Process for the preparation of cinacalcet base

• US 20070259964A1
• Filed: 04/27/2007
• Published: 11/08/2007
• Est. Priority Date: 04/27/2006
• Status: Active Grant

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Lifshitz-Liron, Revital
• Granted Patent: US 7,449,603 B2
• Time in Patent Office: Days
• US Class Current: 514/649
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 209/50 by reduction of carboxylic acid amides
• CPC Class Codes: C07C 211/30 the six-membered aromatic ring being part of a condensed ring system formed by two rings
• CPC Class Codes: C07C 213/02 by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07C 233/11 with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings

Abstract

Provided is a process for preparing Cinacalcet, (R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalenemethane amine and intermediates thereof.

Claims

1. A process for preparing cinacalcet, comprising:

a) reducing 3-trifluoromethyl cinnamic acid to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid;

b) converting the 3-[3-(trifluoromethyl)phenyl]propanoic acid into a compound of the following formula III

c) combining the compound of formula III with (R)-1-naphthylethyl amine in the presence of a base to obtain N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide; and

d) reducing the N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl propanamide to obtain cinacalcet,

wherein X is carboxyl, alkoxy, halogen, or sulfonyl.

2. A process for preparing a pharmaceutically acceptable acid addition salt of cinacalcet, comprising:

a) preparing cinacalcet by the process of claim 1;

and

b) converting the cinacalcet into a pharmaceutically acceptable acid addition salt of cinacalcet.

3. The process of claim 2, wherein the a pharmaceutically acceptable acid addition salt is a hydrochloride salt.

4. A process for preparing 3-[3-(trifluoromethyl)phenyl]propanoic acid, comprising reducing 3-trifluoromethyl cinnamic acid to obtain 3-[3-(trifluoromethyl)phenyl]propanoic acid.

5. The process of claim 4, wherein the 3-trifluoromethyl cinnamic acid is reduced with hydrogen in the presence of a catalyst.

6. The process of claim 5, wherein the catalyst is palladium on carbon, platinum dioxide, or Raney nickel.

7. The process of claim 5, wherein the reduction is performed over a period of about 5 to about 24 hours.

8. The process of claim 5, wherein the hydrogen is present at a pressure of about 1 atmosphere to about 1000 psi.

9. A process for preparing a compound of the following formula III

10. A process for preparing N-[(l S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide, comprising:

a) preparing 3-[3-(trifluoromethyl)phenyl]propanoic acid by the process of claim 4;

and

b) converting the 3-[3-(trifluoromethyl)phenyl]propanoic acid into N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl] propanamide.

11. A process for preparing cinacalcet, comprising:

a) preparing 3-[3-(trifluoromethyl)phenyl]propanoic acid by the process of claim 4;

and

b) converting the 3-[3-(trifluoromethyl)phenyl]propanoic acid into cinacalcet.

12. A process for preparing a pharmaceutically acceptable acid addition salt of cinacalcet, comprising:

a) preparing cinacalcet by the process of claim 11;

and

b) converting the cinacalcet into a pharmaceutically acceptable acid addition salt of cinancalcet.

13. The process of claim 12, wherein the pharmaceutically acceptable acid addition salt is a hydrochloride salt.

14. A process for preparing a compound of the following formula III

15. The process of claim 14, wherein the combination is performed at a temperature of about 0°

C. to about 50°

C.

16. The process of claim 14, wherein the combination is maintained for about 0.5 hours to about 24 hours to obtain the compound of formula III.

17. A process for preparing N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide, comprising:

a) preparing the compound of formula III by the process of claim 14;

and

b) converting the compound of formula III into N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide.

18. A process for preparing cinacalcet, comprising:

a) preparing the compound of formula III by the process of claim 14;

and

b) converting the compound of formula III into cinacalcet.

19. A process for preparing a pharmaceutically acceptable acid addition salt of cinacalcet, comprising:

a) preparing cinacalcet by the process of claim 18;

and

b) converting the cinacalcet into a pharmaceutically acceptable acid addition salt of cinacalcet.

20. The process of claim 19, wherein the pharmaceutically acceptable acid addition salt is a hydrochloride salt.

21. A process for preparing N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide, comprising combining a compound of the following formula III

22. The process of claim 21, further comprising combining the compound of formula III, the (R)-1-naphthylethyl amine, and the base with a solvent.

23. The process of claim 22, wherein the solvent is selected from the group consisting of acetonitrile, toluene, isopropyl alcohol, ethanol, ethyl acetate, methyl iso-butyl ketone, and acetone.

24. The process of claim 21, wherein the base is an organic or inorganic base.

25. The process of claim 21, wherein the base is a carbonate or a tri-(C₂ to C₄ alkyl)amine.

26. The process of claim 22, wherein the combination is heated to obtain the N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide.

27. The process of claim 26, wherein the combination is heated at the reflux temperature of the solvent.

28. The process of claim 21, wherein the combination is maintained for about 7 to about 90 hours to obtain the N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide.

30. A process for preparing cinacalcet, comprising:

a) preparing N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide by the process of claim 21;

and

b) converting the N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide into cinacalcet.

31. A process for preparing a pharmaceutically acceptable acid addition salt of cinacalcet, comprising:

a) preparing cinacalcet by the process of claim 30;

and

b) converting the cinacalcet into a pharmaceutically acceptable acid addition salt of cinacalcet.

32. The process of claim 31, wherein the pharmaceutically acceptable acid addition salt is a hydrochloride salt.

29. N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl]propanamide.

33. A process for preparing cinacalcet, comprising reducing N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl propanamide to obtain cinacalcet.

34. The process of claim 33, wherein the N-[(1S)-1-(1-naphthyl)ethyl]-3-[3-trifluoromethyl)phenyl propanamide is reduced with BH₃.

35. The process of claim 33, wherein the reduction is performed in the presence of a solvent.

36. The process of claim 35, wherein the solvent is selected from the group consisting of C₄ to C₈ aliphatic, branched or cyclic ethers.

37. The process of claim 36, wherein the solvent is methyl-tert butyl ether or tetrahydrofuran.

38. The process of claim 36, wherein the reduction is performed at a temperature of about 0°

to about 5°

C.

39. The process of claim 36, wherein the reduction is performed over a period of about 16 to about 24 hours.

40. A process for preparing a pharmaceutically acceptable acid addition salt of cinacalcet, comprising:

a) preparing cinacalcet by the process of claim 33;

and

b) converting the cinacalcet into a pharmaceutically acceptable acid addition salt of cinacalcet.

41. The process of claim 40, wherein the pharmaceutically acceptable acid addition salt is a hydrochloride salt.