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New synthesis method of telaprevir intermediate

A new method and compound technology are applied in the field of synthetic technology for the preparation of telaprevir key intermediates, which can solve the problems of unstable intermediates, long synthetic routes, and high production costs, and achieve increased yields, reduced production costs, and elimination of Effects of Toxic and Hazardous Agents

Active Publication Date: 2015-11-25
CHONGQING HUIZHI PHARMA RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0030] The present invention mainly solves the problems of long synthetic route of existing (3S)-3-amino-2-hydroxy-N-cyclopropylhexanamide, high production cost, unstable intermediates, high toxicity of reagents, etc.

Method used

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  • New synthesis method of telaprevir intermediate
  • New synthesis method of telaprevir intermediate
  • New synthesis method of telaprevir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Ethyl 2-chloro-3-oxohexanoate (compound 2):

[0069] Add 15.8g (100mmol) of ethyl butyroacetate and 200ml of dichloromethane into the reaction flask, cool down to 0-10°C, add 16.2g (120mmol) of sulfuryl chloride dropwise, raise to room temperature after the addition, keep the reaction for 4h, TLC Monitor the complete conversion of reactants to products (developing solvent: ethyl acetate: n-hexane = 1:3). After the reaction is complete, cool down to about 0°C, add 150mL of 1MK 3 PO 4 Aqueous solution, separated into several layers, the aqueous layer was extracted twice by adding 50ml of dichloromethane, the organic layers were combined, washed with water until neutral, dried with 20g of anhydrous magnesium sulfate, filtered off the desiccant, and concentrated under reduced pressure until no slip-outs were obtained. 19.2 g of oily matter, yield 100%, was directly used in the next step reaction without refining. ESI-MS(m / z):193[M+1] + .

[0070] Synthesis of 1-ethoxy-...

Embodiment 2

[0085] Ethyl 2-chloro-3-oxohexanoate (compound 2):

[0086] Add 15.8g (100mmol) of ethyl butyroacetate and 100ml of methyl tert-butyl ether into the reaction flask, cool down to 0-10°C, and dissolve 14.6g (110mmol) of N-chlorosuccinimide in 100ml of methyl In tert-butyl ether, add dropwise to the above reaction solution, keep the temperature for 6 hours after the addition, and monitor the complete conversion of the reactant into the product by TLC (developer: ethyl acetate: n-hexane = 1:3). After the reaction is complete, cool down to about 0°C, add 70mL of 1MK 3 PO 4 Aqueous solution, separate the organic layer, add 50ml of methyl tert-butyl ether to the aqueous layer to extract twice, combine the organic layers, wash with water until neutral, dry with 20g of anhydrous magnesium sulfate, filter off the desiccant, concentrate under reduced pressure until there is no slip-out , to obtain 18.6g of oily substance, yield 97%, directly used for next step reaction without refining...

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Abstract

The invention discloses a method for preparing (3S)-3-amino-2-hydroxyl-N-cyclopropylhexanamide. The compound can be used as an important intermediate for preparing telaprevir. According to the invention, ethyl butyrylacetate is used as a starting raw material, and through steps of helogenation, substitution, amination, reduction, hydrolysis, deprotection, resolution and the like, (3S)-3-amino-2-hydroxyl-N-cyclopropylhexanamide is prepared. The method provided by the invention has advantages as follows: raw materials are cheap and easily available; reaction yield is high; and costs are high.

Description

technical field [0001] The invention relates to pharmaceutical chemical technology, more specifically to a synthesis process for preparing telaprevir key intermediates. Background technique [0002] Telaprevir (telaprevir), the chemical name is (1S,3aR,6aS)-(2S)-2-cyclohexyl-N-(pyrazinecarbonyl)glycyl-3-methyl-L-valyl -N-[(1S)-1-[(cyclopropylamino)oxyacetyl]butyl]octahydrocyclopenta[c]pyrrole-1-carboxamide is a new type of hepatitis C protease inhibitor developed by VertexPharms in the United States On May 23, 2011, the FDA officially approved the listing of tiraprevir. [0003] Chinese common name: Teraprevir [0004] English common name: Telaprevir [0005] Product name: Incivek [0006] Alias: LY-570310; MP-424; VX-950; [0007] CAS number: 402957-28-2 [0008] Molecular formula: C 36 h 53 N 7 o 6 [0009] Molecular weight: 679.8 [0010] Structural formula: [0011] [0012] English name: (3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- [0013] carbo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/04C07C231/12
Inventor 李子清
Owner CHONGQING HUIZHI PHARMA RES INST
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