Methods for the acylation of maytansinol

• US 10,461,449 B2
• Filed: 09/12/2018
• Issued: 10/29/2019
• Est. Priority Date: 09/26/2012
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated
• Original Assignee: ImmunoGen Incorporated
• Inventors: Widdison, Wayne C., Zhao, Robert Yongxin
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US16/129,268
• Publication Number:
  US 20190013604A1
• Time in Patent Office: 412 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 in step c), the compound of formula (1) is reacted with a carboxylic acid having R₃COOH in the presence of a condensing agent.

3. The method of claim 2, wherein the condensing agent is N-(3-dimethylaminopropyl)-N′

-ethylcarbodiimide hydrochloride (EDC).

4. The method of claim 1, wherein the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH₄.

5. The method of claim 4, wherein the reducing agent is dithiothreitol (DTT).

6. The method of claim 1, wherein the reaction mixture in step a) further comprises a drying agent.

7. The method of claim 6, wherein the drying agent is molecular sieve, sodium sulfate, calcium sulfate, calcium chloride, or magnesium sulfate.

8. The method of claim 1, wherein the method is for preparing DM1.

9. The method of claim 1, wherein the method is for preparing DM4.

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

11. The method of claim 10, wherein in step c), the compound of formula (1) is reacted with a carboxylic acid having R₃COOH in the presence of a condensing agent.

12. The method of claim 11, wherein the condensing agent is N-(3-dimethylaminopropyl)-N′

-ethylcarbodiimide hydrochloride (EDC).

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

14. The method of claim 13, wherein the reducing agent is dithiothreitol (DTT).

15. The method of claim 10, wherein the drying agent is molecular sodium sulfate.

16. The method of claim 10, wherein the method is for preparing DM1.

17. The method of claim 10, wherein the method is for preparing DM4.