Synthetic method of proteasome inhibitor MLN9708

A solvent and complexing technology, applied in the field of synthesis of proteasome inhibitor MLN9708, can solve the problems of incomplete reaction, impurities in raw materials, high cost, etc., and achieve the effect of simplifying operation, improving product quality and reducing cost.

Inactive Publication Date: 2017-05-03
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 i

Method used

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  • Synthetic method of proteasome inhibitor MLN9708
  • Synthetic method of proteasome inhibitor MLN9708
  • Synthetic method of proteasome inhibitor MLN9708

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Embodiment Construction

[0047]

[0048] N-(2,5-Dichlorobenzoyl)glycine (II)

[0049]

[0050] 2,5-Dichlorobenzoic acid (1.91 g, 10 mmol), HOBT (1.49 g, 11 mmol), DCC (2.47 g, 12 mmol) were added sequentially to 30 ml of dichloromethane. After the reaction solution was stirred for 30 min, glycine methyl ester hydrochloride (1.26 g, 10 mmol) and DIEA (2.09 ml, 12 mmol) were added. React at room temperature for 12 hours, distill off the solvent under reduced pressure, add 50ml of ethyl acetate, and remove the insoluble matter N,N'-dicyclohexylurea (DCU) by suction filtration; the filtrate is washed with 5% NaHCO 3 solution, washed with saturated brine; the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated to remove the solvent under reduced pressure to obtain crude N-(2,5-dichlorobenzoyl)glycine methyl ester; directly used in the next step without purification.

[0051] Dissolve the crude product N-(2,5-dichlorobenzoyl)glycine methyl ester in THF (10ml), filter...

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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 ...

Claims

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Application Information

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IPC IPC(8): C07F5/02
CPCY02P20/55C07F5/02
Inventor 李润涛葛泽梅程青韩利强王欣程铁明
Owner PEKING UNIV
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