CN104250232A - Preparation method of parecoxib sodium - Google Patents

Preparation method of parecoxib sodium Download PDF

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Publication number
CN104250232A
CN104250232A CN201310259736.6A CN201310259736A CN104250232A CN 104250232 A CN104250232 A CN 104250232A CN 201310259736 A CN201310259736 A CN 201310259736A CN 104250232 A CN104250232 A CN 104250232A
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reaction
sodium
parecoxib
organic solvent
solution
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刘超
叶子峥
彭显峰
戴萍
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SICHUAN WEITUO BIOLOGICAL PHARMACEUTICAL Co Ltd
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SICHUAN WEITUO BIOLOGICAL PHARMACEUTICAL Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42Oxazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06Heterocyclic 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
    • C07D261/08Heterocyclic 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 preparation method of parecoxib sodium. The method comprises the following steps: sulfonating 3,4-diphenyl-5-methylisoxazole as a raw material, ammonolyzing, acylating, salifying, and re-crystallizing to obtain parecoxib sodium. The method has the advantages of simple operation, good repeatability, high yield and low cost, and is suitable for industrialized production, and the parecoxib sodium finished product obtained in the invention has a content of a separate impurity of below 0.1%, and is suitable for preparing medicinal parecoxib sodium preparations.

Description

A kind of preparation method of Parecoxib Sodium
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method of Parecoxib Sodium and the pharmaceutical composition containing the Parecoxib Sodium directly obtained by the method.
Background technology
Parecoxib Sodium is specific cox 2 inhibitor, is mainly used in the treatment of post-operative pain.Its chemical structure is as follows.
Parecoxib Sodium (trade(brand)name: Dynastat) in Europe listing, is mainly used in the short of postoperative pain, can be used for the treatment of moderate or severe postoperative acute pain clinically.
At present, the preparation method about Parecoxib Sodium needs first to synthesize Valdecoxib, then obtains Parecoxib Sodium through propionating, salify.
Chinese patent application CN102329277A discloses a kind of method of synthesizing Parecoxib, reaction formula is as follows, namely by three-step reaction oneself synthesis 4-(5-methyl-3-phenyl-4-isoxzzole) Phenylsulfonic acid, then react with sulfur oxychloride, decompression steams unnecessary sulfur oxychloride, add ethanol, then after reacting 10h under adding ammoniacal liquor high temperature 100 ° of C, obtain Valdecoxib; Parecoxib is obtained by reacting again with propionic anhydride.This route shortcoming is that reaction raw materials 4-(5-methyl-3-phenyl-4-isoxzzole) Phenylsulfonic acid adopted is expensive, and use the sulfur oxychloride stronger to equipment corrosion, aftertreatment adopts the means directly steamed, not only contaminate environment, toxicity is comparatively large, brings larger difficulty and security risk to industrial production.
WO2003029230 discloses the method for synthesis Parecoxib Sodium, the method is with 1,2-phenylbenzyl ketone is raw material, and 5-methyl-3,4-phenylbenzene-isoxzzole reacts with chlorsulfonic acid under trifluoroacetic acid exists, reaction mixture toluene and water process repeatedly, add dense aqua ammonia again and obtain Valdecoxib, repeatedly process with isopropyl alcohol and water and obtain solid-state Valdecoxib, then leave at sulfuric acid and react with propionic anhydride, obtain Parecoxib, after adding sodium hydroxide ethanolic soln salify, obtain Parecoxib Sodium.The method have employed the strong trifluoroacetic acid of corrodibility in sulfonated reaction, and when synthesizing Valdecoxib, its last handling process is comparatively loaded down with trivial details, after the organic phase adopting the process of Virahol continuous print to obtain, then carries out recrystallization by methanol/water, not only wastes time and energy.After this, WO2005123701 is optimized this step last handling process, adopts column chromatography to carry out purifying and substitutes originally loaded down with trivial details operation.But still cost is high, yield is low for column chromatography, after three-step reaction total recovery 25.5%, and be difficult to suitability for industrialized production.
EP1550658 discloses a kind of method preparing Parecoxib Sodium, and reaction formula is as follows.The method with 1-phenyl-acetone for raw material, through number step be obtained by reacting Valdecoxib, and after obtain Parecoxib Sodium through acidylate, salify.Still it is cumbersome to there is the aftertreatment often walking reaction in the method, trivial operations, and production efficiency is low, and three step total recovery low by 29.7%, the present inventor reappears the method, test find total recovery be about 25%, samples contg 97.5%, maximum single impurity 0.28%, total impurities 0.67%.
Therefore, the Measures compare that above-mentioned prior art prepares Parecoxib Sodium is numerous and diverse, yield is low, purity is not high, quality does not reach medicinal standard, and cost is high, indivedual route relates to heavy dose of acid reagent, be unfavorable for safety in production, and be all difficult to suitability for industrialized production, for this reason, the present inventor is through large quantifier elimination, the synthetic method of EP1550658 is improved, obtain and a kind ofly prepare improving one's methods of Parecoxib Sodium, the method eliminates the cumbersome aftertreatment technology of multistep, make whole synthetic method simple to operate, reproducible, yield is high, cost is low, single impurity is all less than 0.1%, suitability for industrialized is produced, the product obtained also is applicable to medicinal.
Summary of the invention
The invention provides a kind of method preparing Parecoxib Sodium, the method is simple to operate, reproducible, yield is high, cost is low, and suitability for industrialized is produced, and the single impurity of Parecoxib Sodium finished product obtained, all below 0.1%, meets medicinal requirements.
For realizing the present invention, provide following embodiment.
In one embodiment, the method preparing Parecoxib Sodium of the present invention: comprise the following steps:
A). be dissolved in organic solvent A by 3, the 4-phenylbenzene-5-methylisoxazole of formula II, add chlorsulfonic acid, temperature of reaction is 20 ~ 60 DEG C; Reaction is finished, and uses frozen water cancellation, and organic solvent A extracts, and is separated the organic solvent A solution containing 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, and described solution, without process, directly carries out next step reaction;
B). the organic solvent A solution of previous step is directly added in ammoniacal liquor, temperature of reaction is 0 ~ 60 DEG C, react complete, direct concentrating under reduced pressure falls organic solvent, adds water dilution, crystallization, filter, dry, obtain the Valdecoxib of formula III, gained Valdecoxib, without the need to further process, directly carries out next step reaction;
C). by step b) Valdecoxib and acylating agent join in reactor, temperature of reaction is 70 ~ 140 DEG C, reaction finish, cooling crystallization, filter, with cold washing with alcohol filter cake, dry, obtain the Parecoxib of formula IV, without further process, directly carry out next step;
D). by step c) undressed Parecoxib be dissolved in organic solvent B, drip alkali reagent solution C, temperature of reaction is 0 ~ 50 DEG C; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product;
E). Parecoxib Sodium crude product is joined in organic solvent B, is heated to backflow and dissolves, add activated carbon decolorizing, filtered while hot, filtrate crystallization, filter, dry, obtain Parecoxib Sodium highly finished product.
In the above-described embodiment, the method preparing Parecoxib Sodium of the present invention, be included in step c further) in add a kind of catalyzer, described catalyzer is selected from the one in hydrochloric acid, sulfuric acid, propionic acid, trifluoroacetic acid, tosic acid, preferred propionic acid or hydrochloric acid.
In the above-described embodiment, the method preparing Parecoxib Sodium of the present invention, described organic solvent A is selected from toluene, methylene dichloride, dimethylbenzene, chloroform and their any mixture, preferred toluene, methylene dichloride or their mixture; Described acylating agent is selected from the one in propionic anhydride, propionyl chloride, ethyl propionate and methyl propionate, preferred propionic anhydride; Described organic solvent B is selected from methyl alcohol, ethanol, Virahol and their any mixture, preferred alcohol and methyl alcohol; Described alkali reagent solution C is selected from the methanol solution of sodium hydroxide, the ethanolic soln of sodium hydroxide, the aqueous solution of sodium hydroxide, the aqueous solution of sodium bicarbonate, the aqueous solution of sodium carbonate, the methanol solution of sodium methylate, the ethanolic soln of sodium ethylate and their any mixture, the ethanolic soln of preferred sodium hydroxide, the methanol solution of sodium hydroxide, the methanol solution of sodium methylate or the ethanolic soln of sodium ethylate.
In a preferred embodiment, the method preparing Parecoxib Sodium of the present invention, comprises the following steps:
A) be dissolved in the organic solvent A being selected from methylene dichloride, toluene, dimethylbenzene and chloroform by 3 of formula II, 4-phenylbenzene-5-methylisoxazole, add chlorsulfonic acid, temperature of reaction is 20 ~ 60 DEG C; Reaction is finished, and uses frozen water cancellation, and organic solvent A extracts, and is separated the organic solution solution A containing 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, and described solution, without process, directly carries out next step reaction;
B) the organic solvent A solution of previous step is directly added in ammoniacal liquor, temperature of reaction is 0 ~ 60 DEG C, react complete, direct concentrating under reduced pressure falls organic solvent A, adds water dilution, crystallization, filter, dry, obtain the Valdecoxib of formula III, gained Valdecoxib, without the need to further process, directly carries out next step reaction;
C) by step b) Valdecoxib and acylating agent propionic anhydride or methyl propionate join in reactor, temperature of reaction is 70 ~ 140 DEG C, reaction is finished, cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtain the Parecoxib of formula IV, without further process, directly carry out next step;
D) by step c) undressed Parecoxib be dissolved in the organic solvent B being selected from methyl alcohol, ethanol, Virahol, drip the alkali reagent solution C of the ethanolic soln of the methanol solution, the ethanolic soln of sodium hydroxide, the methanol solution of sodium methylate and the sodium ethylate that are selected from sodium hydroxide, temperature of reaction is 0 ~ 50 DEG C; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product;
E) Parecoxib Sodium crude product is joined in the organic solvent B being selected from methyl alcohol, ethanol, Virahol, be heated to backflow and dissolve, add activated carbon decolorizing, filtered while hot, filtrate crystallization, filter, dry, obtain Parecoxib Sodium highly finished product.
In the above-described embodiment, the method preparing Parecoxib Sodium of the present invention, preferably, is included in step c further) in add a kind of catalyzer, described catalyzer is selected from the one in hydrochloric acid, sulfuric acid, propionic acid, trifluoroacetic acid, tosic acid, preferred propionic acid or hydrochloric acid.
In above-mentioned preferred embodiment, preferred, the method preparing Parecoxib Sodium of the present invention, described organic solvent B is methyl alcohol, ethanol or their any mixture; Described alkali reagent solution C is the methanol solution of the ethanolic soln of sodium hydroxide, the methanol solution of sodium hydroxide or sodium methylate.
In one embodiment, the method preparing Parecoxib Sodium of the present invention, comprises the following steps:
A) be dissolved in methylene dichloride, toluene or dimethylbenzene by 3 of formula II, 4-phenylbenzene-5-methylisoxazole, add chlorsulfonic acid, temperature of reaction is 30 ~ 60 DEG C of reactions; Reaction is finished, use frozen water cancellation, organic solvent dichloromethane or toluene extraction, be separated the methylene dichloride containing 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, toluene or xylene solution, described solution, without process, directly carries out next step reaction;
B) dichloromethane solution of previous step or toluene solution are directly added in ammoniacal liquor, temperature of reaction is 0 ~ 30 DEG C, react complete, direct concentrating under reduced pressure falls organic solvent, adds water dilution, crystallization, filter, dry, obtain the Valdecoxib of formula III, gained Valdecoxib, without the need to further process, directly carries out next step reaction;
C) by step b) Valdecoxib and propionic anhydride join in reactor, temperature of reaction is 100 ~ 140 DEG C; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains the Parecoxib of formula IV, without further process, directly carries out next step;
D) by step c) undressed Parecoxib be dissolved in methyl alcohol or alcohol solvent, drip and be selected from the alkali reagent solution of the methanol solution of the methanol solution of sodium hydroxide, the ethanolic soln of sodium hydroxide and sodium methylate, temperature of reaction is 0 ~ 50 DEG C; Reaction is finished, and is directly evaporated to dry, is separated and obtains Parecoxib Sodium crude product;
E) Parecoxib Sodium crude product is joined be selected from methyl alcohol or alcohol solvent, be heated to backflow and dissolve, add activated carbon decolorizing, filtered while hot, filtrate crystallization, filter, dry, obtain Parecoxib Sodium highly finished product.
In the method for the invention described above, described " processing further " is also the understandable aftertreatment connotation in this area, as being further purified, refining.Described " dimethylbenzene " refers to p-Xylol, m-xylene, o-Xylol or their mixture.
Method of the present invention has the following advantages:
It can use commercially available starting material to implement with technical scale, and low price; All intermediates, all without being further purified, directly can carry out next step reaction; Total recovery can reach more than 50%, apparently higher than the yield 29.7% of existing bibliographical information; The content of single impurity is low, all below 0.1%, at least with EP1550658 quite or better.
The reaction formula of preparation method of the present invention is as follows:
Embodiment
Following examples are used for explaining essence of the present invention further, but do not limit the scope of the invention.
Embodiment 1
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 50mL methylene dichloride, adds 100g chlorsulfonic acid, be heated to 50 ~ 60 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase dichloromethane extraction, abandons water layer, merges organic phase, obtains the dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 100mL ammoniacal liquor, react under 20 ~ 30 ° of C, react complete, direct concentrating under reduced pressure falls methylene dichloride, then adds water dilution, crystallization, filtration, dry, obtain Valdecoxib and be about 58g, without further process, directly carry out next step.
Valdecoxib 58g, propionic anhydride 58ml, hydrochloric acid 3ml are joined in reactor, is heated to 100 ~ 120 ° of C reactions; Reaction is finished, and cooling, precipitation solid, filter, with cold washing with alcohol filter cake, dry, obtains Parecoxib 48g, without process, directly carry out next step;
Parecoxib 48g is dissolved in dehydrated alcohol 960mL, drips the ethanolic soln of sodium hydroxide, be heated to 40 ~ 50 ° of C reactions; Reaction finish, be directly evaporated to dry, after namely obtain Parecoxib Sodium crude product, about 54g.
Join in dehydrated alcohol 960mL by Parecoxib Sodium crude product 54g, reflux is dissolved, and add activated carbon decolorizing, filtered while hot, filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 45g.
Total recovery is 53.96%.Detect through HPLC, content 99.6%, maximum single impurity 0.07%, total impurities 0.18%.
Embodiment 2
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 300mL toluene, adds 300g chlorsulfonic acid, be heated to 30 ~ 40 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase toluene extracts, and abandons water layer, merges organic phase, obtains the toluene solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The toluene solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 300mL ammoniacal liquor, react at 0 ~ 10 DEG C, react complete, direct concentrating under reduced pressure falls toluene, adds water dilution, separate out solid, filter, dry, obtain Valdecoxib and be about 60g, without further process, directly carry out next step.
Valdecoxib 60g, propionic anhydride 180ml are joined in reactor, is heated to 130 ~ 140 ° of C reactions; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains Parecoxib 52g, without further process, directly carries out next step reaction;
Parecoxib 52g is dissolved in methyl alcohol 520mL, drips the methanol solution (g/g) of the sodium methylate of 30%, be heated to 40 ~ 50 ° of C reactions; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product, about 56g.
Join in methyl alcohol 600mL by Parecoxib Sodium crude product 56g, heating for dissolving, adds activated carbon decolorizing, filtered while hot, and filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 45g.Total recovery 52.76%.Detect through HPLC, content 99.8%, maximum single impurity 0.05%, total impurities 0.17%.
Embodiment 3
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 400mL methylene dichloride, adds 350g chlorsulfonic acid, be heated to 50 ~ 60 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase dichloromethane extraction, abandons water layer, merges organic phase, obtains the dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The dichloromethane solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 100mL ammoniacal liquor, be heated to 45 ~ 60 DEG C of reactions, react complete, direct concentrating under reduced pressure falls methylene dichloride, adds water dilution, separate out solid, filter, dry, obtain Valdecoxib and be about 62g, without further process, directly carry out next step.
Valdecoxib 62g, methyl propionate 124ml are joined in reactor, is heated to 70 ~ 80 ° of C reactions; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains Parecoxib 50g, without further process, directly carries out next step reaction;
Parecoxib 50g is dissolved in anhydrous methanol 500mL, drips the methanol solution (g/g) of 5% sodium hydroxide, react under 20-30 ° of C; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product, about 54g.
Join in Virahol 1500mL by Parecoxib Sodium crude product 54g, reflux is dissolved, and add activated carbon decolorizing, filtered while hot, filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 46g.Total recovery 55.16%.Detect through HPLC, content 99.9%, maximum single impurity 0.06%, total impurities 0.14%.
Embodiment 4
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 400mL p-Xylol, adds 350g chlorsulfonic acid, be heated to 30 ~ 40 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase p-Xylol extracts, and abandons water layer, merges organic phase, obtains the p-Xylol solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The p-Xylol solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 100mL ammoniacal liquor, react at 0 ~ 10 DEG C, react complete, direct concentrating under reduced pressure falls p-Xylol, adds water dilution, separate out solid, filter, dry, obtain Valdecoxib and be about 61.5g, without further process, directly carry out next step.
Valdecoxib 61.5g, propionic anhydride 250ml and propionic acid 2ml are joined in reactor, is heated to 110 ~ 120 ° Creaction; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains Parecoxib 50g, without further process, directly carries out next step;
Parecoxib 50g is dissolved in anhydrous methanol 500mL, drips the methanol solution (g/g) of 5% sodium hydroxide, temperature control 20 ~ 30 ° of C reactions; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product, about 54g.
Join in dehydrated alcohol 1000mL by Parecoxib Sodium crude product 54g, reflux is dissolved, and add activated carbon decolorizing, filtered while hot, filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 46g.Total recovery 55.16%.Detect through HPLC, content 99.9%, maximum single impurity 0.05%, total impurities 0.16%.
Embodiment 5
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 400mL chloroform, adds 500g chlorsulfonic acid, be heated to 20 ~ 35 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase chloroform extraction, abandons water layer, merges organic phase, obtains the chloroformic solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The chloroformic solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 150mL ammoniacal liquor, temperature control 25 ~ 35 DEG C reaction, react complete, direct concentrating under reduced pressure falls chloroform, adds water dilution, separate out solid, filter, dry, obtain Valdecoxib and be about 63g, without further process, directly carry out next step.
Valdecoxib 63g, propionic anhydride 252mL, propionic acid 2mL are joined in reactor, is heated to 120 ~ 130 ° of C reactions; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains Parecoxib 51g, without further process, directly carries out next step;
Parecoxib 51g is dissolved in dehydrated alcohol 800mL, drips the ethanolic soln (g/g) of sodium ethylate, temperature control 0 ~ 25 ° of C reaction; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product, about 55g.
Join in methyl alcohol 830mL by Parecoxib Sodium crude product 55g, reflux is dissolved, and add activated carbon decolorizing, filtered while hot, filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 43g.Total recovery 51.56%.Detect through HPLC, content 99.5%, maximum single impurity 0.05%, total impurities 0.16%.
Embodiment 6
3,4-phenylbenzene-5-methylisoxazole 50g is dissolved in 300mL toluene, adds 300g chlorsulfonic acid, be heated to 20 ~ 30 ° of C reactions; Reaction is finished, and use frozen water cancellation, separatory, aqueous phase toluene extracts, and abandons water layer, merges organic phase, obtains the toluene solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, without process, directly carry out next step.
The toluene solution of 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride is directly added in 300mL ammoniacal liquor, temperature control 0 ~ 10 DEG C reaction, react complete, direct concentrating under reduced pressure falls toluene, adds water dilution, separate out solid, filter, dry, obtain Valdecoxib and be about 61g, without further process, directly carry out next step.
Valdecoxib 61g, propionic anhydride 180ml are joined in reactor, is heated to 130 ~ 140 ° Creaction; Reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains Parecoxib 52g, without further process, directly carries out next step;
Parecoxib 52g is dissolved in methyl alcohol 520mL, drips the methanol solution (g/g) of the sodium hydroxide of 30%, be heated to 0 ~ 10 ° of C reaction; Reaction is finished, and is directly evaporated to dry, obtains Parecoxib Sodium crude product, about 56g.
Join in methyl alcohol 600mL by Parecoxib Sodium crude product 56g, heating for dissolving, adds activated carbon decolorizing, filtered while hot, and filtrate crystallization, filters, dry, obtains Parecoxib Sodium highly finished product 46g.Total recovery 55.16%.Detect through HPLC, content 99.7%, maximum single impurity 0.05%, total impurities 0.14%.
Related substance contrast sees the following form
Following table is the detected result of the Parecoxib sodium sample related substance of embodiment 1-6 and comparative example:
Related substance Single maximum contaminant Total impurities Content
Embodiment 1 0.07% 0.18% 99.6%
Embodiment 2 0.05% 0.17% 99.8%
Embodiment 3 0.06% 0.14% 99.9%
Embodiment 4 0.05% 0.16% 99.9%
Embodiment 5 0.05% 0.16% 99.5%
Embodiment 6 0.05% 0.14% 99.7%
* comparative example 0.28% 0.67% 97.5%
* comparative example is the Parecoxib sodium sample obtained by the method preparation of the embodiment 15-17 of EP1550658, and total recovery is 25%, and impurity adopts HPLC to measure.
Show from the result of upper table, method of the present invention, the maximum single impurity of the Parecoxib sodium sample obtained all is less than 0.1%, and quality product and yield are all better than the method for prior art EP1550658.

Claims (10)

1. a method for the Parecoxib Sodium of preparation formula I, comprises the following steps:
A). by 3 of formula II, 4-phenylbenzene-5-methylisoxazole is dissolved in organic solvent A, add chlorsulfonic acid, reaction is finished, use frozen water cancellation, organic solvent A extracts, and is separated the organic solvent A solution containing 4-(5-methyl-3-phenyl-4-isoxzzole) benzene sulfonyl chloride, described solution, without process, directly carries out next step reaction;
B). the organic solvent A solution of previous step is directly added ammoniacal liquor reaction, react complete, directly concentrate organic solvent, add water dilution, crystallization, filters, dry, obtain the Valdecoxib of formula III, gained Valdecoxib, without the need to further process, directly carries out next step reaction;
C). by step b) Valdecoxib and acylating agent join reaction kettle for reaction, reaction is finished, and cooling crystallization, filters, with cold washing with alcohol filter cake, dry, obtains the Parecoxib of formula IV, without further process, directly carries out next step;
D). by step c) undressed Parecoxib be dissolved in organic solvent B, drip alkali reagent solution C, reaction is finished, and is directly concentrated into dry, obtains Parecoxib Sodium crude product;
E). Parecoxib Sodium crude product is joined in organic solvent B, is heated to backflow and dissolves, add activated carbon decolorizing, filtered while hot, filtrate crystallization, filter, dry, obtain Parecoxib Sodium highly finished product.
2. method according to claim 1, described organic solvent A is selected from toluene, methylene dichloride, dimethylbenzene, chloroform and their any mixture.
3. method according to claim 1, described acylating agent is selected from the one in propionic anhydride, propionyl chloride, methyl propionate and ethyl propionate, is preferably propionic anhydride or methyl propionate.
4. method according to claim 1, is included in step c further) in add a kind of acid catalyst.
5. method according to claim 4, described acid catalyst is selected from the one in hydrochloric acid, sulfuric acid, propionic acid, trifluoroacetic acid, tosic acid, is preferably propionic acid or hydrochloric acid.
6. method according to claim 1, described organic solvent B is selected from methyl alcohol, ethanol, Virahol and their any mixture.
7. method according to claim 1, described alkali reagent solution C is selected from the methanol solution of sodium hydroxide, the ethanolic soln of sodium hydroxide, the aqueous solution of sodium hydroxide, the aqueous solution of sodium bicarbonate, the aqueous solution of sodium carbonate, the methanol solution of sodium methylate, the ethanolic soln of sodium ethylate and their any mixture.
8. method according to claim 7, described alkali reagent solution C is selected from the ethanolic soln of the methanol solution of sodium hydroxide, the ethanolic soln of sodium hydroxide, the methanol solution of sodium methylate and sodium ethylate.
9. method according to claim 1, step temperature of reaction a) is 20 ~ 60 DEG C, or step b) temperature of reaction be 0 ~ 60 DEG C, or step c) temperature of reaction be 70 ~ 140 DEG C, or steps d) temperature of reaction be 0 ~ 50 DEG C.
10. a pharmaceutical composition, comprises the Parecoxib Sodium of method acquisition as arbitrary in claim 1 ~ 9 and pharmaceutically acceptable carrier.
CN201310259736.6A 2013-06-26 2013-06-26 Preparation method of parecoxib sodium Pending CN104250232A (en)

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CN104945343A (en) * 2015-01-04 2015-09-30 成都克莱蒙医药科技有限公司 Synthesis method of parecoxib sodium impurity
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
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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

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Publication number Priority date Publication date Assignee Title
CN104557756A (en) * 2015-01-04 2015-04-29 成都克莱蒙医药科技有限公司 Synthetic method of parecoxib sodium impurity
CN104557754A (en) * 2015-01-04 2015-04-29 成都克莱蒙医药科技有限公司 Synthesis method for parecoxib sodium impurity
CN104557755A (en) * 2015-01-04 2015-04-29 成都克莱蒙医药科技有限公司 Synthesis method for parecoxib sodium impurity
CN104592141A (en) * 2015-01-04 2015-05-06 成都克莱蒙医药科技有限公司 Synthesis method of parecoxib sodium
CN104945343A (en) * 2015-01-04 2015-09-30 成都克莱蒙医药科技有限公司 Synthesis method of parecoxib sodium impurity
CN104557756B (en) * 2015-01-04 2017-02-22 成都克莱蒙医药科技有限公司 Synthetic method of parecoxib sodium impurity
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
CN106674142A (en) * 2016-12-07 2017-05-17 上海博志研新药物技术有限公司 Preparation methods of parecoxib sodium and intermediate thereof
CN107056721A (en) * 2017-04-12 2017-08-18 山东裕欣药业有限公司 A kind of Parecoxib Sodium crystalline compounds and preparation method thereof
CN107056721B (en) * 2017-04-12 2019-09-06 山东裕欣药业有限公司 A kind of Parecoxib Sodium crystalline compounds and preparation method thereof
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
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

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