CN102911057B

CN102911057B - A kind of preparation method of ketoprofen

Info

Publication number: CN102911057B
Application number: CN201110222136.3A
Authority: CN
Inventors: 徐明东; 石德送
Original assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Current assignee: Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority date: 2011-08-04
Filing date: 2011-08-04
Publication date: 2016-01-27
Anticipated expiration: 2031-08-04
Also published as: CN102911057A

Abstract

The invention belongs to chemical and medicine industry field, a kind of preparation method of ketoprofen is provided.The method is in the presence of sulphuric acid, obtains ketoprofen with 2-(3-benzoylphenyl) propionitrile and ethanol synthesis, and reaction solution is separated through post-processing operation and obtains ketoprofen finished product.The method technique is simple, easy to operate, yield is high, is applicable to the suitability for industrialized production of ketoprofen.

Description

A kind of preparation method of ketoprofen

Technical field

The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of ketoprofen.

Background technology

Ketoprofen, English name: Ketoprofenethylester, chemical name: Alpha-Methyl-3-benzoyl-Phenylacetic acid ethylester, the intermediate of Chang Zuowei Ketoprofen, is used for synthesizing ketoprofen and chiral enantiomer thereof.As Tetrahedron, 50 (36), 10749-60,1994 disclose the method that the lipase-catalyzed ketoprofen of Candidacylindracea prepares S-Ketoprofen; Chinese invention patent 01126617.1 discloses the method being prepared R-Ketoprofen by Citeromycesbaodingensis bacterial strain CGMCC0573 catalysis ketoprofen.

Ketoprofen, has another name called Ketoprofen BP 93, English name: Ketoprofen, chemical name: Alpha-Methyl-3-benzoyl-toluylic acid, and structural formula is as follows,

。

Ketoprofen is a kind of aromatic acid derivative, cyclooxygenase can be suppressed, and have certain effect suppressing lipoxygenase and reduce bradykinin, thus the damage location pain perception that can reduce inflammation, can be used as anti-inflammation analgesia medicine, be mainly used in rheumatism such as treatment rheumatoid arthritis, osteoarthritis etc.

Now, the exploitation of single enantiomer is paid attention to very much, and FDA just issued the governing principle about chiral drug as far back as 1992, and new drug research is also day by day towards the future development of single enantiomer.The use of dexketoprofen be conducive to reducing medicine toxicity and and nonactive enantiomorph between influence each other, because their activity is 2 times of racemic modification, so the dosage of racemic modification half can be used for Clinical practice, the burden of liver and the formation of whole metabolite can be alleviated like this.Potential acylation reaction is had in addition between the acyl glucose aldehydic acid metabolite of Ketoprofen and protein; easily bring out the selective toxicity of Immune Sensibility and tissue; and dextrorotatory form is because eliminating the acyl glucose aldehydic acid of levo form thus reducing the quantity of this active metabolite, this is particularly useful to the patient that those hepatic and renal functions are bad.

The S-enantiomorph of Ketoprofen is efficient non-steroidal anti-inflammatory agent, anti-inflammatory ratio (R)-mapping height more than 100 times, and R-Ketoprofen then has analgesia and prevents and treats and osteoporoticly does use.

Summary of the invention

The object of the present invention is to provide a kind of preparation method of ketoprofen, in the presence of sulphuric acid, 2-(3-benzoylphenyl) propionitrile and ethanol synthesis are prepared ketoprofen.

Further, described preparation method is: mixed with ethanol by 2-(3-benzoylphenyl) propionitrile, control temperature adds sulfuric acid, is heated to backflow, and insulation back flow reaction obtains described ketoprofen.

The described temperature adding sulfuric acid controls to be less than 60 DEG C, and the time of described insulation back flow reaction is 5 ~ 18 hours.Preferably, sulfuric acid can drip at twice, and each post-heating that drips to backflow, and is incubated 5 ~ 9 hours.

After insulation back flow reaction terminates, can post-processing operation be carried out, obtain ketoprofen finished product through separation and Extraction process.Described post-processing step comprises: reaction solution decompression recycling ethanol, adds organic solvent and water makes solution layering, and dry organic layer, obtains ketoprofen finished product.Described organic solvent comprises ethyl acetate, methyl acetate, methylene dichloride, ethylene dichloride or toluene.

Described drying operation can select siccative as described below: anhydrous sodium sulphate, anhydrous magnesium sulfate etc., can also add activated carbon decolorizing, with the ketoprofen finished product that obtained color and luster is qualified.

Further, described post-processing step technological operation can be: after reaction terminates, reaction solution decompression recycling ethanol, cooling, add organic solvent, drip water, stratification after stirring, organic layer adds desiccant dryness, filter, organic solvent washing, reclaim under reduced pressure organic solvent is to residual qualified, cooling, obtains finished product.

Preferably, the preparation of described ketoprofen can be carried out according to following technological operation: in reaction flask, drop into ethanol, adds 2-(3-benzoylphenyl) propionitrile; control temperature, below 60 DEG C, drips sulfuric acid, is heated to backflow; be incubated 5 ~ 18 hours, TLC detects to reacting end.Treat chilly, reaction solution decompression recycling ethanol.Be cooled to interior temperature less than 50 DEG C, add organic solvent, continue to be cooled to interior temperature less than 10 DEG C, add water stirring, stratification, and organic layer adds desiccant dryness, filters, and with organic solvent washing, reclaim under reduced pressure organic solvent is to residual qualified, and cooling, obtains finished product.

Ketoprofen preparation method technique provided by the invention is simple, easy to operate, yield is high, is applicable to the suitability for industrialized production of ketoprofen.

Embodiment

In order to understand the present invention further, below in conjunction with embodiment, the preparation method to ketoprofen provided by the invention is described in detail.It is to be appreciated that these embodiments describe just for further describing feature of the present invention, instead of the restriction to the scope of the invention or the claims in the present invention scope.

embodiment 1:

In clean dry 300ml reaction flask, drop into 50g ethanol, add 30g2-(3-benzoylphenyl) propionitrile.Control temperature, at 50 DEG C, starts to drip 50g sulfuric acid, terminates to drip post-heating to backflow, and insulation backflow 5 ~ 12 hours, TLC detects to reacting end.Treat chilly, decompression recycling ethanol, be cooled to interior temperature 45 DEG C, add toluene 100g, continue to be cooled to interior temperature 10 DEG C, drip water 45g, temperature less than 15 DEG C in controlling, stir 1 ~ 5 minute, leave standstill layering in 20 minutes, water layer adds 40g toluene, stir 10 minutes, leave standstill layering in 10 minutes, water layer is placed, combining methylbenzene liquid layer.Toluene liquid layer adds 70g water washing, washs 3 times.Toluene liquid layer adds anhydrous sodium sulphate 10g and activated carbon 1.5g, keeps 2 ~ 3 hours under room temperature, and filter, use a small amount of toluene wash, drain, reclaim under reduced pressure toluene is qualified to Residual Toluene.Cooling, obtains finished product, yield 86.0%.

embodiment 2:

In clean dry 300ml reaction flask, drop into 50g ethanol, add 40g2-(3-benzoylphenyl) propionitrile.Control temperature, at 40 DEG C, starts to drip 20g sulfuric acid, terminates to drip post-heating to backflow, insulation backflow 5 ~ 9 hours.Cooling, control temperature, at 50 DEG C, drips 15g sulfuric acid again, drips and terminates, and is heated to backflow, is incubated 5 ~ 9 hours, and TLC detects to reacting end.Treat chilly, decompression recycling ethanol, be cooled to interior temperature 40 DEG C, add methylene dichloride 100g, continue to be cooled to interior temperature 5 DEG C, drip water 45g.In controlling, temperature 15 DEG C, stirs 1 ~ 5 minute, leaves standstill layering in 20 minutes.Water layer adds 40g methylene dichloride, stirs 10 minutes, leaves standstill layering in 10 minutes, combined dichloromethane liquid layer.Temperature 20 DEG C in controlling, methylene dichloride liquid layer adds 80g5% sodium carbonate liquid, stirs 2 ~ 3 hours, and TLC detection terminates to Ketoprofen reaction.Reaction terminates, and leave standstill layering in 20 minutes, methylene dichloride liquid layer adds 70g water washing, washs 3 times.Methylene dichloride liquid layer adds anhydrous sodium sulphate 15g and gac 1.5g, keeps 2 ~ 3 hours under room temperature, filters, uses a small amount of washed with dichloromethane, drain, and reclaim under reduced pressure methylene dichloride is to residual qualified.Cooling, obtains finished product, yield 90.4%.

embodiment 3:

In clean dry 300ml reaction flask, drop into 50g ethanol, add 20g2-(3-benzoylphenyl) propionitrile.Control temperature, at 20 DEG C, starts to drip 20g sulfuric acid, terminates to drip post-heating to backflow, is incubated 9 hours.Cooling, control temperature, at 50 DEG C, drips 10g sulfuric acid again, drips and terminates, and is heated to backflow, is incubated 7 ~ 9 hours, and TLC detects to reacting end.Treat chilly, decompression recycling ethanol, be cooled to interior temperature 30 DEG C, add ethyl acetate 80g, continue to be cooled to interior temperature 10 DEG C, drip water 50g.In controlling, temperature 10 DEG C, stirs 1 ~ 5 minute, leaves standstill 20 minutes, layering.Water layer adds 40g ethyl acetate, stirs 10 minutes, leaves standstill layering in 10 minutes, and water layer is placed, combined ethyl acetate liquid layer.In controlling in temperature 20 DEG C, ethyl acetate liquid layer adds 50g5% sodium methoxide solution, stirs 2 ~ 3 hours, and TLC detection terminates to Ketoprofen reaction.Reaction terminates, and leaves standstill layering in 20 minutes, and basic aqueous layer is placed, and ethyl acetate liquid layer adds 50g water washing, washs 3 times.Ethyl acetate liquid layer adds anhydrous magnesium sulfate 15g and activated carbon 1g, keeps 2 ~ 3 hours under room temperature, filters, washs, drain by a small amount of ethyl acetate, and reclaim under reduced pressure ethyl acetate is to residual qualified.Cooling, obtains finished product, yield 89.2%.

With sodium methoxide solution washing water layer and basic aqueous layer, adding hydrochloric acid to PH is 2 ~ 3, adds ethyl acetate 50ml and washes twice, stratification, and organic layer reclaim under reduced pressure ethyl acetate, to dry, obtains recovery Ketoprofen.

Claims

1. a preparation method for ketoprofen, is characterized in that, mixed with ethanol by 2-(3-benzoylphenyl) propionitrile, control temperature adds sulfuric acid below 60 DEG C, is obtained by reacting described ketoprofen.

2. preparation method according to claim 1, is characterized in that, described reaction is carried out at a reflux temperature.

3. preparation method according to claim 2, is characterized in that, the time of described back flow reaction is 5 ~ 18 hours.

4. preparation method according to claim 3, is characterized in that, after reaction terminates, by reaction solution decompression recycling ethanol, add organic solvent and water makes solution layering, dry organic layer, obtains ketoprofen finished product.

5. preparation method according to claim 4, is characterized in that, described organic solvent is selected from ethyl acetate, methyl acetate, methylene dichloride or toluene.