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Preparation method of ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid

A technology of azabicyclo, -2-boc-2-, applied to ledipasvir intermediate (1R,3S,4S)‑2‑Boc‑2‑azabicyclo[2.2.1]pentane‑3 ‑The field of carboxylic acid preparation can solve the problems of low selectivity of the target product, large amount of Lewis acid used, and complicated post-treatment process, and achieve good industrialization prospects, easy separation and purification, and reduced hazards to personnel and the environment

Active Publication Date: 2016-11-16
启东东岳药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The above preparation methods all have the disadvantages of expensive chiral raw materials, a large amount of Lewis acid in the substrate-controlled asymmetric addition, complex post-treatment process and a lot of waste water, low selectivity of the target product and difficult separation.

Method used

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  • Preparation method of ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid
  • Preparation method of ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid
  • Preparation method of ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0031] In a dry round bottom flask, add 20 milliliters of anhydrous toluene, 5.0 g (53.8 mmol) of benzylamine and 11 g (53.8 mmol) of ethyl glyoxylate in toluene (mass content 50%), and the resulting reaction solution is stirred at room temperature After 30 minutes. 0.5% equivalent of catalyst and 1% equivalent of chiral ligand were added, the resulting mixture was cooled to -78 °C, and 4.3 g (64.6 mmol) of freshly distilled cyclopentadiene was added at this temperature, and the resulting reaction mixture was The reaction was continued for 5 hours, and the chromatographic analysis of the imine reaction was complete. 20 ml of saturated sodium bicarbonate solution was added to the reaction solution, the organic phase was separated, the aqueous phase was extracted once with toluene, the toluene phase was combined, and the toluene phase was dried over anhydrous sodium sulfate. After filtration, the ethyl acetate solution of hydrogen chloride was added dropwise to the filtrate unti...

Embodiment 2

[0033] In a dry round-bottomed flask, add 20 milliliters of anhydrous THF, 5.0 g (53.8 mmol) of benzylamine and 11 g (53.8 mmol) of ethyl glyoxylate in toluene (50% by mass), and stir the resulting reaction solution at room temperature After 30 minutes. 0.5% equivalent of catalyst and 1% equivalent of chiral ligand were added, the resulting mixture was cooled to -78 °C, and 4.3 g (64.6 mmol) of freshly distilled cyclopentadiene was added at this temperature, and the resulting reaction mixture was The reaction was continued for 5 hours, and the chromatographic analysis of the imine reaction was complete. 20 milliliters of saturated sodium bicarbonate solution was added to the reaction solution, and the reaction mixture was extracted twice with ether, and the ether phase was combined. The ether phase was dried over anhydrous sodium sulfate and filtered, and the filtrate Hydrogen chloride in ethyl acetate solution was added dropwise until no solid precipitated, filtered, and the ...

Embodiment 3

[0035] In a dry round-bottomed flask, add 20 milliliters of anhydrous dichloromethane, 5.0 g (53.8 mmol) benzylamine and 11 g (53.8 mmol) ethyl glyoxylate in toluene (mass content 50%), the resulting reaction solution in After stirring at room temperature for 30 minutes. 0.5% equivalent of catalyst and 1% equivalent of chiral ligand were added, the resulting mixture was cooled to -78 °C, and 4.3 g (64.6 mmol) of freshly distilled cyclopentadiene was added at this temperature, and the resulting reaction mixture was The reaction was continued for 5 hours, and the chromatographic analysis of the imine reaction was complete. Add 20 ml of saturated sodium bicarbonate solution to the reaction solution, separate the organic phase, extract the aqueous phase once with dichloromethane, combine the dichloromethane phase, dry the dichloromethane phase over anhydrous sodium sulfate, filter and concentrate to dryness under reduced pressure Get crude products. The crude product was dissolv...

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Abstract

The invention discloses a preparation method of a ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid. Benzylamine and glyoxylic ester are adopted as raw materials, under the effect of a chiral catalyst, the raw materials react with cyclopentadiene to generate (1S,3S,4R)-2-benzyl-2-azabicyalo [2,2,2] penta-5-alkene-3-carboxylic ethyl ester in a high-selective mode, the (1S,3S,4R)-2-benzyl-2-azabicyalo [2,2,2] penta-5-alkene-3-carboxylic ethyl ester is subjected to debenzylation and Boc protection and then hydrolyzed to obtain ledipasvir intermediate (1R,3R,4R)-2-Boc-2-azabicyalo [2,2,1] pentane-3-carboxylic acid. The method is good in selectivity, easy to implement and environmentally friendly.

Description

technical field [0001] The invention relates to a preparation method of ledipasvir intermediate (1R, 3S, 4S)-2-Boc-2-azabicyclo[2.2.1]pentane-3-carboxylic acid. Background technique [0002] Ledipasvir, formerly known as GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. After completion of phase III clinical trials of ledipasvir, tablets for the treatment of genotype I hepatitis C fixed-dose combination of ledipasvir / sofosbuvir were included in the United States Pharmacopoeia on February 10, 2014. On October 10, 2014, the combination product Ledipasvir / Sofolbuvir was approved by the US FDA, and the trade name is "Harvoni" (Haveni). Redipasvir blocks the replication of viral RNA by inhibiting the NS5A protease. Since December 6, 2014, the new hepatitis C treatment drug SOVALDI (sofosbuvir) was launched in the United States and raised the cure rate of hepatitis C to over 90%, creating a new era of hepatitis C treatment. Since then, Gilead Sciences has mad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 滕大为黄龙江张文文张晴晴龙中柱蔡水洪
Owner 启东东岳药业有限公司
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