Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation
The invention relates to a method for preparing a sulphoxide compound of formula (I) either as a single enantiomer or in an enantiomerically enriched form, comprising the steps of: a) contacting a pro-chiral sulphide of formula (II) with a metal chiral complex, a base and an oxidizing agent in an organic solvent; and optionally b) isolating the obtained sulphoxide of formula (I). wherein n, Y, R 1 , R 1a , R 2 and R 2a are as defined in claim 1.
1. A three-step method for preparing (R)-modafinil having an enantiomeric excess of at least about 99.0%, wherein the steps comprise:
a. dissolving (R)-modafinil having an enantiomeric excess of about 91.6% to about 98.8% in a solvent to form a solution;
b. crystallizing (R)-modafinil from the solution; and
c. isolating the crystallized (R)-modafinil, wherein the isolated (R)-modafinil has an enantiomeric excess of at least about 99.0%.
2. The method of claim 1 , wherein the solvent comprises ethanol, tetrahydrofuran, acetone, dichloromethane, acetonitrile, or ethyl acetate.
3. The method of claim 2 , wherein the solvent comprises ethanol.
4. The method of claim 2 , wherein the solvent comprises tetrahydrofuran, acetone, dichloromethane, acetonitrile, or ethyl acetate.
5. The method of claim 4 , wherein the solvent comprises tetrahydrofuran.
6. The method of claim 5 , wherein the solvent comprises a mixture of tetrahydrofuran and water.
7. The method of claim 6 , wherein the solvent comprises a mixture of about 95/5 tetrahydrofuran/water.
8. The method of claim 4 , wherein the solvent comprises dichloromethane.
9. The method of claim 4 , wherein the solvent comprises acetonitrile.
10. The method of claim 4 , wherein the solvent comprises ethyl acetate.
11. The method of claim 10 , wherein the solvent comprises a mixture of ethyl acetate and methanol.
12. The method of claim 11 , wherein the solvent comprises a mixture of about 6/1 ethyl acetate/methanol.
13. The method of claim 4 , wherein the solvent comprises acetone.
14. The method of claim 13 , wherein the solvent comprises a mixture of acetone and water.
15. The method of claim 14 , wherein the solvent comprises a mixture of about 95/5 acetone/water.
16. The method of claim 1 , wherein the crystallized (R)-modafinil is isolated by filtration.
17. The method of claim 1 , wherein the isolated (R)-modafinil has an enantiomeric excess of at least about 99.5%.
18. The method of claim 1 , wherein the isolated (R)-modafinil has an enantiomeric excess of at least about 99.8%.
19. The method of claim 4 , wherein the isolated (R)-modafinil has an enantiomeric excess of at least about 99.5%.
20. The method of claim 4 , wherein the isolated (R)-modafinil has an enantiomeric excess of at least about 99.8%.
21. The method of claim 1 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 98%.
22. The method of claim 1 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 97%.
23. The method of claim 1 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 96%.
24. The method of claim 1 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 95%.
25. The method of claim 2 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 98%.
26. The method of claim 2 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 97%.
27. The method of claim 2 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 96%.
28. The method of claim 2 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 95%.
29. The method of claim 3 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 98%.
30. The method of claim 3 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 97%.
31. The method of claim 3 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 96%.
32. The method of claim 3 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 95%.
33. The method of claim 4 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 98%.
34. The method of claim 4 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 97%.
35. The method of claim 4 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 96%.
36. The method of claim 4 , wherein the (R)-modafinil in step (a) has an enantiomeric excess of less than about 95%.
37. The method of claim 1 , further comprising the step of recrystallizing the isolated crystallized (R)-modafinil.
38. The method of claim 2 , further comprising the step of recrystallizing the isolated crystallized (R)-modafinil.