Convergent Process for the Synthesis of Taxane Derivatives

Abstract

The present invention is broadly directed to novel compounds useful for the synthesis of biologically active compounds, including taxane derivatives, and convergent processes for the preparation of these taxane derivatives and their intermediates.

Description

DESCRIPTION OF THE FIGURES

FIG. 1 shows a schematic representation of one embodiment of the process for the preparation of compound 10.

FIG. 2 shows a schematic representation of one embodiment of the process for the preparation of compound 4.

FIG. 3 shows a schematic representation of another embodiment of the process for the preparation of compound 10.

FIG. 4 shows a schematic representation of one embodiment of the process for the preparation of compound 8b.

FIG. 5 shows a schematic representation of one embodiment of the process for the preparation of compound 9b.

Claims

1. A process for preparing a 9,10-di-ketobaccatin derivative 2:

2. The process of claim 1, wherein the base is an amine base.

3. The process of claim 2, wherein the amine base is TEA, and the process is carried out in an organic solvent or a mixture of solvents.

4. The process of claim 3, wherein the mixture of solvents comprises EtOH and EtOAc, and the process is carried out below room temperatures to form the desired product 2 in less than 3 hours.

5. The process claim 1 to afford a mixture of 2a:2b in ratio of at least 95:5 and at least 85% yield.

6. A process for the preparation of a 9,10-di-ol baccatin derivative 4:

7. The process of claim 6, wherein the silylation reagent is TES-OTf, and NMP in pyridine and the di-silyl ether 3 is formed in at least 97%.

8. The process of claim 6, wherein the reducing reagent is LiBH4 and the reduction reaction is performed in THF/ethanol solvent to provide the 9,10-di-ol 4 in >90% yield.

9. A process for the preparation of an allylidene acetal baccatin derivative 7:

10. The process of claim 9, wherein the acylation reagent is Ac2O, TEA and DMAP in IPAC, and the selective hydrolysis is performed with acetic acid in aqueous methanol.

11. The process of claim 9, wherein acetalization of the 7,9-di-ol of compound 6 is performed with acrolein diethyl acetal or acrolein dimethyl acetal in a non-polar solvent to provide the allylidene acetal 7, and an acid selected from the group consisting of TFA, TFA/TFAA, CSA and CDSA.

12. The process of claim 9, wherein the selective hydrolysis and the acetalization reaction steps are performed to provide the allylidene acetal 7 without isolation of compound 6.

13. The process of claim 9, wherein the selective acylation and selective hydrolysis are performed to form the tetra-ol 6 without isolation of the intermediate compound 5.

14. A compound comprising a 10-acylated alcohol 5 of the formula:

15. A compound comprising a tetra-ol 6 of the formula:

16. A compound comprising allylidene acetal 7 of the formulae:

17. A process for the preparation of compound 10:

18. The process of claim 17 wherein the coupling reaction condition comprises contacting the allylidene acetal 7 with the side chain 8 in Piv-Cl, TEA, DMAP and THF or Piv-Cl, NMM, DMAP and THF for a sufficient amount of time to form compound 9 which is hydrolyzed to form compound 10 in >95% yield.

19. A compound comprising the formula 9:

20. A process for preparing compound 9:

21. The process of claim 20, wherein compound 9 is further hydrolyzed to form compound 10:

22. The process of claim 21, where the hydrolyzed compound is compound 10a:

23. The process of claim 21, where the hydrolyzed compound is compound 10b:

24. The process of claim 20, wherein the side chain is compound 8, R8 and R9 together with the nitrogen and oxygen to which they are attached form a cyclic 2,4-dimethoxy benzylidene N,O-acetal or a cyclic 2,6-dimethoxy benzylidene N,O-acetal; andM is H or an alkali metal selected from the group consisting of Li, Na and K.

25. The process of claim 20, wherein the coupling reagent is selected from the group consisting of alkyl, aryl or arylalkyl acid anhydrides; dicarbonates; alkyl, aryl or arylalkyl chloroformates; alkyl, aryl or arylalkyl acid halides; chlorosulfonates, alkyl or aryl sulfonic anhydrides; alkyl isocyanates; alkyl, aryl or arylalkyl isocyanate; and sulfonic anhydrides.

26. The process of claim 25, wherein the coupling condition comprises THF or toluene or mixtures thereof, and NMM and DMAP.

27. The process of claim 25, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, phenoxyacetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, acetic anhydride, hexanoic anhydride, benzyl chloroformate, tri-chloroethyl chloroformate, methyl chloroformate, 4-nitrophenyl chloroformate, benzoyl chloride, 2-methoxybenzoyl chloride, 2-chloro-2,2-diphenylbenzoyl chloride, 2,4,6-trichlorobenzoyl chloride, pentafluorobenzoyl chloride, 4-nitro-benzoyl chloride, 2-chloro-benzoyl chloride, phenoxyacetyl chloride, 4-chloromethyl-benzoyl chloride, acetyl chloride, trimethylacetyl chloride, hexanoyl chloride, trimethylacetyl chloride, methane sulfonyl chloride, p-tosyl chlorothionoformate, phenylisocyanate and p-toluene sulfonic anhydride.

28. The process of claim 25, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, 2,4,6-trichlorobenzoyl chloride and di-t-butyl dicarbonate.

29. The process of claim 25, wherein the product from the coupling reaction is further hydrolyzed to form compound 10 in >90% yield, wherein R8 and R9 are hydrogen.

30. A process for preparing compound 20:

31. The process of claim 30, wherein the side chain is compound 22; R8 and R9 together with the nitrogen and oxygen to which they are attached form a cyclic 2,4-dimethoxy benzylidene N,O-acetal or a cyclic 2,6-dimethoxy benzylidene N,O-acetal;and M is H or is Na or K; and R10 is C1-C6 alkyl or phenyl.

32. The process of claim 30, wherein the coupling reagent is selected from the group consisting of acid anhydrides, dicarbonates, chloroformates, acid halides, chlorosulfonates, sulfonic anhydrides, alkyl isocyanates and aryl isocyanates.

33. The process of claim 30, wherein the coupling condition comprises THF or toluene or mixtures thereof, and NMM and DMAP.

34. The process of claim 30, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, phenoxyacetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, acetic anhydride, hexanoic anhydride, benzyl chloroformate, trichloroethyl chloroformate, methyl chloroformate, 4-nitrophenyl chloroformate, benzoyl chloride, 2-methoxybenzoyl chloride, 2-chloro-2,2-diphenylbenzoyl chloride, 2,4,6-trichlorobenzoyl chloride, pentafluorobenzoyl chloride, 4-nitro-benzoyl chloride, 2-chloro-benzoyl chloride, phenoxyacetyl chloride, 4-chloromethyl-benzoyl chloride, acetyl chloride, trimethylacetyl chloride, hexanoyl chloride, trimethylacetyl chloride, methane sulfonyl chloride, p-tosyl chlorothionoformate, phenylisocyanate and p-toluene sulfonic anhydride.

35. The process of claim 30, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, 2,4,6-trichlorobenzoyl chloride and di-t-butyl dicarbonate.

36. The process of claim 30, wherein the coupling product from the coupling reaction is further hydrolyzed to form compound 20 in >95% yield, wherein R8 and R9 are hydrogen.

37. The process of claim 30, wherein: in compound 21, R11 is α-OAc-; R12′ is α-OR12′ and R13 is —R13′, wherein R12′ and R13′ together with the oxygen atoms to which they are attached form a cyclic allyl acetal; R14 is CH3CO; R15 is PhCO; andin compound 22, M is Na; R8 is H, R9 is BOM; and R10 is C1-C6 alkyl;to form the corresponding substituted product 20.

38. The process of claim 30, wherein: in compound 21, R11 is P3O— wherein P3 is CBz; R12 is oxo; R13 is CBz; R14 is CH3CO; R15 is PhCO; andin compound 22, M is Na; R8 is H, R9 is BOM; and R10 is C1-C6 alkyl or aryl, to form the corresponding substituted product 20.

39. The process of claim 30, wherein: in compound 21, R11 is β-OAc; R12 is oxo; R13 is CBz; R14 is CH3CO; R15 is PhCO; andin compound 22, M is Na; R8 is H, R9 is BOM; and R10 is C1-C6 alkyl or aryl to form the corresponding substituted product 20.

40. A process for preparing compound 30:

41. The process of claim 40, wherein the side chain is compound 32; P4 and R9 together with the nitrogen and oxygen to which they are attached form a cyclic 2,4-dimethoxy benzylidene N,O-acetal or a cyclic 2,6-dimethoxy benzylidene N,O-acetal;and M is H or is Na or K; and R10 is C1-C6 alkyl or phenyl.

42. The process of claim 40, wherein the coupling reagent is selected from the group consisting of acid anhydrides, dicarbonates, chloroformates, acid halides, chlorosulfonates, sulfonic anhydrides, alkyl isocyanates and aryl isocyanates.

43. The process of claim 40, wherein the coupling condition comprises THF or toluene or mixtures thereof, and NMM and DMAP.

44. The process of claim 40, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, phenoxyacetic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, acetic anhydride, hexanoic anhydride, benzyl chloroformate, trichloroethyl chloroformate, methyl chloroformate, 4-nitrophenyl chloroformate, benzoyl chloride, 2-methoxybenzoyl chloride, 2-chloro-2,2-diphenylbenzoyl chloride, 2,4,6-trichlorobenzoyl chloride, pentafluorobenzoyl chloride, 4-nitro-benzoyl chloride, 2-chloro-benzoyl chloride, phenoxyacetyl chloride, 4-chloromethyl-benzoyl chloride, acetyl chloride, trimethylacetyl chloride, hexanoyl chloride, trimethylacetyl chloride, methane sulfonyl chloride, p-tosyl chlorothionoformate, phenylisocyanate and p-toluene sulfonic anhydride.

45. The process of claim 40, wherein the coupling reagent is selected from the group consisting of benzoic anhydride, 2,4,6-trichlorobenzoyl chloride and di-t-butyl dicarbonate.

46. The process of claim 40, wherein the coupling product from the coupling reaction is further hydrolyzed to form compound 30 in >95% yield, wherein P4 and R9 are hydrogen.

47. A compound selected from the formulae:

48. A compound selected from the formulae:

49. A compound comprising the formulae:

50. A compound comprising the formula: