CN108033929A - A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity - Google Patents

A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity Download PDF

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CN108033929A
CN108033929A CN201711444700.XA CN201711444700A CN108033929A CN 108033929 A CN108033929 A CN 108033929A CN 201711444700 A CN201711444700 A CN 201711444700A CN 108033929 A CN108033929 A CN 108033929A
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ratio
impurity
concentrated
mass ratio
silica gel
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刘传飞
李延顺
陈晓涛
辛海强
李飞飞
冷晓
杨克宝
刘宁宁
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Qingdao Huanghai Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation

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Abstract

The present invention relates to field of medicaments, and in particular to a kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity.(1) using 4 hydroxythiobenzamides as starting material, react with chlroacetone, Duff reaction generation impurity As then occur with trifluoroacetic acid and methenamine；(2) using 4 hydroxythiobenzamides as starting material, react with 2 chlorine, 3 ethyl 3-oxopropanoate, Duff reaction generation impurity Bs then occur with trifluoroacetic acid and methenamine；(3) structure of impurity A and impurity B is confirmed by nuclear-magnetism.Synthetic method of the present invention is simple, is easy to get；The purity of obtained impurity A and impurity B is high, is respectively 99.55% and 98.13%.

Description

The synthetic method and its synthesis impurity of a kind of gout suppressant Febustat intermediate impurities Application
Technical field
The present invention relates to field of medicaments, and in particular to a kind of synthetic method of gout suppressant Febustat intermediate impurities and It synthesizes the application of impurity.
Background technology
Febustat (Febuxostat), chemical name：2- (3- cyano-4-isobutoxy phenyls) -4- methyl-5-thiazoles Formic acid, is a kind of xanthine oxidase inhibitor developed by Japanese Teijin (Di Ren companies), and in 2008 on Europe City, compared with the medicine of other treatment gout, has the inhibitory action of xanthine oxidase the selectivity and higher of higher Activity, can quickly reduce the level of blood uric acid, have remarkable effect to treatment gout, have very in treatment hyperuricemia and gout Big application prospect.
Febustat is just progressively substituting original treatment gout medicine at present, and progressively it is widely applied.On Febustat The patent document of preparation is relatively more, more classical syntheti c route such as Fig. 1：
In medicine API research process, miscellaneous Quality Research is the key entirely studied, its effect is that clear impurity produces Reason and whereabouts, so as to control the generation of impurity by controlling technological parameter, in terms of the source of impurity, impurity is divided into starting The impurity that material introduces impurity and technique produces, the present invention is to study 2 introducing impurity of starting material, so that in starting material The source of middle control impurity.
The synthetic route of starting material such as Fig. 2, uses 2- chloroacetyl acetacetic esters in Step 2, due in 2- chloracetyls Contain chlroacetone and the chloro- 3- ethyl 3-oxopropanoates impurity of 2- in ethyl acetate, therefore, Step 3 occur accordingly impurity A and Impurity B, its structure are shown below：
In the Step2 of the synthetic route of above-mentioned starting material, 4- hydroxythiobenzamides and 2- chloroacetyl acetacetic esters In chlroacetone reaction generation intermediate 1, Duff reaction generation impurity As then occur, its route is shown below：
At the same time in Step2,4- hydroxythiobenzamides and the chloro- 3- oxopropanoic acids of 2- in 2- chloroacetyl acetacetic esters Ethyl ester road reaction generation intermediate 2, then occurs Duff reaction generation impurity Bs, its route is shown below：
The standard of identification can't be reached by producing still gained impurity there are impurity in above-mentioned Febustat preparation process, into And pure impurity in product control Febustat preparation process can be controlled by being badly in need of acquisition.
The content of the invention
Synthetic method and its synthesis it is an object of the invention to provide a kind of gout suppressant Febustat intermediate impurities The application of impurity.
To achieve the above object, the present invention use technical solution for：
A kind of synthetic method of gout suppressant Febustat intermediate impurities, the synthesis of Febustat intermediate impurities A, such as Shown in following formula：
Ethanol is mixed with 4- hydroxythiobenzamides, chlroacetone is added during being stirred, is warming up to after mixing 75~80 DEG C, equality of temperature reacts 1~5h, cools down 20~30 DEG C after question response, filters, washing, filtration cakes torrefaction obtains white solid；
Trifluoroacetic acid (TFA) and above-mentioned obtained solid are stirred to clarification, methenamine (HMTA) is added after stirring, 100~110 DEG C are warming up to, equality of temperature reacts 6~8h, cools down 20~30 DEG C after question response, then extracts, washs, filtering, filter Liquid is concentrated to give yellow solid impurity A；
The synthesis of Febustat intermediate impurities B：
Ethanol is mixed with 4- hydroxythiobenzamides, the chloro- 3- ethyl 3-oxopropanoates of 2- are added during being stirred, 75~80 DEG C are warming up to after mixing, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response beam, is concentrated to give crude oil；
By obtained grease purifying crude, white solid is concentrated to give, clarification is then mixed to TFA, after stirring HMTA is added, is warming up to 100~110 DEG C, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response, then extracts, washes Wash, filter, filtrate is concentrated to give oily liquids, and oily liquids purifies to obtain white solid impurity B.
According to the ratio of 8~15g/g of mass ratio, ethanol is mixed with 4- hydroxythiobenzamides, is added in whipping process Enter chlroacetone, the mass ratio of chlroacetone and 4- hydroxythiobenzamides is 0.5~1.0g/g, is warming up to 75~80 DEG C, equality of temperature 1~5h is reacted, is cooled down 20~30 DEG C after question response, filtering, is washed, filtration cakes torrefaction obtains white solid with ethanol.
The ratio of 5~10g/g in mass ratio, trifluoroacetic acid (TFA) is mixed with above-mentioned obtained solid, and stirring clarification, adds Enter 5~10g of mass ratio/g of methenamine (HMTA), TFA and HMTA, 100~110 DEG C are warming up to after charging, equality of temperature is anti- 6~8h is answered, cools down 20~30 DEG C after question response, adds purified water according to the ratio of 3~8g/g of mass ratio with TFA, according to Add methylene chloride extraction with the ratio of 3~5g/g of mass ratio of TFA, organic phase is collected after liquid separation and uses saturation NaHCO successively3It is molten Liquid, saturated common salt water washing, filtrate are concentrated to give yellow solid impurity A.
According to the ratio of 5~10g/g of mass ratio, ethanol is mixed with 4- hydroxythiobenzamides, is added in whipping process Enter the chloro- 3- ethyl 3-oxopropanoates of 2-, the mass ratio 1.0 of the chloro- 3- ethyl 3-oxopropanoates of 2- and 4- hydroxythiobenzamides~ 2.0g/g, is warming up to 75~80 DEG C, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response, is concentrated into after charging There is no drop to drip for condenser pipe, obtains grease crude product；
Obtained grease crude product is isolated and purified, then according to the ratio of 10~15g/g of mass ratio, by trifluoro second Sour (TFA) mixes to clarification with above-mentioned obtained solid, and the quality of methenamine (HMTA), TFA and HMTA is added after stirring Than 10~15g/g, 100~110 DEG C are warming up to after charging, equality of temperature reacts 2~5h, cools down 20~30 after question response DEG C, add purified water according to the ratio of 5~10g/g of mass ratio, the ratio of 5~10g/g of mass ratio adds methylene chloride extraction, after liquid separation Organic phase uses saturation NaHCO successively3Solution, saturated salt solution are washed, through anhydrous Na after washing2SO4It is dry, filtering, filtrate Oily liquids is concentrated to give, oily liquids purifies to obtain white solid impurity B.
Gained grease crude product is isolated and purified, is specially：Obtained grease crude product is mixed into (silica gel with silica gel For 200 mesh), the mass ratio of silica gel and crude product is 1~3g/g, adds after dichloromethane mixes and is concentrated into condenser pipe there is no liquid Drop is dripped, column chromatography for separation, and quality and the crude product quality ratio of lower berth silica gel are 5~10g/g, with volume ratio normal heptane：Acetic acid second Ester is 10：1~5：1 eluent elution, collects the eluent of impure B, is concentrated to give white solid.
Gained concentration oily liquids is isolated and purified, is specially mixed obtained concentration oily liquids with silica gel (silica gel is 200 mesh), the mass ratio of silica gel and crude product is 1~3g/g, adds after dichloromethane mixes and is concentrated into condenser pipe not There is drop to drip again, column chromatography for separation, quality and the crude product quality ratio of lower berth silica gel are 5~10g/g, with volume ratio normal heptane： Ethyl acetate is 10：1~5：1 eluent elution, collects the eluent of impurity B, is concentrated to give white solid impurity B.
One kind synthesis obtain gout suppressant Febustat intermediate impurities as system of identification in gout suppressant Fei Busi Application.
Advantage for present invention：Synthetic method of the present invention is simple, is easy to get；The purity of obtained impurity A and impurity B Height, is respectively 99.55% and 98.13%.
Brief description of the drawings
Fig. 1 is the more classical syntheti c route figure of Febustat.
Fig. 2 is the synthetic route chart of the raw material of synthesis Febustat.
Fig. 3 is impurity A provided in an embodiment of the present invention1H NMR and HPLC scheme.
Fig. 4 is impurity B provided in an embodiment of the present invention1H NMR and HPLC scheme.
Embodiment
It is embodied by following embodiments, the above of the present invention is further described.
Embodiment 1
The synthesis of impurity A
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 5.00 g (32.63mmol) are added 4- hydroxythiobenzamides, 40g absolute ethyl alcohols, 3.60g (39.16mmol) chlroacetones stirred at 75 DEG C reaction 2 it is small when (TLC monitorings), after reaction stops, cooling to 20~25 DEG C, filtering, filter cake washs to obtain 1 white solid of intermediate with absolute ethyl alcohol 6.18g HPLC：98.25 %, yield：99.03%；
In the 100mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 10.00g is added (52.28mmol) intermediate 1 and TFA 60g are stirred, and 10.55 g HMTA (73.19mmol) are added after clarification, are warming up to 100~110 DEG C, when equality of temperature reaction 5 is small, after reaction stops, 20~25 DEG C are cooled to, adds 100g purified waters, 100g dichloromethanes Alkane extracts, and organic phase uses saturation NaHCO successively after liquid separation3Solution washs, saturated common salt water washing, anhydrous Na2SO4It is dry, mistake Filter, filtrate are concentrated to give 5.78g impurity As (referring to Fig. 1), yield：39.80%, purity 99.55%.
The synthesis of impurity B
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 2.50 g (16.31mmol) are added 4- hydroxythiobenzamides, the chloro- 3- ethyl 3-oxopropanoates of 3.00g (19.92mmol) 2- and 20g absolute ethyl alcohols, at 70 DEG C When stirring reaction 2 is small (TLC monitorings), after reaction stops, 20~30 DEG C are cooled to, system directly concentrates, and obtains pale yellowish oil liquid 14.00 g of body；
Column chromatography for separation：Above-mentioned acquisition pale yellowish oil liquid is added into silica gel 18g (200 mesh), adds dichloromethane Be concentrated under reduced pressure after 50mL dissolvings, be concentrated into that there is no drop to drip, chromatographic column lower berth silica gel 80g, and after through volume ratio normal heptane： Ethyl acetate=6：1 elution, obtains 0.80g white solids intermediate 2, HPLC：90.00%, yield：18.58%；
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 0.90 g (3.60mmol) is added Intermediate 2 and TFA 10g are stirred, and 0.73g HMTA (5.04mmol) are added after clarification, are warming up to 100~110 DEG C, together When temperature reaction 3 is small, after reaction stops, 20~25 DEG C are cooled to, adds 10g purified waters, the extraction of 10g dichloromethane, has after liquid separation Machine mutually uses saturation NaHCO successively3Solution washs, saturated common salt water washing, anhydrous Na2SO4Dry, filtering, filtrate is concentrated to give crude product 5.00g；
Column chromatography for separation：Crude product adds silica gel 18g (200 mesh), is concentrated under reduced pressure, concentrates after adding dichloromethane 50mL dissolvings To drip to there is no drop, chromatographic column lower berth silica gel 20g, and after through volume ratio normal heptane：Ethyl acetate=6：1 is eluted, Obtain 0.20g impurity Bs (referring to Fig. 2), purity：98.13%.
Embodiment 2
The synthesis of impurity A
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 10.00 g are added (65.26mmol) 4- hydroxythiobenzamides, 80g absolute ethyl alcohols, 7.20g (78.32mmol) chlroacetones stir at 78 DEG C React 3 it is small when (TLC monitorings), after reaction stops, cooling to room temperature, filter, filter cake is washed to obtain the white of intermediate 1 with absolute ethyl alcohol Solid 11.18g, yield：89.58%；
In the 100mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 15.00g is added (78.43mmol) intermediate 1 and TFA 90g are stirred, and 15.83 g HMTA (109.79mmol) are added after clarification, are warming up to 100 DEG C, when equality of temperature reaction 6 is small, after reaction stops, 25 DEG C being cooled to, adds 100g purified waters, 100g dichloromethane extracts, point Organic phase uses saturation NaHCO successively after liquid3Solution washs, saturated common salt water washing, anhydrous Na2SO4It is dry, filtering, filtrate concentration Obtain impurity A 8.50g, yield：38.60%；Purity：99.39%.
The synthesis of impurity B
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 5.00 g (32.62mmol) are added 4- hydroxythiobenzamides, the chloro- 3- ethyl 3-oxopropanoates of 6.00g (39.84mmol) 2- and 40g absolute ethyl alcohols, at 78 DEG C When stirring reaction 3 is small (TLC monitorings), after reaction stops, room temperature is cooled to, system directly concentrates, and obtains pale yellowish oil liquid 25.00g；
Column chromatography for separation：Above-mentioned acquisition pale yellowish oil liquid is added into silica gel 18g (200 mesh), adds dichloromethane Be concentrated under reduced pressure after 100mL dissolvings, be concentrated into that there is no drop to drip, chromatographic column lower berth silica gel 150g, and after through volume ratio positive heptan Alkane：Ethyl acetate=5：1 is eluted, and obtains 1.76g white solids intermediate 2, yield：19.44%；
In the 50mL three-neck flasks equipped with magnetic stirring apparatus, condenser pipe and thermometer, 1.80 g (7.20mmol) are added Above-mentioned intermediate 2 and TFA 20g are stirred, and 1.46g HMTA (10.08mmol) are added after clarification, are warming up to 100 DEG C, together When temperature reaction 5 is small, after reaction stops, 25 DEG C are cooled to, adds 10g purified waters, the extraction of 10g dichloromethane, organic phase after liquid separation Saturation NaHCO is used successively3Solution washs, saturated common salt water washing, anhydrous Na2SO4Dry, filtering, filtrate is concentrated to give crude product 9.00g；
Column chromatography for separation：Crude product adds silica gel 18g (200 mesh), is concentrated under reduced pressure, concentrates after adding dichloromethane 50mL dissolvings To drip to there is no drop, chromatographic column lower berth silica gel 20g, volume ratio normal heptane：Ethyl acetate=8：1 elution, it is miscellaneous to obtain 0.50g Matter B, (purity 99.20%).
Above-mentioned 2 impurity of acquisition are applied on the impurity of starting material differentiates, can differentiate structure and the research of impurity The source whereabouts of impurity, so as to control technological parameter to produce the product of qualification.
What is finally illustrated is that while to illustrate this programme in detail with reference to preferable example, but not limited to this, only It is to be used to help understand the present invention, for those skilled in the art, on the basis of the principle of the invention is not departed from, may be used also To carry out some improvement to the present invention, and these improvement are also fallen into the protection domain of the claims in the present invention.

