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Method for splitting cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and intermediate

A hydroxyl and formic acid technology, applied in the separation/purification of carboxylic acid compounds, chemical instruments and methods, preparation of carboxylate, etc., can solve the problem of low yield of quinine splitting, inconsistent with green chemistry, and expensive resolving agents And other issues

Active Publication Date: 2018-05-25
SHANGHAI INST OF PHARMA IND +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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  • Method for splitting cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and intermediate
  • Method for splitting cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and intermediate
  • Method for splitting cis-1-hydroxy-[1,1'-bi(cyclohexyl)]-2-formic acid and intermediate

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-phenethylamine (8.05g, 1eq) to it, continue stirring for 10min, and slowly cool down , A white solid precipitated, stirred for 2h in an ice bath, filtered, and dried the filter cake to obtain a crude white solid II-1 (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-phenethylamine (6.44g, 0.8eq) to it, continue to stir for 10min, slowly After cooling, a white solid precipitated out, stirred for 2h in an ice bath, filtered, and dried the filter cake to obtain a crude white solid II-1 (9.72g, 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-phenethylamine (8.85g, 1.1eq) to it, continue to stir for 10min, slowly After cooling down, a white solid precipitated, stirred for 2h in an ice bath, filtered, and dried the filter cake to obtain a crude white solid II-1 (10.32g, 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 intermediates of cis-1-hydroxy-[1,1'-bis(cyclohexyl)]-2-carboxylic acid. Background technique [0002] Rociverine is an M choline receptor antagonist developed by Laboratori Guidotti SpA, a subsidiary of Menarini Group in Italy. It is mainly used to treat gastrointestinal muscle spasm. Acute and subacute abdominal pain, urogenital and biliary tract spasmolysis, analgesia, dynamic dystocia, etc. Rosiverine is marketed as a racemate and contains four stereoisomers in which the hydroxyl group and the ester group are in cis. In order to meet the requirements of drug application and registration, it is necessary to confirm the ratio and configuration of each stereoisomer. The synthesis and preparation of a single isomer of rosiverin will provide a reference for the quality study of the stereoisomers of rosiverin. [0003] Cis-1-hydroxy-[1,1'-bis(cyclohexyl)]-2-carboxylic acid is the racemate of the key intermediat...

Claims

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Application Information

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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
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