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 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 (6a); and
b) reacting unreacted N-carboxyanhydride from the reaction mixture in step a) with a nucleophilic reagent that is water;
wherein the drying agent is a molecular sieve, sodium sulfate, calcium sulfate, calcium chloride or magnesium chloride; and 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.
2. 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.
3. The method of claim 1 , wherein the base is a trialkylamine.
4. The method of claim 3 , wherein the trialkylamine is diisopropylethylamine.
5. The method of claim 1 , wherein the drying agent is a molecular sieve.
6. The method of claim 1 , wherein the Lewis acid is zinc triflate.
7. The method of claim 1 , further comprising the step of reacting the compound of formula (6a) 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.
8. The method of claim 7 , wherein —COX is a reactive ester.
9. The method of claim 8 , wherein R 3 is —Y—S—SR 4 , in which Y is —CH 2 CH 2 — or —CH 2 CH 2 C(CH 3 ) 2 —, and R 4 is —CH 3 .
10. The method of claim 9 , further comprising reacting the compound of formula (IIIa) with a reducing agent to form a compound represented by the following formula:
11. The method of claim 10 , wherein the reducing agent is the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH 4 .
12. The method of claim 10 , the compound of formula (IVa) is DM4 represented by he following formula:
13. The method of claim 10 , wherein the compound of formula (IVa) is DM1 represented by the following formula:
14. The method of claim 1 , further comprising the step of reacting the compound of formula (6a) with a carboxylic acid having the formula R 3 COOH in the presence of a condensing agent to form a compound represented by the following formula:
wherein R 3 is an alkyl group or a substituted alkyl group.
15. The method of claim 14 , wherein the condensing agent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.
16. The method of claim 14 , wherein R 3 is —Y—S—SR 4 , in which Y is —CH 2 CH 2 — or —CH 2 CH 2 C(CH 3 ) 2 —, and R 4 is —CH 3 .
17. The method of claim 16 , further comprising reacting the compound of formula (Ma) with a reducing agent to form a compound represented by the following formula:
18. The method of claim 17 , wherein the reducing agent is the reducing agent is dithiothreitol (DTT), (tris(2-carboxyethyl)phosphine) (TCEP) or NaBH 4 .
19. The method of claim 17 , the compound of formula (IVa) is DM4 represented by the following formula:
20. The method of claim 17 , wherein the compound of formula (IVa) is DM1 represented by the following formula: