CN102746232A - Preparation method of celecoxib impurity - Google Patents
Preparation method of celecoxib impurity Download PDFInfo
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- CN102746232A CN102746232A CN2012102260517A CN201210226051A CN102746232A CN 102746232 A CN102746232 A CN 102746232A CN 2012102260517 A CN2012102260517 A CN 2012102260517A CN 201210226051 A CN201210226051 A CN 201210226051A CN 102746232 A CN102746232 A CN 102746232A
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Abstract
The invention discloses a preparation method of impurities shown as a formula II, a formula III and a formula VII in celecoxib. According to the method, intermediates obtained in a reaction process can directly participate into a next reaction without separation, so as to simplify the operation process and shorten the reaction time. A final product has purity higher than 99%, can be used in drug testing as a reference, and has high economic benefit.
Description
Technical field
The invention belongs to medical technical field, relate to the preparation method of impurities in a kind of medicine, specifically be meant the preparation method of impurity in the celecoxib.
Background technology
The untoward reaction that medicine produces in clinical use also has much relations except outside the Pass the pharmacologically active with principal constituent has with the impurity that exists in the medicine.For guaranteeing clinical application safety, need the impurity in the strict control medicine.And in order to control the amount of impurity in the medicine, in drug quality detects, will inevitably use the higher single impurity compound of purity as reference substance, so the preparation of impurities just seems particularly important in the medicine.
Celecoxib (Celecoxib) is II type cyclooxygenase (COX-2) suppressor factor of first listing; Develop by U.S. Searle company; Be used to treat diseases associated with inflammation such as osteo-arthritis and rheumatoid arthritis in U.S.'s listing, and had advantages such as gi tract and Toxicity of Kidney are little in 1999.The chemical name of celecoxib is 4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, and structural formula is following:
。
Impurity in the celecoxib bulk drug of discovering at present has nine kinds, and its structural formula is respectively:
Its chemical name is respectively:
I: 4-(3-p-methylphenyl-5-Trifluoromethyl-1 H-pyrazol-1-yl) methyl benzenesulfonamide
II: 4-(5-o-tolyl-3-Trifluoromethyl-1 H-pyrazol-1-yl) methyl benzenesulfonamide
III: 4-(tolyl between 5--3-Trifluoromethyl-1 H-pyrazol-1-yl) methyl benzenesulfonamide
IV: (E)-4-(2-(1-p-methylphenyl ethylidene) diazanyl) benzsulfamide
V: (E)-4-(2-(tolyl ethylidene between 1-) diazanyl) benzsulfamide
VI: (E)-4-(2-(1-o-tolyl ethylidene) diazanyl) benzsulfamide
VII: 3-methyl fluoride-5-p-methylphenyl-1H-pyrazoles
VIII: methyl p-methyl benzoate
IX: p-methyl aceto phenone.
The article that people such as Satyanarayana deliver " Isolation; Synthesis and characterization of impurities in Celecoxib a cox-2 inhibitor " in disclose that structural formula is five kinds of impurity of I, II, VII, VIII, IX in the celecoxib, and provided the preparation method of impurity II and VII.This method gained midbody a need separate just can carry out next step reaction, and operating process is loaded down with trivial details, and the reaction times is long, more than 14 hours, has greatly increased production cost, is inappropriate for practical application.The reaction equation of this method is as follows:
Summary of the invention
Technical problem to be solved by this invention provides the preparation method of impurity in a kind of celecoxib, and this method need not separation of intermediates, and is simple to operate, and cost is low, can produce high economic benefit.
Purpose according to the invention realizes through following technical scheme:
The preparation method of the impurity of contained formula II, formula III, formula VII in a kind of celecoxib,
Ⅱ Ⅲ Ⅶ
Operate as follows:
A. in the organic solvent, be starting raw material, in the alcoholic solution of strong alkaline substance, generate corresponding midbody with the Trifluoroacetic Acid Ethyl Ester reaction with the methyl acetophenone;
B. the gained midbody is regulated pH value without separation with hydrochloric acid soln or sulphuric acid soln among the step a, and diazanyl benzsulfamide hydrochloride or Hydrazine Hydrate 80 is reacted, and obtains the impurity bullion of formula II, formula III or formula VII;
C. the impurity bullion that obtains among the step b is carried out recrystallization in mixed solvent, promptly obtain the impurity of purity in the formula II more than 99%, formula III or formula VII.
Above-mentioned preparation method, methyl acetophenone described in the step a is the o-methyl-benzene ethyl ketone, reacts among the step b with to diazanyl benzsulfamide hydrochloride, and the impurity bullion that obtains is the impurity bullion of formula II, and the impurity among the step c is the impurity of formula II.
Above-mentioned preparation method, methyl acetophenone described in the step a be between methyl acetophenone, among the step b with to diazanyl benzsulfamide hydrochloride reaction, the impurity bullion that obtains is the impurity bullion of formula III, the impurity among the step c is the impurity of formula III.
Above-mentioned preparation method, methyl acetophenone described in the step a is the o-methyl-benzene ethyl ketone, and with the Hydrazine Hydrate 80 reaction, the impurity bullion that obtains is the impurity bullion of formula VII among the step b, and the impurity among the step c is the impurity of formula VII.
Above-mentioned preparation method, organic solvent described in the step a is THF, MTBE, ether or isopropyl ether.
Above-mentioned preparation method, strong alkaline substance described in the step a is sodium methylate, sodium ethylate or sodium tert-butoxide.
Above-mentioned preparation method regulates the pH value to 1-6 among the step b.
Above-mentioned preparation method, mixed solvent described in the step c is C
1-C
3Alcohol and the mixed solvent of water or the mixed solvent of carboxylicesters and straight-chain paraffin, said C
1-C
3Alcohol be methyl alcohol, ethanol or Virahol, said carboxylicesters is methyl-formiate, ethyl formate, methyl acetate, ETHYLE ACETATE or butylacetate, said straight-chain paraffin is Skellysolve A, normal hexane or normal heptane.
Preparing method's according to the invention reaction equation is following:
In the method for the invention, the midbody that methyl acetophenone and Trifluoroacetic Acid Ethyl Ester reaction obtain need not be separated, and can directly in its reaction solution, add follow-up material and react, and can obtain celecoxib impurity.Steps such as this method saved the required extraction of separation of intermediates, concentrate have greatly been simplified operation, and entire reaction course is no more than 5 hours, have improved working efficiency greatly, have obviously reduced production cost, can produce remarkable economic efficiency.
Description of drawings
Fig. 1 is the HPLC purity collection of illustrative plates of embodiment 1 gained celecoxib impurity II.
Fig. 2 is the HPLC purity collection of illustrative plates of embodiment 2 gained celecoxib impurity III.
Fig. 3 is the HPLC purity collection of illustrative plates of embodiment 3 gained celecoxib impurity VII.
Embodiment
The preparation of embodiment 1 celecoxib impurity II
Under the agitation condition, in the 50mL there-necked flask, add 2g THF, 1g o-methyl-benzene ethyl ketone, 20% methanol solution of sodium methylate 10mL, 1.4g Trifluoroacetic Acid Ethyl Ester successively; Heating, 50-60 ℃ of insulation reaction 1.5h, hydrochloric acid soln conditioned reaction liquid pH=2-3 with 10%; Agitation condition adds 1.65g down to diazanyl benzsulfamide hydrochloride and 6g absolute ethyl alcohol, is warming up to 60-70 ℃, reaction 1h; Be cooled to 50 ℃ under the agitation condition, continue again behind the crystallization to stir 30min, be cooled to 0-5 ℃; Stir 2h, cross the bullion that filters celecoxib impurity II.Be weighed as 1.60g after the drying.
Celecoxib impurity II bullion is added the 50mL there-necked flask,, the mixed solvent 9.1g of adding absolute ethyl alcohol: water=1:1.2 (volume ratio); Be heated with stirring to 70 ℃, solid dissolves continued entirely and stirs 10min, is cooled to 50 ℃ of crystallizatioies; Continue again to stir 30min, be cooled to 0-5 ℃, stir 2h; Filter, get celecoxib impurity II.Be weighed as 1.54g after the drying, yield 54.4%, HPLC purity is 99.84%.
The preparation of embodiment 2 celecoxib impurity III
Under the agitation condition, in the 50mL there-necked flask, add methyl acetophenone between 2g THF, 1g, 20% methanol solution of sodium methylate 10mL, 1.4g Trifluoroacetic Acid Ethyl Ester successively; Heating, 50-60 ℃ of insulation reaction 1.5h, hydrochloric acid soln conditioned reaction liquid pH=2-3 with 10%; Agitation condition adds 1.65g down to diazanyl benzsulfamide hydrochloride and 6g absolute ethyl alcohol, is warming up to 60-70 ℃, reaction 1h; Be cooled to 50 ℃ under the agitation condition, continue again behind the crystallization to stir 30min, be cooled to 0-5 ℃; Stir 2h, cross the bullion that filters celecoxib impurity III.
Celecoxib impurity III bullion is added the 50mL there-necked flask, add the mixed solvent 9.1g of absolute ethyl alcohol: water=1:1.2 (volume ratio), be heated with stirring to 70 ℃; Solid dissolves continued entirely and stirs 10min, is cooled to 50 ℃ of crystallizatioies, continues to stir 30min again; Be cooled to 0-5 ℃; Stir 2h, filter, get celecoxib impurity III.Weigh after the drying, yield 55.3%, HPLC purity is 99.95%.
The preparation of embodiment 3 celecoxib impurity VII
Under the agitation condition, in the 50mL there-necked flask, add 2g MTBE, 1g p-methyl aceto phenone, 25% methanol solution of sodium methylate 8mL, 1.4g Trifluoroacetic Acid Ethyl Ester successively; Heating, 50-60 ℃ of insulation reaction 1.5h, hydrochloric acid soln conditioned reaction liquid pH=2-3 with 10%; Agitation condition adds 0.5g Hydrazine Hydrate 80 and 6g anhydrous methanol down, is warming up to 60-70 ℃, reaction 1h; Be cooled to 50 ℃ under the agitation condition, continue again behind the crystallization to stir 30min, be cooled to 0-5 ℃; Stir 2h, cross the bullion that filters celecoxib impurity VII.Drying is weighed as 1.0g.
Celecoxib impurity VII bullion is added the 50mL there-necked flask, add the mixed solvent 8.0g of Virahol: water=1:1.2 (volume ratio), be heated with stirring to 75 ℃; Solid dissolves continued entirely and stirs 10min, is cooled to 50 ℃ of crystallizatioies, continues to stir 30min again; Be cooled to 0-5 ℃; Stir 2h, filter, get celecoxib impurity VII.Get white crystalline powder after the drying, be weighed as 0.92, yield 57.3%, HPLC purity is 99.97%.
Embodiment 4-10
The method that following embodiment and embodiment 1-3 adopt is basic identical; Solvent types and volume ratio when difference is the kind of the first step reaction solvent, the scope of regulating the pH value, temperature of reaction and recrystallization, table 1 has provided the representative control node of part.
Table 1
| Numbering | The first step reaction solvent | The first step is regulated pH | The first step temperature of reaction | Recrystallization solvent kind and volume ratio | Title product | | Yield |
| Embodiment | |||||||
| 4 | THF | 1 | 20℃ | The mixed solvent of methyl alcohol and water (1:1.1) | The impurity II | 99.35% | 50.6% |
| Embodiment 5 | |
3 | 55℃ | Virahol and water mixed solvent (1:1.3) | The impurity II | 99.92% | 55.3% |
| Embodiment 6 | |
4 | 35℃ | The mixed solvent of ETHYLE ACETATE and normal hexane (1:1.2) | The impurity III | 99.26% | 53.5% |
| Embodiment 7 | Ether | 5 | 65℃ | Methyl acetate and Skellysolve A mixed solvent (1:1.4) | The impurity III | 99.65% | 48.1% |
| Embodiment 8 | Isopropyl ether | 6 | 80℃ | Butylacetate and normal hexane (1:1.5) | The impurity VII | 99.34% | 49.6% |
| Embodiment 9 | |
2 | 55℃ | The mixed solvent of ethanol and water (1:1.1) | The impurity VII | 99.94% | 55.1% |
| |
|
3 | 50℃ | Virahol and water mixed solvent (1:1.3) | The impurity VII | 99.95% | 56.6% |
Claims (11)
1. the preparation method of the impurity of contained formula II, formula III, formula VII in the celecoxib,
Ⅱ Ⅲ Ⅶ
It is characterized in that, operate as follows:
A. in the organic solvent, be starting raw material, in the alcoholic solution of strong alkaline substance, generate corresponding midbody with the Trifluoroacetic Acid Ethyl Ester reaction with the methyl acetophenone;
B. the gained midbody is regulated pH value without separation with hydrochloric acid soln or sulphuric acid soln among the step a, and diazanyl benzsulfamide hydrochloride or Hydrazine Hydrate 80 is reacted, and obtains the impurity bullion of formula II, formula III or formula VII;
C. the impurity bullion that obtains among the step b is carried out recrystallization in mixed solvent, promptly obtain the impurity of purity in the formula II more than 99%, formula III or formula VII.
2. according to the said preparation method of claim 1, methyl acetophenone described in the step a is the o-methyl-benzene ethyl ketone, reacts among the step b with to diazanyl benzsulfamide hydrochloride, and the impurity bullion that obtains is the impurity bullion of formula II, and the impurity among the step c is the impurity of formula II.
3. according to the said preparation method of claim 1, methyl acetophenone described in the step a be between methyl acetophenone, among the step b with to the reaction of diazanyl benzsulfamide hydrochloride, the impurity bullion that obtains is the impurity bullion of formula III, the impurity among the step c is the impurity of formula III.
4. according to the said preparation method of claim 1, methyl acetophenone described in the step a is the o-methyl-benzene ethyl ketone, and with the Hydrazine Hydrate 80 reaction, the impurity bullion that obtains is the impurity bullion of formula VII among the step b, and the impurity among the step c is the impurity of formula VII.
5. according to the said preparation method of claim 1, organic solvent described in the step a is THF, MTBE, ether or isopropyl ether.
6. according to the said preparation method of claim 1, strong alkaline substance described in the step a is sodium methylate, sodium ethylate or sodium tert-butoxide.
7. according to the said preparation method of claim 1, regulate the pH value among the step b to 1-6.
8. according to the said preparation method of claim 1, mixed solvent described in the step c is C
1-C
3Alcohol and the mixed solvent of water or the mixed solvent of carboxylicesters and straight-chain paraffin.
9. said according to Claim 8 preparation method, said C
1-C
3Alcohol be methyl alcohol, ethanol or Virahol.
10. said according to Claim 8 preparation method, said carboxylicesters is methyl-formiate, ethyl formate, methyl acetate, ETHYLE ACETATE or butylacetate.
11. said according to Claim 8 preparation method, said straight-chain paraffin is Skellysolve A, normal hexane or normal heptane.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104418804A (en) * | 2013-09-06 | 2015-03-18 | 南京圣和药业股份有限公司 | Celecoxib impurity as well as preparation method and application thereof |
| CN107011265A (en) * | 2017-05-19 | 2017-08-04 | 福建省福抗药业股份有限公司 | Synthesize 4 [base of 5 (2 aminomethyl phenyl) 3 (trifluoromethyl) 1 hydrogen pyrazoles 1] benzsulfamides |
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1495170A (en) * | 1993-11-30 | 2004-05-12 | G.D.ɪ����˾ | Substituted pyrazolyl benzsulfamide compound for curing inflammation |
-
2012
- 2012-07-03 CN CN2012102260517A patent/CN102746232A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1495170A (en) * | 1993-11-30 | 2004-05-12 | G.D.ɪ����˾ | Substituted pyrazolyl benzsulfamide compound for curing inflammation |
Non-Patent Citations (2)
| Title |
|---|
| THOMAS D. PENNING ET AL.: "Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)", 《J. MED. CHEM.》 * |
| U.SATYANARAYANA ET AL.: "Isolation, synthesis and characterization of impurities in Celecoxib a cox-2 inhibitor", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104418804A (en) * | 2013-09-06 | 2015-03-18 | 南京圣和药业股份有限公司 | Celecoxib impurity as well as preparation method and application thereof |
| CN107011265A (en) * | 2017-05-19 | 2017-08-04 | 福建省福抗药业股份有限公司 | Synthesize 4 [base of 5 (2 aminomethyl phenyl) 3 (trifluoromethyl) 1 hydrogen pyrazoles 1] benzsulfamides |
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
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Application publication date: 20121024 |