Methods for the acylation of maytansinol

• US 10,100,062 B2
• Filed: 09/19/2017
• Issued: 10/16/2018
• Est. Priority Date: 09/26/2012
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Widdison, Wayne C., Zhao, Robert Yongxin
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US15/708,346
• Publication Number:
  US 20180099980A1
• Time in Patent Office: 392 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 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.

3. The method of claim 1, wherein the base is a trialkylamine.

4. The method of claim 3, wherein the trialkylamine is diisopropylethylamine.

5. The method of claim 1, wherein the drying agent is a molecular sieve.

6. The method of claim 1, wherein the Lewis acid is zinc triflate.

7. The method of claim 1, further comprising the step of reacting the compound of formula (6a) with an activated carboxylic acid having the formula R₃COX, to form a compound represented by the following formula:

8. The method of claim 7, wherein —

COX is a reactive ester.

9. The method of claim 8, wherein R₃ is —

Y—

S—

SR₄, in which Y is —

CH₂CH₂—

or —

CH₂CH₂C(CH₃)₂—

, and R₄ is —

CH₃.

10. The method of claim 9, further comprising reacting the compound of formula (IIIa) with a reducing agent to form a compound represented by the following formula:

11. The method of claim 10, wherein the reducing agent is the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH₄.

12. The method of claim 10, the compound of formula (IVa) is DM4 represented by he following formula:

13. The method of claim 10, wherein the compound of formula (IVa) is DM1 represented by the following formula:

14. The method of claim 1, further comprising the step of reacting the compound of formula (6a) with a carboxylic acid having the formula R₃COOH in the presence of a condensing agent to form a compound represented by the following formula:

15. The method of claim 14, wherein the condensing agent is N-(3-dimethylaminopropyl)-N′

-ethylcarbodiimide hydrochloride.

16. The method of claim 14, wherein R₃ is —

Y—

S—

SR₄, in which Y is —

CH₂CH₂—

or —

CH₂CH₂C(CH₃)₂—

, and R₄ is —

CH₃.

17. The method of claim 16, further comprising reacting the compound of formula (Ma) with a reducing agent to form a compound represented by the following formula:

18. The method of claim 17, wherein the reducing agent is the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH₄.

19. The method of claim 17, the compound of formula (IVa) is DM4 represented by the following formula:

20. The method of claim 17, wherein the compound of formula (IVa) is DM1 represented by the following formula: