CN108484516A - A kind of SC 69124 sodium impurity and preparation method thereof - Google Patents
A kind of SC 69124 sodium impurity and preparation method thereof Download PDFInfo
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- CN108484516A CN108484516A CN201810456013.8A CN201810456013A CN108484516A CN 108484516 A CN108484516 A CN 108484516A CN 201810456013 A CN201810456013 A CN 201810456013A CN 108484516 A CN108484516 A CN 108484516A
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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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Abstract
The invention discloses a kind of SC 69124 sodium impurity N [[3 (5 methyl, 4 phenyl, 3 isoxazolyl) phenyl] sulfonyl] propionamides and preparation method thereof; the method is with 1 phenyl 1; 2 propanedione are raw material; SC 69124 sodium impurity is obtained after cyclisation, sulfonation, ammonolysis, bromo, coupling, acylation; gained compound of the invention confirms structure through 1H NMR, 1H NMR+D2O, 13C NMR spectras; preparation method is novel; obtained compound is detected through HPLC, related material purity >=98%.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of SC 69124 sodium impurity N- [[3- (5- methyl -4- benzene
Base -3- isoxazolyls) phenyl] sulfonyl] propionamide and preparation method thereof.
Background technology
Parecoxib Sodium is the cox 2 inhibitor of specificity, is mainly used for the treatment of postoperative pain, on Europe
City is mainly used for the short of postoperative pain, can be clinically used for the treatment of moderate or severe postoperative acute pain.
The preparation method of Parecoxib Sodium passes through sulfonation, ammonolysis mainly with 3,4- diphenyl -5- methylisoxazoles for raw material
Reaction synthesis Valdecoxib, then process is propionating, Parecoxib Sodium is made at salt.However, in the process of synthesis Valdecoxib
In, sulfonating reaction may greatly will produce intermediate V, and generation and pa auspicious former times are very likely reacted with subsequent acylating reagent
The similar impurity N- of cloth sodium structure [[3- (5- methyl 4-phenyl -3- isoxazolyls) phenyl] sulfonyl] propionamide, remains on end
In product, the quality of Parecoxib Sodium product is influenced.Since compound structure is more similar, to the Parecoxib Sodium subsequently synthesized
Quality control brings bigger difficulty.
Currently, related SC 69124 sodium impurity N- [[3- (5- methyl 4-phenyl -3- isoxazolyls) phenyl] sulfonyl] third
The synthetic method of amide has no any document report, and it is miscellaneous successfully to have synthesized this by designed, designed synthetic route by the present inventor
Matter, and structural confirmation has been carried out by 1H-NMR, 1H-NMR+D2O, 13C-NMR.
The SC 69124 sodium impurity of high-purity can be used as the preparation of the impurity reference substance in Parecoxib Sodium finished product detection standard
Reference, can be promoted Parecoxib Sodium finished product detection analysis for impurity positioning analysis and qualitative detection, effectively control pa
The quality of auspicious former times cloth sodium finished product, ensures the safety of drug.Therefore, it is necessary to obtain a kind of SC 69124 sodium impurity of high-purity, supply
Reference substance uses.The present invention provides a kind of synthesis high-purity SC 69124 sodium impurity N- [[3- (5- methyl 4-phenyls-thus
3- isoxazolyls) phenyl] sulfonyl] the novel synthetic method of propionamide, and high-purity SC 69124 sodium impurity is obtained, for having
The quality of effect control Parecoxib Sodium product has important practical significance.
Invention content
It is an object of the invention to provide a kind of Parecoxib Sodium impurity compound N- [[3- (different evils of 5- methyl 4-phenyls -3-
Oxazolyl) phenyl] sulfonyl] propionamide and preparation method thereof, which can be used as Parecoxib Sodium finished product detection standard
In impurity reference substance.The sample purity that preparation method is novel, raw material is easy to get, is easy to operate, obtaining is high,
To achieve the purpose of the present invention, following embodiment is provided.
