Methods for the acylation of maytansinol

Patent metadata

Field	Value
Publication number	US-9796731-B2
Application number	US-201615269163-A
Country	US
Kind code	B2
Filing date	Sep 19, 2016
Priority date	Sep 26, 2012
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

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.

First claim

What is claimed is:

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

the method comprising:
a) reacting maytansinol with an N-carboxyanhydride in a reaction mixture additionally comprising diisopropylethylamine and zinc triflate, wherein the N-carboxyanhydride is represented by the following formula:

thereby forming the compound of Formula (1);
b) reacting unreacted N-carboxyanhydride from the reaction mixture in step a) with methanol.

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

3. 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.

4. The method of claim 1 , further comprising the step of reacting the compound of formula d(1) with a carboxylic acid having the formula R 3 COOH in the presence of a condensing agent or with an activated carboxylic acid having the formula R 3 COX, to form a compound represented by the following formula:

wherein R 3 is —Y—S—SR 4 ; Y is —CH 2 CH 2 — or —CH 2 CH 2 C(CH 3 ) 2 —; R 4 is —CH 3 ; —COX is a reactive ester selected from the group consisting of N-succinimidyl, N-sulfosuccinimidyl, N-phthalimidyl, N-sulfophthalimidyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 3-sulfonyl-4-nitrophenyl and 3-carboxy-4-nitrophenyl ester; and the condensing agent is a carbodiimide.

5. The method of claim 4 , further comprising reacting the compound of formula (3) with a reducing agent to form a compound represented by the following formula:

6. The method of claim 4 , wherein the condensing agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC).

7. The method of claim 2 , wherein the drying agent is a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride, or magnesium sulfate.

8. The method of claim 7 , wherein the drying agent is sodium sulfate.

9. The method of claim 4 , wherein the reactive ester is N-succinimidyl ester.

10. The method of claim 5 , wherein the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH 4 .

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

12. The method of claim 5 , wherein the compound of formula (4) is DM4 represented by the following formula:

13. The method of claim 5 , wherein the compound of formula (4) is DM1 represented by the following formula:

Assignees

• Immunogen Inc

Inventors

• Widdison Wayne C
• Zhao Robert Yongxin

Classifications

• H05K1/116

  Lands, clearance holes or other lay-out details concerning the surrounding of a via · CPC title

• C07D498/18 Primary

  Bridged systems · CPC title

• H05K1/0203

  Cooling of mounted components (H05K1/0272 takes precedence) · CPC title

• C07D498/16 Primary

  Peri-condensed systems · CPC title

• H01R12/585 Primary

  Terminals having a press fit or a compliant portion and a shank passing through a hole in the printed circuit board · CPC title