CN102746231A

CN102746231A - Celecoxib preparation process

Info

Publication number: CN102746231A
Application number: CN201110099663XA
Authority: CN
Inventors: 梅林雨; 罗振福; 郑志超; 靳朝东; 高晶; 梁忠信
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2011-04-20
Filing date: 2011-04-20
Publication date: 2012-10-24

Abstract

The invention provides a process for simply and efficiently preparing a selective cyclooxygenase-2 (COX-2) inhibitor 4-[3-trifluoromethyl-5-(4-methylphenyl)-1H-pyrazolyl]benzenesulfonamide (celecoxib, I). The process comprises the following steps: reacting an alkyl trifluoroacetate and 4-methylacetophenone which are initial raw materials under the action of an organic alkali solution, directly adding a dilute acid, an organic solvent and 4-aminosulfonylhydrazinobenzene or its acid salt to the resulting system, and heating to prepare the celecoxib. Above reaction adopts one kettle way, so the process has the advantages of mild condition, simple operation, high product yield and high product purity, and is suitable for industrialized production.

Description

Celecoxib preparation technology

Technical field

The invention belongs to medical technical field, be specifically related to a kind of simple and efficient and prepare selective epoxidation enzyme-2 (COX-2) inhibitors 4-[3-trifluoromethyl-5-(4-aminomethyl phenyl)-1H-pyrazolyl] benzsulfamide (celecoxib, Celecoxib, method I).

Background technology

Effects such as that NSAIDs (NSAIDs) has is analgesic, analgesia, anti-inflammatory, rheumatism and anticoagulation are widely used in the treatment of osteo-arthritis, rheumatic arthritis and the alleviation of various pain and heating paresthesia clinically.Traditional NSAIDs brings into play therapeutic action through suppressing COX, but the untoward reaction that unavoidably brings gi tract aspects such as (GI).Selective COX-2-2 suppressor factor only reduces and induces the synthetic of type COX-2, and does not influence the synthetic of physiological COX-1, has both had significant anti-inflammatory activity, has reduced gastrointestinal injury again.Celecoxib, commodity are called celecoxib, are a kind of 1, and 5-diaryl pyrazole azole cox 2 inhibitor is mainly used in treatment osteo-arthritis and rheumatoid arthritis clinically.1998 through FDA approval in U.S.'s listing, existing in more than 70 countries (areas) listing.

The pharmacologically active of celecoxib or its pharmacologically acceptable salt has been described by G.D Se Er company in WO 1995/15316.

The compound method of celecoxib is existing report in many documents.Indian J Chem for example, SectB, 2005,44 (5): 1115-1118; Bioorg Med Chem, 2008,16 (22): 9694-9698; J MedChem, 1997,40 (9): 1347-1365; WO 2005/49014; US 2002/16351; WO 1997/11704; US 2008/234491 etc.But, obtain celecoxib, single step yield 46-81% with (IV) with (V) reaction in these compound methods; And the employing method of fractional steps in the document of promptly first synthetic intermediate (IV), all will be carried out purification processes to (IV), comprises processes such as extraction, drying and removal solvent, and this has increased operation sequence undoubtedly, has prolonged the reaction times, and cost increases.

In addition, also can be by another midbody 4-p-methylphenyl-1,1,1-three fluoro-4-oxos-2-butylene sodium alkoxide (VII) with (V) make (I), and this midbody need be separated equally.

Summary of the invention

The object of the present invention is to provide a kind of " one kettle way " of simple and efficient to prepare the method for selective COX-2-2 suppressor factor celecoxib, make product.Present method reaction conditions is gentle, simple to operate, with low cost, is fit to large-scale industrial production.

For realizing above-mentioned technical purpose, the present invention adopts following technical scheme:

A kind of method for preparing celecoxib (I); It is characterized in that, (II) after the organic bases solution effects, add (III) temperature reaction; Not purified entry or organic solvent or both mixtures of directly in reaction system, adding of products therefrom; Transfer to acidity with hydrochloric acid, add 4-amino-sulfonyl phenylhydrazine or its salt (V) temperature reaction at last, " one kettle way " makes celecoxib.

Wherein:

Described organic bases includes but not limited to sodium methylate, sodium ethylate, sodium hydride etc., is mixed with the required solvent of solution and includes but not limited to C ₁-C ₄Alcohol, ether, THF, toluene etc., particular methanol.

The radicals R of described (II) includes but not limited to C ₁-C ₄Alkyl, preferable methyl or ethyl.

The described organic solvent that directly in reaction system, adds includes but not limited to C ₁-C ₄Alcohol, trifluoroethanol, ETHYLE ACETATE, toluene, acid amides etc.

Described (V) includes but not limited to hydrochloride, hydrobromate, vitriol, nitrate salt, oxalate, mesylate, tartrate, trifluoroacetate, hexafluorophosphate, a tetrafluoro borate, trichloroacetate, difluoroacetic acid salt and the dichloro acetic acid etc. of 4-amino-sulfonyl phenylhydrazine, the hydrochloride of preferred 4-amino-sulfonyl phenylhydrazine.

Described compound (II) and temperature of reaction (III) they are 20-100 ℃, are preferably 50-100 ℃, more preferably 55-80 ℃, and from system, steam in case of necessity and remove the lower boiling composition of part, this is one of key factor of reaction.

Described preparation method, wherein the concentration of hydrochloric acid (wt) is 1%-36%, is preferably 10%-20%, more preferably 10%; PH should be between 0-7, preferred pH=1-2, and this is another key factor of reaction.

Described preparation method wherein adds (V) temperature reaction, and temperature is 20-100 ℃, is preferably 50-100 ℃, the temperature when more preferably reaching reflux state, and reflux state can effectively reduce the content of isomer (VI) down.

Process flow diagram is seen Fig. 1.

Description of drawings

Fig. 1 is a process flow diagram,

Fig. 2 a and Fig. 2 b are the crystalline XRD figures of celecoxib,

Fig. 3 is a celecoxib crystalline thermogram,

Fig. 4 is the crystalline infrared spectrogram of celecoxib.

Embodiment

Below in conjunction with embodiment the present invention is done further explanation, it is indicative that embodiment is merely, and the present invention is not produced any restriction.

Embodiment 1

Under the nitrogen protection, in the four-hole bottle that reflux condensing tube, mechanical stirrer are housed, add the dry methyl alcohol of 80mL, 1.5g (65.2mmol) sodium Metal 99.5, the preparation sodium methoxide solution.At normal temperatures, slowly splash into the methanol solution that 20mL contains 13.9mL (96.2mmol) Trifluoroacetic Acid Ethyl Ester, after the stirring, add 15mL and contain 10.5mL (77.0mmol) methanol solution (III), heat up 40 ℃.Slowly be warming up to 70 ℃, under this temperature, continue reaction 2h.Stop heating, add 30mL cold water, 10% Hydrogen chloride and ETHYLE ACETATE, record pH=2 this moment.To wherein adding 18.5g (77.0mmol), stir and be warming up to reflux state the amino-sulfonyl hydrazinobenzene hydrochloride salt.Reaction finishes, and reduces to room temperature, separates out the off-white color solid.Suction filtration obtains the celecoxib solid of white, vacuum-drying, the 25.4g that weighs (HPLC:I 99.08%, and VI 0.92%), yield 85%.

Embodiment 2

Under the nitrogen protection, in the four-hole bottle that reflux condensing tube, mechanical stirrer are housed, add 160mL 20% (474.1mmol) alcohol sodium solution.Under the stirring at room, slowly splash into the ethanolic soln that 60mL contains 58.4g (447.1mmol) trifluoro-acetate, behind the stirring 0.5h, add 60mL and contain 50.9g (372.6mmol) ethanolic soln (III).Slowly be warming up to 90 ℃, reaction 2h.Be cooled to 30 ℃, in system, add 10% Hydrogen chloride and ETHYLE ACETATE, record pH=1 this moment.To wherein adding the amino sulphur nitrophenyl hydrazine hydrochloride of 80g (357.0mmol) 4-, stir and be warming up to reflux state.Reaction finishes, and reduces to room temperature, separates out the off-white color solid.Suction filtration obtains the celecoxib solid of white, vacuum-drying, the 114.3g that weighs (HPLC:I 99.05%, VI0.95%), and yield 80%.

Embodiment 3

Under the nitrogen protection, in the four-hole bottle that reflux condensing tube, mechanical stirrer are housed, add 46.8g (323.0mmol) Trifluoroacetic Acid Ethyl Ester, the 50mL THF.Stirring is cooled to below 5 ℃, slowly adds 130g 60% (323.0mmol) sodium hydride, behind the stirring 0.5h, adds 36.9g (270.0mmol) (III).Stop refrigeration, rise to room temperature, slowly the system of being heated to is reflux state then.Under this temperature, reaction 2h.Add cold water, and be cooled to below 30 ℃.In system, add 10% Hydrogen chloride and ETHYLE ACETATE, record pH=1 this moment.To wherein adding the amino sulphur nitrophenyl hydrazine hydrochloride of 62.0g (260.0mmol) 4-, stir and be warming up to reflux state.Reaction finishes, and reduces to room temperature, separates out the off-white color solid.Suction filtration obtains the celecoxib solid of white, vacuum-drying, the 95g that weighs (HPLC:I 99.01%, and VI 0.99%), yield 80%.

The celecoxib XRD figure has the peak 5.40,10.72,16.10,21.52 and 27.00; Its DSC endothermic transition is at about 158-163 ℃; This infrared absorption spectrum (IR) (KBr, cm ^-1) 3338.3,3231.94,3098.64,1347.48,1164.18 and 1135.58cm ^-1Characteristic spectrum belt is arranged, see Fig. 2 a, Fig. 2 b, Fig. 3, Fig. 4.

Claims

A celecoxib (Celecoxib, preparation method I) is characterized in that; Trifluoroacetic acid alkyl ester (II) is after the organic bases solution effects; Add 4-methyl acetophenone (III) temperature reaction, products therefrom is not purified directly to add entry or organic solvent or both mixtures in reaction system, transfer to acidity with hydrochloric acid; Add 4-amino-sulfonyl phenylhydrazine or its salt (V) temperature reaction at last, make celecoxib
2. preparation method according to claim 1 is characterized in that organic bases includes but not limited to sodium methylate, sodium ethylate, sodium hydride, potassium tert.-butoxide etc., is mixed with the required solvent of solution and includes but not limited to C ₁-C ₄Alcohol, ether, THF, toluene etc., particular methanol.
3. preparation method according to claim 1 is characterized in that, the radicals R of formula (II) includes but not limited to C ₁-C ₄Alkyl, preferable methyl or ethyl.
4. preparation method according to claim 1 is characterized in that, the described organic solvent that directly in reaction system, adds includes but not limited to C ₁-C ₄Alcohol, trifluoroethanol, ETHYLE ACETATE, toluene, acid amides etc.
5. preparation method according to claim 1; It is characterized in that; The salt of 4-amino-sulfonyl phenylhydrazine includes but not limited to hydrochloride, hydrobromate, vitriol, nitrate salt, oxalate, mesylate, tartrate, trifluoroacetate, hexafluorophosphate, a tetrafluoro borate, trichloroacetate, difluoroacetic acid salt and dichloro acetic acid etc., preferably salt hydrochlorate.
6. preparation method according to claim 1 is characterized in that, compound (II) and temperature of reaction (III) are 20-100 ℃, are preferably 50-100 ℃, more preferably 55-80 ℃.
7. preparation method according to claim 1 is characterized in that, wherein the concentration of hydrochloric acid (wt) is 1%-36%, is preferably 10%-20%, more preferably 10%; PH should be between 0-7, preferred pH=1-2.
8. preparation method according to claim 1 is characterized in that, adding (V) temperature reaction temperature is 20-100 ℃, is preferably 50-100 ℃, and the temperature when more preferably reaching reflux state can effectively reduce the content of isomer (VI) under this temperature
9. preparation method according to claim 1, the celecoxib XRD figure has the peak 5.40,10.72,16.10,21.52 and 27.00; Its DSC endothermic transition is at about 158-163 ℃; This infrared absorption spectrum (IR) (KBr, cm ^-1) 3338.3,3231.94,3098.64,1347.48,1164.18 and 1135.58cm ^-1Characteristic spectrum belt is arranged.