CN104557756A - Synthetic method of parecoxib sodium impurity - Google Patents
Synthetic method of parecoxib sodium impurity Download PDFInfo
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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 synthetic method of a parecoxib sodium impurity, namely N-[[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide, belonging to the technical field of chemical pharmacy; the parecoxib sodium impurity is obtained by carrying out sulfonation reaction, amination reaction and propionylation reaction by taking 5-methyl-3,4-diphenyl isoxazole as the raw material; the synthesized high-purity parecoxib sodium impurity can be used as an impurity standard sample in detection and analysis of parecoxib sodium finished products; therefore, the accurate positioning property and the qualitative diagnosis to impurities in detection and analysis of parecoxib sodium finished products are increased; control of the impurity is strengthened easily, so that the quality of the parecoxib sodium finished products is increased; the synthetic method disclosed by the invention is cheap and available in raw materials and simple to operate; the yield of the prepared parecoxib sodium impurity is 85+/-5%; and the HPLC (High Performance Liquid Chromatography) purity is more 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 I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide.
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 I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide be in Parecoxib Sodium building-up process sulfonation occur between position time produce the further amination of isomer, propionating come; 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 the synthetic method of a kind of Parecoxib sodium impurity H 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 I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide 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: the synthetic method of a kind of Parecoxib sodium impurity I, and described impurity I is N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide, and synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonation reaction: add chlorsulfonic acid, zinc chloride and 5-methyl-3 in reaction flask, 4-phenylbenzene isoxzzole, controlling temperature of reaction is 50 ~ 70 DEG C, and reaction 1.5 ~ 2.5h, generates N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE;
S2. amination reaction: add N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, the ammoniacal liquor that dissolve with methylene dichloride in reaction flask, reaction 3 ~ 5h, generates N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide;
S3. propionating reaction: N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide, triethylamine, propionic anhydride, DMAP and methylene dichloride are joined in reaction flask; reaction 50 ~ 70min, generates N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide.
Further, the weight ratio of described 5-methyl-3,4-phenylbenzene isoxzzole, zinc chloride and chlorsulfonic acid is 1:0.5 ~ 1:1 ~ 5.
Further, the weight ratio of described N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE and ammoniacal liquor is 1:40 ~ 70.
Further, the weight ratio of described N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide, triethylamine, propionic anhydride and DMAP is 1:3 ~ 6:3 ~ 6:0.1 ~ 0.4.
The present invention has the following advantages: the present invention is with 5-methyl-3, 4-phenylbenzene isoxzzole is raw material, through sulfonation reaction, amination reaction and be propionatingly obtained by reacting Parecoxib sodium impurity I, the Parecoxib sodium impurity I of synthesis of high purity can be used as the impurity H 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 I 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 85% ± 5%, HPLC purity >=98%.
Accompanying drawing explanation
Fig. 1 is Parecoxib sodium impurity I HPLC collection of illustrative plates;
Fig. 2 is Parecoxib sodium impurity I mass spectrum;
Fig. 3 is Parecoxib sodium impurity I 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 synthetic method of Parecoxib sodium impurity I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 7g zinc chloride, 20g chlorsulfonic acid are added in reaction flask, 60 DEG C are reacted 2 hours, 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 ~ 60 DEG C of constant pressure and dries are about 8h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.42g, yield 38.2%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, 200g methylene dichloride adds in reaction flask, after dissolution of solid, drop in 250g ammoniacal liquor, react 4 hours, concentrating under reduced pressure is done, filter, washing, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide 4.22g, yield 89.6%.
By above-mentioned for 3g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonamide molecules amount, 15g triethylamine, 15g propionic anhydride; 0.3g DMAP; 100g methylene dichloride is added in reaction flask, and react after 1 hour, TLC is until react complete; pressurization is concentrated; add 150g ethyl acetate, wash 3 times, concentrating under reduced pressure; obtain N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide 3.02g, yield 85.4%.
As shown in Figure 1, purity is 99.6% to Parecoxib sodium impurity I HPLC collection of illustrative plates.
Parecoxib sodium impurity I mass spectrum as shown in Figure 2, MS:371 (M+1);
As shown in Figure 3, it is unimodal that trial-product H composes display chemical shift δ (8.151) to Parecoxib sodium impurity I proton nmr spectra, and 1 hydrogen is NH hydrogen.Chemical shift δ (7.240-7.995) totally 9 hydrogen is benzene ring hydrogen.Chemical shift δ (2.488-2.499) is unimodal, totally 3 hydrogen, is methyl hydrogen.Chemical shift δ (2.227-2.264) totally 2 hydrogen is CH
2hydrogen.Chemical shift δ (1.056-1.164) totally 3 hydrogen is straight chain C H
3hydrogen, detected result conforms to Parecoxib sodium impurity I structure.
Embodiment 2: the synthetic method of Parecoxib sodium impurity I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 5g zinc chloride, 10g chlorsulfonic acid are added in reaction flask, 60 DEG C are reacted 2 hours, 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 ~ 60 DEG C of constant pressure and dries are about 8h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.13g, yield 36.1%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, 200g methylene dichloride adds in reaction flask, after dissolution of solid, drop in 200g ammoniacal liquor, react 4 hours, concentrating under reduced pressure is done, filter, washing, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide 4.18g, yield 88.7%.
By above-mentioned for 3g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonamide molecules amount, 9g triethylamine, 9g propionic anhydride; 0.6g DMAP, 100g methylene dichloride is added in reaction flask, reacts after 1 hour; TLC is until react complete; pressurization is concentrated, adds 150g ethyl acetate, washes 3 times; concentrating under reduced pressure; obtain N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide 2.87g, yield 81.2%, purity >=98.7%.
Embodiment 3: the synthetic method of Parecoxib sodium impurity I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide:
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 10g zinc chloride, 50g chlorsulfonic acid are added in reaction flask, 60 DEG C are reacted 2 hours, 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 ~ 60 DEG C of constant pressure and dries are about 8h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.54g, yield 39.0%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, 200g methylene dichloride adds in reaction flask, after dissolution of solid, drop in 350g ammoniacal liquor, react 4 hours, concentrating under reduced pressure is done, filter, washing, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide 4.30g, yield 91.3%.
By above-mentioned for 4g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonamide molecules amount, 16g triethylamine, 16g propionic anhydride; 1.2gDMAP, 120g methylene dichloride is added in reaction flask, reacts after 1 hour; TLC is until react complete; pressurization is concentrated, adds 150g ethyl acetate, washes 3 times; concentrating under reduced pressure; obtain N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide 3.96g, yield 84.0%, purity >=99.5%.
Embodiment 4: the synthetic method of Parecoxib sodium impurity I N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide:
By 10g 5-methyl-3,4-phenylbenzene isoxzzole, 8g zinc chloride, 50g chlorsulfonic acid are added in reaction flask, 60 DEG C are reacted 2 hours, 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 ~ 60 DEG C of constant pressure and dries are about 8h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE 5.51g, yield 38.8%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, 200g methylene dichloride adds in reaction flask, after dissolution of solid, drop in 300g ammoniacal liquor, react 4 hours, concentrating under reduced pressure is done, filter, washing, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide 4.28g, yield 90.9%.
By above-mentioned for 4g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonamide molecules amount, 24g triethylamine, 24g propionic anhydride; 2.4g DMAP, 1200g methylene dichloride is added in reaction flask, reacts after 1 hour; TLC is until react complete; pressurization is concentrated, adds 150g ethyl acetate, washes 3 times; concentrating under reduced pressure; obtain N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide 3.95g, yield 83.8%, purity >=98.4%.
Claims (4)
1. a synthetic method for Parecoxib sodium impurity, described impurity is N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide, and it is characterized in that, synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonation reaction: add chlorsulfonic acid, zinc chloride and 5-methyl-3 in reaction flask, 4-phenylbenzene isoxzzole, controlling temperature of reaction is 50 ~ 70 DEG C, and reaction 1.5 ~ 2.5h, generates N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE;
S2. amination reaction: add N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE, the ammoniacal liquor that dissolve with methylene dichloride in reaction flask, reaction 3 ~ 5h, generates N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide;
S3. propionating reaction: N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide, triethylamine, propionic anhydride, DMAP and methylene dichloride are joined in reaction flask; reaction 50 ~ 70min, generates N-[[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionic acid amide.
2. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, is characterized in that, the weight ratio of described 5-methyl-3,4-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, is characterized in that, the weight ratio of described N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] SULPHURYL CHLORIDE and ammoniacal liquor is 1:40 ~ 70.
4. the synthetic method of a kind of Parecoxib sodium impurity as claimed in claim 1, it is characterized in that, the weight ratio of described N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide, triethylamine, propionic anhydride and DMAP is 1:3 ~ 6:3 ~ 6:0.1 ~ 0.4.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN107976500A (en) * | 2017-11-29 | 2018-05-01 | 浙江震元制药有限公司 | A kind of isoxazole compound of double aryl substitutions and its preparation method and application |
| CN108047155A (en) * | 2017-11-29 | 2018-05-18 | 浙江震元制药有限公司 | A kind of orientation Preparation method and use of the isoxazole compound of double aryl substitutions |
| CN110041282A (en) * | 2018-01-15 | 2019-07-23 | 正大天晴药业集团股份有限公司 | Related substance of Parecoxib Sodium and its preparation method and application |
| CN110240570A (en) * | 2018-03-07 | 2019-09-17 | 浙江震元制药有限公司 | A kind of preparation method of SC 69124 sodium impurity |
| CN110642801A (en) * | 2019-09-20 | 2020-01-03 | 深圳市祥根生物科技有限公司 | Preparation method of parecoxib meta-isomer impurity |
| CN112390764A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Parecoxib sodium impurity compound |
| CN115304555A (en) * | 2021-05-06 | 2022-11-08 | 北京新康哌森医药科技有限公司 | Synthesis method of parecoxib sodium impurity |
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| 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 |
| CN107976500A (en) * | 2017-11-29 | 2018-05-01 | 浙江震元制药有限公司 | A kind of isoxazole compound of double aryl substitutions and its preparation method and application |
| CN108047155A (en) * | 2017-11-29 | 2018-05-18 | 浙江震元制药有限公司 | A kind of orientation Preparation method and use of the isoxazole compound of double aryl substitutions |
| CN107976500B (en) * | 2017-11-29 | 2021-09-28 | 浙江震元制药有限公司 | Diaryl-substituted isoxazole compound and preparation method and application thereof |
| CN110041282A (en) * | 2018-01-15 | 2019-07-23 | 正大天晴药业集团股份有限公司 | Related substance of Parecoxib Sodium and its preparation method and application |
| CN110041282B (en) * | 2018-01-15 | 2022-05-20 | 正大天晴药业集团股份有限公司 | Parecoxib sodium related substance, preparation method and application thereof |
| CN110240570A (en) * | 2018-03-07 | 2019-09-17 | 浙江震元制药有限公司 | A kind of preparation method of SC 69124 sodium impurity |
| CN112390764A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Parecoxib sodium impurity compound |
| CN110642801A (en) * | 2019-09-20 | 2020-01-03 | 深圳市祥根生物科技有限公司 | Preparation method of parecoxib meta-isomer impurity |
| CN115304555A (en) * | 2021-05-06 | 2022-11-08 | 北京新康哌森医药科技有限公司 | Synthesis method of parecoxib sodium impurity |
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