[(lS,2S,4S,5R)-2-[(R)- hydroxy-(6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-l-ium-l-yl]methyl]phenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]methanol dibromide.In the process according to the present invention, the amount of the chiral catalyst can be from 0.001 to 1.0 molar equivalents, preferably from 0.01 to 0.5 molar equivalents, and more preferably from 0.03 to 0.2 molar equivalent.

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

The reaction time is usually from 30 minutes to 48 hours, and preferably from 1 to 4 hours.The process can be carried out in dosing at least one of the reactants selected among the hydroxylamine or its salt; the anion exchange resin; the chiral catalyst; the compound of formula II; and any combinations thereof. Dosing a reactant is well-known in the art and refers to the addition of several amounts or a continuous flow of a compound over a predetermined period of time.

In a particular embodiment, the process according to the present invention can further comprise, after yielding the compound of formula III, a separation step to remove the anion exchange resin. In the case wherein there is an hydrolysis step before the formation of the compound of formula III, the separation step can occur after yielding the compound of formula IIT.This separation step can be carried out by techniques well-known in the art such as for example by decantation, centrifugation or filtration (e.g. in using a centrifuge, a filternutsche, a candle filter, or a pocket filter). Before and/or after the separation of the resin, the pH of the reaction mixture can be adjusted and, if necessary, the reaction mixture heated to dissolve the compound of formula III. The reaction mixture can be adjusted to a pH of from 4 to 8, and preferably of from 5 to 6, using, for example, an acid such as hydrochloric acid (HQ). To dissolve the compound of formula III, the reaction mixture can be heated up to a temperature from 15 to 50°C.

The preparation of the compound of formula II is based on an aldol reaction followed by a dehydration step, said reactions being well-known in the art.More particularly, the compound of formula II can be prepared by reacting a compound of formula la (la) with a compound of formula Ib ch3 ס ch3 (lb), and in the presence of a base, and preferably an anhydrous base such as for example triethylamine, to form the aldol product, and then by dehydration in the presence of a dehydration agent such as for example thionyl chloride, acetic anhydride, or acetyl chloride, and a catalyst such as forexample 4-dimethylaminopyridine or 4-pyrrolidinopyridine.

The process according to the present invention can further comprise the step of reacting the compound of formula III with a chlorinating agent, such as thionyl chloride or phosgene, to prepare a compound of formula IV preferably a compound of formula IVa The process according to the present invention can further comprise the step of reacting thecompound of formula IV with a compound of formula V8 (V), and preferably a compound of formula Va (Va), to prepare a compound of formula VI preferably a compound of formula Via (Via).

This step is well-know in the art, and can be performed in presence of an organic solvent and a base, more preferably an aqueous base. For organic solvents which display low water immiscibility for example aromatic solvents such as chlorobenzene or toluene, esters such as ethyl acetate or propylacetate, chlorinated solvents such as dichloromethane or di chloroethane, 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 alkali metal base such as sodium, potassium or lithium hydroxide, or potassium or sodium carbonate. Where it is desirable to use solvents which have much greater water miscibility such as acetonitrile, propionitrile, methylacetate, tetrahydrofuran or diethylether, tertiary amine bases such as for example triethylamine, N,N-dimethyl aniline, pyridine or diisopropylethylamine, can be used. More preferably, a non-water miscible solvent and an aqueous base can be used.

More particularly, the step of reacting the compound of formula IV with the compound of formula V can be to prepare a compound of formula VIb or an enriched composition comprising a compound of formula VIb (VIb).

The enriched composition can comprise the compound of formula VIb (5S,4R) and at least one of the isomers of the compound of formula VI selected among isomer (5S,4S), isomer (5R,4R), isomer (5R,4S), and any combinations thereof.In a preferred embodiment, the enriched composition can comprise the compound of formula VIb (5S,4R) and the isomer (5R,4R) of the compound of formula VI.The enriched composition can comprise a molar proportion of the isomer (5S,4R) greater than 50%, e.g. at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%, over the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S).In a particular embodiment, the enriched composition can comprise:- a molar proportion of the isomer (5S,4S) of the compound of formula VI lower than 2%, preferably lower than 1%, preferably lower than 0.5%, preferably lower than 0.1 %, and more preferably 0%, over the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S), and/or - a molar proportion of the isomer (5R,4S) of the compound of formula VI lower than 2%, preferably lower than 1%, preferably lower than 0.5%, preferably lower than 0.1 %, and more preferably 0%, over the total amount of the isomers (5S,4R), (5S,4S), (5R,4R) and (5R,4S).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 process according to the present invention can also relate to the preparation of an enriched composition comprising the compound of formula VI (5S,4R) and at least one of the isomers of the compound of formula VI selected among isomer (5S,4S), isomer (5R,4R), isomer (5R,4S), and any combinations 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; the isomer (5R,4R) is 4-[(5R)-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; 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.

