CN101643440B - Nimesulide compound and purification method thereof - Google Patents
Nimesulide compound and purification method thereof Download PDFInfo
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- CN101643440B CN101643440B CN 200910146948 CN200910146948A CN101643440B CN 101643440 B CN101643440 B CN 101643440B CN 200910146948 CN200910146948 CN 200910146948 CN 200910146948 A CN200910146948 A CN 200910146948A CN 101643440 B CN101643440 B CN 101643440B
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- nimesulide
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Abstract
The invention relates to a Nimesulide compound and a purification method thereof. The method adopts the simple and convenient silica-gel column chromatography method and uses appropriate immobile phase and mobile phase, concretely, the method adopts silica gel as the immobile phase and mixed solvent of trichloromethane and methyl alcohol of certain proportion as the mobile phase, thus efficiently refining and purifying Nimesulide with high yield and purity, and being an effective method for obtaining high purity Nimesulide. The method is simple and convenient and has low cost.
Description
Technical field
The present invention relates to a kind of compound and purification process thereof, be specifically related to a kind of purification process of Nimesulide compound, belong to technical field of pharmaceuticals.
Background technology
Nimesulide (Nimesulide), chemical name is: nimesulide, molecular formula: C
13H
12N
2O
5S, molecular weight: 308.3, chemical structural formula:
This product belongs to non-steroidal anti-inflammatory drugs, has anti-inflammatory, analgesia, refrigeration function.Its mechanism of action is not yet fully clear, may mainly discharge relevant with the oxidizing reaction of polymorphonuclear leukocyte with synthetic, the leukocytic medium that suppresses prostaglandin(PG).According to reports, nimesulide reached maximum plasma concentration in 1～2 hour by oral absorption after taking medicine, and the transformation period is 3～5 hours, and 6～8 hours still can continuous action.This product accumulation phenomenon can not occur almost all by urine excretion even repeatedly take yet.Can be used for clinically chronic arthritis disease (such as rheumatoid arthritis and osteoarthritis etc.), pain and inflammation behind operation and the acute injury, the pain that the ear nasopharynx inflam mation causes, the treatment of the symptoms such as heating that dysmenorrhoea, upper respiratory tract infection cause.
Synthetic external main 2-anilino methylsulfonylphenylamine selective nitration and 2-bromo-4-nitro methylsulfonylphenylamine and two kinds of methods of potassium phenylate generation permutoid reaction of adopting of nimesulide.About the refining or purification process of Nimesulide compound, the prior art report is less." Guangdong pharmacy " the 3rd phase of the 12nd volume in 2002, introduced a kind of synthesis technique and process for purification of nimesulide, be that the nimesulide crude product is dissolved in ethanol, charcoal absorption is filtered, cooling crystallization, recrystallization gets the nimesulide highly finished product.The method is purified and is made with extra care nimesulide, and purity is still lower, and yield is not high yet.
Summary of the invention
The object of the present invention is to provide a kind of purification process of Nimesulide compound, adopt silica gel column chromatography, can obtain highly purified Nimesulide compound.
The technical scope that the present invention solves comprises:
The process for purification of the Nimesulide compound of a kind of formula (I) structure,
It is characterized in that comprising the step that obtains the nimesulide sterling by column chromatography for separation, and described column chromatography be with silica gel as stationary phase, the mixed solvent of trichloromethane and methyl alcohol is as moving phase.
Process for purification described above, wherein said moving phase is trichloromethane: the methyl alcohol volume ratio is 1: the mixed solvent of (0～0.2), wherein the methyl alcohol volume is not 0; Wherein preferred described moving phase is trichloromethane: the methyl alcohol volume ratio is 1: the mixed solvent of (0～0.1).
Process for purification described above, wherein said stationary phase silica gel is column chromatography silica gel, for example can be that particle diameter is 45-250 μ m, the aperture is 20-100A
0Preferable particle size is 75-150 μ m, and the aperture is 20-30A
0Kiselgel A.
Process for purification described above, the pressure of wherein said column chromatography is 0.1-4.0pa, is preferably 0.5-2.0pa.
Process for purification described above, the column temperature of wherein said column chromatography keeps 30-40 ℃.
Process for purification described above, wherein the flow velocity of column chromatography is preferably 0.1-2.0cm/min.
Process for purification described above, wherein the applied sample amount of column chromatography is 100～300mg/ml column volume.
As the present invention's one specific embodiments, described process for purification, wherein said column chromatography for separation is to carry out the silicagel column loading after the nimesulide crude product is dissolved with moving phase, use the moving phase wash-out, collect the nimesulide position, wash with water, solid drier is dry, concentrating under reduced pressure steams except elutriant, gets the nimesulide sterling.
