CN1594296A - Process for preparing 4-[3-trifluoromethyl-5-(p-tolyl)-1H-pyrazolyl] benzene sulfonamide - Google Patents
Process for preparing 4-[3-trifluoromethyl-5-(p-tolyl)-1H-pyrazolyl] benzene sulfonamide Download PDFInfo
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- CN1594296A CN1594296A CN 200410025417 CN200410025417A CN1594296A CN 1594296 A CN1594296 A CN 1594296A CN 200410025417 CN200410025417 CN 200410025417 CN 200410025417 A CN200410025417 A CN 200410025417A CN 1594296 A CN1594296 A CN 1594296A
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- methylphenyl
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Abstract
The invention discloses a process for preparing type II epoxidation enzyme (COX-2) inhibiting agent 4-[3-trifluoromethyl-5-(p-tolyl)-1H-pyrazolyl] benzene sulfonamide (Celecoxib) by using 1-(p-cresyl)-4,4,4-trifluoro-1,3-butanedione and p-sulfamoyl phenylhydrazine hydrochlorate as raw material for reaction with homogeneous system comprising water and organic solvent including methanol or ethanol, ethylene glycol, propylene glycol, propanetriol, N, N-dimethyl formamide, N, N-dimethyl dimethylacetamide, 1-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolone, dimethyl sulfoxide, sulfolane, dioxane at room temperature.
Description
Technical field
The present invention relates to a kind of simple and efficient and prepare selectivity II type cyclooxygenase (COX-2) inhibitors 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib, Celecoxib, 1)) method.
Background technology
Selectivity II type cyclooxygenase (COX-2) inhibitor is clinically to the better curative effect of having of osteoarthritis, rheumatoid arthritis, polyp of colon and senile dementia.4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib (Celecoxib, 1)) is the inhibitor of first selectivity II type epoxidase (COX-2) of using clinically.
4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib; Celecoxib, 1) document method for making is by 1-(p-methylphenyl)-4,4; 4-three fluoro-1,3-dimethyl diketone (2) and to amino-sulfonyl hydrazinobenzene hydrochloride salt (3) cyclization forms.According to the difference of the difference of ring-closure reaction condition, particularly reaction solvent, have following several:
1,1-(p-methylphenyl)-4; 4, the 4-trifluoro--1,3-dimethyl diketone (2) and to amino-sulfonyl hydrazinobenzene hydrochloride salt (3) under argon gas stream protection; in ethanol, reflux and got 4-[3-(trifluoromethyl)-5-(p-methylphenyl)-1H-pyrazolyl in 24 hours] benzsulfamide, yield has only 46%-48.3%.(J Med Chem, 1997,40 (9): 1347-1365; Chinese Journal of New Drugs, 2002,11 (11): 859～861; China's pharmaceutical chemistry magazine, 2003,13 (1): 44-45; Chinese Journal of Pharmaceuticals, 2001,32 (3): 97-98.)。This method is because of reacting under comparatively high temps, and reaction preference reduces, and generates more cyclization isomer by product, and causes product yield and downgrade.
2, (2) and (3) are in the mixed solvent that ethanol, methyl alcohol and methyl tertiary butyl ether are formed, the 4mol/L hydrochloric acid catalysis refluxed 3 hours down, get 4-[3-(trifluoromethyl)-5-p-methylphenyl-1H-pyrazolyl] benzsulfamide (1), yield is 76%, it is 99.0% (HPLC) that content is not less than, and (WO 2000 less than 1.0% for content of isomer; 042021).This method get product (1) quality and yield all good.But adopted inflammable and explosive organic mixed solvent, brought danger and inconvenience to industrialization.
3, (2) and (3) are at amides polar aprotic solvent: N, N-N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone or 1-Methyl-2-Pyrrolidone are solvent, under 6～12mol/L hydrochloric acid catalysis, cyclization generates 4-[3-(trifluoromethyl)-5-p-methylphenyl-1H-pyrazolyl] 1: 1 cocrystallization thing of benzsulfamide (1) and amide solvent, in Virahol and water, remove recrystallisation solvent then and get (1) (WO2000; 42021).This method reaction conditions gentleness, product purity and yield are higher, but what obtain is the cocrystallization thing that contains a part recrystallisation solvent, aftertreatment is comparatively loaded down with trivial details.
In addition, 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib (Celecoxib, 1)) also can be by 4-p-methylphenyl-1,1,1-three fluoro-4-oxo-2-butylene sodium alkoxide and amino-sulfonyl hydrazinobenzene hydrochloride salt back flow reaction in 50% ethanol spent the night and get (synthetic chemistry; 2002; 10; 260-262).The used 4-p-methylphenyl-1,1 of this method, 1-three fluoro-4-oxo-2-butylene sodium alkoxide are more difficult to get, and long reaction time, yield are 69%.
Summary of the invention
What the object of the present invention is to provide a kind of highly effective prepares 4-[3-trifluoromethyl-5-p-methylphenyl-1H-pyrazolyl] method of benzene sulfonamide selectivity II type cyclooxygenase (COX-2) inhibitor.Reaction conditions gentleness, yield height, agents useful for same is inexpensive and environmentally friendly.
Technical scheme
4-[3-trifluoromethyl involved in the present invention-5-p-methylphenyl-1H-pyrazolyl] preparation method of benzenesulfonamide compounds (1) is with 1-p-methylphenyl-4; 4; 4-three fluoro-1; 3-dimethyl diketone (2) and be raw material to amino-sulfonyl hydrazinobenzene hydrochloride salt (3); under the reaction conditions of gentleness; in the homogeneous system of water and organic solvent composition, react, generate target product.