The compmound of formula V can be prepared from a compound of the type: , and preferably under basic conditions, for example as described in WO2015166094 (incorporated by reference).

Another object of the present invention relates to the use of an anionic exchange resin as defined in the present invention, in a process for preparing a compound of formula III.

The following non-limiting examples demonstrate the improved behaviour associated with a process according to the present invention, wherein Examples (Ex.) 1, 3a, 3b, 4a, 4b, 5 and are examples according to the present invention, and Example 2 is a comparative example.

The components used in the below Examples are detailed as follows: - Resin is an anion exchange resin (solid form), commercialized by Dupont under the name AmberLite™ IRN78 OH Ion Exchange Resin;hydroxylamine is hydroxylamine 50% aqueous solution;chiral catalyst is TFBBQ (CAS-No. 1879067-61-4) (rac-(R)-(6-methoxy-4- quinolyl)-[rac-(2S,5R)-l-[[2,3,5,6-tetrafluoro-4-[[rac-(2S,5R)-2-[rac-(R)-hydroxy- (6-methoxy-4-quinolyl)methyl]-5-vinyl-quinuclidin-l-ium-l- yl]methyl]phenyl]methyl]-5-vinyl-quinuclidin-l-ium-2-yl]methanol dibromide); andorganic solvent is acetonitrile or tetrahydrofuran (THE).

Example 1: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yll-2-methyl-benzoic acidTo a solution of 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl- benzoic acid (20,0g, 47,5 mmol) in acetonitrile (230g), a 25% aqueous solution of sodium hydroxide (7,6g, 47,5 mmol) was added and the resulting mixture was cooled to -15oC. Once the mixture was at -15°C, AmberLite™ IRN78 OH resin (3,8g, 20%w/w of the compound of formula II as defined in table 1) and TFBBQ (5,6g, 5,7 mmol) were added. A 50% aqueous solution of hydroxylamine (3,64g, 55,2 mmol) was dosed over 1 hour to the reaction mixture. The reaction is then stirred for 6 hours at -15°C. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (13,3 g, 114 mmol) was added to give a pH of 3,5. The mixture was heated to 40°C and filtered to screen 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 adjust to pH 4 with a 32% aqueous solution of 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 (19,4g, 39,mmol, 78,8% yield, two stereoisomers, S isomer was obtained in 81% of enantiomeric excess (ee)) without further purification.

Comparative Example 2: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yll-2-methyl-benzoic acid using NaOH onlyTo a solution of 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl- benzoic acid (20,0g, 47,5 mmol) in acetonitrile (230g), a 25% aqueous solution of sodium hydroxide (7,6g, 47,5 mmol) was added and the resulting mixture was cooled to -150C. Once the mixture is at -15°C, a second equivalent of a 25% aqueous solution of sodium hydroxide (7,6g, 47,5 mmol) and TFBBQ (5,6g, 5,7 mmol) were added to the mixture. A 50% aqueous solution of hydroxylamine (3,64g, 55,2 mmol) was dosed over 1 hour to the reaction mixture. The reaction is then stirred for 1 hour at -15°C. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (12,2g, 107 mmol) was added to give pH 5,5 and then the mixture was concentrated under vacuum to remove the solvent. The residue was then dissolved in 2- Methyltetrahydrofuran (181,9 g) and the pH adjusted to pH 4 with a 32% aqueous solution of hydrochloric acid. The organic solution was then extracted with water (179,5g). 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 (19,8g, 39,9 mmol, 84,0% yield, two isomers, S- isomer was obtained in 16%ee) without further purification.

Example 3: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yll-2-methyl-benzoic acid using methyl ester type starting material3a) Preparation of methyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoate (Compound of formula IIF 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 (2,0g, 4,6 mmol) in acetonitrile (22,3 g), a 25% aqueous solution of sodium hydroxide (0,7g, 4 mmol) was added and the resulting reaction mixture was cooled to -15°C. Once the mixture is at -15°C, AmberLite™ IRN78 OH resin (0,4g, 20%w/w of the compound of formula II as defined in table 1) and TFBBQ (0,6g, 0,6 mmol) were added to the mixture. A 50% aqueous solution of hydroxylamine (0,4g, 6,0 mmol) was dosed over 1 hour to the reaction mixture. The reaction is then stirred for 6 hours at -15°C. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (1,0 g, 8,8 mmol) was added to give a pH of 4,0. The mixture was heated to 40°C and filtered to screen off the resin. The filtrate was then concentrated under vacuum to remove the solvent. The obtained 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-di chi oro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (1,8g, 3,3 mmol, 71,7% yield, two stereoisomers were obtained with S- isomer in 76%ee) without further purification.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-methyl-benzoate (100.2 mg, 0.22 mmol) in tetrahydrofuran (310.5mg) was added a 25% aqueous solution of sodium hydroxide (157.2 mg, 0.98 mmol). The reaction mixture was stirred at 25°C for 24h. After completion of the reaction (99.8% conversion), a 32% aqueous solution of hydrochloric acid (112.4 mg, 0.99 mmol) and water (112.7mg) were added to the reaction mixture. The mixture was stirred at 25°C and the organic layer was separated and concentrated under vacuum to afford the crude product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (75.5mg, 0.173 mmol, 77.6% yield, two isomers with S- isomer in 77.6%ee) without further purification.

Example 4: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yll-2-methyl-benzoic acid using t-butyl ester starting material4a) Preparation of tert-butyl 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoate (Compound of formula IIF with 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 (2,0g, 4,2 mmol) in acetonitrile (20,3 g), a 25% aqueous solution of sodium hydroxide (0,7g, 4 mmol) was added and the resulting reaction mixture was cooled to -15°C. Once the mixture is at -15°C, AmberLite™ IRN78 OH resin (0,4g, 20%w/w of the compound of formula II as defined in table 1) and TFBBQ (0,5g, 0,5 mmol) was added to the mixture. A 50% aqueous solution of hydroxylamine (0,3g, 5,0 mmol) was dosed over 1 hour to the reaction mixture. The reaction is then stirred for 6 hours at -15°C. After completion of the reaction, a 32% aqueous solution of hydrochloric acid (1,0 g, 8,8 mmol) was added to give a pH of 4,0, the mixture was heated to 40°C and filtered to screen the resin. The filtrate was then concentrated under vacuum to remove the solvent. The obtained residue was then dissolved in 2-Methyltetrahydrofurane (16,1 g). The organic solution was then extracted with water (16,g). The organic layer was then concentrated under vacuum to obtain the crude product tert-butyl 4-[5-(3,5-di chi oro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (2,1g, 3,7 mmol, 88% yield, two stereoisomers with S- isomer obtained in 57,6%ee) without further purification.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 (312.2mg) and water (130.8 mg) was added trifluoroacetic acid (TFAA) (144.4 mg, 1.266 mmol) at 25°C. The reaction mixture was then heated at 60°C for 18h. After completion of the reaction (98.0% conversion), the mixture was concentrated under vacuum. To the residue were added dichloromethane (227 mg) and water (257 mg). The mixture was stirred for 5 minutes at 250C. The organic layer was separated and concentrated under vacuum to afford the crude product 4- [5-(3,5-di chi oro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (54.3mg, 0.124 mmol, 60.4% yield, two stereoisomers with S- isomer at 56.6%ee) without further purification.

Example 5: Preparation of Compound of formula IV by phosgenation of the compound of formula III prepared in Example 1To a solution of 4-[3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl- benzoic acid (81.1g, 187 mmol) in chlorobenzene (190.4g) was added N-methyl-2-pyrrolidone (0.23g, 2.3 mmol). The reaction mixture was then stirred at 85°C and Phosgene (37.0g, 3mmol) was dosed over 1.5h. The mixture was then stirred at 85°C during 4h. After completion of the reaction, the chlorobenzene is distilled off under high vacuum (800 to 16mbar) with a Tj = 90°C. After distillation, the crude oily brown product 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-477-isoxazol-3-yl]-2-methyl-benzoyl chloride was recovered in a flask. (79.6g, 158 mmol, 84.7%yield). It was then dissolved in butyronitrile (116 g) to be engaged in the next step without further purification.

Example 6: Preparation of Compound of formula VI by coupling with the compound of formula V prepared in Example 5To a solution of (47?)-7V-ethyl-7V-hydroxy-2-oxo-oxazolidine-4-carboxamide (22.2g, 127 mmol) in water (122 g) at 25°C and pH 4.9 was added a 25% aqueous solution of NaOH (21.2g, 1mmol) to adjust the pH at 9.0. Once the pH was set up at 9.0, the solution was heated at 45°C. The pH was maintained at 9.0 by adding a 25% aqueous solution of NaOH at 45°C and butyronitrile was added (127.5g). A solution of 4-[5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-4/7-isoxazol-3-yl]-2-methyl-benzoyl chloride in butyronitrile (192.5 g; Example 7) was then dosed over Ih. the pH was maintained at 6.0 during the dosing by adding a 25% aqueous solution of NaOH (4.9g, 31.2 mmol). The reaction mixture was then stirred at 45°C and pH 6.0 during 30min. The stirring was then stopped, and the reaction mixture was settled and separated, and the organic layer concentrated under vacuum. The brown oil crude was dried to the oven at 50°C lOh to afford a beige powder corresponding to the 4-[5-(3,5- dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4/7-isoxazol-3-yl]-7V-(2-ethyl-3-oxo- isoxazolidin-4-yl)-2-methyl-benzamide (87.6g, 160 mmol, 81% yield, two diastereoisomers with 5S,4R- isomer obtained in 75%ee).

Comparative Example 7: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl1-2 -methyl-benzoic acid using Li OH only Compound II (21mg, 0.045mmol) and catalyst (0.1 mol eq) were weighed into glass shell vials in a 96-position reaction block. The block was then transferred to a glovebox (02 <1%). Acetonitrile (0.225ml, to give a 0.2M solution of Compound II) was added, followed by cooling to -15°C. Base (16% w/v; LiOH 4.75% w/v, 2eq.) was added, followed by hydroxylamine (3.5pL of 50% w/v hydroxylamine in water, 1.3 mol eq). The reaction block was sealed andstirred for 20h. The vessels were allowed to warm to -10°C, and then HC1 (100g/L, 40uL, 2.mol eq) was added.

Example 8: Preparation of 4-r5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yll-2-methyl-benzoic acidCompound II (21mg, 0.045mmol) and catalyst (0.1 mol eq) were weighed into glass shell vials in a 96-position reaction block. The block was then transferred to a glovebox (02 <1%) and AmberLite™ IRN78 OH resin (0.005g, 20%w/w of the compound of formula II as defined in table 1) was added tothe vessels. Acetonitrile (0.225ml, to give a 0.2M solution of Compound II) was added, followed by cooling to -15 °C. Base (16% w/v; LiOH 4.75% w/v, 1.2 mol eq) was added, followed by hydroxylamine (3.5pL of 50% w/v hydroxylamine in water, 1.3 mol eq). The reaction block was sealed and stirred for 20h. The vessels were allowed to warm to - 10°C, and then HC1 (100g/L, 40uL, 2.5 mol eq) was added.

Ex. Compound of formula 11 Organic solvent Alkali metal salt Hydrolysing agent Resin Chiral catalyst X R Weight 1 F -COOH 20g CH3CN NaOH (25% aq) 1.equiv. / 3.8g, 20%w/w0.12 equiv. ofTFBBQ 2 F -COOH 20g CH3CN NaOH (25% aq) 2.equiv. / 0 0.12 equiv. ofTFBBQ 3a FC(C=0)OCH31.8g CH3CN NaOH (25% aq) 1.equiv. / 0.4g, 20%w/w0.12 equiv. ofTFBBQ 3b F Hydrolysis 0.1g THF / NaOH 4.2 equiv/ / Table 1 4a FC(C=0)OC(C H3)3 2.0g ch3cn NaOH (25% aq) 1.equiv. / 0.4g, 20%w/w0.12 equiv. of TFBBQ 4b F Hydrolysis 0.1g THF / TFAA equiv/ / 7 F -COOH 0.021g ch3cn LiOH (4.75% aq.) 2.equiv / / 0.1 equiv of TFBBQ 8 F -COOH 0.021g ch3cn LiOH (4.75% aq.) 1.equiv / 0.005g, 20%w/w0.1 equiv of TFBBQ The results are gathered in the below table 2, wherein the compounds of formula Illa and Illb are as follow: (Illa) (Illb) The X and R groups in the compounds III, IIT, Illa and Illb, are defined in table 1.

Table 2 Ex. Chemical yield to compound III/ III’ Yield to compound Illa Selectivity IIIa:IIIb ee (enantiomeric excess) 1 79% 72% 9.8 : 1.(90.5% of Illa)81% 2 84% 49% 1.4 : 1.(58% of Illa)16% 3a 71% / 7.5 : 1.(88% of Illa)76% 3b 78% 49% 7.9 : 1.(88.8% of Illa)78% 4a 88% / 3.7 : 1.(78.8% of Illa)58% 4b 60% 42% 3.6 : 1.(78.3% of Illa)57% 7 100% 69% 2.2:1(69.0% of Illa)38% 8 100% 75% 3.0:1(75.0% of Illa)50% The results in Table 2 clearly show that the present invention provides an increased enantioselectivity and/or an increased of the chemical yield of the desired isomer Illa.

Claims (15)

1. A process for the preparation of a compound of formula III by reacting a compound of formula II with hydroxylamine or its salt, a base, a chiral catalyst, and an organic solvent, wherein said base comprises an anion exchange resin and optionally alkali metal salt,wherein X is hydrogen or halogen, and R is selected among -COOH, -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl, and -C(O)N(R1R2) wherein R1 and R2 are independently selected from H and C1-6 alkyl, andwherein when R is selected among -C(=O)OC1-6alkyl, -CN, -C(=O)Obenzyl, and -C(O)N(R1R2), a compound of formula III’ is obtained being then hydrolysed to obtain the compound of formula III.

2. A process according to claim 1, characterized in that the resin is an OH anion exchange resin.

3. A process according to any one of the preceding claims, characterized in that the anion exchange resin comprises quaternary ammonium functional group.

4. A process according to any one of the preceding claims, characterized in that the matrix of the anion exchange resin comprises a copolymer of styrene-divinylbenzene.

5. A process according to any one of the preceding claims, characterized in that the amount of exchangeable anions is from 0.01 to 10 molar equivalents, preferably from 0.05 to 5 molar equivalents, preferably from 0.05 to 1.5 molar equivalents, and more preferably from 0.05 to 0.2 molar equivalents, based on the number of moles of the compound of formula II.

6. A process according to any one of the preceding claims, characterized in that the amount of the alkali metal salt is from 0.01 to 3.00 molar equivalents, and preferably from 0.04 to 1.40 molar equivalents, based on the number of moles of the compound of formula II.

7. A process according to any one of the preceding claims, characterized in that the amount of the organic solvent is from 10 to 200 molar equivalents, and preferably from 20 to 130 molar equivalents, based on the number of moles of the compound of formula II.

8. A process according to any one of the preceding claims, characterized in that it further comprises the addition of water.

9. A process according to any one of the preceding claims, characterized in that the amount of hydroxylamine or its salts can be from 0.5 to 10 molar equivalents, preferably from 0.7 to molar equivalents, and more preferably from 1.0 to 1.5 molar equivalents, based on the number of moles of the compound of formula 11.

10. A process according to any one of the preceding claims, characterized in that the amount of the chiral catalyst is from 0.001 to 1.0 molar equivalents, and preferably from 0.01 to 0.5 molar equivalents, based on the number of moles of the compound of formula II.

11. A process according to any one of the preceding claims, characterized in that it further comprises the step of reacting the compound of formula III with a chlorinating agent, to prepare a compound of formula IV

12. A process according to claim 11, characterized in that it further comprises the step of reacting the compound of formula IV with a compound of formula V nh2 o-V/Av״■ox(V), to prepare a compound of formula VI (VI).

13. A process according to claim 12, characterized in that the step of reacting the compound of formula IV with the compound of formula V is to prepare a compound of formula VIb or anenriched composition comprising a compound of formula VIb (VIb).

14. A process according to claim 13, characterized in that the enriched composition comprises the compound of formula VIb (5S,4R) and at least one of the isomers of the compound of formula VI selected among isomer (5S,4S), isomer (5R,4R), isomer (5R,4S), and any combinations thereof.

15. Use of an anion exchange resin, and preferably an OH anion exchange resin, in a process for preparing a compound of formula III (HI), wherein X is hydrogen or halogen.