阅读说明：本技术 一种塞来昔布的制备方法 (A kind of preparation method of celecoxib ) 是由 梁松军 苗华明 梁晓艳 王宁宁 李明叶 毕可兴 张启超 刘东华 于 2019-08-29 设计创作，主要内容包括：本发明涉及一种塞来昔布的制备方法,属于原料药制备方法的技术领域。本发明所述塞来昔布的制备方法,首先式II所述4-肼基苯磺酰胺与乙醛反应,得含有式III化合物的反应液；然后向第一步所得反应液中,加入式IV所述对甲基苯甲酰氯,得含有式V的反应液；向第二步所得反应液中,加入盐酸乙醇,得化合物VI,再与1,1,1-三氟丙酮合环生成塞来昔布。环方式的改变从根本上避免了区域异构体杂质的生成,该制备方法将上保护、缩合、脱保护使用一锅法反应,反应条件温和,后处理操作简便,总收率可达到90%以上,更适合大规模工业化生产。(The present invention relates to a kind of preparation methods of celecoxib, belong to the technical field of raw material medicament preparation.The preparation method of celecoxib of the present invention, first 4- Hydrazinobenzenesulfonamide described in Formula II are reacted with acetaldehyde, obtain the reaction solution containing formula III compound；Then it into reaction solution obtained by the first step, is added described in formula IV to methyl benzoyl chloride, obtains the reaction solution containing Formula V；Into reaction solution obtained by second step, acidic alcohol is added, obtains compound VI, then generate celecoxib with 1,1,1-trifluoroacetone cyclization.The change of ring mode fundamentally avoids the generation of region isomer impurity; upper protection, condensation, deprotection are used one pot reaction by the preparation method, and reaction condition is mild, and post-processing operation is easy; total recovery can reach 90% or more, be more suitable for large-scale industrial production.)

1. a kind of preparation method of celecoxib, which comprises the following steps:

4- Hydrazinobenzenesulfonamide described in first step Formula II is reacted with acetaldehyde, obtains the reaction solution containing formula III compound, is reacted molten Agent is selected from one of toluene, 2- methyltetrahydrofuran, ether；

Second step is added described in formula IV to methyl benzoyl chloride into reaction solution obtained by the first step, obtains the reaction containing Formula V Liquid, reaction temperature are -10 ~ 40 DEG C；

Acidic alcohol is added into reaction solution obtained by second step in third step, obtains Formula IV compound, and reaction temperature is -10 ~ 80 ℃；

4th step Formula IV compound and 1,1,1-trifluoroacetone cyclization generate celecoxib, reaction dissolvent be selected from methanol, ethyl alcohol, One of isopropanol, water or a variety of mixtures, reaction temperature are 0 ~ 80 DEG C, and reaction equation is as follows:

。

2. the preparation method of celecoxib according to claim 1, which is characterized in that first step reaction temperature is 0 ~ 70 DEG C.

3. the preparation method of celecoxib according to claim 1, which is characterized in that first step reaction temperature is 20 ~ 30 DEG C.

4. the preparation method of celecoxib according to claim 1, which is characterized in that 4- diazanyl benzene sulphur described in first step Formula II The molar ratio of amide and acetaldehyde is 1:1 ~ 1.2.

5. the preparation method of celecoxib according to claim 1, which is characterized in that the reaction temperature of second step is 10 ~ 20 ℃。

6. the preparation method of celecoxib according to claim 1, which is characterized in that 4- diazanyl benzene sulphur described in second step Formula II Amide is 1:1 ~ 2 with the molar ratio to methyl benzoyl chloride.

7. the preparation method of celecoxib according to claim 1, which is characterized in that 4- diazanyl benzene sulphur described in third step Formula II The molar ratio of amide and acidic alcohol is 1:2 ~ 5.

8. the preparation method of celecoxib according to claim 1, which is characterized in that third step reaction temperature is 0 ~ 5 DEG C.

9. the preparation method of celecoxib according to claim 1, which is characterized in that the 4th step 4- [1- (4- methylbenzene first Acyl group) diazanyl] molar ratio of benzenesulfonamide, hydrochloride and 1,1,1- trifluoroacetone is 1:0.95 ~ 1.2.

10. the preparation method of celecoxib according to claim 1, which is characterized in that four-step reaction temperature is 20 ~ 30 ℃。

Technical field

The present invention relates to a kind of preparation methods of celecoxib, belong to the technical field of raw material medicament preparation.

Background technique

Celecoxib (trade name: Celebrex, chemical name: 4- [5- (4- aminomethyl phenyl) -3- (trifluoromethyl) -1HPyrazoles- 1- yl] benzsulfamide) it is a kind of non-steroid antiinflammatory, chemical structure such as following formula I:

。

Celecoxib is a kind of non-steroid antiinflammatory for having Xi Er (searle) company in the U.S. to develop, II type ring oxygen rouge Enzyme (COX-2) inhibitor.It can be used for treating the inflammatory diseases such as all kinds of acute and chronic arthritis and rheumatoid arthritis.Due to answering With extensive, demand is big, the synthetic method of a variety of celecoxibs has been proposed at present, but it is lower mostly to there is yield, impurity Content is big, is not suitable for the defect of big industrialized production, and document report is mainly the following preparation method:

Method one, patent WO03024958 report, toluene is mixed under the conditions of zinc chloride with ethyoxyl trifluorobutene ketone α, the β-ketenes that both ends replace are eliminated under alkaline condition further with bromine reaction and are obtained α, β-acetylenic ketone, finally and to sulfoamido Celecoxib is made in phenylhydrazine cyclization.Document mentions this route and is also easy to produce isomer impurities B, principal product and isomer impurities ratio It can reach 90%:10%, need repeatedly to refine, and use the reagents such as bromine, will cause biggish pollution, be not suitable for industry metaplasia It produces.Its route is as follows:

。

Method two, Oh etc. [Tetrahedron Lett., 2006,47,7943] report, first to sulfoamido benzene Hydrazine and trifluoroacetic acid anhydride reactant, trifluoroacetyl phenylhydrazine obtained and benzene sulfonyl chloride are condensed, and obtain tosylate derivative.Further Celecoxib is obtained with p-methylstyrene derivative cyclization, which is also easy to generate isomer impurities B, and the route Step is longer, cumbersome, and total recovery is low, and only 52%, and also the protecting group used is easily introduced genotoxicity impurity benzene sulphur Sour fatty ester is not suitable for industrialized production, and route is as follows:

。

Method three, Gaulier etc. [Tetrahedron Lett., 2011,52,6000] report, to iodobenzene sulphonyl Chlorine and benzhydrylamine prepare the sulfonamide of benzyl protection, are successively condensed with trifluoromethyl pyrazol and parabromotoluene, finally with dense sulphur Acid deprotection obtains celecoxib.This route raw material is difficult to buy and expensive, and higher cost, total recovery is low, and only 33%, Be not suitable for industrialized production.Its route is as follows:

。

Method four, You Yuanyan company disclose in patent US5466823, and industrial main preparation method at present, It is condensed to yield beta-diketon intermediate through Claisen by melilotal and trifluoro-acetate, then and to Hydrazinobenzenesulfonamide Celecoxib is made in hydrochloride cyclization, and document report total recovery only has 35%-45%.[Cui Zhiyan, celecoxib synthetic method It is studied with impurity, master thesis, Hebei University of Science and Technology, 2013.] by optimization, yield can reach 80.8%.Its route is such as Shown in lower:

。

Wherein critical process: the region isomer impurity that dehydration condensation process affects finally obtained celecoxib is (miscellaneous Matter B, sees below formula) content.The route is also also easy to produce isomer impurities B, and enlarge-effect is obvious, with putting for industrial mass Greatly, content is higher and higher, and laboratory hectogram scale can reach 0.2% or so, and more than ten multikilogram of pilot scale can reach 1% or so, work Hundred multikilogram of industryization is up to 3% or more, and the limit of United States pharmacopoeia specifications is not higher than 0.10%, therefore product needs multiple fine System can just meet pharmacopoeial requirements, cause product yield low, productivity is not also high.

。

Summary of the invention

Goal of the invention: in order to solve the above technical problems, providing a kind of method of suitable industrialized production celecoxib.

The technical scheme is that a kind of preparation method of celecoxib, comprising the following steps:

4- Hydrazinobenzenesulfonamide described in first step Formula II is reacted with acetaldehyde, obtains the reaction solution containing formula III compound；React molten Agent is selected from one of toluene, 2- methyltetrahydrofuran, ether.

Preferably, this step reaction temperature is 0 ~ 70 DEG C, and preferably 20 ~ 30 DEG C, the reaction time is 2 ~ 10 hours.

Preferably, in this step, the molar ratio of 4- Hydrazinobenzenesulfonamide and acetaldehyde described in Formula II is 1:1 ~ 1.2.

Second step is added described in formula IV to methyl benzoyl chloride, obtains containing the anti-of Formula V into reaction solution obtained by the first step Liquid is answered, this step reaction temperature is -10 ~ 40 DEG C.

Preferably, this step reaction temperature is 10 ~ 20 DEG C, and the reaction time is 2 ~ 4 hours.

Preferably, 4- Hydrazinobenzenesulfonamide described in Formula II and the molar ratio to methyl benzoyl chloride are 1:1 ~ 2.

Third step is added acidic alcohol, obtains compound VI, this step reaction temperature is into reaction solution obtained by second step -10~80℃。

Preferably, the molar ratio of 4- Hydrazinobenzenesulfonamide and acidic alcohol described in Formula II is 1:2 ~ 5.

Preferably, this step reaction temperature is 0 ~ 5 DEG C, and the reaction time is 1 ~ 6 hour.

Compound described in 4th step Formula IV and 1,1,1-trifluoroacetone cyclization generate celecoxib, this step reaction solvent Selected from one of methanol, ethyl alcohol, isopropanol, water or a variety of mixtures, reaction temperature is 0 ~ 80 DEG C.

Preferably, in this step, 4- [1- (4- methyl benzoyl) diazanyl] benzenesulfonamide, hydrochloride and 1,1,1- tri- The molar ratio of fluorine acetone is 1:(0.95 ~ 1.2).

Preferably, this step reaction temperature is 20 ~ 30 DEG C, and the reaction time is 2 ~ 10 hours.

Reaction equation of the present invention is as follows:

The utility model has the advantages that being had the advantage that compared with prior art the present invention provides a kind of preparation method of celecoxib

The change of cyclization mode fundamentally avoids the generation of region isomer impurity, the preparation method by upper protection, condensation, Deprotection uses one pot reaction, and reaction condition is mild, and post-processing operation is easy, and total recovery can reach 90% or more, is more suitable for big Technical scale metaplasia produces.

Specific embodiment

The principles and features of the present invention are described below, and lifted embodiment is used to that the present invention to be explained further, but It does not limit the scope of the invention.