Wherein: said organic solvent is methyl alcohol, ethanol, ethylene glycol, glycerol, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, 1,3-dimethyl-2-imidazolone, methyl-sulphoxide, tetramethylene sulfone, dioxane are preferably methyl alcohol, ethanol and N, dinethylformamide;
1-p-methylphenyl-4,4,4-three fluoro-1,3-dimethyl diketone (2) be 1 to the mol ratio of amino-sulfonyl hydrazinobenzene hydrochloride salt (3): (0.5～2.0), preferred 1: (1.15～1.35);
Temperature of reaction is 0～50 ℃, preferred 15～30 ℃;
Reaction times is 0.5～24 hour.
Its reaction equation is as follows:
Owing to increased the hardness of reaction system, reduced temperature of reaction, and the cyclization selectivity is improved greatly, cyclization isomer by product significantly reduces.
Reaction conditions gentleness, the yield of gained target product and purity height.Be suitable for suitability for industrialized production.
Embodiment
Content of the present invention is further elaborated by following embodiment and accompanying drawing, but does not limit the scope of the invention.
Embodiment 1
1-(p-methylphenyl)-4,4,4-three fluoro-1,3-dimethyl diketone (2) 0.5g (21.7mmol) are dissolved in the mixed solution of 20mL methyl alcohol and 2mL water, add the hydrochloric acid 0.5mL to amino-sulfonyl hydrazinobenzene hydrochloride salt 0.6g (26.8mmol) and 4mol/L.Stir under 30 ℃ and obtained weak yellow liquid in 5 hours, evaporated under reduced pressure obtains white crude product.The alcohol-water recrystallization, the cooling, filter 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib, 1) white solid 0.69g, yield 83.3%.mp157-159℃。IR (KBr compressing tablet, cm
-1): 3350 (s), 3250 (s), 3100 (s), 1600 (s), 1500～1405 (d), 1350 (s).
1H-NMR：2.35(3H，s，CH
3)，4.90(2H，s，NH
2)，6.74(1H，s，＝CH)，7.12(2H，d，C
6H
4)，7.47(2H，d，C
6H
4)，7.91(2H，d，C
6H
4)。
Embodiment 2
Remove and change organic solvent into N, dinethylformamide, temperature is outside 15 ℃, other condition is with embodiment 1.Yield 91%, 157～159 ℃ of fusing points (alcohol-water).Infrared spectra is with embodiment 1.
Embodiment 3
Except that organic solvent is changed into the ethanol, other condition is with embodiment 1.Yield 92%, 157～159 ℃ of fusing points (alcohol-water).Infrared spectra is with embodiment 1.
Embodiment 4
1-p-methylphenyl-4,4,4-three fluoro-1,3-dimethyl diketone (2) 0.5g (21.7mmol), ethanol 10mL add amino-sulfonyl hydrazinobenzene hydrochloride salt 0.6g (26.8mmol) and water 1mL, and the hydrochloric acid 0.5mL of 4mol/L stirs 24h under the room temperature.Reaction finishes after-filtration, and concentrating under reduced pressure gets 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib, 1) 0.77g, yield 93.0%, 157～159 ℃ of fusing points (alcohol-water).Infrared spectra is with embodiment 1.
Claims (5)
1. one kind prepares 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide (celecoxib, method Celecoxib) is characterized in that,
1-(p-methylphenyl)-4,4,4-three fluoro-1,3-dimethyl diketone and the amino-sulfonyl hydrazinobenzene hydrochloride salt reacted in the homogeneous system that water and organic solvent are formed, temperature of reaction is 0～50 ℃, reacted 0.5～24 hour, and promptly got 4-[3-trifluoromethyl-5-(p-methylphenyl)-1H-pyrazolyl] benzsulfamide;
Wherein:
1-(p-methylphenyl)-4,4,4-three fluoro-1, the 3-dimethyl diketone be 1 to the mol ratio of amino-sulfonyl hydrazinobenzene hydrochloride salt: (0.9～1.5);
Water is 1 with the ratio of organic solvent: (1～20);
Described organic solvent is methyl alcohol, ethanol, ethylene glycol, propylene glycol, glycerol, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, 1-Methyl-2-Pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, 1, a kind of in 3-dimethyl-2-imidazolone, methyl-sulphoxide, tetramethylene sulfone, the dioxane.
2. preparation method as claimed in claim 1 is characterized in that, 1-(p-methylphenyl)-4,4,4-three fluoro-1, the 3-dimethyl diketone be 1 to the mol ratio of amino-sulfonyl hydrazinobenzene hydrochloride salt: (1.15～1.35).
3. preparation method as claimed in claim 1 is characterized in that, temperature of reaction is 15～30 ℃.
4. preparation method as claimed in claim 1 is characterized in that, the ratio of water and organic solvent is 1: 5-10.
5. preparation method as claimed in claim 1 is characterized in that, organic solvent is methyl alcohol, ethanol and N, dinethylformamide.
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| CN 200410025417 CN1594296A (en) | 2004-06-24 | 2004-06-24 | Process for preparing 4-[3-trifluoromethyl-5-(p-tolyl)-1H-pyrazolyl] benzene sulfonamide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949403A (en) * | 2011-08-24 | 2013-03-06 | 天津药物研究院 | Celecoxib composition, and preparation method and application thereof |
| CN103570622A (en) * | 2012-09-07 | 2014-02-12 | 北京京卫燕康药物研究所有限公司 | Preparation method of celecoxib |
-
2004
- 2004-06-24 CN CN 200410025417 patent/CN1594296A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949403A (en) * | 2011-08-24 | 2013-03-06 | 天津药物研究院 | Celecoxib composition, and preparation method and application thereof |
| CN103570622A (en) * | 2012-09-07 | 2014-02-12 | 北京京卫燕康药物研究所有限公司 | Preparation method of celecoxib |
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