Synthetic method of proteasome inhibitor MLN9708

Abstract

The invention provides a synthetic method of a proteasome inhibitor MLN9708. The method comprises: taking 2,5-dichloro benzoic acid as an initial raw material, and performing condensation and saponification to prepare N-(2,5-dichlorobenzoyl) glycine; joining N-(2,5-dichlorobenzoyl) glycine to L-leucine boronic acid pinacol ester hydrochloride; purifying the obtained product through forming a complex with diethanolamine and performing hydrolysis for deprotection to obtain corresponding free boric acid; and reacting the obtained product with citric acid to obtain MLN9708. The method is cheap and available in raw materials, simple and convenient to operate, mild in reaction conditions and easy for industrial production.

Description

technical field [0001] The invention relates to a pharmaceutical technology, in particular to a synthesis method of a proteasome inhibitor MLN9708. Background technique [0002] MLN9708 is an orally available dipeptide boronic acid proteasome inhibitor, which can be used for the treatment of multiple myeloma and other malignant tumors, and is currently in phase III clinical research. As a prodrug, MLN9708 is rapidly hydrolyzed into the active structure MLN2238 in vivo to exert pharmacological activity. [0003] [0004] The current patent WO2009154737 synthesis route of MLN9708 is as follows: [0005] [0006] The patented synthesis route uses 2,5-dichlorobenzoyl chloride as the starting material, and the final product MLN9708 is obtained through 4 steps of reaction. This synthetic route has the following disadvantages: [0007] 1) Use 2,5-dichlorobenzoyl chloride as a starting material, which is expensive and difficult to operate; [0008] 2) The key raw material ...

AI Technical Summary

Problems solved by technology

[0010] The synthesis process is complex and expensive

[0011] 3) Use isobutyl boronic acid to remove the pinanediol protecting group. First, isobutyl boronic acid is more expensive, and this reaction requires the use of multiple equivalents of isobutyl boronic acid, resulting in higher costs

And because the reaction of this replacement removal method is not complete, the raw materials in the next step will contain impurities, making the purification of the final product more difficult.

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