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A kind of preparation method of telaprevir intermediate

A technology of telaprevir and intermediates, which is applied in the field of preparation of telaprevir intermediates, can solve the problems of long routes, expensive reagents and high costs, and achieve the effects of high optical purity, cheap reagents and easy operation

Inactive Publication Date: 2016-04-27
HUNAN KEYUAN BIO PRODS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The reagents used in the patent US2005197301 method for synthesizing telaprevir intermediates are expensive and costly, and the yield is low, so it is not suitable for industrial production
Although the method of the patent US2010292219 has a high yield, sec-butyllithium is used in the reaction process, the reaction needs to be isolated from the air, the reaction is not easy to control, the cost is high, and another auxiliary agent is needed to synthesize, the process is more troublesome
[0008] In summary, the existing preparation methods of Cyclopenta[c]pyrrole-1-carboxylic acid, octahydro-, ethylenester, (1S, 3aR, 6aS)-, hydrochloride have disadvantages such as long route, low yield, and difficult reaction control. , not suitable for industrial production

Method used

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  • A kind of preparation method of telaprevir intermediate

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Embodiment

[0045] The preparation method of the telaprevir intermediate of the present embodiment comprises the following steps:

[0046] (1) Synthesis of (3aR,6aS)-1,3a,4,5,6,6a-hexahydrocyclopentapyrrole

[0047] Add 1500g of 10wt% sodium hypochlorite solution to a 10L reaction flask, then add 1200mL of MTBE, stir well, add (3aR, 6aS) octahydrocyclopentapyrrole 200g (1.33mol), control the temperature at 15±1°C, and react for 2.0 hours , get the reaction solution;

[0048] Then add 10g tetrabutylammonium bromide to the reaction flask, 1000g mass concentration is 25% NaOH aqueous solution, then add the resulting reaction solution, stir and react at 35°C for 12 hours, static layering, then extract 3 times with MTBE, combine MTBE layer;

[0049] (2) Synthesis of (3aR,6aS)-octahydrocyclopentapyrrole-1-sodium sulfate

[0050] In the reaction flask, add 800mL of water, then add 140g of NaHSO 3 , then add the MTBE layer obtained in step (1), react at 20±1°C for 2.0 hours, static layering, ...

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Abstract

The invention provides a telaprevir intermediate preparation method. The telaprevir intermediate preparation method comprises the following steps: (1) synthesizing (3aR, 6aS)-1,3a,4,5,6,6a-hexahydrocyclopentapyrrol; (2) synthesizing (3aR, 6aS)-octahydrocyclopentapyrrol-1-sodium sulfate; (3) synthesizing (3aR, 6aS)- octahydrocyclopentapyrrol-1-cyanogen; (4) synthesizing (3aR, 6aS)- octahydrocyclopentapyrrol-1-carboxylic acid; (5) synthesizing (3aR, 6aS)-2-Boc octahydrocyclopentapyrrol-1-carboxylic acid; (6) synthesizing (1s, 3aR, 6aS)-2-Boc octahydrocyclopentapyrrol-1-carboxylic acid; (7) synthesizing (1s, 3aR, 6aS)-2-Boc octahydrocyclopentapyrrol-1-carboxylic acid ethyl ester salt. The telaprevir intermediate preparation method is reasonable in process, low in cost and simple and convenient to operate, reagents are inexpensive and easy to obtain, and the control on reaction is easy.

Description

technical field [0001] The invention relates to a preparation method of a telaprevir intermediate. Background technique [0002] Telaprevir (Telaprevir, structural formula shown below) has three chiral centers, chemical name (1S,3aR,6aS)-2-((S)-2-((S)-2--2-( pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-octahydrocyclopenta[c]pyrrole-1-carboxamide( telaprevir). Telaprevir (VX-950) is a new drug developed by Vertex Pharmaceuticals of the United States for the treatment of hepatitis C. It was approved by the FDA on May 23, 2011, and its trade name is Incivek. The drug is an oral tablet, which is a reversible protease inhibitor, used in combination with pegylated α-interferon and ribavirin, can effectively inhibit the replication of HVC virus, and is used for chronic hepatitis C. It has a good clinical application prospect. [0003] Its structural formula: [0004] . [0005] The synthesis of the side chain Cyclo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 蔡春林
Owner HUNAN KEYUAN BIO PRODS
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