CN101143815B - Method for preparing felbinac - Google Patents
Method for preparing felbinac Download PDFInfo
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- CN101143815B CN101143815B CN200710052668A CN200710052668A CN101143815B CN 101143815 B CN101143815 B CN 101143815B CN 200710052668 A CN200710052668 A CN 200710052668A CN 200710052668 A CN200710052668 A CN 200710052668A CN 101143815 B CN101143815 B CN 101143815B
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- felbinac
- biphenyl
- chloromethylation
- biphenylacetic
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Abstract
The invention relates to a preparation method of the biphenylacetic aicd of a non-steroidal anti-inflammatory drug, which includes two steps. The first step is to synthesize the biphenylacetic aicd, biphenyl is used as material, and a crude biphenylacetic aicd product is synthesized by chloromethylation, grignard reaction and hydrolysis, wherein, the molar ratio of the biphenyl, formaldehyde, phosphoric acid and acetic acid is 1:1:3:3, concentrated hydrochloric acid is overdosed, while the chloromethylation reacts, chlorine hydride gas is infused into reaction solution, and the flow of the chlorine hydride gas is 1 to 50l/h; the second step is refinement, the crude biphenylacetic aicd product produced in the first step is recrystallized by utilizing thirty to seventy percent (weight) of acetic acid solution, so that a pure biphenylacetic aicd product is produced. In the reaction process, the invention does not use and generate compounds with high toxicity and has little environmental pollution; materials can be easily got, and prices are low; all the used devices are conventional mechanical devices, operation is simple, and the total yield of crude products is thirty eight to fortysix persent.
Description
Technical field
The present invention relates to the preparation method of chemosynthesis field of medicaments, particularly a kind of non-steroid anti-inflammatory agent felbinac.
Background technology
Felbinac is a kind of NSAID (non-steroidal anti-inflammatory drug), the similar fenbufen of anti-inflammatory activity, have anti-inflammatory analgesic and good transdermal performance, its 3% gel ointment is widely used in arthritis deformans, scapulohumeral periarthritis, tenosynovitis, myalgia, soft tissue injury etc., has higher effective and security.In September, 1986 Japan Lederle company with " Napageln " be the ointment of trade(brand)name first in Japan's listing, afterwards this medicine again with trade(brand)name " Traxamgel " in Britain's listing, this medicine goes on the market in tens countries at present.According to the domestic and foreign literature report, kind surplus the synthetic route of felbinac has ten, starting raw material just has seven kinds.For example:
(1) with to bromo-acid or to the bromo-acid ethyl ester be raw material can one step or synthetic felbinac of two steps, being that the raw material synthetic route is as follows to bromo-acid:
Though operational path is short, simple to operate, expensive raw material price, be difficult for obtaining the cost height;
(2) be raw material with 4-xenyl formaldehyde, wherein a synthetic route is as follows:
This route complicated operation, productive rate are low, and raw material is difficult for obtaining the cost height;
(3) be raw material with benzyl cyanide and biphenyl acetonitrile, big for environment pollution, also big to the murder by poisoning of operator's health, be to be the synthetic route of raw material with the benzyl cyanide below:
(4) with the toluylic acid be raw material, complicated operation, productive rate are low, and synthetic route is as follows:
(5) cheap and easy to get because of biphenyl, normally be the synthetic felbinac of raw material with biphenyl, synthetic route just has five kinds at present, but mostly complicated operation, pollute that agents useful for same is difficult to preparation in big, the reaction process, wherein a synthetic route is as follows:
In sum, each operational path all is not suitable for carrying out enterprise's production more than.
Summary of the invention
Technical problem to be solved by this invention be the deficiency that exists at prior art and provide a kind of simple to operate, pollutions is little, cost is low, be easy to a kind of new preparation method that obtains starting material, be fit to the felbinac of enterprise's production.
The present invention for the technical scheme that problem adopted of the above-mentioned proposition of solution is: the preparation method of felbinac includes the next coming in order step:
1) synthetic felbinac
With biphenyl is raw material, by chloromethylation, grignard reaction, hydrolysis three-step reaction synthetic the felbinac crude product; Wherein the mol ratio of biphenyl, formaldehyde, phosphoric acid, acetic acid is 1: 1: 3: 3, and concentrated hydrochloric acid is excessive, and feeds hydrogen chloride gas in chloromethylation in reaction soln, and the flow of described hydrogen chloride gas is 1～50L/h;
2) refining
Above-mentioned steps 1) gained felbinac crude product carries out recrystallization with 30～70% (weight) acetic acid solution, gets the pure product of felbinac.
