Synthesis of epothilones, intermediates thereto and analogues thereof

• US 20030208080A1
• Filed: 12/23/2002
• Published: 11/06/2003
• Est. Priority Date: 12/03/1996
• Status: Active Grant

• Current Assignee: Aaron Balog, Christina Harris, Dai-Shi Su, Dongfang Meng, Erik J. Sorensen, Joseph R. Bertino, Kenneth A. Savin, Peter Bertinato, Samuel J. Danishefsky, Scott Kuduk, Ted Kamenecka, Ting-Chao Chou, Xiu-Guo Zhang
• Original Assignee: Aaron Balog, Christina Harris, Dai-Shi Su, Dongfang Meng, Erik J. Sorensen, Joseph R. Bertino, Kenneth A. Savin, Peter Bertinato, Samuel J. Danishefsky, Scott Kuduk, Ted Kamenecka, Ting-Chao Chou, Xiu-Guo Zhang
• Inventors: Balog, Aaron, Danishefsky, Samuel J., Bertino, Joseph R., Chou, Ting-Chao, Kamenecka, Ted, Bertinato, Peter, Savin, Kenneth A., Su, Dai-Shi, Sorensen, Erik J., Kuduk, Scott, Harris, Christina, Zhang, Xiu-Guo, Meng, DongFang
• Granted Patent: US 6,965,034 B2
• Time in Patent Office: Days
• US Class Current: 546/281.7
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 59/76 containing keto groups
• CPC Class Codes: C07C 69/007 Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 313/00 Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof, useful in the treatment of cancer and cancer which has developed a multidrug-resistant phenotype. Also provided are intermediates useful for preparing said epothilones.

Claims

1. A method of preparing a desoxyepothilone having the structure:

2. The method of claim 1 wherein desoxyepothilone has the structure:

3. The method of claim 1 wherein the epothilone is deoxygenated using a zinc/copper couple.

4. The method of claim 1 wherein the epothilone is deoxygenated in the presence of a polar solvent comprising isopropanol and water.

5. A method of preparing a desoxyepothilone having the structure:

6. The method of claim 5 wherein the desoxyepothilone has the structure:

7. The method of claim 5 wherein the epothilone is deoxygenated using a zinc/copper couple.

8. The method of claim 5 wherein the epothilone is deoxygenated in the presence of a polar solvent comprising isopropanol and water.

9. A method of preparing a desoxyepothilone having the structure:

10. The method of claim 9 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

11. The method of claim 9 wherein R_A is TES and R_B is Troc.

12. The method of claim 9 wherein the treating step comprises contacting the protected desoxyepothilone (i) with SmX₂, where X is Cl, Br or I, in the presence of a polar nonaqueous solvent selected from the group consisting of tetrahydrofuran, p-dioxane, diethyl ether, acetonitrile and N,N-dimethylformamide, and optionally in the presence of N,N-dimethyl-N′

-propylurea or hexamethylphosphoramide and (ii) with a source of fluoride ion selected from the group consisting of tetra-n-methylammonium fluoride, tetra-n-butylammonium fluoride and HF.pyridine.

13. A method of preparing a protected desoxyepothilone having the structure:

14. The method of claim 13 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

15. The method of claim 13 wherein R_A is TES and R_B is Troc.

16. The method of claim 13 wherein the hydroxy acid desoxyepothilone precursor is cyclocondensed using a cyclocondensing reagent selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride and 2,4,6-trichlorobenzoyl chloride.

17. The method of claim 13 wherein the hydroxyacid is cyclocondensed using 2,4,6-trichlorobenzoyl chloride in the presence of a tertiary amine selected from the group consisting of triethyl amine, tri-n-propylamine, diisopropylethylamine and diethyliso-propylamine, and optionally in the presence of pyridine or N,N-dimethylaminopyridine.

18. A method of preparing a hydroxy acid desoxyepothilone precursor having the structure:

19. The method of claim 18 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

20. The method of claim 18 wherein R_A is TES and R_B is Troc.

21. The method of claim 18 wherein the selective etherifying step comprises contacting the hydroxy ester desoxyepothilone precursor with a silylating reagent to form an ether intermediate, and the hydrolyzing step comprises contacting the ether intermediate with a protic acid or tetra-n-butylammonium fluoride.

22. The method of claim 21 wherein the silylating reagent is TESOTf in the presence of 2,6-lutidine.

23. The method of claim 21 wherein the protic acid is HCl in the presence of methyl alcohol.

24. A method of preparing a hydroxy ester desoxyepothilone precursor having the structure:

25. The method of claim 24 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

26. The method of claim 24 wherein R_A is TES and R_B is Troc.

27. The method of claim 24 wherein the reducing step comprises contacting the hydroxy ketoester desoxyepothilone precursor with a stereospecific reducing reagent.

28. The method of claim 24 wherein the stereospecific reducing reagent comprises hydrogen gas at from about 900 pounds per square inch to about 2200 pounds per square inch in the presence of (R)-(BINAP)RuCl₂ and optionally in the presence of HCl and an alcohol selected from the group consisting of MeOH, EtOH, and i-PrOH.

29. A method of preparing a hydroxy ketoester desoxyepothilone precursor having the structure:

30. The method of claim 29 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

31. The method of claim 29 wherein R_A is TES and R_B is Troc.

32. The method of claim 29 wherein P is TBS.

33. The method of claim 29 wherein the deprotecting step comprises contacting the protected ketoester desoxy,epothilone precursor with a protic acid.

34. The method of claim 33 wherein the protic acid is HCl in methyl alcohol or ethyl alcohol.

35. A method of preparing a protected ketoester desoxylepothilone precursor having the structure:

36. The method of claim 35 wherein n is 3 and R″

is 2-methyl-1,3-thiazolinyl.

37. The method of claim 35 wherein R_A is TES and R_B is Troc.

38. The method of claim 35 wherein P is TBS or TES.

39. The method of claim 35 wherein Q is iodine or bromine.

40. The method of claim 35 wherein R_D is methyl or TES.

41. The method of claim 35 wherein the coupling step comprises contacting the terminal vinyl enol ether ester and the protected halovinyl compound with noble metal complex capable of effecting a Suzuki coupling.

42. The method of claim 35 wherein the noble metal complex is Pd(dppf)₂Cl₂ in the presence of Ph₃As and Cs₂CO₃.

43. A method of preparing a terminal vinyl enol ether ester having the structure:

44. The method of claim 43 wherein the treating step comprises contacting the keto enol ester with a strong nonnucleophilic base selected from the group consisting of lithium diethylamide, lithium diethylamide, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride and potassium t-butoxide.

45. The method of claim 44 wherein the treating step is effected in a polar nonaqueous solvent selected from the group consisting of tetrahydrofuran, diethyl ether, di-n-propyl ether and dimethylformamide at a temperature from about −

100°

C. to about +10°

C.

46. The method of claim 44 wherein the temperature is from about −

20°

C. to −

40°

C.

47. The method of claim 43 wherein the coupling step comprises contacting the enolate enol ester with the vinyl aldehyde at a temperature from about −

130°

C. to about −

78°

C.