Process for the preparation of enantiomerically enriched cyclic beta-aryl or heteroaryl carbocyclic acids

Abstract

The present invention relates to a process for the preparation of cis substituted cyclic β-aryl or heteroaryl carboxylic acid derivatives in high diastereo- and enantioselectivity by enantioselective hydrogenation in accordance with the following scheme

Description

Claims

1. A process for the preparation of enantiomerically enriched cyclic β-arylcarboxylic acid derivatives of formula

2. The process of claim 1, wherein Z is CH3COO, CF3COO or a halogenide.

3. The process of claim 1, wherein the chiral diphosphine ligand is selected from the group consisting of

4. The process of claim 3, wherein D represents a chiral diphosphine ligand selected from the group consisting of formula (7), (9), (10) or (12).

5. The process of claim 4, wherein the chiral diphosphine is selected from the group consisting of (R) and (S)-enantiomers of MeOBIPHEP, BIPHEMP, TMBTP, 2-Naphthyl)-MeOBIPHEP, (6-MeO-2-Naphthyl)-MeOBIPHEP, 2-(Thienyl)-MeOBIPHEP, 3,5-tBu-MeOBIPHEP, PHANEPHOS, BICP, TriMeOBIPHEP, (R,R,S,S)-Mandyphos, BnOBIPHEP, BenzoylBIPHEP, pTol-BIPHEMP, tButylCOOBIPHEP, iPrOBIPHEP, p-Phenyl-MeOBIPHEP, pAn-MeOBIPHEP, pTol-MeOBIPHEP, 3,5-Xyl-MeOBIPHEP, 3,5-Xyl-BIPHEMP, BINAP and 2-Furyl-MeOBIPHEP, 3,5-Xyl-4-MeO-MeOBIPHEP, 2-Furyl-MeOBIPHEP, and BITIANP.

6. The process of claim 5, wherein the chiral diphosphine is (S)-(6-MeO-2-Naphthyl)-MeOBIPHEP, 3,5-Xyl-4-MeO-MeOBIPHEP, (S)-2-Furyl-MeOBIPHEP or BITIANP.

7. The process of claim 1, wherein the catalyst is selected from the group consisting of (R) and (S) enantiomers of [Ru(CH3COO−)2(TMBTP)], [Ru(CF3COO−)2(TMBTP)], [Ru(CH3COO−)2(2-naphthyl)-MeOBIPHEP)], [Ru(CF3COO−)2(2-naphthyl)-MeOBIPHEP)], [Ru(CH3COO−)2(6-MeO-2-naphthyl)-MeOBIPHEP)] and [Ru(CF3COO−)2(6-MeO-2-naphthyl)-MeOBIPHEP)].

8. The process of claim 1, wherein the catalytic hydrogenation is carried out at a pressure of 1 to 150 bar.

9. The process of claim 8, wherein the catalytic hydrogenation is carried out at a pressure of 10 to 100 bar.

10. The process of claim 1, wherein the catalytic hydrogenation is carried out at a temperature of 10 to 100° C.

11. The process of claim 10, wherein the catalytic hydrogenation is carried out at a temperature of 20 to 80° C.

12. The process claim 1, wherein the catalytic hydrogenation is carried out in the presence of a base.

13. The process of claim 12, wherein the base is selected from the group consisting of NEt3, i-Pr2NEt, i-Pr2NH, C6H5CH2NH2, 1-phenyl-benzylamine, (R) or (S) ethylene diamine, tetramethylethylene diamine, NaOAc, NaOEt, NaOH and Bu4NX, wherein X is F, Cl, Br or I.

14. The process of claim 13, wherein the base is NEt3 or i-Pr2Net.

15. The process of claim 1, wherein the catalytic hydrogenation is carried out in a solvent.

16. The process of claim 15, wherein the solvent is selected from the group consisting of an alcohol, hydrocarbon, chlorinated hydrocarbon, THF, water, and a mixture thereof.

17. The process of claim 16, wherein the solvent is methanol or ethanol.

18. The process of claim 15, wherein the concentration of solvents is 1-50 W %.

19. The process of claim 1, wherein the ratio of substrate/catalyst (s/C) is 5:30000.

20. The process of claim 1, wherein the compound of formula (I) is selected from the group consisting of

21. The process of claim 1, wherein the compound of formula (I) is selected from the group consisting of

22. A compound selected from the group consisting of

23. A compound selected from the group consisting of

24. A process of claim 1, wherein the starting compound of formula (II)

25. A process of claim 1, wherein the starting compound of formula (II)

26. A process for the preparation of enantiomerically enriched cyclic β-arylcarboxylic acid derivatives of formula

27. The process of claim 26, wherein the chiral diphosphine ligand is selected from the group consisting of

28. The process of claim 27, wherein D represents a chiral diphosphine ligand selected from the group consisting of formula (7), (9), (10) or (12).

29. The process of claim 28, wherein the chiral diphosphine is selected from the group consisting of (R) and (S)-enantiomers of MeOBIPHEP, BIPHEMP, TMBTP, 2-Naphthyl)-MeOBIPHEP, (6-MeO-2-Naphthyl)-MeOBIPHEP, 2-(Thienyl)-MeOBIPHEP, 3,5-tBu-MeOBIPHEP, PHANEPHOS, BICP, TriMeOBIPHEP, (R,R,S,S)-Mandyphos, BnOBIPHEP, BenzoylBIPHEP, pTol-BIPHEMP, tButylCOOBIPHEP, iPrOBIPHEP, p-Phenyl-MeOBIPHEP, pAn-MeOBIPHEP, pTol-MeOBIPHEP, 3,5-Xyl-MeOBIPHEP, 3,5-Xyl-BIPHEMP, BINAP and 2-Furyl-MeOBIPHEP, 3,5-Xyl-4-MeO-MeOBIPHEP, 2-Furyl-MeOBIPHEP, and BITIANP.

30. The process of claim 29, wherein the chiral diphosphine is (S)-(6-MeO-2-Naphthyl)-MeOBIPHEP, 3,5-Xyl-4-MeO-MeOBIPHEP, (S)-2-Furyl-MeOBIPHEP or BITIANP.

31. The process of claim 26, wherein the catalytic hydrogenation is carried out at a pressure of 1 to 150 bar.

32. The process of claim 31, wherein the catalytic hydrogenation is carried out at a pressure of 10 to 100 bar.

33. The process of claim 26, wherein the catalytic hydrogenation is carried out at a temperature of 10 to 100° C.

34. The process of claim 33, wherein the catalytic hydrogenation is carried out at a temperature of 20 to 80° C.

35. The process claim 26, wherein the catalytic hydrogenation is carried out in the presence of a base.

36. The process of claim 35, wherein the base is selected from the group consisting of NEt3, i-Pr2NEt, i-Pr2NH, C6H5CH2NH2, 1-phenyl-benzylamine, (R) or (S) ethylene diamine, tetramethylethylene diamine, NaOAc, NaOEt, NaOH and Bu4NX, wherein X is F, Cl, Br or I.

37. The process of claim 36, wherein the base is NEt3 or i-Pr2Net.

38. The process of claim 26, wherein the catalytic hydrogenation is carried out in a solvent.

39. The process of claim 38, wherein the solvent is selected from the group consisting of alkanols, benzene, toluene, trifluoro toluene, dichloromethane, dichlororethane, ethylene glycole, DMF, DMA, N-methylpyrrolidinone, acetonitrile, DMSO, and a mixture thereof.

40. The process of claim 38, wherein the concentration of solvents is 1-50 W %.

41. The process of claim 26, wherein the ratio of substrate/catalyst (s/C) is 5:30000.