Methods for the acylation of maytansinol
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.
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 molar ratio of maytansinol to N-carboxyanhydride ranges from 1:1 to 1:10, and the molar ratio of maytansinol to the Lewis acid ranges from 1:5 to 1:8, and 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 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.
5. 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 molar ratio of maytansinol to N-carboxyanhydride ranges from 1:1 to 1:10, and the molar ratio of maytansinol to Lewis acid ranges from 1:5 to 1:8, and 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.
6. The method of claim 5 , wherein the compound of Formula (I) is represented by the following formula:
and the N-carboxyanhydride 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.
11. The method of claim 1 , 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 an alkyl group or a substituted alkyl group, and X is a leaving group.
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 R 3 is —Y—S—SR 4 , in which Y is C1-C10 alkylene and R 4 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:
15. The method of 11 , wherein R 3 is -L-E;
L is
or —(CH 2 CH 2 O) m CH 2 CH 2 NHC(═O)CH 2 CH 2 — or
E is
X′ is a halide;
n is 2, 3, 4, 5 or 6;
m is 0 or an integer from 1 to 20; and
q is 0 or 1.
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.