Press such scheme, chloromethylation gained biphenyl methyl chloride carries out recrystallization with hexanaphthene in the described step 1).
Press such scheme, grignard reaction causes the Grignard reagent generation with monobromethane in the described step 1).
Press such scheme, the grignard reaction solvent for use is ether or tetrahydrofuran (THF) in the described step 1).
The present invention prepares the method for felbinac, and synthetic route is as follows:
The feeding hydrogen chloride gas helps improving the productive rate of biphenyl methyl chloride; With hexanaphthene recrystallization biphenyl methyl chloride, can reduce the generation of by product in the grignard reaction; Cause grignard reaction with monobromethane, reduced temperature of reaction, shortened the reaction times, its infrared spectra and nuclear magnetic resonance spectrum are seen accompanying drawing 1～3.
Beneficial effect of the present invention is:
Use in the reaction process of the present invention, the bigger compound of toxigenicity not, environmental pollution is less; Raw material all is easy to obtain low price; Employed equipment also is the chemical industry common equipment, and is simple to operate, and the crude product total recovery is 38%～46%.
Description of drawings
Fig. 1 is the infrared spectrogram of products obtained therefrom felbinac of the present invention;
Fig. 2 is a products obtained therefrom of the present invention
1The H nmr spectrum;
Fig. 3 is a products obtained therefrom of the present invention
13The C nmr spectrum.
Embodiment
Further specify the present invention below by example, but the present invention not only that.
Embodiment 1:
(1) preparation biphenyl methyl chloride
On the 250ml there-necked flask, thermometer, mechanical stirrer, airway are housed by pipe connecting, reflux condensing tube, add biphenyl 15.4g (0.1mol) successively, formaldehyde 8.3g (0.1mol), phosphoric acid 34.5g (0.3mol), acetic acid 18.75g (0.3mol), concentrated hydrochloric acid 25ml.Be heated to 80～90 ℃ on the heating jacket that adjusts the temperature electronically, vigorous stirring 18～24 hours feeds HCl gas every 30 fens clockwise reaction solns, and the flow of hydrogen chloride gas is 45L/h.Stopped reaction is cooled to below 15 ℃, separates out solid.Filtration under diminished pressure, filter cake washing twice, about at every turn 40ml water is used the K of 20ml 5% again
2CO
3Solution washing once.Drain filter cake, change in the 250ml separating funnel, add the K of 40ml ether and 10ml 5%
2CO
3Solution, vibration is left standstill, and divides the lixiviating liquid layer, and ether layer adds Anhydrous potassium carbonate 20g placement and carried out drying in 24 hours.Boil off ether, with thick product hexanaphthene recrystallization 1 time that obtains.Product vacuum-drying.Get product 18.27g, purity is 83.62%, and this step yield is 75.4%.
(2) preparation felbinac
Condenser (top with calcium chloride tube) is housed, temperature is taken into account in the 250ml there-necked flask of normal pressure dropping funnel, adds magnesium chips 2.4g (0.1mol), the brilliant 0.2g (0.002mol) of iodine.Measure the 90ml ether, pour an amount of ether into and just cover magnesium chips, the biphenyl methyl chloride of residue ether dissolution previous step gained is stand-by in the normal pressure dropping funnel.Add the initiation reaction of 3ml monobromethane, slowly drip the diethyl ether solution of chloromethyl biphenyl after the brilliant color of iodine disappears, the dropping process is kept reaction with cooling bath a small amount of backflow.Dropwise, dropping funnel washes with the 10ml ether, and stirring at room is after 15 minutes, and 35 ℃ were refluxed 2 hours.Reaction finishes, and is cooled to below 8 ℃ with ice-water bath, feeds CO
2Gas 2～3 hours.Finish, in reaction solution, add an amount of ice cube, drip 10% dilute hydrochloric acid to acid.Ether is removed in distillation, filtration under diminished pressure, and washing leaching cake is drained.Filter cake is changed in the beaker, add 80ml 8%NaOH solution, be heated to 80 ℃ of dissolvings, cool to room temperature gets white casse solution, and filtration under diminished pressure is collected filtrate; Filter cake repeats twice by top operation again.Merge the filtrate of collecting, add 20% hcl acidifying, separate out white colloid.Filtration under diminished pressure, drying gets white flakey solid 8.80g, and fusing point is 158～161 ℃, and felbinac crude product total recovery is 41.9%.
