CN104557584A - Method for synthesizing tolfenamic acid - Google Patents
Method for synthesizing tolfenamic acid Download PDFInfo
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- CN104557584A CN104557584A CN201310500878.7A CN201310500878A CN104557584A CN 104557584 A CN104557584 A CN 104557584A CN 201310500878 A CN201310500878 A CN 201310500878A CN 104557584 A CN104557584 A CN 104557584A
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- acid
- tolfenamic acid
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- tolfenamic
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Abstract
The invention discloses a method for synthesizing tolfenamic acid. The method includes the following steps: adding o-chlorobenzoic acid and alkali metal hydroxide into methyl isobutyl ketone to obtain a mixture, and then heating up and enabling the mixture to react; adding 3-chloro-2-methylaniline and an alumina supported inorganic base acid-binding agent into the reacted mixture obtained in the previous step, and then heating up and enabling the mixture to react; cooling, adding water to extract, skimming, acidizing and crystallizing an aqueous phase using hydrochloric acid, filtering to obtain filter cakes which are tolfenamic acid crude products, and then recrystallizing the crude products to obtain tolfenamic acid refined products. According to the invention, the alumina supported inorganic base can be used not only as the acid-binding agent but also as a catalyst of the reaction, thereby improving the cleanness of industrial synthetic reactions and reducing environmental pollution.
Description
Technical field
The present invention relates to a kind of preparation method of anodyne, particularly a kind of synthetic method of tolfenamic acid, belong to medical chemistry synthesis field.
Background technology
Anthranilic acid derivative tolfenamic acid (the Tolfenamic acid developed by GEA company of Denmark, TA, 2-[(3-chloro-2-methyl phenyl) is amino] phenylformic acid) be a kind of widely used nonsteroidal anti-inflammatory drug (NSAID), it suppresses the IC of epoxidase COX-1/COX-2
50be 15.0, show that tolfenamic acid has stronger selectivity to COX-2, so have stronger anti-inflammatory and analgesic effect and less side effect.Lot of domestic and foreign scholar has carried out many-sided research to TA for many years, summarizes the pharmacological toxicology etc. of TA, provides reference by the clinical application etc. for TA.At present, TA is mainly used in the treatment of sacroiliitis and migraine, is also widely used in the treatment of the diseases such as gout, bursitis and dysmenorrhoea.In addition also alleviate the relevant inflammation of osteoarthrosis and pain as pet medicine for dog, cat, also can be used for the assisting therapy of the domestic animal such as pig, ox upper respiratory disease.Numerous research shows, TA has anti-inflammatory, analgesia and refrigeration function, and almost the complete glycine as TA and glucuronide conjugate form, by urine drains (90%), do not have serious specific toxic reaction to medicine in vivo.TA can be applied to people simultaneously and use and market for animals, has boundless market potential.
Chinese patent: 201210291976.X describes a kind of synthetic method of tolfenamic acid, 0-chloro-benzoic acid and alkali metal hydroxide are joined in methyl iso-butyl ketone (MIBK), heat temperature raising reacts, then the chloro-2-monomethylaniline of 3-is added wherein, acid binding agent and catalyzer, reacting by heating, through extraction, acidifying, filter, obtain tolfenamic acid crude product, crude product recrystallization obtains tolfenamic acid purified product, mineral alkali or organic bases is adopted to be acid binding agent in this synthetic method, with cuprous bromide, cuprous chloride, copper powder or venus crystals are catalyzer, a large amount of organic basess or organic metal salt refuse can be formed after reaction, and selectivity is low, reaction product difficulty is separated.
Summary of the invention
The object of the invention is to overcome prior art Problems existing, a kind of synthetic method of tolfenamic acid is provided.
Technical scheme of the present invention is as follows: a kind of synthetic method of tolfenamic acid, comprises the steps:
Step 1, join in methyl iso-butyl ketone (MIBK) by 0-chloro-benzoic acid and alkali metal hydroxide, heat temperature raising reacts;
Step 2, upwards walk gained reaction mixture in add the mineral alkali acid binding agent of the chloro-2-monomethylaniline of 3-, alumina load, heat temperature raising reacts;
Step 3, cooling, then add water and extract, separatory, aqueous phase hcl acidifying crystallization, and filter, filter cake is tolfenamic acid crude product, and crude product recrystallization obtains tolfenamic acid purified product.
Alkali metal hydroxide described in step 1 be selected from sodium hydroxide or potassium hydroxide one or both.
Acid binding agent described in step 2 is the sodium hydroxide of alumina load or the potassium hydroxide of alumina load.
The mass ratio of the acid binding agent described in step 2 and 0-chloro-benzoic acid is 0.2-0.5:1.
0-chloro-benzoic acid described in step 2 and 3-chloro-2-monomethylaniline mol ratio are 1:1.
Compared with prior art, the synthetic method of tolfenamic acid of the present invention not only increases the atom utilization of reaction with the mineral alkali of alumina load for acid binding agent and avoids in prior synthesizing method and use high poison, easily the acid binding agent of system poison and catalyzer; In the present invention, the mineral alkali of alumina load not only can be used as acid binding agent but also be the catalyzer reacted, and improves the spatter property of commercial synthesis reaction, reduces environmental pollution.
