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US 7,598,375 B2Granted
Method of acylating maytansinol with chiral amino acids
AssigneeMillenium Pharmaceuticals, Inc.
InventorsGuojie Ho, Darren J. Carrozzella
Life of this patent
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Abstract
This invention provides a method for making maytansinoids having a chiral amino acid side chain, such as DM1 and DM4 that are used to treat cancer. According to this method, the side chain may be added with little epimerization of the amino acid chiral center.
Claims10
A method of making a compound of formula A:
- where:
- X is Cl or H, and
- R is
- R1 is a naturally-occurring amino acid side chain;
- R2 is hydrogen or a C1-6 alkyl group;
- said method comprising:
- (a) providing a mixture comprising
- (i) a starting material which has a formula identical to formula A except that R is hydrogen,
- (ii) a compound of formula 2:
- (iii) a Lewis acid,
- (iv) a non-nucleophilic base and
- (v) an organic solvent;
- (b) allowing the mixture of step (a) to react until some of the starting material is converted to the compound of formula A;
- (c) removing crude compound of formula A from the mixture of step (b);
- and
- (d) optionally purifying the compound of formula A obtained in step (c).
13 more elements
A method of making a compound of formula II:
- wherein:
- X is Cl or H;
- R1 is a naturally-occurring amino acid side chain;
- R2 is hydrogen, C1-6 alkyl, aryl or aralkyl;
- L is a C2-6 alkylene chain having 0-2 substituents independently selected from the group consisting of halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy;
- R3 is hydrogen or S—R4;
- and
- R4 is C1-6 alkyl, aryl, or aralkyl;
- the method comprising:
- (a) obtaining a compound of formula I:
- by a coupling reaction of 2 with maytansinol or its analogue where X=H, wherein the coupling reaction is performed in the presence of a Lewis acid, a non-nucleophilic base and an organic solvent;
- (b) coupling the compound of formula I obtained from step (a) with R5O2C—L—S—S—R4, where R5 is hydrogen or an activating group to provide the compound of formula II where R3 is S—R4;
- and
- (c) optionally treating the compound of formula II obtained in step (b) with a reducing agent to provide a compound of formula II where R3 is hydrogen.
11 more elements
Dependencies are inferred from the claim text.