(3) felbinac is refining
Above-mentioned felbinac crude product carries out recrystallization with 50% acetate, gets the pure product 5.52g of felbinac, content 99.74%, and 163～165 ℃ of fusing points, this step yield is 62.7%.
Embodiment 2:
(1) preparation biphenyl methyl chloride is with embodiment 1.
(2) condenser (top with calcium chloride tube) is housed, temperature is taken into account in the 250ml there-necked flask of normal pressure dropping funnel, adds magnesium chips 2.4g (0.1mol), the brilliant 0.2g (0.002mol) of iodine.Measure the 90ml tetrahydrofuran (THF), pour an amount of tetrahydrofuran (THF) into and just cover magnesium chips, the biphenyl methyl chloride of residue tetrahydrofuran (THF) dissolving previous step gained is stand-by in the normal pressure dropping funnel.Other the same step.Get felbinac crude product 9.7 grams, the crude product total recovery is 45.6%.
(3) felbinac is refining carries out recrystallization with embodiment 1 with 70% acetate, gets the pure product 5.78g of felbinac, content 99.79%, and 163～165 ℃ of fusing points, this step yield is 59.5%.
Claims (4)
1. the preparation method of felbinac is characterized in that including the next coming in order step:
1) synthetic felbinac
With biphenyl is raw material, by chloromethylation, grignard reaction, hydrolysis three-step reaction synthetic the felbinac crude product; Wherein the mol ratio of the biphenyl in the chloromethylation, formaldehyde, phosphoric acid, acetic acid is 1: 1: 3: 3, and concentrated hydrochloric acid is excessive, and feeds hydrogen chloride gas in chloromethylation in reaction soln, and the flow of described hydrogen chloride gas is 1～50L/h;
2) refining
Above-mentioned steps 1) gained felbinac crude product carries out recrystallization with 30～70% (weight) acetic acid solution, gets the pure product of felbinac.
2. by the preparation method of the described felbinac of claim 1, it is characterized in that chloromethylation gained biphenyl methyl chloride carries out recrystallization with hexanaphthene in the described step 1).
3. by the preparation method of claim 1 or 2 described felbinac, it is characterized in that grignard reaction causes the Grignard reagent generation with monobromethane in the described step 1).
4. by the preparation method of claim 1 or 2 described felbinac, it is characterized in that the grignard reaction solvent for use is ether or tetrahydrofuran (THF) in the described step 1).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710052668A CN101143815B (en) | 2007-07-09 | 2007-07-09 | Method for preparing felbinac |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710052668A CN101143815B (en) | 2007-07-09 | 2007-07-09 | Method for preparing felbinac |
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| CN101143815A CN101143815A (en) | 2008-03-19 |
| CN101143815B true CN101143815B (en) | 2010-05-19 |
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| CN200710052668A Expired - Fee Related CN101143815B (en) | 2007-07-09 | 2007-07-09 | Method for preparing felbinac |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102503805B (en) * | 2011-10-26 | 2013-11-13 | 上海图帕医药科技有限公司 | Method for preparing 4-felbinac through rearrangement reaction |
| CN103086875A (en) * | 2013-02-01 | 2013-05-08 | 山东省医药工业研究所 | Synthetic method of felbinac non-steroidal anti-inflammatory agent |
| CN106431911B (en) * | 2016-09-28 | 2021-05-28 | 黄石市利福达医药化工有限公司 | Preparation and purification method of 4-felbinac |
| CN110028403B (en) * | 2019-04-19 | 2020-08-11 | 四川大学 | Method for synthesizing succinic acid compound |
| CN111574354A (en) * | 2020-06-18 | 2020-08-25 | 安徽鼎旺医药有限公司 | Biphenylacetic acid and preparation method thereof |
| CN116063153A (en) * | 2021-10-29 | 2023-05-05 | 中国科学院大连化学物理研究所 | Synthesis method of 4-diphenyl methanol |
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- 2007-07-09 CN CN200710052668A patent/CN101143815B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| 张田林等.4－联苯乙酸的新法合成.中国医药工业杂质34 7.2003,34(7),318-319. |
| 张田林等.4-联苯乙酸的新法合成.中国医药工业杂质34 7.2003,34(7),318-319. * |
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| C14 | Grant of patent or utility model | ||
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| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Yongan Pharmaceutical Co., Ltd., Qianjiang Assignor: Wuhan Institute of Technology Contract record no.: 2011420000184 Denomination of invention: Preparation of non-steroidal anti-inflammatory medicine biphenylacetic acid Granted publication date: 20100519 License type: Exclusive License Open date: 20080319 Record date: 20110714 |
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