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New method for synthesizing Ledipasvir chiral intermediate

A technology for chiral intermediates and synthesis methods, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of complex drug structure, single synthesis route, and increased synthesis cost, and achieves simple process, high yield, and production cycle. short effect

Active Publication Date: 2016-10-12
CHENGDU BAISHIXING SCI & TECH IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] As the first specific new drug for oral treatment of hepatitis C, ledipasvir has a complex drug structure and a relatively simple synthesis route. It is used in industrial production, and the total yield is relatively low, which greatly increases the cost of synthesis

Method used

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  • New method for synthesizing Ledipasvir chiral intermediate
  • New method for synthesizing Ledipasvir chiral intermediate
  • New method for synthesizing Ledipasvir chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: A new method for synthesizing the chiral intermediate of Ledipavir as S-5-azaspirocyclo[2,4]heptane-6-carboxylic acid

[0053] The specific synthesis method includes the following steps:

[0054] S1. A compound of formula A is prepared by ring closure of 1,1-dihalomethylcyclopropane and N-Boc-glycine ethyl ester in a basic reaction solvent; wherein, the reaction solvent is an amide solvent; the base It is potassium alkoxide; the reaction temperature is -10℃;

[0055] S2. The compound of formula A is saponified and hydrolyzed, and the BOC protection is removed to obtain 5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate; the saponification and hydrolysis is carried out in an alkaline solvent. The solvent is alcohols, the alkali is sodium hydroxide; the acid used for the BOC deprotection is hydrochloric acid; the reaction temperature is 0°C;

[0056] S3.5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate was asymmetrically resolved to prepare S-5-azaspirocyclo[...

Embodiment 2

[0057] Example 2: A new method for synthesizing the chiral intermediate of Ledipavir as S-5-azaspirocyclo[2,4]heptane-6-carboxylic acid

[0058] The specific synthesis method includes the following steps:

[0059] S1. Ring-closure of 1,1-dihalomethylcyclopropane and N-Boc-glycine ethyl ester in a basic reaction solvent to prepare a compound of formula A; wherein, the reaction solvent is an ether solvent; the base It is sodium alkoxide; the reaction temperature is 100℃;

[0060] S2. The compound of formula A is saponified and hydrolyzed, and the BOC protection is removed to obtain 5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate; the saponification and hydrolysis is carried out in an alkaline solvent. The solvent is ethers, the alkali is potassium hydroxide; the acid used in the de-BOC protection is sulfuric acid; the reaction temperature is 100°C;

[0061] S3.5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate was asymmetrically resolved to prepare S-5-azaspirocyclo[2,4]hept...

Embodiment 3

[0062] Example 3: A new method for synthesizing the chiral intermediate of Ledipavir as S-5-azaspirocyclo[2,4]heptane-6-carboxylic acid

[0063] The specific synthesis method includes the following steps:

[0064] S1. A compound of formula A is prepared by ring closure of 1,1-dihalomethylcyclopropane and N-Boc-glycine ethyl ester in a basic reaction solvent; wherein, the reaction solvent is an amide solvent; the base It is sodium hydride; the reaction temperature is 45°C;

[0065] S2. The compound of formula A is saponified and hydrolyzed, and the BOC protection is removed to obtain 5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate; the saponification and hydrolysis is carried out in an alkaline solvent. The solvent is alcohols, the alkali is strong sodium oxide; the acid used for the BOC protection is phosphoric acid; the reaction temperature is 38°C;

[0066] S3.5-azaspirocyclo[2,4]heptane-6-carboxylic acid racemate was asymmetrically resolved to prepare S-5-azaspirocyclo[2,4]...

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Abstract

The invention discloses a new method for synthesizing a Ledipasvir chiral intermediate. The specific synthetic method includes the following steps that 1,1-dihalo-methyl cyclopropane and N-Boc-glycine ethyl ester are subjected to cyclization in an alkaline environment, and a spiro-compound is obtained; the spiro-compound is subjected to saponification hydrolysis and BOC deprotection, and a 5-diazaspiro[2,4]heptane-6-carboxylic acid raceme is obtained; the 5-diazaspiro[2,4]heptane-6-carboxylic acid raceme is subjected to asymmetric resolution, and S-5-diazaspiro[2,4]heptane-6-carboxylic acid is obtained. By means of the new method for synthesizing the Ledipasvir chiral intermediate, the atom economy is improved, the production cost is reduced, synthesis is easy, preparation is convenient, and large-scale industrial production is promoted.

Description

Technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a new method for synthesizing a chiral intermediate of Ledipavir. Background technique [0002] Ledipasvir (Ledipasvir), formerly known as GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. After the completion of the Phase III clinical trial of Redituvir, a fixed-dose combination tablet of Redipavir / Sofosbuvir for the treatment of genotype 1 hepatitis C was included in the United States Pharmacopoeia on February 10, 2014. On October 10, 2014, the combination product Reditevir / Sofosbuvir was approved by the U.S. FDA under the trade name Harvoni. Radipavir is the world's first drug approved for the full oral treatment of hepatitis C, eliminating the need for traditional injectable interferon (IFN). The mechanism of action of Ledipasvir is to block the replication of viral RNA to treat hepatitis C by inhibiting NS5A protein. [0003] Ledipasv...

Claims

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Application Information

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IPC IPC(8): C07D209/54
CPCC07D209/54Y02P20/55
Inventor 石常青
Owner CHENGDU BAISHIXING SCI & TECH IND
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