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:
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 (6a):
b) reacting unreacted N-carboxyanhydride from the reaction mixture in step a) with methanol;
c) reacting the compound of formula (6a) 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 2 is methyl; 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 N-succinimidyl ester; and
d) reacting the compound of formula (IIIa) with a reducing agent to form the compound DM1 or DM4.
2. The method of claim 1 , wherein in step c), the compound of formula (1) is reacted with a carboxylic acid having R 3 COOH 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 NaBH 4 .
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:
the method comprising:
a) reacting maytansinol with an N-carboxyanhydride in a reaction mixture additionally comprising diisopropylethylamine, zinc triflate and a drying agent selected from the group consisting of a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride and magnesium chloride, wherein the N-carboxyanhydride is represented by the following formula:
thereby forming the compound of Formula (6a):
and
b) reacting unreacted N-carboxyanhydride from the reaction mixture in step a) with a nucleophilic reagent that is water;
c) reacting the compound of formula (6a) 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 2 is methyl; 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 N-succinimidyl ester; and
d) reacting the compound of formula (IIIa) with a reducing agent to form the compound DM1 or DM4.
11. The method of claim 10 , wherein in step c), the compound of formula (1) is reacted with a carboxylic acid having R 3 COOH 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 NaBH 4 .
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.