Process for enantioselective synthesis of single enantiomers of modafinil by asymmetric oxidation
View Patent ↗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 enantiomerically enriched modafinil, wherein the steps comprise:
a) dissolving non-racemic modafinil in a solvent to form a solution;
b) crystallizing a modafinil enantiomer from the solution; and
c) isolating the crystallized modafinil enantiomer, wherein the isolated modafinil enantiomer has an enantiomeric excess at least about 3% higher than the non-racemic modafinil dissolved in step (a).
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 modafinil enantiomer is isolated by filtration.
17. The method of claim 2 , wherein the modafinil in step (a) has an enantiomeric excess of at least about 80%.
18. The method of claim 2 , wherein the modafinil in step (a) has an enantiomeric excess of at least about 91.6%.
19. The method of claim 4 , wherein the modafinil in step (a) has an enantiomeric excess of at least about 80%.
20. The method of claim 4 , wherein the modafinil in step (a) has an enantiomeric excess of at least about 91.6%.
21. The method of claim 17 , wherein the modafinil in step (a) has an enantiomeric excess of less than about 95%.
22. The method of claim 18 , wherein the modafinil in step (a) has an enantiomeric excess of less than about 95%.
23. The method of claim 19 , wherein the modafinil in step (a) has an enantiomeric excess of less than about 95%.
24. The method of claim 20 , wherein the modafinil in step (a) has an enantiomeric excess of less than about 95%.
25. The method of claim 2 , further comprising the step of recrystallizing the isolated modafinil enantiomer.
26. The method of claim 1 , wherein the isolated modafinil enantiomer has an enantiomeric excess that is at least about 4% higher than the non-racemic modafinil dissolved in step (a).
27. The method of claim 2 , wherein the isolated modafinil enantiomer has an enantiomeric excess that is at least about 4% higher than the non-racemic modafinil dissolved in step (a).
28. The method of claim 1 , wherein the isolated modafinil enantiomer has an enantiomeric excess that is at least about 5% higher than the non-racemic modafinil dissolved in step (a).
29. The method of claim 2 , wherein the isolated modafinil enantiomer has an enantiomeric excess that is at least about 5% higher than the non-racemic modafinil dissolved in step (a).
30. The method of claim 1 , wherein the isolated modafinil enantiomer is (R)-modafinil.
31. The method of claim 1 , wherein the isolated modafinil enantiomer is (S)-modafinil.