Methods for the acylation of maytansinol

• US 10,944,190 B2
• Filed: 09/18/2019
• Issued: 03/09/2021
• 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:
  US16/574,718
• Publication Number:
  US 20200153130A1
• Time in Patent Office: 538 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, 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 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.

11. The method of claim 1, 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:

12. The method of claim 11, 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 C2-C10 alkenyl group.

13. The method of claim 11, wherein R₃ is —

Y—

S—

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

14. The method of claim 13, further comprising reacting the compound of formula (III) with a reducing agent to form a compound represented by the following formula:

16. The method of claim 11, 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.

17. The method of claim 1, 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.

18. The method of claim 1, wherein the drying agent is a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride, or magnesium sulfate.

19. The method of claim 1, wherein the molar ratio of maytansinol to N-carboxyanhydride is in the range of 1:

1 to 1;

4.

20. The method of claim 1, wherein the molar ratio of maytansinol to Lewis acid is 1:

7.

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

6. The method of claim 5, wherein the compound of Formula (I) is represented by the following formula:

7. The method of claim 6, 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.

8. The method of claim 5, wherein the reaction mixture in step a) further comprises a drying agent.

9. The method of claim 5, wherein the nucleophilic reagent is water or an alcohol.

10. The method of claim 5, 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.

15. The method of 11, wherein R₃ is -L-E;

L is