METHODS FOR THE ACYLATION OF MAYTANSINOL

• US 20190013604A1
• Filed: 09/12/2018
• Published: 01/10/2019
• Est. Priority Date: 09/26/2012
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Widdison, Wayne C., Zhao, Robert Yongxin
• Granted Patent: US 10,461,449 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 498/16 Peri-condensed systems
• CPC Class Codes: C07D 498/18 Bridged systems
• CPC Class Codes: H01R 12/585 Terminals having a press fit or a compliant portion and a shank passing through a hole in the printed circuit board
• CPC Class Codes: H05K 1/0203 Cooling of mounted components H05K1/0272 takes precedence
• CPC Class Codes: H05K 1/116 Lands, clearance holes or other lay-out details concerning the surrounding of a via
• CPC Class Codes: H05K 1/181 associated with surface mounted components

Abstract

Disclosed is a method of preparing an amino acid ester of maytansinol by reacting maytansinol with an N-carboxyanhydride of an amino acid (NCA) in the presence of a drying agent. Also disclosed is an improved method of preparing an amino acid ester of maytansinol in which a nucleophile is added to the reaction mixture after completion of the reaction between maytansinol and an N-carboxyanhydride of an amino acid.

Claims

1. A method of preparing a compound represented by the following formula:

2. The method of claim 1, wherein the compound of Formula (I) is represented by the following formula:

3. The method of claim 1 or 2, wherein the reaction mixture further comprises a Lewis acid.

4. The method of claim 3, wherein the Lewis acid is selected from the group consisting of zinc triflate, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, copper (II) bromide, copper (II) chloride, and magnesium chloride.

5. The method of claim 3, wherein the Lewis acid is zinc triflate.

6. The method of any one of claims 1-5, wherein further comprising contacting the reaction mixture after the reaction of maytansinol and the N-carboxyanhydride with an aqueous solution containing bicarbonate or carbonate or contacting the reaction mixture with a metal scavenger.

17. The method of any one of claims 1-16, further comprising the step of reacting the compound of formula (I) with a carboxylic acid having the formula R₃COOH in the presence of a condensing agent or with an activated carboxylic acid having the formula R₃COX, to form a compound represented by the following formula:

18. The method of claim 17, wherein X is a halide, an alkoxy group, an aryloxy group, an imidazole, —

S-phenyl optionally substituted with nitro or chloride, or —

OCOR, in which R is a linear C1-C10 alkyl group, a branched C1-C10 alkyl group, a cyclic C3-C10 alkyl group, or a C1-C10 alkenyl group.

19. The method of claim 17, wherein —

COX is a reactive ester.

20. The method of claim 17, wherein R₃ is —

Y—

S—

SR₄, in which Y is C1-C10 alkylene and R₄ is C1-C10 alkyl, aryl, or heteroaryl (pyridyl).

21. The method of claim 20, wherein Y is —

CH₂CH₂—

or —

CH₂CH₂C(CH₃)₂— and

R₄ is —

CH₃.

22. The method of claim 20 or 21, further comprising reacting the compound of formula (III) with a reducing agent to form a compound represented by the following formula:

29. The method of any one of claims 17-28, wherein the condensing agent is a carbodiimide, a uronium, an active ester, a phosphonium, 2-alkyl-1-alkylcarbonyl-1,2-dihydroquinoline, 2-alkoxy-1˜

alkoxycarbonyl-1,2-dihydroquinoline, or alkylchloroformate.

30. The method of claim 29, wherein the condensing agent is a carbodiimide.

31. The method of claim 30, wherein the condensing agent is N-(3-dimethylaminopropyl)-N′

-ethylcarbodiimide hydrochloride.

32. The method of any one of claims 1-31, wherein R₁ is the side chain of a naturally occurring amino acid, provided that, if the side chain has a functional group, the functional group is optionally protected;

and R₂ is methyl.

33. The method of claim 32, wherein R₁ is methyl.

34. The method of claims 1-33, wherein the base is a trialkylamine, a metal alkoxide, an alkyl metal, an aryl metal, a metal hydride, a metal amide, or a silicon-based amide.

35. The method of claim 34, wherein the base is a trialkylamine.

36. The method of claim 35, wherein the trialkylamine is diisopropylethylamine.

37. The method of any one of claims 1-6 and 12-36, wherein the drying agent is a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride, or magnesium sulfate.

38. The method of claim 37, wherein the drying agent is a molecular sieve.

39. The method of claim 37 or 38, wherein the drying agent is in the form of granular beads or powders.

7. A method of preparing a compound represented by the following formula:

8. The method of claim 7, wherein the compound of Formula (I) is represented by the following formula:

9. The method of claim 7 or 8, wherein the reaction mixture in step a) further comprises a Lewis acid.

10. The method of claim 9, wherein the Lewis acid is selected from the group consisting of zinc triflate, zinc chloride, magnesium bromide, magnesium triflate, copper triflate, copper (II) bromide copper (II) chloride, and magnesium chloride.

11. The method of claim 10, wherein the Lewis acid is zinc triflate.

12. The method of any one of claims 7-11, wherein the reaction mixture in step a) further comprises a drying agent.

13. The method of any one of claims 7-12, wherein the nucleophilic reagent is water or an alcohol.

14. The method of claim 13, wherein the nucleophilic reagent is an alcohol.

15. The method of claim 14, wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, or tert-butanol.

16. The method of any one of 9-15, wherein the method further comprises contacting the reaction mixture after step b) with an aqueous solution containing bicarbonate or carbonate or contacting the reaction mixture with a metal scavenger.

23. The method of 17, wherein R₃ is -L-E;

L is

24. The method of claim 23, wherein L is —

(CH₂)_n—

.

25. The method of claim 24, wherein n is 5.

26. The method of claim 23, wherein L is

27. The method of claim 26, wherein n is 4 and m is 3.

28. The method of claim 23, wherein R₃ is represented by one of the following: