Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation

1. A method for preparing a sulphoxide compound of formula (I) either as a single enantiomer or in an enantiomerically enriched form:

wherein:

Y is —C(═O)X wherein X is —OR 5 ;

R1, R1 a , R2 and R2 a are each independently H, halo, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C 6 -C 10 )aryl, —CN, —CF 3 , —NO 2 , —OH, (C1-C8)alkoxy, —O(CH 2 ) m NR 6 R 7 , —OC(═O)R 8 , —C(═O)OR 8 , —C(═O)R 8 , —OC(═O)NR 6 R 7 , —O(CH 2 ) m OR 8 , —(CH 2 ) m OR 8 , —NR 6 R 7 , or —C(═O)NR 6 R 7 ;

R5 is alkyl, cycloalkyl, aralkyl, alkaryl, or aryl;

R6 and R7 are each independently H, (C1-C6) alkyl, or hydroxy(C1-C6)alkyl;

R8 is H, alkyl, cycloalkyl, aralkyl, alkaryl, or aryl;

n is 1, 2 or 3; and

m is 1, 2, 3, or 4;

comprising the steps of:

a) contacting a pro-chiral sulphide of formula (II):

wherein R1, R2, R1 a , R2 a , Y, and n are as defined above,

with a metal chiral ligand complex, a base, and an oxidizing agent in an organic solvent, for a time and under conditions effective to produce the sulphoxide of formula I; and optionally

b) isolating the sulphoxide of formula (I);

wherein said metal chiral ligand complex is selected from the group consisting of C 2 -symmetric diol titanium (IV) complexes, C 3 -symmetric trialkanolamine titanium (IV) complexes, C 3 -symmetric trialkanolamine zirconium (IV) complexes, chiral (salen) manganese (III) complexes, and chiral (salen) vanadium (IV) complexes.

2. The method according to claim 1 , wherein R 1 , R 2 , R 1a and R 2a are each H.

3. The method according to claim 1 , wherein n is 1.

4. The method according to claim 1 , wherein the metal chiral ligand complex is selected from the group consisting of C 2 -symmetric diol titanium(IV) complexes and C 3 -symmetric trialkanolamine titanium(IV) complexes.

5. The method according to claim 4 , wherein the metal chiral ligand is diethyltartrate titanium(IV) complex.

6. The method according to claim 1 , wherein the metal chiral complex is prepared from a metal compound, a chiral ligand, and water.

7. The method according to claim 6 , wherein the metal chiral ligand complex is prepared with 0.1-1 equivalent of water, with respect to the metal compound.

8. The method according to claim 7 , wherein the metal chiral ligand complex is prepared with 0.4-0.8 equivalent of water, with respect to the metal compound.

9. The method according to claim 1 , wherein the base is a tertiary amine.

10. The method according to claim 9 , wherein the tertiary amine is diisopropylethylamine or triethylamine.

11. The method according to claim 1 , wherein step a) is performed in the presence of 0.01 to 2 equivalents of base, with respect to the sulphide.

12. The method according to claim 11 , wherein step a) is performed in presence of 0.05-0.5 equivalents of base, with respect to the sulphide.

13. The method according to claim 12 , wherein step a) is performed in the presence of 0.1 to 0.3 equivalents of base, with respect to the sulphide.

14. The method according to claim 1 , wherein step a) is performed in the presence of 0.05-0.5 equivalents of the metal chiral ligand complex, with respect to the sulphide.

15. The method according to claim 14 , wherein step a) is performed in the presence of 0.1-0.3 equivalents of the metal chiral ligand complex, with respect to the sulphide.

16. The method according to claim 1 , wherein the metal chiral ligand complex is prepared at a temperature between 20-70° C.

17. The method according to claim 16 , wherein the metal chiral ligand complex is prepared at a temperature between 40-60° C.

18. The method according to claim 17 , wherein the metal chiral ligand complex is prepared at a temperature between 50-55° C.

19. The method according to claim 1 , wherein the sulphide is contacted with the metal chiral ligand complex, the base, and the oxidizing agent at a temperature between 0-60° C.

20. The method according to claim 19 , wherein the sulphide is contacted with the metal chiral ligand complex, the base, and the oxidizing agent at room temperature.

21. The method according to claim 1 , wherein the oxidizing agent is hydrogen peroxide, tert-butyl hydroperoxide, or cumene hydroperoxide.

22. The method according to claim 21 , wherein the oxidizing agent is cumene hydroperoxide.

23. The method according to claim 1 , wherein the sulphoxide is isolated by filtration.

24. The method according to claim 1 , wherein the method further comprises a step of crystallization of the sulphoxide obtained in step b).

25. The method according to claim 24 , wherein the crystallization is carried out in a mixture of an organic solvent and water.

26. The method according to claim 25 , wherein the organic solvent is an alcohol.

27. The method according to claim 25 , wherein the water represents up to 40% by volume of the mixture.

28. The method according to claim 24 , wherein the crystallization is a preferential crystallization.

29. The method according to claim 1 , wherein the sulphoxide compound of formula (I) is an ester of modafinic acid.

30. The method according to claim 29 , which further comprises a step of converting X=—OR 5 of the sulphoxide of formula (I) into X=—NH 2 .

31. The method according to claim 30 , wherein X=—OR 5 of the sulphoxide of formula (I) is converted into X=—NH 2 by an amidation reaction.

32. The method according to claim 1 , wherein the compound of formula (II) is methyldiphenylmethylthioacetate:

33. The method according to claim 32 , wherein the compound of formula (II) is prepared from benzhydrol:

34. The method according to claim 33 , wherein the methyldiphenylmethylthioacetate is prepared from benzhydrol by the method comprising the steps of:

i) conversion of benzhydrol into benzhydryl acetate, and

ii) conversion of benzhydryl acetate into methyldiphenylmethylthioacetate.

35. The method of claim 1 wherein the sulphoxide of formula (I) is produced with an enantiomeric excess of more than about 80%.

36. The method of claim 1 wherein the sulphoxide of formula (I) is produced with an enantiomeric excess of more than about 90%.

37. The method of claim 1 wherein the sulphoxide of formula (I) is produced with an enantiomeric excess of more than about 98%.