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Process for preparing antimer of 2-fluo-alpha-methyl-[1,1'-diphenyl]-4-acetic acid

A diphenyl and methyl technology, applied in the separation/purification of carboxylic acid compounds, chemical recovery and other directions, can solve the problems of only 90-95% optical purity, very severe reaction conditions, and not allowed to obtain, etc., to achieve high yield High, simple method, complete effect of split

Inactive Publication Date: 2004-06-30
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

[0005] The method for preparing optically pure 2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid by chemical resolution has been reported in the following literature: Boots Co., Ltd. Heating the racemate of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid and the salt of a nitrogen-containing organic base (such as α-methylbenzylamine) can be obtained from the racemate However, in some examples, the reaction conditions are very severe, such as heating at reflux temperature for several days, and do not allow optically pure compounds to be obtained from racemates (U.S. Pat. No. 4,209,638) ; Medice Chem.-Pharm.Fabrik Putter Co., Ltd. uses D-(-)-threo-1-p-nitrophenyl-2-aminopropane-1,3-diol to prepare (S)-p enantiomer, but its optical purity is only 90-95% (U.S.Pat.No.4,973,745); PAZ Arzneimittel-Entwicklungsgesellschaft company uses phenylethylamine as a resolving agent from 2-fluoro-α-methyl-[1,1′- The (S)-enantiomer is obtained from the racemate of diphenyl]-4-acetic acid or a mixture of (S)- and (R)-enantiomers, although its optical purity is greater than 99%, but the yield is low At 50% (based on (S)-enantiomer) (U.S.Pat.No.4,983,765); Sepracor et al. used (1R, 2S)-cis-1-aminoindan-2-ol as a resolving agent to prepare ( S)-enantiomer, its optical purity is only 44.6% (U.S.Pat.No.5,677,469); Boots company makes (R)-enantiomer with (R)-alpha-methylbenzylamine as resolution agent, uses (S)-α-Methylbenzylamine was used as a resolving agent to obtain (S)-enantiomer (U.S.Pat.No.5,599,969); Zambon Group used (1S,2S)-threo-1-(4-methylthio Phenyl)-2-amine-1,3-propanediol was used as a resolving agent to obtain (S)-enantiomer (U.S.Pat.No.5,840,964); Lin Guoqiang et al. used N-octyl-D-glucosamine as a resolution Preparation (S)-enantiomer, ee value is 99%, yield rate is 66.8% (based on (S)-enantiomer) (CN01113303.1)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Example 1: Preparation of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid

[0019] Take 48.8g (200mmol) of the racemate of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid and (1R,2S)-threo-1-p-thiamphenylbenzene Put 28.7 g (100 mmol) of ethyl serine into a reaction flask, add 210 ml of absolute ethanol, and heat to reflux in an oil bath for 15 minutes. After the reaction was completed, it was allowed to stand at room temperature for more than 10 hours to crystallize, and filtered to obtain 44.5 g of a white solid. The white solid was recrystallized twice, salt / absolute ethanol was 1g / 8ml, and (S)-(+)-2-fluoro-α-methyl-[1,1′-diphenyl]-4- Acetic acid and (1R,2S)-threo-1-p-thiamphenylphenylserine ethyl ester salt 34.5g (65.0mmol), yield 65.0%.

[0020] Take 34.5g (65.0mmol) of salt, put it into a round bottom flask, add 350ml of 2N sulfuric acid aqueous solution and 230ml of ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange, extrac...

Embodiment 2

[0022] Example 2: Racemization

[0023] The filtrate obtained by combining the reaction and recrystallization in Example 1 was concentrated under reduced pressure to obtain 43 g of a light yellow solid, which was put into a reaction flask, 200 ml of 4N sodium hydroxide solution was added, and the mixture was heated to reflux in an oil bath for 6 hours. After the reaction, cool to room temperature, add 70ml concentrated hydrochloric acid and 150ml 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 until neutral, anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 32.2 g (132.0 mmol) of the racemate ([α] D 20 =0° (c=1, EtOH)), yield 97.8%.

Embodiment 3

[0024] Example 3: Preparation of (S)-(+)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid

[0025] Take 48.8g (200mmol) of the racemate of 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid and (1R,2S)-threo-1-p-thiamphenylbenzene Put 28.7 g (100 mmol) of ethyl serine into a reaction flask, add 210 ml of methanol, and heat to reflux in an oil bath for 15 minutes. After the reaction was completed, it was allowed to stand at room temperature for more than 10 hours to crystallize, and filtered to obtain 35.7 g (67.2 mmol) of a white solid, with a yield of 67.2%.

[0026] The resulting white solid 35.7g (67.2mmol) was put into a beaker, added 2150ml of water to dissolve, then added dropwise 710ml of 2N sulfuric acid aqueous solution under stirring, and stirred for 15 minutes after adding, filtered, and the solid was washed with a small amount of water until neutral. Dry to get (S)-(+)-2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid 15.9g (65.2mmol) ([α] D 20 =+41.0° (c=1, EtO...

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Abstract

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

Description

technical field [0001] The present invention relates to a method for the preparation of optically pure 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid from the racemate '-diphenyl]-4-acetic acid method. Furthermore, it is a diastereomeric salt formed by reacting 2-fluoro-α-methyl-[1,1′-diphenyl]-4-acetic acid racemate with a resolving agent (optical pure amine), After crystallization and purification, an optically pure salt of a certain enantiomer was obtained, which was converted into (S)-(+)-2-fluoro-α-methyl-[1,1′-diphenyl by acid treatment or hydrolysis ]-4-acetic acid or (R)-(-)-2-fluoro-α-methyl-[1,1'-diphenyl]-4-acetic acid is a convenient method. 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 clinicall...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/42C07C57/58
CPCY02P20/582
Inventor 林国强骆宏丰夏立钧
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI