CN104592142A - Synthesis method of parecoxib sodium impurity - Google Patents
Synthesis method of parecoxib sodium impurity Download PDFInfo
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- CN104592142A CN104592142A CN201510002076.2A CN201510002076A CN104592142A CN 104592142 A CN104592142 A CN 104592142A CN 201510002076 A CN201510002076 A CN 201510002076A CN 104592142 A CN104592142 A CN 104592142A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract
The invention discloses a synthesis method of a parecoxib sodium impurity, namely N-[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonic acid, belonging to the technical field of chemical pharmacy. The synthesis method comprises the step of carrying out sulfonation reaction and hydrolysis reaction by taking 5-methyl-3, 4-diphenylisoxazole as a raw material to obtain the parecoxib sodium impurity. The synthesized high-purity parecoxib sodium impurity can be used as a standard impurity in parecoxib sodium finished product detection and analysis, so that the accurate impurity location and qualification realized through the parecoxib sodium finished product detection and analysis are improved, the impurity can be better controlled, and furthermore the quality of a parecoxib sodium finished product is improved. The synthesis method disclosed by the invention is simple in operation; the raw material is cheap and available; and the yield of the obtained product is up to 95+/-5%, and the HPLC purity is larger than or equal to 98%.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to the synthetic method of a kind of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.
Background technology
After the noxious stimulations such as operation, wound, Inflammatory response can cause the release of inflammatory mediator and algogenic substance, they are except direct induced pain, also can distend the blood vessels, tissue edema, make that effector ceptor susceptibility increases, the threshold of pain reduces, thus cause peripheral pain perception irritated.Selective COX-2 inhibitor can effectively suppress periphery COX-2 to express, reduce periphery prostaglandin(PG) synthesis, thus play analgesic and anti-inflammatory effects, maincenter COX-2 can be suppressed to express simultaneously, suppression maincenter prostaglandin(PG) synthesizes and inhibition of pain is super quick, plays periphery, the dual analgesia advantage of maincenter.
Parecoxib Sodium chemistry is by name: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionamide sodium salt; Parecoxib Sodium is a kind of highly selective inhibition of COX-2; can be used for the short of postoperative pain, there is desirable water-soluble physico-chemical property.
Impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid is that in Parecoxib Sodium building-up process, after sulfonation reaction, hydrolysis produces, may remain in Parecoxib Sodium finished product, affect quality product, its structural formula is as shown in (I).
Through retrieval, not yet there is the bibliographical information synthesized about this impurity, therefore, provide a kind of synthetic method of Parecoxib Sodium impurity E to have important practical significance for the preparation of contamination levels product.
Summary of the invention
The object of the invention is to the shortcoming overcoming prior art, the synthetic method of a kind of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid is provided, this synthetic method has simple to operate, raw material and is cheaply easy to get, the advantage that yield is high, purity is high.
Object of the present invention is achieved through the following technical solutions: a kind of synthetic method of Parecoxib Sodium impurity E, and described impurity E is N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid, and synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonation reaction: be added in reaction flask by 5-methyl-3,4-phenylbenzene isoxzzole, methylene dichloride, chlorsulfonic acid, 40 ~ 50 DEG C of back flow reaction 4 ~ 8h, reaction solution obtains intermediate I through aftertreatment;
S2. hydrolysis reaction: above-mentioned gained intermediate I added in reaction flask, then add water and acetonitrile, 85 ~ 95 DEG C of back flow reaction 12 ~ 20h, concentrating under reduced pressure obtains Parecoxib Sodium impurity E.
Further, the weight ratio of the methyl-3,4-of 5-described in step S1 phenylbenzene isoxzzole, methylene dichloride and chlorsulfonic acid is 1:3 ~ 6:2 ~ 5.
Further, the weight ratio of intermediate I described in step S2, water and acetonitrile is 1:2 ~ 5:2 ~ 5.
Further, post-treating method described in step S1 is: drop in water by reaction solution after completion of the reaction, and with dichloromethane extraction, organic phase adds ethyl acetate crystallization 1.5 ~ 2.5h after concentrated, and gained crystal is intermediate I.
Further, the pressure≤-0.07MPa of concentrating under reduced pressure described in step S2.
The present invention has the following advantages: the present invention is with 5-methyl-3, 4-phenylbenzene isoxzzole is raw material, Parecoxib Sodium impurity E is obtained through sulfonation reaction and hydrolysis reaction, the Parecoxib Sodium impurity E of synthesis of high purity can be used as the impurity E standard substance in the analysis of Parecoxib Sodium finished product detection, thus promote Parecoxib Sodium finished product detection and analyze the accurate polarization of impurity E and qualitative, be conducive to strengthening the control to this impurity, and then improve Parecoxib Sodium final product quality, method raw material provided by the invention is cheaply easy to get, simple to operate, products obtained therefrom yield 95% ± 5%, HPLC purity >=98%.
Accompanying drawing explanation
Fig. 1 is Parecoxib Sodium impurity E purity detecting HPLC collection of illustrative plates;
Fig. 2 is Parecoxib Sodium impurity E mass spectrum;
Fig. 3 is Parecoxib Sodium impurity E hydrogen nuclear magnetic resonance spectrogram.
Embodiment
Below in conjunction with drawings and Examples, the present invention will be further described, and protection scope of the present invention is not limited to the following stated.
Embodiment 1: the synthesis of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 3g 5-methyl-3,4-phenylbenzene isoxzzole, 9g methylene dichloride, 6g chlorsulfonic acid adds in reaction flask, 40 DEG C of back flow reaction 4 hours, reaction solution is dropped in 50g water, 12g dichloromethane extraction, concentrated dry, add 3g ethyl acetate, 12g sherwood oil crystallization 1.5 hours, filters to obtain 3.24g intermediate compound I, yield 76.1%.
By 2g intermediate compound I, add in reaction flask, add 4g water, 4g acetonitrile, 85 DEG C of back flow reaction 12h, be decompressed to-0.07MPa and concentrate to obtain white solid 1.78g, yield 94.2%.
As shown in Figure 1, purity is 99.0% to Parecoxib Sodium impurity E purity detecting HPLC collection of illustrative plates.；
Parecoxib Sodium impurity E mass spectrum as shown in Figure 2, MS:316 (M+1);
Parecoxib Sodium impurity E proton nmr spectra as shown in Figure 3.H spectrum heavy water exchange rear display chemical shift chemical shift δ (7.192-7.655) totally 9 hydrogen is benzene ring hydrogen, and chemical shift δ (2.451-2.529) is unimodal, totally three hydrogen, and this hydrogen is methyl hydrogen.Detected result conforms to Parecoxib Sodium impurity E structure.
Embodiment 2: the synthesis of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 3g 5-methyl-3,4-phenylbenzene isoxzzole, 18g methylene dichloride, 15g chlorsulfonic acid adds in reaction flask, 50 DEG C of back flow reaction 8 hours, reaction solution is dropped in 50g water, 12g dichloromethane extraction, concentrated dry, add 3g ethyl acetate, 12g sherwood oil crystallization 2.5 hours, filters to obtain 3.17g intermediate compound I, yield 74.5%.
By 2g intermediate compound I, add in reaction flask, add 10g water, 10g acetonitrile, 95 DEG C of back flow reaction 20h, be decompressed to-0.08MPa and concentrate to obtain white solid 1.82g, yield 96.3%, HPLC purity 98.7%.
Embodiment 3: the synthesis of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 5g 5-methyl-3,4-phenylbenzene isoxzzole, 20g methylene dichloride, 20g chlorsulfonic acid adds in reaction flask, 42 DEG C of back flow reaction 6 hours, reaction solution is dropped in 85g water, 20g dichloromethane extraction, concentrated dry, add 5g ethyl acetate, 20g sherwood oil crystallization 2 hours, filters to obtain 5.80g intermediate compound I, yield 81.7%.
By 5g intermediate compound I, add in reaction flask, add 15g water, 15g acetonitrile, 90 DEG C of back flow reaction 16h, be decompressed to-0.10MPa and concentrate to obtain white solid 4.45g, yield 94.2%, HPLC purity 98.8%.
Embodiment 4: the synthesis of Parecoxib Sodium impurity E N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 5g 5-methyl-3,4-phenylbenzene isoxzzole, 26g methylene dichloride, 25g chlorsulfonic acid adds in reaction flask, 47 DEG C of back flow reaction 5 hours, reaction solution is dropped in 85g water, 20g dichloromethane extraction, concentrated dry, add 5g ethyl acetate, 20g sherwood oil crystallization 1.8 hours, filters to obtain 5.54g intermediate compound I, yield 78.1%.
By 5g intermediate compound I, add in reaction flask, add 20g water, 15g acetonitrile, 93 DEG C of back flow reaction 18h, be decompressed to-0.09MPa and concentrate to obtain white solid 4.57g, yield 96.8%, HPLC purity 99.2%.
Claims (5)
1. a synthetic method for Parecoxib sodium impurity, described impurity is N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid, and it is characterized in that, synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonation reaction: be added in reaction flask by 5-methyl-3,4-phenylbenzene isoxzzole, methylene dichloride, chlorsulfonic acid, 40 ~ 50 DEG C of back flow reaction 4 ~ 8h, reaction solution obtains intermediate I through aftertreatment;
S2. hydrolysis reaction: above-mentioned gained intermediate I added in reaction flask, then add water and acetonitrile, 85 ~ 95 DEG C of back flow reaction 12 ~ 20h, concentrating under reduced pressure obtains Parecoxib sodium impurity.
2. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, is characterized in that, the weight ratio of the methyl-3,4-of 5-described in step S1 phenylbenzene isoxzzole, methylene dichloride and chlorsulfonic acid is 1:3 ~ 6:2 ~ 5.
3. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, is characterized in that, the weight ratio of intermediate I described in step S2, water and acetonitrile is 1:2 ~ 5:2 ~ 5.
4. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, it is characterized in that post-treating method described in step S1 is: drop in water by reaction solution after completion of the reaction, with dichloromethane extraction, organic phase adds ethyl acetate crystallization 1.5 ~ 2.5h after concentrated, and gained crystal is intermediate I.
5. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, is characterized in that, the pressure≤-0.07MPa of concentrating under reduced pressure described in step S2.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104965041A (en) * | 2015-06-11 | 2015-10-07 | 成都克莱蒙医药科技有限公司 | High performance liquid chromatography detection method for parecoxib sodium isomer |
| CN105130919A (en) * | 2015-09-11 | 2015-12-09 | 江苏嘉逸医药有限公司 | Method and equipment for preparing 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonyl chloride |
| CN105367508A (en) * | 2015-11-25 | 2016-03-02 | 蚌埠丰原医药科技发展有限公司 | Preparation method of parecoxib sodium synthesis technology impurities |
| CN109734681A (en) * | 2019-02-13 | 2019-05-10 | 四川蓝励医药科技有限公司 | SC 69124 sodium impurity and preparation method thereof |
| CN114441666A (en) * | 2020-11-05 | 2022-05-06 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
-
2015
- 2015-01-04 CN CN201510002076.2A patent/CN104592142A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| A. R. REDDY ET AL.: "APPLICATION OF [3+2]-CYCLOADDITION IN THE SYNTHESIS OF VALDECOXIB", 《SYNTHETIC COMMUNICATIONS》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104965041A (en) * | 2015-06-11 | 2015-10-07 | 成都克莱蒙医药科技有限公司 | High performance liquid chromatography detection method for parecoxib sodium isomer |
| CN104965041B (en) * | 2015-06-11 | 2016-06-29 | 成都克莱蒙医药科技有限公司 | A kind of high-efficiency liquid chromatography method for detecting of Parecoxib Sodium isomer |
| CN105130919A (en) * | 2015-09-11 | 2015-12-09 | 江苏嘉逸医药有限公司 | Method and equipment for preparing 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonyl chloride |
| CN105130919B (en) * | 2015-09-11 | 2017-04-19 | 江苏嘉逸医药有限公司 | Method and equipment for preparing 4-(5-methyl-3-phenyl-4-isoxazolyl) benzenesulfonyl chloride |
| CN105367508A (en) * | 2015-11-25 | 2016-03-02 | 蚌埠丰原医药科技发展有限公司 | Preparation method of parecoxib sodium synthesis technology impurities |
| CN109734681A (en) * | 2019-02-13 | 2019-05-10 | 四川蓝励医药科技有限公司 | SC 69124 sodium impurity and preparation method thereof |
| CN114441666A (en) * | 2020-11-05 | 2022-05-06 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
| CN114441666B (en) * | 2020-11-05 | 2024-02-27 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
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Application publication date: 20150506 |