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Method for preparing (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylate or salt thereof

A technology of octahydrocyclopentene and carboxylate, which is applied in the field of preparing octahydrocyclopenta[c]pyrrole-1-carboxylate or its salt, and can solve the problem that it is not suitable for industrial production requirements and cannot be purchased in batches , Difficult synthesis of starting materials and other issues, to achieve strong practical value, simple operation, and less environmental pollution

Inactive Publication Date: 2014-06-18
SHANGHAI DESANO CHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Since the starting material of this route is difficult to synthesize and cannot be purchased in batches, it is not suitable for industrial production requirements

Method used

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  • Method for preparing (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylate or salt thereof
  • Method for preparing (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylate or salt thereof
  • Method for preparing (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylate or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: preparation formula IV compound

[0042]

[0043] Sodium hydroxide (31g, 0.77mol) was dissolved in 350mL water, cooled to -10~0°C, and K 2 S 2 o 8 (70.7g, 0.26mol), 70mL acetonitrile and compound of formula V (35g, 0.24mol), react at -10~0℃ for 1~3 hours; add AgNO 3 (2.0g, 0.012mol), reacted at -5~0°C for 2~5h; ended the reaction, extracted three times with methyl tert-butyl ether (100mL×3); filtered, concentrated the filtrate under reduced pressure to obtain the compound of formula IV and 32 g of the mixed solution of methyl tert-butyl ether, and the GC content is 90.3%.

Embodiment 2

[0044] Embodiment 2: preparation formula III compound

[0045]

[0046] Dissolve 32 g of the mixed solution of the compound of formula IV prepared in Example 1 and methyl tert-butyl ether in 100 mL of absolute ethanol, and add trimethylsilyl cyanide (26.2 g, 0.26 mol ), followed by dropwise addition of 47% boron trifluoride diethyl ether solution (27.04g, 0.13mol), after the dropwise addition, keep warm at -10-0°C for 5-10 hours; to complete the reaction, add 80mL of methanol, filter, and concentrate under reduced pressure The filtrate obtained 31.5 g of the compound of formula III, and the molar yield was 89.3%.

Embodiment 3

[0047] Embodiment 3: preparation formula II compound

[0048]

[0049] Add 186g of HCl-EtOH solution (wherein the content of HCl is 28.8wt%) dropwise to 31.5g of the compound of formula III prepared in Example 2, after the dropwise addition is completed, rise to room temperature and react overnight at room temperature; add triethylamine dropwise Adjust the pH value to 8-9, and then concentrate the ethanol to dryness under reduced pressure; add 100mL water to the concentrated residue, extract three times with ethyl acetate (100mL×3), separate the liquids, dry the organic phase with anhydrous sodium sulfate, and filter , and concentrated the filtrate under reduced pressure to obtain 36.2 g of the compound of formula II, with a molar yield of 85.2%.

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Abstract

The invention discloses a method for preparing (1S,3aR,6aS)-octahydro-cyclopenta[c]pyrrole-1-carboxylate or a salt thereof. The method comprises the following reactions: a, under the action of an oxidizing agent, allowing a compound represented by a formula V to undergo an oxidation reaction, and thus obtaining a compound represented by a formula IV; b, under the action of a cyanating reagent, allowing the compound represented by the formula IV to undergo a cyanation reaction, and thus obtaining a compound represented by a formula III; c, hydrolyzing the compound represented by the formula III with an acid-alkyl alcohol solution, and thus obtaining a compound represented by a formula II; and d, carrying out resolution of the compound represented by the formula II, and thus obtaining the optical-pure compound represented by a formula I or the salt thereof. The method comprises the following specific reaction route as shown in the description, wherein R is selected from C1-C4 alkyl. By adopting the method of the invention, the purpose that the high-purity target is synthesized by utilization of cheap and easily available raw materials and with low cost and simple operation is achieved, and the method not only has high yield, but also has small environmental pollution, moreover, has no special requirements on equipment, is quite suitable for large-scale production, and has an extremely strong practical value for realization of industrialization of telaprevir.

Description

technical field [0001] The invention relates to a method for preparing (1S, 3aR, 6aS) octahydrocyclopenta[c]pyrrole-1-carboxylate or a salt thereof, and belongs to the technical field of chemical drug synthesis. Background technique [0002] Telaprevir is an HCV direct protease inhibitor for the treatment of genotype 1 chronic hepatitis C. Compared with other HCV protease inhibitors, telaprevir combined with PEGylated interferon α or ribavirin can significantly improve the cure rate of hepatitis C patients and shorten the course of treatment. The specific chemical structural formula of telaprevir is as follows: [0003] [0004] (1S,3aR,6aS)octahydrocyclopenta[c]pyrrole-1-carboxylate or its salt is one of the key intermediates for synthesizing telaprevir at present, (1S,3aR,6aS)octahydrocyclone The chemical structural formula of penteno[c]pyrrole-1-carboxylate is shown below: [0005] where R is selected from C 1 ~C 4 Alkyl, such as methyl, ethyl, tert-butyl, etc.;...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 李金亮赵楠葛瑞娟
Owner SHANGHAI DESANO CHEM PHARMA
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