Methods for preparing sulfonamide substituted alcohols and intermediates thereof

Abstract

Processes for preparing amino alcohols or salts thereof and sulfonamide substituted alcohol compounds are provided. Desirably, the sulfonamide substituted alcohol compounds are heterocyclic sulfonamide trifluoroalkyl-substituted alcohol compounds or phenyl sulfonamide trifluoroalkyl-substituted alcohol compounds.

Description

Claims

1. A method for preparing an amino alcohol, or salt thereof, from an aminoester comprising reducing said aminoester by adding said aminoester to a hydride reducing agent at about −60° to about −10° C.

2. The method according to claim 1, wherein said aminoester is of the structure:

3. The method according to claim 1, wherein said aminoester is of the structure:

4. The method according to claim 3, wherein said aminoester is:

5. The method according to claim 1, wherein said amino alcohol is of the structure:

6. The method according to claim 5, wherein said amino alcohol is:

7. The method according to claim 1, wherein said amino alcohol salt is of the structure:

8. The method according to claim 7, wherein said amino alcohol salt is:

9. The method according to claim 1, wherein said hydride reducing agent is diisobutylaluminum hydride.

10. The method according to claim 1, further comprising quenching the reduction with a protic solvent.

11. The method according to claim 10, wherein said protic solvent is hydrochloric acid, acetic acid, or ethanol.

12. The method according to claim 1, wherein the reduction is performed at about −20 to about −10° C.

13. The method according to claim 1, wherein said amino alcohol is prepared in a yield of about 90 to about 95%.

14. A method for preparing an amino alcohol of the structure:

15. A method for preparing a sulfonamide substituted alcohol, comprising: (a) isolating one diastereomer of a N-protected aminoester by reacting a mixture of diastereomers of a N-protected aminoester with a protic acid to form a N-protected aminoester salt;(b) neutralizing said N-protected aminoester salt with a base to form an N-protected aminoester;(c) reducing said N-protected aminoester by adding said N-protected aminoester to diisobutylaluminum hydride at −60° C. to about −10° C.;(d) quenching the reaction of step (c) with a protic solvent;(e) reacting the N-protected amino alcohol of step (d) with a protic acid to form a N-protected amino alcohol salt;(f) hydrogenating said N-protected amino alcohol salt to form an unprotected amino alcohol salt; and(g) sulfonylating said unprotected amino alcohol with a sulfonyl chloride in the presence of a base/solvent system.

16. The method according to claim 15, wherein said base/solvent system is selected from the group consisting of 4-methyl morpholine/isopropyl acetate, Hünig's base/tetrahydrofuran, 4-methyl morpholine/acetonitrile, 4-methyl morpholine/propionitrile, and 4-methyl morpholine/toluene.

17. The method according to claim 15, wherein said sulfonylation is performed in the absence of protection and deprotection steps.

18. The method according to claim 15, further comprising: (h) purifying said sulfonamide substituted alcohol,wherein said purification is performed in the absence of silica gel.

19. The method according to claim 15, wherein said sulfonamide substituted alcohol is substituted with one or more trifluoroalkyl groups.

20. The method according to claim 15, wherein said sulfonamide substituted alcohol is of the structure:

21. The method according to claim 20, wherein said sulfonamide substituted alcohol is:

22. The method according to claim 21, wherein said sulfonamide substituted alcohol is:

23. The method according to claim 15, wherein the hydrogenation is performed with a catalyst.

24. The method according to claim 15, wherein said unprotected amino alcohol salt is of the structure:

25. The method according to claim 24, wherein said unprotected amino alcohol salt is:

26. The method according to claim 15, wherein said sulfonyl chloride is of the structure:

27. The method according to claim 26, wherein said sulfonyl chloride is:

28. The method according to claim 15, wherein said N-protected aminoester is of the structure:

29. The method according to claim 28, wherein said N-protected aminoester is:

30. The method according to claim 15, wherein said N-protected aminoester salt is of the structure:

31. The method according to claim 30, wherein said N-protected aminoester salt is:

32. The method according to claim 15, wherein said N-protected amino alcohol salt is of the structure:

33. The method according to claim 32, wherein said N-protected amino alcohol hydrochloride salt is: