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 —CN, —C(═O)X wherein X is selected from, —NR 3 R 4 , —OH, —NHNH 2 ;

R 1 , R 1a , R 2 and R 2a are the same or different and are selected from H, halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 6 -C 10 )aryl, (C 5 -C 10 )heteroaryl, —CN, —CF 3 , —NO 2 , —OH, (C 1 -C 8 )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 , —C(═O)NR 6 R 7 ;

R 3 and R 4 are the same or different and are each selected from H, (C 1 -C 6 ) alkyl, hydroxy(C 1 -C 6 )alkyl, —NHOH or —OH;

R 6 and R 7 are the same or different and selected from H, (C 1 -C 6 ) alkyl, hydroxy(C 1 -C 6 )alkyl;

R 8 represents H, alkyl, cycloalkyl, aralkyl, alkaryl, or aryl;

n is 1, 2 or 3; and

m is from 1, 2, 3, or 4;

comprising the steps of:

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

wherein R 1 , R 2 , R 1a , R 2a , Y and n are as defined above,

with a metal chiral ligand complex, a base and an oxidizing agent in an organic solvent; and optionally

b) isolating the obtained 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 Y is —C(═O)X.

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

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

5. The method according to claim 1 , wherein X is NH 2 or NHOH.

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

7. The method according to claim 6 , wherein the metal chiral ligand is a diethyl tartrate titanium (IV) complex.

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

9. The method according to claim 8 , wherein the metal chiral ligand complex is prepared with 0.1-1 equivalent of water with respect to the metal compound.

10. The method according to claim 9 , wherein the metal chiral ligand complex is prepared with 0.4-0.8 equivalent of water with respect to the metal compound.

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

12. The method according to claim 11 , wherein the tertiary amine is diisopropylethylamine or triethylamine.

13. The method according to claim 1 , wherein step a) is performed in presence of 0.05-0.5 equivalent of base with respect to the sulphide.

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

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

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

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

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

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

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

21. The method according to claim 20 , wherein the oxidizing agent is contacted with the sulphide of formula (II), the metal chiral ligand complex and the base at room temperature.

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

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

24. The method according to claim 1 , wherein the obtained sulphoxide is directly isolated by filtration.

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

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

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

28. The method according to claim 26 , wherein the water represents up to 40% by volume of the mixture.

29. The method according to claim 25 , wherein the crystallization is a preferential crystallization.

30. The method according to claim 1 , wherein Y of the sulphoxide compound of formula (I) is —C(═O)X and X is —OH.

31. The method according to claim 30 , wherein the sulphoxide compound of formula (I) is modafinic acid.

32. The method according to claim 30 , which further comprises the subsequent steps of converting X═—OH of the sulphoxide of formula (I) into X═—NH 2 .

33. The method according to claim 32 , which comprises the steps of:

a. esterification of the carboxylic acid function; and

b. amidation of the resulting ester.

34. The method according to claim 1 , wherein Y of the sulphoxide of formula (I) is CN.

35. The method according to claim 34 , which further comprises the step of converting Y═CN of the sulphoxide compound of formula (I) into Y═C(═O)NH 2 .

36. The method according to claim 35 , wherein Y═CN is converted into Y═C(═O)NH 2 by oxidation or hydrolysis of the CN group.

37. The method according to claim 35 , wherein diphenylmethyl-sulphinylacetonitrile is converted into modafinil.

38. The method according to claim 5 , wherein the pro-chiral sulphide is of the following formula (IIa):

and is prepared from a pro-chiral sulphide of the following formula (IIb):

wherein R 1 , R 1a , R 2 , R 2a , and n are as defined in claim 1 , and R 5 is alkyl, cycloalkyl, aralkyl, alkaryl or aryl.

39. The method according to claim 38 , wherein R 1 , R 1a , R 2 , R 2a are H, n is 1 and R 5 is alkyl.

40. The method according to claim 39 , wherein the compound of formula (IIb) is methyldiphenylmethylthioacetate (MDMTA).

41. The method according to claim 39 , wherein the compound of formula (IIb) is prepared from benzhydrol.

42. The method according to claim 40 , wherein the MDMTA is prepared from benzhydrol by the method comprising the steps of:

a1) conversion of benzhydrol into benzhydryl carboxylate, and

b1) conversion of benzhydryl carboxylate into MDMTA.