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Prepn of 2-(3-benzoylphenyl) propionic acid enantiomer

A technology of benzoylphenyl and propionic acid, which is applied in the field of preparation of enantiomers of 2-(3-benzoylphenyl)propionic acid, can solve the problem of lack of cyclooxygenase inhibitory activity and different pharmacological activities and other problems, to achieve the effect of complete split, low cost and high yield

Inactive Publication Date: 2004-08-18
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

[0003] The racemate contains a pair of enantiomers of 2-(3-benzoylphenyl)propionic acid, but its pharmacological activity is not the same, Brune, K. et al. (Brune, K, et a1, Experientia, 1991, 47 , 257) found that the anti-inflammatory activity of 2-(3-benzoylphenyl)propionic acid was mainly derived from its (S)-enantiomer, while the (R)-enantiomer lacked significant cyclooxygenase inhibitory activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Preparation of (S)-(+)-2-(3-benzoylphenyl)propionic acid

[0018] Take 100g (394mmol) of the racemate of 2-(3-benzoylphenyl)propionic acid and 57.6g (197mmol) of (-)-1-deoxy-1-n-octylamino-D-glucitol and put it in Add 750ml of isopropanol to the reaction flask, and heat the oil bath to reflux for 15 minutes. After the reaction is over, a small amount of (S)-(+)-2-(3-benzoylphenyl)propionic acid and (-)-1-deoxy-1-n-octylamino-D-glucitol salt are added as Seed crystals stand for more than 10 hours at 5~10℃ to crystallize and filter to obtain 91.7g (168mmol) of white solid([α] D 20 = -14.8° (c=1, MeOH)), the yield is 85.2%.

[0019] The above white solid was recrystallized twice at 5~10℃, salt / isopropanol was 1g / 7ml, 74g (135mmol) of white solid was obtained ([α] D 20 = -16.4° (c=1, MeOH)), the yield is 68.8%.

[0020] Take 74g (135mmol) of the solid obtained from the third crystallization, put it into a round bottom flask, add 740ml of 2N sulfuric acid aqueous so...

Embodiment 2

[0022]Example 2: Racemization

[0023] The filtrate obtained from the reaction and recrystallization in Example 1 was combined and concentrated under reduced pressure to obtain 83 g of light yellow solid, which was put into the reaction flask, 400 ml of 4N sodium hydroxide solution was added, and the oil bath was heated to reflux for 6 hours. After the reaction is over, cool to room temperature, add 140ml of concentrated hydrochloric acid and 300ml of ethyl acetate, stir to dissolve the solid, perform liquid-liquid exchange, and then extract the aqueous solution with ethyl acetate, combine the ethyl acetate extracts, wash with water, and dry with anhydrous sodium sulfate , Filtered, and the filtrate was concentrated under reduced pressure to obtain 62.7g of racemate ([α] D 20 =0°(c=1, CHCl 3 )), the yield is 95.6%.

Embodiment 3

[0024] Example 3: Preparation of (S)-(+)-2-(3-benzoylphenyl)propionic acid

[0025] Take 100g (394mmol) of the racemate of 2-(3-benzoylphenyl)propionic acid and 57.6g (197mmol) of (-)-1-deoxy-1-n-octylamino-D-glucitol and put it in Add 540ml of absolute ethanol to the reaction flask, and heat the oil bath to reflux for 15 minutes. After the reaction, add a small amount of seed crystals, stand at room temperature for more than 10 hours to crystallize, and filter to obtain 49.1 g (89.8 mmol) of white solid ([α] D 20 = -15.3° (c=1, MeOH)), the yield is 45.6%.

[0026] The obtained white solid 49.1g (89.8mmol) was put into a round bottom flask, 500ml 2N sulfuric acid aqueous solution was added, stirred for 2 hours, filtered, the solid was washed with a small amount of water and dried to obtain (S)-(+)-2-(3-benzyl) Acylphenyl) propionic acid 21.6g (85.0mmol) ([α] D 20 =+51.2°(c=1, CHCl 3 )), the ee value is 0.93, the yield is 43.2% (based on (S)-enantiomer), and the chemical purity i...

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Abstract

The preparation method of (S)-(+)-2-(3-benzoylphenyl) propanoicacid by utilizing racemate of 2-(3-benzoylphenyl) propanoicacid through chemical resolution process is characterized by that the recemate of 2-(3-benzoylphenyl) propanoicacide and alkylamino-D-glucose alcohol of (-)-1-deoxy-1-C1-15 are reacted to produce diastereomeric salt, then said diastenomeric salt is undergone the processes of crystallizing, purifying, acid treatment or hydrolysis, and converted into the invented (S)-(+)-2-(3-benzoylphenyl) propanoicacid. Said method is simple, high in yield, low in cost, complte in resolution and suitable for industrial production.

Description

Technical field [0001] The invention relates to a method for preparing optically pure (S)-(+)-2-(3-benzoylphenyl)propionic acid from the racemate of 2-(3-benzoylphenyl)propionic acid . Furthermore, it is a kind of reaction between 2-(3-benzoylphenyl)propionic acid racemate and optically pure amine of resolving agent to form diastereomeric salt, which is then purified by crystallization, acid treatment or hydrolysis to convert into ( S)-(+)-2-(3-benzoylphenyl)propionic acid is a simple method. Background technique [0002] 2-(3-Benzoylphenyl)propionic 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. It is used to treat rheumatic diseases. It is currently on the market and The clinical application is its racemate. [0003] The racemate contains a pair of enantiomers of 2-(3-benzoylphenyl) propionic acid, but its pharmacological activity is different. Brune, K. et al. (Bru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/347C07C51/42C07C59/84
CPCY02P20/582
Inventor 林国强骆宏丰夏立钧
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI