Method for producing (5,S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4Hisoxazol-3-yl]-2-methyl-benzoic acid

1. A Method for preparing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3yl]-2-methyl-benzoic acid according to Formula (1a)

from (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3yl]-2-methyl-benzoic acid according to Formula (1)

comprising the steps of:

(i) reacting (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid with a compound of Formula (2A), (2B) or (2C)

wherein R is an alkyl with 1 or 2 carbon atoms,

wherein X is Cl or Br,

in an organic solvent having a polarity E T (30) between 180 and 230 kJ/mol to form a precipitate and a supernatant solution

(ii) separating the precipitate from step (i) from the supernatant solution

(iii) treating the precipitate from step (ii) with acidic aqueous solution, and

(iv) separating (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid from the acidic aqueous solution of step (iii).

2. The Method according to claim 1 , wherein from (5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3yl]-2-methyl-benzoic acid is reacted in step (i) with a compound of Formula (2A), (2B) or (2C) in a molar ratio of between 1:0.4 and 1:5.

3. The Method according to claim 1 , wherein in step (i) the solvent is an alcohol with 2 to 8 carbon atoms.

4. The Method according to claim 1 , wherein the solvent is selected from ethanol, 2-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, and mixtures thereof.

5. The Method according to claim 1 , wherein R of Formula (2A) in step (i) is methyl and the solvent is ethanol or R of Formula (2A) is methyl and the solvent is 2-propanol.

6. The Method according to claim 1 , wherein R of Formula (2A) in step (i) is ethyl and the solvent is ethanol, or R of Formula (2A) is ethyl and the solvent is 2-propanol.

7. The Method according to claim 1 , wherein step (i) comprises heating(5RS)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3yl]-2-methyl-benzoic acid with the compound of Formula (2A), (2B) or (2C) in the solvent to an elevated temperature.

8. The Method according to claim 1 , wherein the separation in step (ii) of the precipitate from step (i) from the supernatant solution is carried out via filtration.

9. The Method according to claim 1 , wherein the acidic aqueous solution in step (iii) is an aqueous solution of an inorganic acid.

10. The Method according to claim 1 , wherein the separation of (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid in step (iv) from the acidic aqueous solution of step (iii) is carried out by an extraction with an organic solvent.

11. The Method according to claim 1 , wherein (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid from step (iv) has an enantiomeric excess (ee) of at least 75%.

12. The Method according to claim 1 , wherein the method further comprises step (v) of recrystallizing (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid.

13. The Method according to claim 1 , comprising a further step (vi) of reacting the supernatant solution with an alkaline compound in a second organic solvent.

14. The Method according to claim 1 , wherein (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid is further reacted with a compound according to Formula (4)

to give (5S)-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-2-methyl-benzamide according to Formula (3)

15. The method of claim 13 , wherein the second organic solvent is the same as the organic solvent having a polarity E T (30) between 180 and 230 kJ/mol of step (i).