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Process for preparing (R)-(-)-2-fluo-alpha-methyl-[1-1'-diphenyl]-4-acetic acid from decomposed mother liquid of (S)-(+)-2-fluo-alpha-methyl-[1-1'-diphenyl]-4-acetic acid

A technology of diphenyl and separating mother liquor is applied in the preparation of separation mother liquor from (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid In the field of (R)-(-)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid, it can solve the problems of enhanced gastrointestinal toxicity and lack of cyclooxygenase inhibitory activity. Achieve the effect of complete separation, high yield and simple method

Inactive Publication Date: 2005-02-02
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Brune, K. et al (Brune, K., et al, Experientia, 1991, 47 , 257) found that the anti-inflammatory activity of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid mainly comes from its (S)-enantiomer, while the (R)-enantiomer Lacks significant cyclooxygenase inhibitory activity; moreover, the gastrointestinal toxicity of the (S)-enantiomer is greatly enhanced by the presence of the (R)-enantiomer (Wechter, W.J., et al, Chirality, 1993, 5 , 492)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1: Preparation of (R)-enantioexcess of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid

[0017] Get the resolution mother liquor 1500ml of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid in Example 1 described in Patent Application No. CN 011 13303.1 , and evaporate the solvent to dryness under reduced pressure to obtain 65 g of a light yellow solid, add 650 ml of 2N sulfuric acid aqueous solution and 430 ml of ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange, extract the aqueous solution with ethyl acetate, combine the ethyl acetate extracts, wash with water to neutrality, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-enantio-excess 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid 54.9 g(225mmol)([α] D 20 =-29.3° (c=1, EtOH)), the ee value was 0.66.

Embodiment 2

[0018] Example 2: Preparation of (R)-enantioexcess of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid

[0019]Get (S)-( +)-2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid resolution mother liquor 210ml, evaporate the solvent under reduced pressure to obtain 32.8g light yellow solid, add 330ml 2N sulfuric acid aqueous solution and 220ml of ethyl acetate, stirred to dissolve the solid, and carried out liquid-liquid exchange, and then extracted the aqueous solution with ethyl acetate, combined the ethyl acetate extracts, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, 28.1 g (115 mmol) ([α] D 20 =-19.1° (c=1, EtOH)), the ee value was 0.42.

Embodiment 3

[0020] Example 3: Preparation of (R)-enantioexcess of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid

[0021] According to the resolution mother liquor of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid in Example 8.1 described in U-S.Pat.No.5,599,969 200ml, evaporate the solvent under reduced pressure to obtain 44.6g of light yellow solid, add 450ml of 2N sulfuric acid aqueous solution and 300ml of ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange, extract the aqueous solution with ethyl acetate, and combine the ethyl acetate extracts , washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (R)-enantiotropic 2-fluoro-α-methyl-[1,1′-diphenyl]-4- Acetic acid 38.8g (159mmol) ([α] D 20 =-18.8° (c=1, EtOH)), the ee value was 0.41.

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Abstract

A process for preparing (R)-(-)-2-fluoro-alpha-methyl-[1,1'-diphenyl]-4- acetic acid includes acid treatment of hydrolysis of the decomposed mother liquid of (S)-(+)-2-fluoro-alpha-methyl-[1,1'-diphenyl]-4- acetic acid to obtain free acid, reaction with (1S, 2R)-threo-1-R-substituent phenyl serine R ester to generate diastereoisomeric salt, crystallizing purification to obtain optical-purity salt of (R)-antimer, and acid treatment or hydrolysis to obtain (R)-(-)-2-fluoro-alpha-methyl-[1,1'-diphenyl]-4- actic acid. Its advantages include high output rate and full decomposition.

Description

technical field [0001] The present invention relates to a preparation of (R)-(-)- 2-Fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid method. Further speaking, it is a kind of separation mother liquor of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid is converted into free acid, and then react with a resolving agent (optical pure amine) to generate diastereomeric salts, which are crystallized and purified to obtain optically pure (R)-enantiomer salts, which are converted into (R)- by acid treatment or hydrolysis A convenient method for (-)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid. Background technique [0002] 2-Fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid is a non-steroidal anti-inflammatory drug, its mechanism of action is to inhibit the cyclooxygenase system, which can reduce inflammation and relieve pain. For the treatment of rheumatic diseases, the racemate is currently marketed and clinically applied. [0003] The racemate contains a pair of enantiomer...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/42C07C57/58
Inventor 林国强骆宏丰夏立钧
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI