CN104592140A - Synthesis method of parecoxib sodium impurity - Google Patents
Synthesis method of parecoxib sodium impurity Download PDFInfo
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- CN104592140A CN104592140A CN201510002045.7A CN201510002045A CN104592140A CN 104592140 A CN104592140 A CN 104592140A CN 201510002045 A CN201510002045 A CN 201510002045A CN 104592140 A CN104592140 A CN 104592140A
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- 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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Abstract
The invention discloses a synthesis method of a parecoxib sodium impurity, namely N-[3-(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 B N-[3-(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 B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid be in Parecoxib Sodium building-up process sulfonation occur between position time the isomer that produces be hydrolyzed further, 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 B 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 B N-[3-(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 B, and described impurity B is N-[3-(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: by 5-methyl-3,4-phenylbenzene isoxzzole, zinc chloride, chlorsulfonic acid are added in reaction flask, 50 ~ 70 DEG C of reaction 1.5 ~ 2.5h, reaction solution obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE through aftertreatment;
S2. hydrolysis reaction: above-mentioned gained N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 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 B.
Further, the weight ratio of the methyl-3,4-of 5-described in step S1 phenylbenzene isoxzzole, zinc chloride and chlorsulfonic acid is 1:0.5 ~ 1:1 ~ 5.
Further, the weight ratio of N-described in step S2 [3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, water and acetonitrile is 1:20 ~ 40:20 ~ 40.
Further, post-treating method described in step S1 is: drop in frozen water by reaction solution after completion of the reaction, with after cake filtration, filter cake is dissolved in ethyl acetate, add sherwood oil and carry out a crystallization, secondary crystallization after crystal concentrating under reduced pressure, gained secondary crystal, at 50 ~ 60 DEG C of drying 6 ~ 10h, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE.
Further, the pressure of concentrating under reduced pressure described in step S2 is≤-0.07MPa.
The present invention has the following advantages: the present invention is with 5-methyl-3, 4-phenylbenzene isoxzzole is raw material, Parecoxib Sodium impurity B is obtained through sulfonation reaction and hydrolysis reaction, the Parecoxib Sodium impurity B of synthesis of high purity can be used as the impurity B 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 B 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 B purity HPLC collection of illustrative plates;
Fig. 2 is Parecoxib Sodium impurity B mass spectrum;
Fig. 3 is Parecoxib Sodium impurity B 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 B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 5g zinc chloride, 10g chlorsulfonic acid are added in reaction flask, 50 DEG C of reaction 1.5h, after completion of the reaction, drop in 100g frozen water, filter, filter cake is dissolved in 10g ethyl acetate, adds 50g sherwood oil crystallization body, filter, filtrate reduced in volume is to dry, concentrated complete, add 200g sherwood oil, filter, 50 DEG C of constant pressure and dries are about 6h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.5g, yield 38.8%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, add in reaction flask, add 100g water, 100g acetonitrile, 85 DEG C of back flow reaction 12h, be decompressed to-0.08MPa and concentrate to obtain white solid 4.5g, be N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid, yield 95.3%.
As shown in Figure 1, purity is 98.5% to Parecoxib Sodium impurity B HPLC collection of illustrative plates.
Parecoxib Sodium impurity B mass spectrum as shown in Figure 2, MS:316 (M+1);
As shown in Figure 3, H spectrum shows chemical shift is 4.825 have a smooth peak to Parecoxib Sodium impurity B proton nmr spectra, and this peak is reactive hydrogen; Chemical shift (7.009-7.604) totally 9 hydrogen is benzene ring hydrogen, and chemical shift (2.384-2.464) is unimodal, totally three hydrogen, and this hydrogen is methyl hydrogen.Detected result conforms to Parecoxib Sodium impurity B structure.
Embodiment 2: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 10g zinc chloride, 50g chlorsulfonic acid are added in reaction flask, 70 DEG C of reaction 2.5h, after completion of the reaction, drop in 100g frozen water, filter, filter cake is dissolved in 10g ethyl acetate, adds 50g sherwood oil crystallization body, filter, filtrate reduced in volume is to dry, concentrated complete, add 200g sherwood oil, filter, 60 DEG C of constant pressure and dries are about 10h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.2g, yield 36.7%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, add in reaction flask, add 200g water, 200g acetonitrile, 95 DEG C of back flow reaction 20h, be decompressed to-0.07MPa and concentrate to obtain white solid 4.3g, be N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 91.0%, purity is 99.1%.
Embodiment 3: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 7g zinc chloride, 30g chlorsulfonic acid are added in reaction flask, 60 DEG C of reaction 1.8h, after completion of the reaction, drop in 100g frozen water, filter, filter cake is dissolved in 10g ethyl acetate, adds 50g sherwood oil crystallization body, filter, filtrate reduced in volume is to dry, concentrated complete, add 200g sherwood oil, filter, 52 DEG C of constant pressure and dries are about 7h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 6.1g, yield 43.0%.
By above-mentioned for 5.5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, add in reaction flask, add 160g water, 160g acetonitrile, 90 DEG C of back flow reaction 16h, be decompressed to-0.09MPa and concentrate to obtain white solid 4.8g, be N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 92.4%, purity is 98.3%.
Embodiment 4: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 9g zinc chloride, 42g chlorsulfonic acid are added in reaction flask, 65 DEG C of reaction 2h, after completion of the reaction, drop in 100g frozen water, filter, filter cake is dissolved in 10g ethyl acetate, adds 50g sherwood oil crystallization body, filter, filtrate reduced in volume is to dry, concentrated complete, add 200g sherwood oil, filter, 58 DEG C of constant pressure and dries are about 9h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.4g, yield 38.1%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, add in reaction flask, add 180g water, 160g acetonitrile, 92 DEG C of back flow reaction 18h, be decompressed to-0.10MPa and concentrate to obtain white solid 4.6g, be N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 97.4%, purity is 98.9%.
Claims (5)
1. a synthetic method for Parecoxib sodium impurity, described impurity is N-[3-(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: by 5-methyl-3,4-phenylbenzene isoxzzole, zinc chloride, chlorsulfonic acid are added in reaction flask, 50 ~ 70 DEG C of reaction 1.5 ~ 2.5h, reaction solution obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE through aftertreatment;
S2. hydrolysis reaction: above-mentioned gained N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 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, zinc chloride and chlorsulfonic acid is 1:0.5 ~ 1:1 ~ 5.
3. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, it is characterized in that, the weight ratio of N-described in step S2 [3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, water and acetonitrile is 1:20 ~ 40:20 ~ 40.
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 frozen water by reaction solution after completion of the reaction, with after cake filtration, filter cake is dissolved in ethyl acetate, add sherwood oil and carry out a crystallization, secondary crystallization after crystal concentrating under reduced pressure, gained secondary crystal, at 50 ~ 60 DEG C of drying 6 ~ 10h, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE.
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 (4)
| 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 |
| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
| CN112028849A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Preparation method of parecoxib sodium impurity compound |
| CN112390764A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Parecoxib sodium impurity compound |
-
2015
- 2015-01-04 CN CN201510002045.7A patent/CN104592140B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| A. R. REDDY ET AL.: "APPLICATION OF [3+2]-CYCLOADDITION IN THE SYNTHESIS OF VALDECOXIB", 《SYNTHETIC COMMUNICATIONS》, vol. 42, 31 December 2012 (2012-12-31) * |
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 |
| 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 |
| CN112028849A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Preparation method of parecoxib sodium impurity compound |
| CN112390764A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Parecoxib sodium impurity compound |
| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
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Denomination of invention: A synthetic method of parecoxib sodium impurity Effective date of registration: 20201029 Granted publication date: 20161005 Pledgee: Zhejiang Mintai commercial bank Limited by Share Ltd. Chengdu Gaoxin Branch Pledgor: CHENGDU CLIMB PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: Y2020510000099 |
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