Methods for the acylation of maytansinol

Patent metadata

Field	Value
Publication number	US-9469655-B2
Application number	US-201514660050-A
Country	US
Kind code	B2
Filing date	Mar 17, 2015
Priority date	Sep 26, 2012
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

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:

wherein R 1 is methyl; and R 2 is methyl, the method comprising:
reacting maytansinol with an N-carboxyanhydride in a reaction mixture additionally comprising a base, a drying agent and a Lewis acid, wherein the N-carboxyanhydride is represented by the following formula:

thereby forming the compound of Formula (I).

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

and the N-carboxyanhydride is represented by the following formula:

3. The method of claim 2 , 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.

4. The method of claim 2 , wherein the Lewis acid is zinc triflate.

5. The method of claim 1 , 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.

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

wherein R 1 is methyl; and R 2 is methyl, the method comprising:
a) reacting maytansinol with an N-carboxyanhydride in a reaction mixture additionally comprising a base and a Lewis acid, wherein the N-carboxyanhydride is represented by the following formula:

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

7. The method of claim 6 , wherein the compound of Formula (I) is represented by the following formula:

and the N-carboxyanhydride is represented by the following formula:

8. The method of claim 7 , 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.

9. The method of claim 8 , wherein the Lewis acid is zinc triflate.

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

11. The method of any one of claims 6 , 7 , and 8 - 10 , wherein the nucleophilic reagent is water or an alcohol.

12. The method of claim 11 , wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, or tert-butanol.

13. The method of claim 6 , 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.

14. The method of claim 1 or 6 , further comprising the step of reacting the compound of formula (I) 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 C 1 -C 10 alkylene, R 4 is C 1 -C 10 alkyl, aryl, or heteroaryl,
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 C 1 -C 10 alkyl group, a branched C 1 -C 10 alkyl group, a cyclic C 3 -C 10 alkyl group, or a C 1 -C 10 alkenyl group, and,
—COX is a reactive ester.

15. The method of claim 14 , wherein Y is —CH 2 CH 2 — or —CH 2 CH 2 C(CH 3 ) 2 —, and R 4 is —CH 3 .

16. The method of claim 15 , further comprising reacting the compound of formula (III) with a reducing agent to form a compound represented by the following formula:

17. The method of claim 14 , 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.

18. The method of claim 17 , wherein the condensing agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.

19. The method of claim 1 , 2 , 3 , 4 , 5 , 6 , 7 , or 8 , 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.

20. The method of claim 19 , wherein the trialkylamine is diisopropylethylamine.

21. The method of any one of claims 1 , 2 , 3 , 4 , and 10 , wherein the drying agent is a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride, or magnesium sulfate.

22. The method of claim 21 , wherein the drying agent is a molecular sieve.

Assignees

• Immunogen Inc

Inventors

• Widdison Wayne C
• Zhao Robert Yongxin

Classifications

• 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

• C07D498/18 Primary

  Bridged systems · CPC title

• C07D498/16 Primary

  Peri-condensed systems · CPC title

• H05K1/181

  associated with surface mounted components · CPC title

• H05K1/116

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