CN104592139A - Synthetic method of impurity H of parecoxib sodium - Google Patents
Synthetic method of impurity H of parecoxib sodium Download PDFInfo
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- CN104592139A CN104592139A CN201510001305.9A CN201510001305A CN104592139A CN 104592139 A CN104592139 A CN 104592139A CN 201510001305 A CN201510001305 A CN 201510001305A CN 104592139 A CN104592139 A CN 104592139A
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- 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
Abstract
The invention discloses a synthetic method of N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonamide dimmer, serving as an impurity H of parecoxib sodium and belongs to the technical field of chemical pharmacy. The synthetic method comprises the following steps: with 5-methyl-3, 4-diphenyl isoxazole as a raw material, carrying out sulfonation, hydrolysis and condensation reaction to obtain the impurity H of parecoxib sodium. According to the synthetic method disclosed by the invention, the synthesized high-purity impurity H of parecoxib sodium can be used as an impurity H standard in detection and analysis of a parecoxib sodium finished product, so that the accurate localization and determination of the impurity H in detection and analysis of the parecoxib sodium finished product, control on the impurity is easily strengthened, and the quality of the parecoxib sodium finished product is improved; the raw materials are cheap and easily acquired, the operation is simple, the yield of the obtained product is 75 percent +/- 5 percent, and the HPLC purity is larger than or equal to 98 percent.
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 H (N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer).
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 H N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer is be the impurity that the intermediate state acyl chlorides that obtains of sulfonation reaction and intermediate II docking reaction generate in Parecoxib Sodium building-up process, may remain in Parecoxib Sodium finished product, affect quality product, its structural formula is as shown in (I), and No. CAS is: 1373038-60-8.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, a kind of Parecoxib sodium impurity H synthetic method of (N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer) 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 H, and described impurity H is N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer, 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. amination reaction: add intermediate compound I, methylene dichloride, ammoniacal liquor in reactor, control temperature is 20 ~ 30 DEG C, and reaction 1 ~ 3h, generates intermediate II;
S3. condensation reaction: under nitrogen protection, triethylamine, tetrahydrofuran (THF), intermediate compound I and intermediate II normal-temperature reaction 0.5 ~ 1.5h, question response is complete, obtains Parecoxib sodium impurity H through aftertreatment.
Further, the weight ratio of described 5-methyl-3,4-phenylbenzene isoxzzole and chlorsulfonic acid is 1:2 ~ 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 weight ratio of intermediate compound I described in step S2 and ammoniacal liquor is 1:2 ~ 4.
Further, the weight ratio of intermediate II described in step S3, intermediate compound I, triethylamine and tetrahydrofuran (THF) is 1:1 ~ 2:1 ~ 2:3 ~ 6.
Further, post-treating method described in step S3 is: after reacting completely, and add water concentrating under reduced pressure, gained solid adds ethyl acetate washing, add ethyl acetate again and carry out crystallization 1.5 ~ 2.5h, gained crystal is constant pressure and dry at 55 ~ 65 DEG C of temperature, obtains Parecoxib sodium impurity H.
The present invention has the following advantages: the present invention is with 5-methyl-3, 4-phenylbenzene isoxzzole is raw material, through sulfonation reaction, hydrolysis reaction and condensation reaction obtain Parecoxib sodium impurity H, the Parecoxib sodium impurity H 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 H 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 75% ± 5%, HPLC purity >=98%.
Accompanying drawing explanation
Fig. 1 is Parecoxib sodium impurity H purity detecting HPLC collection of illustrative plates;
Fig. 2 is Parecoxib sodium impurity H proton nmr spectra;
Fig. 3 is Parecoxib sodium impurity H heavy water exchange spectrum.
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 a kind of Parecoxib sodium impurity H (N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer)
S1. sulfonation reaction: by 3g 5-methyl-3,4-phenylbenzene isoxzzole, 10g methylene dichloride, 9g chlorsulfonic acid adds in reaction flask, 40 DEG C of back flow reaction 5 hours, reaction solution is dropped in 50g water, 12g dichloromethane extraction, concentrated dry, add 5g ethyl acetate, 12g sherwood oil crystallization 1.5 hours, filters to obtain 3.31g intermediate compound I;
S2. amination reaction: add intermediate compound I 1.5g, methylene dichloride 30g, ammoniacal liquor 3g in reaction flask, control temperature is 20 ~ 30 DEG C, be added dropwise to complete rear insulation 1h, monitor once with TLC (EA:PE=1:3) sampling in every 0.5 hour, react to the disappearance of TLC monitoring Parecoxib Sodium intermediate compound I spot.After completion of the reaction, extremely do not become line to drip reaction solution at 45 DEG C of concentrating under reduced pressure reaction solutions, filter, wash filter cake with water 3 times, use water 10g at every turn, by filter cake in 70 DEG C of hot-air ovens dryings 20 hours, obtain intermediate II 1.35kg, yield is 95.5%;
S3. condensation reaction: under nitrogen protection, is added in reaction flask by 5g tetrahydrofuran (THF), triethylamine 1g, adds 1g intermediate II; 1.5g intermediate compound I; normal-temperature reaction is after 1 hour, and V (methylene dichloride: methyl alcohol)=5:1, TLC detect; until intermediate II has been reacted for terminal; add 10g water, after concentrating under reduced pressure, add 10g ethyl acetate; wash twice; each 10g, concentrating under reduced pressure, adds 2g ethyl acetate; stirring and crystallizing 1.5 hours; filter, 55 DEG C of normal pressures are dried, and obtain 1.42g white solid; yield: 72.9%, purity >=98.8%.
As shown in Figure 1, purity is 98.8% to Parecoxib sodium impurity H purity detecting HPLC collection of illustrative plates.；
Parecoxib sodium impurity H proton nmr spectra and heavy water exchange spectrum are as shown in Figures 2 and 3.Hydrogen spectrogram display chemical shift δ (7.191-7.667) totally 18 hydrogen is benzene ring hydrogen, and chemical shift δ (2.424-2.500) is unimodal, totally 3 hydrogen, is methyl hydrogen.Wherein 1 amino hydrogen is reactive hydrogen, does not go out peak, and detected result conforms to Parecoxib sodium impurity H structure.
Embodiment 2: the synthetic method of a kind of Parecoxib sodium impurity H (N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer)
S1. sulfonation reaction: by 3g 5-methyl-3,4-phenylbenzene isoxzzole, 20g methylene dichloride, 15g chlorsulfonic acid adds in reaction flask, 50 DEG C of back flow reaction 8 hours, reaction solution is dropped in 80g water, 15g dichloromethane extraction, concentrated dry, add 5g ethyl acetate, 12g sherwood oil crystallization 2.5 hours, filters to obtain 3.28g intermediate compound I;
S2. amination reaction: add intermediate compound I 1.5g, methylene dichloride 40g, ammoniacal liquor 6g in reaction flask, control temperature is 20 ~ 30 DEG C, be added dropwise to complete rear insulation 3h, monitor once with TLC (EA:PE=1:3) sampling in every 0.5 hour, react to the disappearance of TLC monitoring Parecoxib Sodium intermediate compound I spot.After completion of the reaction, extremely do not become line to drip reaction solution at 45 DEG C of concentrating under reduced pressure reaction solutions, filter, wash filter cake with water 3 times, use water 5kg at every turn, by filter cake in 70 DEG C of hot-air ovens dryings 20 hours, obtain intermediate II 1.39g, yield is 98.4%;
S3. condensation reaction: under nitrogen protection, is added in reaction flask by 3.6g tetrahydrofuran (THF), triethylamine 1.5kg, adds 1.2g intermediate II; 1.2g intermediate compound I; normal-temperature reaction is after 1 hour, and V (methylene dichloride: methyl alcohol)=5:1, TLC detect; until intermediate II has been reacted for terminal; add 20g water, after concentrating under reduced pressure, add 20g ethyl acetate; wash twice; each 20g, concentrating under reduced pressure, adds 4g ethyl acetate; stirring and crystallizing 2.5 hours; filter, 65 DEG C of normal pressures are dried, and obtain 1.72g white solid; yield: 73.6%, purity >=99.3%.
Embodiment 3: the synthetic method of a kind of Parecoxib sodium impurity H (N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer)
S1. sulfonation reaction: by 5g 5-methyl-3,4-phenylbenzene isoxzzole, 30g methylene dichloride, 20g chlorsulfonic acid adds in reaction flask, 45 DEG C of back flow reaction 7 hours, reaction solution is dropped in 100g water, 20g dichloromethane extraction, concentrated dry, add 10g ethyl acetate, 20g sherwood oil crystallization 2 hours, filters to obtain 5.57g intermediate compound I;
S2. amination reaction: reaction flask adds intermediate compound I 2g, methylene dichloride 60g, ammoniacal liquor 6g, control temperature is 20 ~ 30 DEG C, be added dropwise to complete rear insulation 1.5h, monitor once with TLC (EA:PE=1:3) sampling in every 0.5 hour, react to the disappearance of TLC monitoring Parecoxib Sodium intermediate compound I spot.After completion of the reaction, extremely do not become line to drip reaction solution at 45 DEG C of concentrating under reduced pressure reaction solutions, filter, wash filter cake with water 3 times, use water 5kg at every turn, by filter cake in 70 DEG C of hot-air ovens dryings 20 hours, obtain intermediate II 1.83kg, yield is 97.1%;
S3. condensation reaction: under nitrogen protection, is added in reaction flask by 6g tetrahydrofuran (THF), triethylamine 3g, adds 1.5g intermediate II; 3g intermediate compound I; normal-temperature reaction is after 1 hour, and V (methylene dichloride: methyl alcohol)=5:1, TLC detect; until intermediate II has been reacted for terminal; add 30g water, after concentrating under reduced pressure, add 20g ethyl acetate; wash twice; each 20g, concentrating under reduced pressure, adds 10g ethyl acetate; stirring and crystallizing 2 hours; filter, 60 DEG C of normal pressures are dried, and obtain 2.15g white solid; yield: 73.6%, purity >=99.4%.
Embodiment 4: a kind of Parecoxib sodium impurity H N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] the dimeric synthetic method of sulphonamide
S1. sulfonation reaction: by 5g 5-methyl-3,4-phenylbenzene isoxzzole, 30g methylene dichloride, 10g chlorsulfonic acid adds in reaction flask, 40 DEG C of back flow reaction 4 hours, reaction solution is dropped in 100g water, 20g dichloromethane extraction, concentrated dry, add 10g ethyl acetate, 20g sherwood oil crystallization 2 hours, filters to obtain 5.40g intermediate compound I;
S2. amination reaction: add intermediate compound I 2g, methylene dichloride 50g, ammoniacal liquor 5g in reactor, control temperature is 28 DEG C, be added dropwise to complete rear insulation 2.5h, monitor once with TLC (EA:PE=1:3) sampling in every 0.5 hour, react to the disappearance of TLC monitoring Parecoxib Sodium intermediate compound I spot.After completion of the reaction, extremely do not become line to drip reaction solution at 45 DEG C of concentrating under reduced pressure reaction solutions, filter, wash filter cake with water 3 times, use water 10g at every turn, by filter cake in 70 DEG C of hot-air ovens dryings 20 hours, obtain intermediate II 1.75g, yield is 92.9%;
S3. condensation reaction: under nitrogen protection, is added in reaction flask by 12g tetrahydrofuran (THF), triethylamine 2.5g, adds 2g intermediate II; 3.5g intermediate compound I; normal-temperature reaction is after 1 hour, and V (methylene dichloride: methyl alcohol)=5:1, TLC detect; until intermediate II has been reacted for terminal; add 20g water, after concentrating under reduced pressure, add 20g ethyl acetate; wash twice; each 20g, concentrating under reduced pressure, adds 5g ethyl acetate; stirring and crystallizing 2.3 hours; filter, 63 DEG C of normal pressures are dried, and obtain 2.89g white solid; yield: 74.3%, purity >=99.1%.
Claims (6)
1. a synthetic method of Parecoxib sodium impurity H, described impurity H is N-[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulphonamide dimer, 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. amination reaction: add intermediate compound I, methylene dichloride, ammoniacal liquor in reactor, control temperature is 20 ~ 30 DEG C, and reaction 1 ~ 3h, generates intermediate II;
S3. condensation reaction: under nitrogen protection, triethylamine, tetrahydrofuran (THF), intermediate compound I and intermediate II normal-temperature reaction 0.5 ~ 1.5h, question response is complete, obtains Parecoxib sodium impurity H through aftertreatment.
2. the synthetic method of a kind of Parecoxib sodium impurity H as claimed in claim 1, is characterized in that, the weight ratio of described 5-methyl-3,4-phenylbenzene isoxzzole and chlorsulfonic acid is 1:2 ~ 5.
3. the synthetic method of a kind of Parecoxib sodium impurity H 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.
4. the synthetic method of a kind of Parecoxib sodium impurity H as claimed in claim 1, is characterized in that, the weight ratio of intermediate compound I described in step S2 and ammoniacal liquor is 1:2 ~ 4.
5. the synthetic method of a kind of Parecoxib sodium impurity H as claimed in claim 1, is characterized in that, the weight ratio of intermediate II described in step S3, intermediate compound I, triethylamine and tetrahydrofuran (THF) is 1:1 ~ 2:1 ~ 2:3 ~ 6.
6. the synthetic method of a kind of Parecoxib sodium impurity H as claimed in claim 1, it is characterized in that, post-treating method described in step S3 is: after reacting completely, add water concentrating under reduced pressure, gained solid adds ethyl acetate washing, add ethyl acetate again and carry out crystallization 1.5 ~ 2.5h, gained crystal is constant pressure and dry at 55 ~ 65 DEG C of temperature, obtains Parecoxib sodium impurity H.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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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2015
- 2015-01-04 CN CN201510001305.9A patent/CN104592139A/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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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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