Process for purification described above, wherein said solid drier for example can be selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and the activated alumina.
The purity of the nimesulide sterling that process for purification of the present invention obtains is not less than 99.8%.
Silica gel chromatography is separated according to the adsorptive power of material on silica gel is different, the material that polarity is larger generally speaking is easily by silica gel adsorption, the weak material of polarity is difficult for by silica gel adsorption, and whole chromatography process namely is Adsorption and desorption, again absorption, desorption process again.The present invention is by repetition test and groping, be surprised to find that by selecting easy silica gel column chromatography method, use suitable stationary phase and moving phase, specifically, employing silica gel is stationary phase, and a certain proportion of trichloromethane and methanol mixed solvent are moving phase, can make with extra care efficiently and the purifying nimesulide, the yield and the purity that obtain nimesulide are all very high, are a kind of effective ways that obtain the high purity nimesulide.Easy, the easy row of the method, with low cost.
The Nimesulide compound method for detecting purity is: chromatographic column is C
18(150mm * 4.6mm, 5 μ m), moving phase is methyl alcohol-0.1% disodium phosphate soln (volume ratio is 65: 35), flow velocity is 1.0ml/min, the detection wavelength is 254nm, and column temperature is room temperature, sample size 10 μ l, theoretical plate number is calculated with the nimesulide peak should be not less than 4500, and the resolution of nimesulide and impurity peaks is up to specification greater than 1.5 tailing factors.
Embodiment
Further specify by the following examples the present invention, but should not be construed as limitation of the present invention.
Embodiment 1
15g nimesulide crude product (purity 98.5%) is dissolved in 350ml trichloromethane-methyl alcohol (1: 0.2), is added to the silicagel column top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 0.1pa, pump into trichloromethane-methyl alcohol (1: 0.2) again and carry out column chromatography, flow velocity is 0.1cm/min, and column temperature keeps 30 ℃, beginning timing, sampling, tracking monitor carries out Fractional Collections, collect liquid, wash anhydrous sodium sulfate drying with water, concentrating under reduced pressure steams except elutriant, gets nimesulide purifying product 14.3g, yield 95.3%, 151 ℃ of fusing points, purity 99.8%.
Embodiment 2
42g nimesulide crude product (purity 98.3%) is dissolved in 1000ml trichloromethane-methyl alcohol (1: 0.01), is added to the silicagel column top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 4.0pa, pump into trichloromethane-methyl alcohol (1: 0.01) again and carry out column chromatography, flow velocity is 2.0cm/min, and column temperature keeps 40 ℃, beginning timing, sampling, tracking monitor carries out Fractional Collections, collect liquid, wash anhydrous magnesium sulfate drying with water, concentrating under reduced pressure steams except elutriant, gets nimesulide purifying product 40.2g, yield 95.7%, 150 ℃ of fusing points, purity 99.9%.
Embodiment 3
28g nimesulide crude product (purity 98.2%) is dissolved in 500ml trichloromethane-methyl alcohol (1: 0.1), is added to the silicagel column top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 1.8pa, pump into trichloromethane-methyl alcohol (1: 0.1) again and carry out column chromatography, flow velocity is 1.1cm/min, and column temperature keeps 35 ℃, beginning timing, sampling, tracking monitor carries out Fractional Collections, collect liquid, wash with water, activated alumina is dry, concentrating under reduced pressure steams except elutriant, gets nimesulide purifying product 26.9g, yield 96.1%, 151 ℃ of fusing points, purity 99.9%.
Comparative Examples 1
15g nimesulide crude product (purity 98.5%) is dissolved in 350ml trichloromethane-methyl alcohol (1: 0.25), is added to the silicagel column top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 4.2pa, pump into trichloromethane-methyl alcohol (1: 0.25) again and carry out column chromatography, flow velocity is 0.08cm/min, and column temperature keeps 50 ℃, beginning timing, sampling, tracking monitor carries out Fractional Collections, collect liquid, wash anhydrous sodium sulfate drying with water, concentrating under reduced pressure steams except elutriant, gets nimesulide purifying product 10.9g, yield 72.6%, 151 ℃ of fusing points, purity 98.9%.
Comparative Examples 2
42g nimesulide crude product (purity 98.3%) is dissolved in the 1000ml trichloromethane, is added to the silicagel column top, weighting agent is particle diameter 75-150 μ m, aperture 20-30A
0Kiselgel A, the long 20cm of pillar, diameter 3cm, post press 0.08pa, pump into trichloromethane again and carry out column chromatography, flow velocity is 2.2cm/min, and column temperature keeps 25 ℃, beginning timing, sampling, tracking monitor carries out Fractional Collections, collect liquid, wash anhydrous magnesium sulfate drying with water, concentrating under reduced pressure steams except elutriant, gets nimesulide purifying product 31.3g, yield 74.5%, 150 ℃ of fusing points, purity 99.0%.
Compare by above-described embodiment and the used parameter of comparative example and result, can find out, in the process for purification scope of Nimesulide compound provided by the invention, the purifying product yield that makes is high, and purity is good; And the product that the outer parameter of the scope of the invention obtains, purity is low, and yield is also low.Proved absolutely the practical application effect of the inventive method.
According to preferred embodiment the present invention is described.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (8)
1. the Nimesulide compound purification process of a formula (I) structure,
It is characterized in that comprising the step that obtains the nimesulide sterling by column chromatography for separation, and described column chromatography is as stationary phase with silica gel, the mixed solvent of trichloromethane and methyl alcohol is as moving phase, and, described stationary phase is the column chromatography silica gel special, particle diameter is 45-250 μ m, the aperture is 20-100A °, described moving phase is trichloromethane: the methyl alcohol volume ratio is 1: the mixed solvent of (0～0.2), wherein the methyl alcohol volume is not 0, the pressure of column chromatography is 0.1-4.0Pa, and the column temperature of column chromatography keeps 30-40 ℃, and the flow velocity of column chromatography is 0.1-2.0cm/min.
2. purification process according to claim 1, it is characterized in that described moving phase is trichloromethane: the methyl alcohol volume ratio is 1: the mixed solvent of (0～0.1), wherein the methyl alcohol volume is not 0.
3. purification process according to claim 1 is characterized in that described stationary phase is the column chromatography silica gel special, for particle diameter is that 75-150 μ m, aperture are 20-30A ° Kiselgel A.
4. purification process according to claim 1, the pressure that it is characterized in that described column chromatography is 0.5-2.0Pa.
5. purification process according to claim 1, the applied sample amount that it is characterized in that described column chromatography is 100～300mg/mL column volume.
6. each described purification process according to claim 1-5, it is characterized in that described column chromatography for separation is to carry out the silicagel column loading after the nimesulide crude product is dissolved with moving phase, use the moving phase wash-out, collect the nimesulide position, wash with water, solid drier is dry, concentrating under reduced pressure, steam except elutriant, get the nimesulide sterling.
7. purification process according to claim 6, wherein said solid drier is selected from one or more in anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate and the activated alumina.
8. purification process according to claim 6, the purity of wherein said nimesulide sterling is not less than 99.8%.
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| CN 200910146948 CN101643440B (en) | 2009-06-08 | 2009-06-08 | Nimesulide compound and purification method thereof |
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| CN 200910146948 CN101643440B (en) | 2009-06-08 | 2009-06-08 | Nimesulide compound and purification method thereof |
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| CN101643440A CN101643440A (en) | 2010-02-10 |
| CN101643440B true CN101643440B (en) | 2013-04-24 |
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| CN105384664A (en) * | 2015-10-15 | 2016-03-09 | 中国药科大学 | Novel crystal habit of nimesulide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3856859A (en) * | 1973-06-08 | 1974-12-24 | Riker Laboratories Inc | Selective nitration process |
| CN1511828A (en) * | 2002-12-31 | 2004-07-14 | �й������ž�����ҽѧ��ѧԺ����ҽ | Sufonic aniline derivatives and their medicinal use |
-
2009
- 2009-06-08 CN CN 200910146948 patent/CN101643440B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3856859A (en) * | 1973-06-08 | 1974-12-24 | Riker Laboratories Inc | Selective nitration process |
| CN1511828A (en) * | 2002-12-31 | 2004-07-14 | �й������ž�����ҽѧ��ѧԺ����ҽ | Sufonic aniline derivatives and their medicinal use |
Non-Patent Citations (1)
| Title |
|---|
| A. A. Syed et al.CHROMATOGRAPHIC METHODS FOR DETERMINATION OF NIMESULIDE AND FOR STABILITY STUDIES.《ACTA CHROMATOGRAPHICA》.2002,(第12期),第95-103页. * |
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Effective date of registration: 20130729 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co., Ltd. Address before: 310016 room 1, 1801 Qian Tang garden, Jianggan District Shengshi, Hangzhou, Zhejiang Patentee before: Deng Jujuan |
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