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Method for preparing telaprevir intermediate

A compound and selected technology, applied in the field of medicine and chemical industry, can solve the problems of harsh process conditions, high production costs, and unavailable oxalate raw materials, and achieve the effects of easy industrialization, mild process conditions, and avoiding chiral raw materials

Inactive Publication Date: 2016-06-08
CHONGQING SHENGHUAXI PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0027] The invention mainly solves the problems of (1S,3aR,6aS)-octahydrocyclopenteno[C]pyrrole-1-carboxylic acid tert-butyl oxalate raw materials are not easily available, the process conditions are harsh, and the production cost is high.

Method used

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  • Method for preparing telaprevir intermediate
  • Method for preparing telaprevir intermediate
  • Method for preparing telaprevir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] 3-Azabicyclo[3,3,0]oct-2-ene (compound 2):

[0058] Add 14.76g (100mmol) of 3-azabicyclo[3.3.0]octane hydrochloride and 60ml of water into the reaction flask, stir to dissolve, cool down to -5~5°C, add 10.5g (105mmol) of 12% sodium hypochlorite dropwise , After the addition, keep the reaction for 4 hours, TLC monitors the complete conversion of the reactant to the product (developing solvent: ethyl acetate: n-hexane = 1:3). After the reaction is complete, add 50 mL of isopropyl ether and stir, separate the organic layer, add 30 mL of isopropyl ether to the water layer to extract twice, combine the organic layers, wash with water until neutral, dry with 20 g of anhydrous sodium sulfate, filter off the desiccant, and concentrate under reduced pressure Until there is no slip-out, 10.2 g of oily substance is obtained. Dissolve 4.7g of potassium hydroxide in 47ml of 95% ethanol (volume ratio), raise the temperature to about 80°C, dissolve the above oil in 102ml of 95% ethan...

Embodiment 2

[0069] 3-Azabicyclo[3,3,0]oct-2-ene (compound 2):

[0070] Add 14.76g (100mmol) of 3-azabicyclo[3.3.0]octane hydrochloride and 100ml of acetone into the reaction flask, stir to dissolve, cool down to -5~5℃, add N-chlorosuccinimide dropwise 14g (105mmol), keep the reaction for 2h after the addition, and monitor the complete conversion of the reactant to the product by TLC (developing solvent: ethyl acetate: n-hexane = 1:3). After the reaction is complete, spin off the acetone, add 50mL of isopropyl ether and 50ml of water, stir, separate the organic layer, add 30ml of isopropyl ether to the water layer to extract twice, combine the organic layers, wash with water until neutral, dry with 20g of anhydrous sodium sulfate, The desiccant was filtered off, and concentrated under reduced pressure until no slip-out material was obtained to obtain 10.2 g of an oily substance. Dissolve 3.4g of sodium hydroxide in 40ml of 90% methanol (volume ratio), heat up to about 60°C, dissolve the a...

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Abstract

The invention discloses a method for preparing (1S,3aR,6aS)-t-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate, wherein the compound can be used as an important intermediate for preparation of telaprevir. With 3-azabicyclo[3.3.0]octane hydrochloride as a starting raw material, and then the (1S,3aR,6aS)-t-butyl octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate is prepared through halogenation elimination, cyano addition, hydrolysis, resolution, esterification and salifying and other steps. The method has the advantages of cheap and easily obtained raw materials, high reaction yield, easy industrialization and the like.

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 telaprevir. [0003] Chinese common name: telaprevir; [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: C36H53N7O6 [0009] Molecular weight: 679.8 [0010] Structural formula: [0011] [0012] English name: (3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2- [0013] carboxamido)ace...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCY02P20/55
Inventor 李子清贾春荣
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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