Embodiment
Embodiment 1
Take 100g 0-chloro-benzoic acid and 25g sodium hydroxide joins in 500mL methyl iso-butyl ketone (MIBK), be heated to back flow reaction 1 h.
The sodium hydroxide taking 90 g 3-chloro-2-methyl anilines and 20g alumina load joins in the reaction mixture of step reaction gained, heating reflux reaction 3 h, then cools, and adds the extraction of 500mL water, separatory, it is 2-3 that aqueous phase concentrated hydrochloric acid is acidified to pH value, continues to stir 1h crystallization, filters, filter cake is tolfenamic acid crude product, by tolfenamic acid crude product ethanol/water mixed solvent recrystallization, obtain tolfenamic acid purified product 153.4g, yield 87.2%.
Embodiment 2
Take 100g 0-chloro-benzoic acid and 25g sodium hydroxide joins in 500mL methyl iso-butyl ketone (MIBK), be heated to back flow reaction 1 h.
The sodium hydroxide taking 90 g 3-chloro-2-methyl anilines and 50g alumina load joins in the reaction mixture of step reaction gained, heating reflux reaction 3 h, then cools, and adds the extraction of 500mL water, separatory, it is 2-3 that aqueous phase concentrated hydrochloric acid is acidified to pH value, continues to stir 1h crystallization, filters, filter cake is tolfenamic acid crude product, by tolfenamic acid crude product ethanol/water mixed solvent recrystallization, obtain tolfenamic acid purified product 158.2g, yield 88.6%.
Embodiment 3
Take 100g 0-chloro-benzoic acid and 25g sodium hydroxide joins in 500mL methyl iso-butyl ketone (MIBK), be heated to back flow reaction 1 h.
The potassium hydroxide taking 90 g 3-chloro-2-methyl anilines and 30g alumina load joins in the reaction mixture of step reaction gained, heating reflux reaction 3 h, then cools, and adds the extraction of 500mL water, separatory, it is 2-3 that aqueous phase concentrated hydrochloric acid is acidified to pH value, continues to stir 1h crystallization, filters, filter cake is tolfenamic acid crude product, by tolfenamic acid crude product ethanol/water mixed solvent recrystallization, obtain tolfenamic acid purified product 154.9g, yield 87.5%.
Claims (5)
1. a synthetic method for tolfenamic acid, is characterized in that comprising the steps:
Step 1, join in methyl iso-butyl ketone (MIBK) by 0-chloro-benzoic acid and alkali metal hydroxide, heat temperature raising reacts;
Step 2, upwards walk gained reaction mixture in add the mineral alkali acid binding agent of the chloro-2-monomethylaniline of 3-, alumina load, heat temperature raising reacts;
Step 3, cooling, then add water and extract, separatory, aqueous phase hcl acidifying crystallization, and filter, filter cake is tolfenamic acid crude product, and crude product recrystallization obtains tolfenamic acid purified product.
2. the synthetic method of tolfenamic acid according to claim 1, it is characterized in that the alkali metal hydroxide described in step 1 is selected from sodium hydroxide or potassium hydroxide one or both.
3. the synthetic method of tolfenamic acid according to claim 1, is characterized in that in step 2, acid binding agent is the sodium hydroxide of alumina load or the potassium hydroxide of alumina load.
4. the synthetic method of the tolfenamic acid according to claim 1 or 3, is characterized in that the mass ratio of the acid binding agent described in step 2 and 0-chloro-benzoic acid is 0.2-0.5:1.
5. the synthetic method of tolfenamic acid according to claim 1, is characterized in that the 0-chloro-benzoic acid described in step 2 and 3-chloro-2-monomethylaniline mol ratio are 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310500878.7A CN104557584B (en) | 2013-10-23 | 2013-10-23 | A kind of synthetic method of Tolfenamic Acid |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310500878.7A CN104557584B (en) | 2013-10-23 | 2013-10-23 | A kind of synthetic method of Tolfenamic Acid |
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| CN104557584A true CN104557584A (en) | 2015-04-29 |
| CN104557584B CN104557584B (en) | 2016-08-17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107814733A (en) * | 2016-09-14 | 2018-03-20 | 天津科技大学 | A kind of Tolfenamic Acid novel crystal forms and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3313848A (en) * | 1964-06-18 | 1967-04-11 | Parke Davis & Co | Anthranilic acids and derivatives |
| CN102786429A (en) * | 2012-08-16 | 2012-11-21 | 青岛农业大学 | Synthesis method of tolfenamic acid |
| CN103172530A (en) * | 2013-04-12 | 2013-06-26 | 沈阳三九药业有限公司 | Preparation method of tolfenamic acid |
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2013
- 2013-10-23 CN CN201310500878.7A patent/CN104557584B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3313848A (en) * | 1964-06-18 | 1967-04-11 | Parke Davis & Co | Anthranilic acids and derivatives |
| CN102786429A (en) * | 2012-08-16 | 2012-11-21 | 青岛农业大学 | Synthesis method of tolfenamic acid |
| CN103172530A (en) * | 2013-04-12 | 2013-06-26 | 沈阳三九药业有限公司 | Preparation method of tolfenamic acid |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107814733A (en) * | 2016-09-14 | 2018-03-20 | 天津科技大学 | A kind of Tolfenamic Acid novel crystal forms and preparation method thereof |
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| CN104557584B (en) | 2016-08-17 |
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