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Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid

A technology of benzoyl and phenylpropionic acid, applied in chemical instruments and methods, preparation of carboxylate, preparation of organic compounds, etc., can solve the problems of high price, cost reduction, high production cost, and achieve pollution-free production environment , The effect of stable and reliable process and low production cost

Active Publication Date: 2013-04-10
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the enzyme preparation is very expensive and the production cost is too high, it cannot be applied in industrial production
[0007] 3. In the literature "Chemical Reagents, 28(5), 316-317; 2006", N-octyl-D-glucosamine was used as a resolving agent for diastereomeric crystallization resolution, and the single-round resolution rate was low , only 40%
[0008] 4. In Chinese patent CN1252035 (patent name: novel chiral amino acid derivatives and its synthesis method and application, patentee: Wenzhou Teachers College, date of authorization announcement: April 19, 2006), chiral amino acid derivatives are used as The resolving agent carries out inclusion resolution, and the resolving agent is very complicated and expensive, and the chiral purity value of the S-(+)-ketoprofen obtained from the resolution is not very high, and the highest value is only 97%.
[0009] 5. The chemical resolution method mentioned in the document "Organic Process Research & Development (Organic Process Research & Development), 6(3), 291-296; 2002", the resolution reagent used is (S)-3-methyl- 2-phenylbutylamine, although the resolving agent is simple, the price is also very expensive and the source is insufficient, and the cost needs to be further reduced
[0015] The problems in the method described in this patent are: the resolving agent is not easy to obtain and the price is high, and the resolving effect is uneven
[0016] In a word, for the resolution of (±)-2-(3-benzoyl)-phenylpropionic acid i.e. ketoprofen in the prior art, the resolution agent is expensive and the cost is high; Problems and deficiencies such as low separation purity, great pollution to the production environment, and difficulty in realizing industrialized production

Method used

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  • Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid
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  • Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] In a clean 250ml four-neck flask, put 20g of (±)-2-(3-benzoyl)-phenylpropionic acid and 200ml of isopropanol at room temperature, start stirring to make the solid dissolve transparently, stir for 10 minutes, and then Put in 21.2g VEP, 20ml of water, stir until a large amount of material (resolved salt) precipitates, keep warm for 4 hours, filter with suction, get about 30g of wet product, dry with hot air at 60-70°C, and get dry product: 19g, yield : 46% (you can directly vote for the next step without drying).

[0044] In order to improve the separation effect and separation purity, the obtained separation salt can be refined once or more times. According to the description of the content of the invention, the refining process can be carried out according to conventional methods.

Embodiment 2

[0046]In a clean 500ml four-necked flask, put 200g of 2N sulfuric acid, put 20g of S-(+)-2-(3-benzoyl)-phenylpropionic acid and (R)-3,4-dimethoxy -The diastereomeric salt of N-(1-phenylethyl)-benzylamine, i.e. the split salt (compound shown in formula IV), stirring makes it dissolve, after dissolving, add ethyl acetate 200ml for extraction, after extraction, The upper organic layer was washed with deionized water, static and separated, the water layers were combined to recover VEP, the organic layer was dried by adding sodium bicarbonate, filtered, rinsed with a small amount of ethyl acetate, the filtrate was decompressed to recover ethyl acetate to dryness, cooled and weighed to obtain S-(+)-2-(3-benzoyl)-phenylpropionic acid, namely S-(+)-ketoprofen 9.5 g, yield 98%. ee% = 99.9%

[0047] In summary, the present invention provides a new resolution method for (±)-2-(3-benzoyl)-phenylpropionic acid, which uses a method that has not been used in the past for (±)-2-( The resolu...

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Abstract

The invention provides a novel splitting method of (+ / -)-2-(3-benzoyl)-phenylpropionic acid, comprising the following steps of: making a splitting reagent of (R)-3,4-dimethoxy-N-(1-phenethyl)-benzene methanamine which is not used for splitting the (+ / -)-2-(3-benzoyl)-phenylpropionic acid formerly reacts with the (+ / -)-2-(3-benzoyl)-phenylpropionic acid to obtain diastereomeric salt; and dissociating by using acid to obtain S-(+)-2-(3-benzoyl)-phenylpropionic acid. The splitting agent is simple and easy to obtain and has cheap price, a splitting route ensures high yield, high splitting purity and stable and reliable technology and is easy to realize industrialized production.

Description

technical field [0001] The invention relates to a resolution method of a racemate compound, in particular to a resolution method of (±)-2-(3-benzoyl)-phenylpropionic acid. Background technique [0002] (±)-2-(3-benzoyl)-phenylpropionic acid is an α-aryl propionic acid non-steroidal anti-inflammatory compound, which has analgesic and anti-inflammatory effects. Its general name in the field of medicine is : Ketoprofen. What is sold on the market now is the racemic body of ketoprofen, which is mainly used clinically for the treatment of chronic rheumatoid arthritis, osteoarthritis, spondylitis and soft tissue injuries, such as tendonitis and bursitis, trauma and surgery Post pain etc. Racemic ketoprofen is potentially toxic to the gastrointestinal tract, liver, and kidney, and causes leukopenia. Drug structure-activity relationship shows that S-(+)-ketoprofen (i.e. (S)-(+)-2-(3-benzoyl)-phenylpropionic acid, structure as shown in formula I) has more obvious The clinical eff...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C59/84C07C51/487
Inventor 徐明东徐建康胡永江曹斌
Owner 浙江瑞博制药有限公司