Resolution method and intermediate of cis-1-hydroxy-[1,1′-bis(cyclohexyl)]-2-carboxylic acid

A hydroxyl and formic acid technology, applied in the separation/purification of carboxylic acid compounds, chemical instruments and methods, preparation of carboxylate salts, etc., can solve the problem of expensive resolving agents, low quinine resolution yield, and inconsistent with green chemistry and other problems, to achieve the effect of low process cost and low price

Active Publication Date: 2020-11-03
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The resolving agent that this route uses is more expensive and quinine resolution yield is not high (14.1%); Need high pressure and adopt heavy metal rhodium to make catalyst in the hydrogenation benzene ring step, do not meet the idea of ​​"green chemistry"

Method used

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  • Resolution method and intermediate of cis-1-hydroxy-[1,1′-bis(cyclohexyl)]-2-carboxylic acid
  • Resolution method and intermediate of cis-1-hydroxy-[1,1′-bis(cyclohexyl)]-2-carboxylic acid
  • Resolution method and intermediate of cis-1-hydroxy-[1,1′-bis(cyclohexyl)]-2-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Dissolve compound I (15g, 0.066mol) in 75ml of absolute ethanol, stir and heat to 45°C, add S-(-)-α-phenylethylamine (8.05g, 1eq) to it, continue stirring for 10min, and slowly cool down , a white solid was precipitated, stirred for 2h in an ice bath, filtered, and the filter cake was dried to obtain a white solid II-1 crude product (10.78g, 46.8%),

Embodiment 2

[0055] Dissolve compound I (15g, 0.066mol) in 75ml of absolute ethanol, stir and heat to 45°C, add S-(-)-α-phenylethylamine (6.44g, 0.8eq) to it, continue stirring for 10min, slowly After cooling down, a white solid precipitated, stirred in an ice bath for 2 h, filtered, and the filter cake was dried to obtain a crude white solid II-1 (9.72 g, 42.2%).

Embodiment 3

[0057] Dissolve compound I (15g, 0.066mol) in 75ml of absolute ethanol, stir and heat to 45°C, add S-(-)-α-phenylethylamine (8.85g, 1.1eq) to it, continue stirring for 10min, slowly After cooling down, a white solid precipitated, stirred in an ice bath for 2 h, filtered, and the filter cake was dried to obtain a crude white solid II-1 (10.32 g, 44.0%).

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Abstract

The invention discloses a method for splitting cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and an intermediate. The method is characterized in that S-(-)-alpha-phenylethylamine or R-(+)-alpha-phenylethylamine is taken as a splitting agent for splitting the cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid to obtain S-(-)-alpha-phenylethylamine salt of (1S, 2S)-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and R-(+)-alpha phenylethylamine salt of (1R, 2R)-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid; high-pressure hydrogenation of a benzene ring and catalyzation of precious metal are avoided in the conventional preparation of rociverine single isomer. The S-(-)-alpha-phenylethylamine salt and the R-(+)-alpha phenylethylamine salt have the advantages of low cost, low process cost, environmental friendliness and suitability for industrial production.

Description

technical field [0001] The invention relates to a resolution method and an intermediate of cis-1-hydroxyl-[1,1'-bis(cyclohexyl)]-2-carboxylic acid. Background technique [0002] Rociverine is an M-cholinergic receptor antagonist developed by Laboratori Guidotti S.p.A., a subsidiary of Italy's Menarini Group. It is mainly used clinically to treat gastrointestinal muscle spasm Acute and subacute abdominal pain, spasmolysis and analgesia of genitourinary tract and biliary tract, dynamic dystocia, etc. Rosiverine is marketed as a racemate, comprising four stereoisomers with the hydroxyl and ester groups in cis. In order to meet the requirements for drug application and registration, the ratio and configuration of each stereoisomer need to be confirmed. The synthesis and preparation of a single isomer of rosivirine will provide a reference for the quality research of rosivirine stereoisomer components. [0003] Cis-1-hydroxyl-[1,1'-bis(cyclohexyl)]-2-carboxylic acid is the race...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/02C07C51/42C07C51/41C07C62/06C07C209/00C07C211/27
CPCC07C51/02C07C51/412C07C51/42C07C62/06C07C209/00C07C211/27
Inventor 杜贵郭晔堃韩强毕增钟静芬
Owner SHANGHAI INST OF PHARMA IND CO LTD
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