In one embodiment, of the invention a kind of to prepare SC 69124 sodium impurity N- [[3- (5- methyl 4-phenyls -3-
Isoxazolyl) phenyl] sulfonyl] and propionamide method, synthetic route is as follows：
This approach includes the following steps：
G) 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride are added in organic solvent by, and catalyst is added, and temperature rising reflux is anti-
It answers, obtains intermediate I；
H) intermediate I is dissolved in organic solvent by, (, dichloromethane be added reaction bulb in), and chlorosulfonic acid is added dropwise, and drop finishes, and rises
Reaction solution is added in mixture of ice and water and is quenched to get to intermediate II organic solution, locates without further by warm reaction overnight
Reason directly carries out next step reaction；
I) ammonium hydroxide is added dropwise in intermediate II organic solution, room temperature reaction, and separation after reaction obtains intermediate III；
J) intermediate III, n,N-Dimethylformamide are added in reaction bulb, and N-bromosuccinimide is added dropwise, and drop finishes,
Room temperature reaction, after reaction separation obtain intermediate IV；
K) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium are added in aqueous alcoholic solvent by, nitrogen is protected
Shield, back flow reaction is overnight, and reaction finishes, and separation obtains intermediate V；
L) intermediate V, propionic andydride, propionic acid are added in reaction bulb by, and temperature reaction is to get SC 69124 sodium impurity.
The method of aforementioned present invention, the one kind of organic solvent in methanol, ethyl alcohol, isopropanol in the step a),
The catalyst is silico-tungstic acid；Organic solvent in the step b) is dichloromethane；The alcohol of the step e) is selected from methanol, second
One kind in alcohol, isopropanol；Step e) the coupling reactions intermediate IV, phenyl boric acid, tetrakis triphenylphosphine palladium, base reagent rub
Your amount ratio is 1:1.2~2:0.05~0.1:0.006~0.01, the intermediate IV, phenyl boric acid, tetrakis triphenylphosphine palladium, alkali
The mole ratio of reagent is 1:1.2:0.05:0.006, the base reagent is sodium carbonate or cesium carbonate；Step f) the intermediates
V, propionic andydride, propionic acid w/v be 1:4~6:0.1, preferably 1:5:0.1；
The method of aforementioned present invention, the reaction temperature that the reaction temperature of step a) is 60~80 DEG C or step b) is 40~
60 DEG C or step f) of reaction temperature is 120~130 DEG C.
In one embodiment, of the invention a kind of to prepare SC 69124 sodium impurity N- [[3- (5- methyl -4- benzene
Base -3- isoxazolyls) phenyl] sulfonyl] and propionamide method, include the following steps：
A) starting material 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride, organic solvent are added in reaction bulb cyclization,
The silico-tungstic acid of catalytic amount is added, temperature rising reflux reacts about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain yellow
Intermediate I；
B) intermediate I, dichloromethane are added in reaction bulb sulfonating reaction, and chlorosulfonic acid is added dropwise in cooling.Drop finishes, and heating is overnight
Reaction.Obtained system is slowly added to be quenched in mixture of ice and water, liquid separation, water phase is extracted with dichloromethane, merges organic phase,
Washing, without being further processed, directly carries out next step reaction to get to the dichloromethane solution of intermediate II；
C) dichloromethane solution of intermediate II is added in reaction bulb ammonolysis reaction, and ammonium hydroxide is added dropwise, and reacts at room temperature about 2h,
Being concentrated under reduced pressure into system has solid generation, and filtering, filtration cakes torrefaction is to get intermediate III, without processing, directly carries out next
Step；
D) intermediate III, n,N-Dimethylformamide are added in reaction bulb bromo-reaction, and N- bromo ambers are added dropwise in cooling
Acid imide.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
Intermediate IV；
E) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium, ethyl alcohol, a small amount of water are added to by coupling reaction
In reaction bulb, nitrogen protection, back flow reaction is overnight.Reaction finishes, and is directly concentrated under reduced pressure, and column chromatography for separation is to get to intermediate
Ⅴ。
F) intermediate V, propionic andydride, propionic acid are added in reaction bulb by acylation reaction, temperature reaction about 2h, filtering, filter cake
Drying is to get SC 69124 sodium impurity.
In the above-described embodiment, of the invention to prepare SC 69124 sodium impurity 3- [the different evils of (4- phenyl) -5- methyl -3-
Azoles] benzsulfamide method, step a) cyclizations 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride, silico-tungstic acid mole
Than being 1:1~1.5:0.01~0.1, preferably 1:1:0.01, the one kind of organic solvent in methanol, ethyl alcohol, isopropanol, preferably
Ethyl alcohol, the reaction temperature are 60~80 DEG C；Step b) sulfonating reactions intermediate I, the mole ratio of chlorosulfonic acid are 1:5~8, it is excellent
Select 1:5, reaction temperature is 40~60 DEG C；Step d) bromo-reactions intermediate III, N-bromosuccinimide mole ratio be
1:3~5, preferably 1:3；The mole ratio of step e) coupling reactions intermediate IV, phenyl boric acid, tetrakis triphenylphosphine palladium, base reagent
It is 1:1.2~2:0.05~0.1:0.006~0.01, preferably 1:1.2:0.05:0.006, the base reagent sodium bicarbonate, carbonic acid
One kind in sodium, potassium carbonate, cesium carbonate, preferably sodium carbonate；The bulking value of the step f) intermediates V, propionic andydride, propionic acid
Than being 1:4~6:0.1, preferably 1:5:0.1, reaction temperature is 120~130 DEG C.
Parecoxib Sodium impurity compound 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide of the present invention is used as
The purposes of SC 69124 sodium impurity reference substance or the purposes in controlling Parecoxib Sodium quality.
The method of the present invention has the following advantages：
The novel synthetic method of designed, designed, raw material is easy to get, easy to operate, and the impurity sample purity HPLC detection of acquisition >=
98%, obtained impurity sample confirms structure by 1H-NMR and 13C-NMR collection of illustrative plates, can be used as Parecoxib Sodium finished product detection
Reference prepared by the impurity reference substance in standard can promote positioning analysis of the Parecoxib Sodium finished product detection analysis for impurity
And qualitative detection, the quality of Parecoxib Sodium finished product is effectively controlled, ensures the safety of drug.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide；
Fig. 2~3 are that the 1H-NMR of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide schemes
Spectrum；
Fig. 4 is that the 1H-NMR+D2O of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide schemes
Spectrum
Fig. 5 is the 13C-NMR collection of illustrative plates of SC 69124 sodium impurity 3- [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide；
Specific implementation mode
Following embodiment is used to be explained further the essence of the present invention, but does not limit the scope of the invention.
The preparation of 1 SC 69124 sodium impurity 3- of embodiment [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide
1- phenyl -1,2- propanedione 10g is dissolved in 50mL ethyl alcohol, 4.7g hydroxylamine hydrochlorides are added, 2.0g silicon tungsten is added
Acid is warming up to 80 DEG C of back flow reaction about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain the intermediate I of yellow about
9.6g；
Intermediate I 9.6g, dichloromethane 40mL are added in reaction bulb, chlorosulfonic acid 40g is added dropwise in cooling.Drop finishes, and is warming up to
55 DEG C of reaction overnights.Obtained system is slowly added to be quenched in 80mL mixture of ice and water, liquid separation, water phase is extracted with dichloromethane
It takes, merges organic phase, washing, without being further processed, directly carries out in next step to get to the dichloromethane solution of intermediate II
Reaction；
The dichloromethane solution of intermediate II is added in reaction bulb, ammonium hydroxide 80mL is added dropwise, reacts at room temperature about 2h, decompression is dense
Being reduced in system has solid generation, and filtering, filtration cakes torrefaction directly carries out down to get the about 12.5g of intermediate III without processing
One step；
III 12.5g of intermediate, n,N-Dimethylformamide 60mL are added in reaction bulb, N- bromo succinyls are added dropwise in cooling
Imines 30g.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
The about 11.4g of intermediate IV；
IV 11.4g of intermediate, phenyl boric acid 6.5g, sodium carbonate 0.20g, tetrakis triphenylphosphine palladium 0.25g are added to reaction
In bottle, ethyl alcohol 30mL, water 1mL are added in reaction bulb, and nitrogen protection, back flow reaction is overnight.Reaction finishes, and directly depressurizes dense
Contracting, column chromatography for separation is to get to V 7.6g of intermediate.
V 7.6g of intermediate, propionic andydride 22mL, propionic acid 0.7mL are added in reaction bulb, are warming up to 125 DEG C of reactions about
2h, filtering, filtration cakes torrefaction to get title SC 69124 sodium impurity 5.5g.
Obtained SC 69124 sodium impurity confirms through 1H-NMR, 1H-NMR+D2O, 13C-NMR collection of illustrative plates (see Fig. 2-5) to be tied
Structure is correct, and HPLC detects purity and is more than 98% (see Fig. 1).
The preparation of 2 SC 69124 sodium impurity 3- of embodiment [(4- phenyl) -5- methyl -3- isoxazoles] benzsulfamide
1- phenyl -1,2- propanedione 10g is dissolved in 50mL ethyl alcohol, 5.0g hydroxylamine hydrochlorides are added, 2.2g silicon tungsten is added
Acid is warming up to 80 DEG C of back flow reaction about 2h.Filtering, filtrate decompression concentration, column chromatography for separation obtain the intermediate I of yellow about
9.5g；
Intermediate I 9.5g, dichloromethane 50mL are added in reaction bulb, chlorosulfonic acid 48g is added dropwise in cooling.Drop finishes, and is warming up to
50 DEG C of reaction overnights.Obtained system is slowly added to be quenched in 100mL mixture of ice and water, liquid separation, water phase is extracted with dichloromethane
It takes, merges organic phase, washing, without being further processed, directly carries out in next step to get to the dichloromethane solution of intermediate II
Reaction；
The dichloromethane solution of intermediate II is added in reaction bulb, ammonium hydroxide 100mL is added dropwise, reacts at room temperature about 2h, decompression
Being concentrated into system has solid generation, filtering, and filtration cakes torrefaction is to get the about 11.2g of intermediate III, without processing, directly carries out
In next step；
III 11.2g of intermediate, n,N-Dimethylformamide 45mL are added in reaction bulb, N- bromo succinyls are added dropwise in cooling
Imines 35g.Drop finishes, and reacts at room temperature about 2h, and water is added and reaction is quenched in ethyl acetate.Liquid separation, water phase are extracted with ethyl acetate, and close
And organic phase, with water, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, filtrate decompression concentration, column chromatography for separation to get
The about 9.8g of intermediate IV；
IV 9.8g of intermediate, phenyl boric acid 6.0g, sodium carbonate 0.18g, tetrakis triphenylphosphine palladium 0.20g are added to reaction bulb
In, ethyl alcohol 20mL, water 0.8mL are added in reaction bulb, and nitrogen protection, back flow reaction is overnight.Reaction finishes, and directly depressurizes dense
Contracting, column chromatography for separation is to get to V 6.4g of intermediate.
V 6.4g of intermediate, propionic andydride 36mL, propionic acid 0.6mL are added in reaction bulb, are warming up to 130 DEG C of reactions about
2h, filtering, filtration cakes torrefaction to get title SC 69124 sodium impurity 4.8g.
Obtained SC 69124 sodium impurity is more than 98% through HPLC detection purity.
Claims (10)
1. a kind of Parecoxib Sodium impurity compound, the compound is N- [[3- (5- methyl 4-phenyl -3- isoxazolyls) benzene
Base] sulfonyl] propionamide.
2. a kind of method preparing SC 69124 sodium impurity, the impurity is N- [[3- (5- methyl 4-phenyl -3- isoxazoles
Base) phenyl] sulfonyl] propionamide, synthetic route is as follows：
This approach includes the following steps：
A) 1- phenyl -1,2- propanedione, hydroxylamine hydrochloride are added in organic solvent by, and catalyst is added, and temperature rising reflux reacts,
Obtain intermediate I；
B) intermediate I is dissolved in organic solvent by, (, dichloromethane be added reaction bulb in), and chlorosulfonic acid is added dropwise, and drop finishes, heated up
Night reacts, and reaction solution is added in mixture of ice and water and is quenched to get to intermediate II organic solution, without being further processed, directly
Row is tapped into react in next step；
C) ammonium hydroxide is added dropwise in intermediate II organic solution, room temperature reaction, and separation after reaction obtains intermediate III；
D) intermediate III, n,N-Dimethylformamide are added in reaction bulb, and N-bromosuccinimide is added dropwise, and drop finishes, room temperature
Reaction, after reaction separation obtain intermediate IV；
E) intermediate IV, phenyl boric acid, base reagent, tetrakis triphenylphosphine palladium are added in aqueous alcoholic solvent, nitrogen protection, return
Overnight, reaction finishes for stream reaction, and separation obtains intermediate V；
F) intermediate V, propionic andydride, propionic acid are added in reaction bulb by, and temperature reaction is to get SC 69124 sodium impurity.
3. according to the method described in claim 2, the organic solvent in the step a) is in methanol, ethyl alcohol, isopropanol
It is a kind of.
4. according to the method described in claim 2, the catalyst in the step a) is silico-tungstic acid.
5. according to the method described in claim 2, the organic solvent in the step b) is dichloromethane.
6. according to the method described in claim 2, the one kind of the alcohol of the step e) in methanol, ethyl alcohol, isopropanol.
7. according to the method described in claim 2, step e) the coupling reactions intermediate IV, phenyl boric acid, four (triphenylphosphines)
Palladium, base reagent mole ratio be 1:1.2~2:0.05~0.1:0.006~0.01.
8. according to the method described in claim 2, the reaction temperature that the reaction temperature of step a) is 60~80 DEG C or step b) is
40~60 DEG C or step f) of reaction temperature is 120~130 DEG C.
9. according to the method described in claim 2, the base reagent in the step e) is sodium carbonate or cesium carbonate.
10. the impurity compound of claim 1 is used as the purposes of SC 69124 sodium impurity reference substance or in control Parecoxib Sodium
Purposes in quality.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2098593A (en) * | 1981-05-11 | 1982-11-24 | Sterling Drug Inc | Isoxazoles |
| CN106008385A (en) * | 2016-05-25 | 2016-10-12 | 浙江宏冠生物药业有限公司 | Synthesis method of parecoxib sodium |
| CN106588803A (en) * | 2016-11-16 | 2017-04-26 | 西南科技大学 | Novel method for preparing 5-acetylisoxazole |
-
2018
- 2018-05-14 CN CN201810456013.8A patent/CN108484516A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2098593A (en) * | 1981-05-11 | 1982-11-24 | Sterling Drug Inc | Isoxazoles |
| CN106008385A (en) * | 2016-05-25 | 2016-10-12 | 浙江宏冠生物药业有限公司 | Synthesis method of parecoxib sodium |
| CN106588803A (en) * | 2016-11-16 | 2017-04-26 | 西南科技大学 | Novel method for preparing 5-acetylisoxazole |
Non-Patent Citations (3)
| Title |
|---|
| MAJID M. HERAVI等: "Heteropolyacids as green and reusable catalysts for the synthesis of isoxazole derivatives", 《SYNTHETIC COMMUNICATIONS》 * |
| 周邦昌: "围术期镇痛药帕瑞昔布钠的合成及工艺优化", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 王凯 等: "帕瑞昔布的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Application publication date: 20180904 |