Preparation method of N-(pyrazine-2-radical carbonyl)-L-phenyl alanine

A technology of phenylalanine and phenylalanine methyl ester, which is applied in the field of preparation of bortezomib intermediates, can solve the problems of unsuitability for industrial production, cumbersome operation, and high cost, and achieve low cost, reduction of three wastes, and easy reagent production The effect

Active Publication Date: 2011-10-12
SUZHOU ERYE PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route uses CDI and BSA protection reagents, the operation is cumbersome, the cost is high and it is not suitable for industrial production

Method used

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  • Preparation method of N-(pyrazine-2-radical carbonyl)-L-phenyl alanine
  • Preparation method of N-(pyrazine-2-radical carbonyl)-L-phenyl alanine
  • Preparation method of N-(pyrazine-2-radical carbonyl)-L-phenyl alanine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add thionyl chloride (53.7ml, 0.733mol) dropwise into pyrazine-2-carboxylic acid (9.1g, 73.3mmol) and react at 78°C for 3h. After concentration under reduced pressure, it was dissolved in 1,4-dioxane to obtain an acid chloride solution.

[0020] Dissolve L-phenylalanine (12.1g, 73.3mmol) in methanol (50ml), add thionyl chloride (53.7ml, 0.703mol) under stirring at room temperature, keep the reaction at 55-60°C for 2 hours, then cool to After concentrated under reduced pressure at room temperature, it was dissolved with 1,4-dioxane to obtain L-phenylalanine methyl ester hydrochloride solution.

[0021] At room temperature, the 1,4-dioxane solution of L-phenylalanine methyl ester hydrochloride (15.8g, 73.3mmol) and Zn powder (4.8g, 73.3mmol) were dissolved in 20ml of tetrahydrofuran, and then added A solution of pyrazine-2-carbonyl chloride (10.4g, 73.3mmol) in 1,4-dioxane and Zn powder (4.8g, 73.3mmol) in tetrahydrofuran (20ml) was stirred at room temperature for 1 hour...

Embodiment 2

[0024] Thionyl chloride (37.1ml, 0.506mol) was added dropwise into pyrazine-2-carboxylic acid (7.0g, 50.6mmol), and reacted at 78°C for 3h. After concentration under reduced pressure, it was dissolved in 1,4-dioxane to obtain an acid chloride solution.

[0025] Dissolve L-phenylalanine (8.4g, 50.6mmol) in methanol (30ml), add thionyl chloride (37.1ml, 0.506mol) under stirring at room temperature, keep at 55-60°C for 2 hours, then cool to After concentrated under reduced pressure at room temperature, it was dissolved with 1,4-dioxane to obtain L-phenylalanine methyl ester hydrochloride solution.

[0026] At room temperature, the 1,4-dioxane solution of L-phenylalanine methyl ester hydrochloride (10.9g, 50.6mmol) and Zn powder (3.3g, 50.6mmol) were dissolved in 20ml of tetrahydrofuran, and then added A solution of pyrazine-2-carbonyl chloride (7.2g, 50.6mmol) in 1,4-dioxane and Zn powder (3.3g, 50.6mmol) in tetrahydrofuran (20ml) was stirred at room temperature for 1 hour. The...

Embodiment 3

[0029] Thionyl chloride (59.0ml, 0.806mol) was added dropwise into pyrazine-2-carboxylic acid (10.0g, 80.6mmol), and reacted at 78°C for 3h. After concentration under reduced pressure, it was dissolved in 1,4-dioxane to obtain an acid chloride solution.

[0030] Dissolve L-phenylalanine (12.1g, 73.3mmol) in methanol (50ml), add thionyl chloride (53.7ml, 0.703mol) under stirring at room temperature, keep the reaction at 55-60°C for 2 hours, then cool to After concentrated under reduced pressure at room temperature, it was dissolved with 1,4-dioxane to obtain L-phenylalanine methyl ester hydrochloride solution.

[0031] At room temperature, the 1,4-dioxane solution of L-phenylalanine methyl ester hydrochloride (15.8g, 73.3mmol) and Mg powder (1.8g, 73.3mmol) were dissolved in 20ml of tetrahydrofuran, and then added A solution of pyrazine-2-carbonyl chloride (10.4g, 73.3mmol) in 1,4-dioxane and Mg powder (1.8g, 73.3mmol) in tetrahydrofuran (20ml) was stirred at room temperature ...

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Abstract

The invention discloses a preparation method of N-(pyrazine-2-radical carbonyl)-L-phenyl alanine. The preparation method comprises the following steps of: (1) making thionyl chloride react with pyrazine-2-formic acid in an organic solvent to obtain pyrazine-2-formyl chloride; (2) making thionyl chloride react with L-phenyl alanine in methanol to obtain L-phenyl alanine methyl ester hydrochloride; (3) dissolving pyrazine-2-formyl chloride and a metal M in tetrahydrofuran and adding the solution into a tetrahydrofuran solution of the L-phenyl alanine methyl ester hydrochloride and the metal M to obtain N-(pyrazine-2-radical carbonyl)-L-phenyl alanine methyl ester; and (4) dissolving the N-(pyrazine-2-radical carbonyl)-L-phenyl alanine methyl ester in an organic solvent and hydrolyzing under an alkaline condition to obtain N-(pyrazine-2-radical carbonyl)-L-phenyl alanine. A synthetic method has the advantages of less operation steps, high yield, readily-available raw materials and low environmental pollution, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a bortezomib intermediate, in particular to a preparation method of a bortezomib intermediate which has high yield, less environmental pollution and is suitable for industrial production. Background technique [0002] Bortezomib (bortezomib) was developed by Millennium Pharmaceuticals in Cambridge, Massachusetts, USA. Bortezomib is the first dipeptide boronic acid proteasome inhibitor, which reversibly binds to the 26S proteasome and blocks Protein degradation, prevent malignant proliferation of tumor cells. Mainly used in the treatment of multiple myeloma. Its chemical name is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarbonyl)amino]propyl]amino]butyl]- boric acid. It was launched in the United States in May 2003 and in China in September 2005. [0003] Bortezomib is composed of (1R)-(S)-pinanediol-1-amino(trifluoroacetate)-3-methylbutane-1-boronate and N-(pyrazin-2-yl Carbonyl)-L-phenylal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
Inventor 毛化钟静芬陈学文刘志时惠麟
Owner SUZHOU ERYE PHARMA CO LTD
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