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Preparation method of telaprevir intermediate and salt thereof

A cyclohexyl glycinate, pyrazine technology, applied in the direction of organic chemistry and the like, can solve the problems of oxidative side reactions, cumbersome synthesis routes, easy to produce carcinogens, etc., and achieves low price, simple post-processing and reduced production costs. Effect

Inactive Publication Date: 2015-04-15
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem solved by the present invention is to overcome the existing N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycine preparation method with high cost, cumbersome synthetic route, easy to produce carcinogens, and oxidative side reactions. Defects, providing a telaprevir intermediate (i.e. N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycine) and its salt preparation method

Method used

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  • Preparation method of telaprevir intermediate and salt thereof
  • Preparation method of telaprevir intermediate and salt thereof
  • Preparation method of telaprevir intermediate and salt thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0033] At room temperature, thionyl chloride (29mL, 0.4mol) was added dropwise to pyrazine-2-carboxylic acid (5g, 0.04mol), 1 drop of DMF was added as a catalyst, and the reaction was refluxed at 78°C for 3h. Concentrate under reduced pressure and dissolve with 1,4-dioxane to prepare a pyrazine-2-formyl chloride solution for use.

Embodiment 2

[0035] At room temperature, thionyl chloride (14.5mL, 0.2mol) was added dropwise to pyrazine-2-carboxylic acid (5g, 0.04mol), 1 drop of DMF was added as a catalyst, and the reaction was refluxed at 78°C for 3h. Concentrate under reduced pressure and dissolve with 1,4-dioxane to prepare a pyrazine-2-formyl chloride solution for use.

Embodiment 3

[0037] At room temperature, oxalyl chloride (50.8g, 0.4mol) was slowly added dropwise to pyrazine-2-carboxylic acid (5g, 0.04mol) in 50mL dichloromethane solution, and 1 drop of DMF was added dropwise to catalyze. After the addition, the temperature was slowly raised to room temperature, stirred overnight, dried over anhydrous magnesium sulfate, and spin-dried to obtain pyrazine-2-formyl chloride. Dissolve in 1,4-dioxane solution for use.

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Abstract

The invention discloses a preparation method of a telaprevir intermediate and a salt thereof. The preparation method includes following steps: performing a reaction between pyrazine-2-formyl chloride and L-cyclohexylglycine in an organic solvent under the effect of an alkali to obtain N-(pyrazine-2-ylcarboxyl)-L-cyclohexyl glycinate, wherein the pH value of a reaction liquid is 9-10; and after the reaction finished, adding an acid until the pH value of the solution is 3-4 to obtain the N-(pyrazine-2-ylcarboxyl)-L-cyclohexyl glycine. The pyrazine-2-formyl chloride is prepared by carrying out an acylation reaction to pyrazine-2-formic acid and thionyl chloride or oxalyl chloride. The preparation method of the N-(pyrazine-2-ylcarboxyl)-L-cyclohexyl glycine only includes two steps and is more than 85% in total yield. Compared with a method employing a condensating agent in the prior art, the raw materials in the preparation method is easy to obtain. The method is low in cost and can greatly reduce a production cost in large-scale production.

Description

Technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of telaprevir intermediates and salts thereof. Background technique [0002] Telaprevir (Telaprevir) is a new type of hepatitis C protease inhibitor developed by Vertex Pharmaceuticals Co., Ltd. (VERTEXPHARMS). The drug is an oral tablet that is combined with polyethylene glycol interferon alpha and ribavirin. Combined use, can effectively inhibit the replication of HCV virus (hepatitis C virus), suitable for hepatitis C type I patients. Its chemical name is (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-(cyclohexyl-2-[(pyrazine-2-carbonyl)amino]-acetyl}amino )-3,3-Dimethylbutyryl]-N-[(3S)-1-(cyclopropylamino)-1,2-dicarbonyl-3-propyl]-3,3a,4,5, 6,6a-hexahydro-1-H-cyclopenta[c]pyrrole-1-carboxamide. Approved by the FDA on May 23, 2011, and its trade name is Incivek. [0003] Trapevir is a tetrapeptide composed of five parts connected by amide bonds. Patent WO2011103932 reports the ...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 薛燕王哲烽益兵王圣利韩璐时惠麟
Owner SHANGHAI INST OF PHARMA IND
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