Claims (7)

  1. A kind of 1. synthetic method of gout suppressant Febustat intermediate impurities, it is characterised in that Febustat intermediate impurities A Synthesis, be shown below：
    Ethanol is mixed with 4- hydroxythiobenzamides, chlroacetone is added during being stirred, it is warming up to 75 after mixing~ 80 DEG C, equality of temperature reacts 1~5h, cools down 20~30 DEG C after question response, filters, washing, filtration cakes torrefaction obtains white solid；
    Trifluoroacetic acid (TFA) and above-mentioned obtained solid are stirred to clarification, methenamine (HMTA), heating are added after stirring To 100~110 DEG C, equality of temperature reacts 6~8h, cools down 20~30 DEG C after question response, and then extraction, washing, filtering, filtrate are dense Contract to obtain yellow solid impurity A；
    The synthesis of Febustat intermediate impurities B：
    Ethanol is mixed with 4- hydroxythiobenzamides, the chloro- 3- ethyl 3-oxopropanoates of 2-, mixing are added during being stirred After be warming up to 75~80 DEG C, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response beam, is concentrated to give crude oil；
    By obtained grease purifying crude, white solid is concentrated to give, clarification is then mixed to TFA, is added after stirring HMTA, is warming up to 100~110 DEG C, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response, then extracts, washs, mistake Filter, filtrate are concentrated to give oily liquids, and oily liquids purifies to obtain white solid impurity B.
  2. 2. the synthetic method of the gout suppressant Febustat intermediate impurities as described in claim 1, it is characterised in that：According to matter The ratio than 8~15g/g is measured, ethanol is mixed with 4- hydroxythiobenzamides, chlroacetone, chlroacetone are added in whipping process Mass ratio with 4- hydroxythiobenzamides is 0.5~1.0g/g, is warming up to 75~80 DEG C, equality of temperature reacts 1~5h, question response After cool down 20~30 DEG C, filtering, washed with ethanol, filtration cakes torrefaction obtains white solid.
  3. 3. the synthetic method of the gout suppressant Febustat intermediate impurities as described in claim 1 or 2, it is characterised in that：Press The ratio of 5~10g/g of mass ratio, trifluoroacetic acid (TFA) is mixed with above-mentioned obtained solid, and stirring clarification, adds methenamine (HMTA), 5~10g/g of mass ratio of TFA and HMTA, is warming up to 100~110 DEG C, equality of temperature reacts 6~8h, treats after charging Cool down 20~30 DEG C after reaction, add purified water according to the ratio of 3~8g/g of mass ratio with TFA, according to the quality with TFA Ratio than 3~5g/g adds methylene chloride extraction, and organic phase is collected after liquid separation and uses saturation NaHCO successively3Solution, saturated salt solution Washing, filtrate are concentrated to give yellow solid impurity A.
  4. 4. the synthetic method of the gout suppressant Febustat intermediate impurities as described in claim 1, it is characterised in that：According to matter The ratio than 5~10g/g is measured, ethanol is mixed with 4- hydroxythiobenzamides, the chloro- 3- oxos third of 2- are added in whipping process Acetoacetic ester, 1.0~2.0g/g of mass ratio of the chloro- 3- ethyl 3-oxopropanoates of 2- and 4- hydroxythiobenzamides, after charging 75~80 DEG C are warming up to, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response, being concentrated into condenser pipe, there is no drop Drip, obtain grease crude product；
    Obtained grease crude product is isolated and purified, then according to the ratio of 10~15g/g of mass ratio, by trifluoroacetic acid (TFA) clarification is mixed to above-mentioned obtained solid, the mass ratio of methenamine (HMTA), TFA and HMTA is added after stirring 10~15g/g, is warming up to 100~110 DEG C after charging, equality of temperature reacts 2~5h, cools down 20~30 DEG C after question response, Ratio according to 5~10g/g of mass ratio adds purified water, and the ratio of 5~10g/g of mass ratio adds methylene chloride extraction, has after liquid separation Machine mutually uses saturation NaHCO successively3Solution, saturated salt solution are washed, through anhydrous Na after washing2SO4It is dry, filter, filtrate is dense Contract to obtain oily liquids, and oily liquids purifies to obtain white solid impurity B.
  5. 5. the synthetic method of the gout suppressant Febustat intermediate impurities as described in claim 1 or 4, it is characterised in that：Will Gained grease crude product is isolated and purified, and is specially：Obtained grease crude product is mixed into (silica gel is 200 mesh) with silica gel, The mass ratio of silica gel and crude product is 1~3g/g, adds after dichloromethane mixes and be concentrated into condenser pipe there is no drop to drip, column Chromatography, quality and the crude product quality ratio of lower berth silica gel are 5~10g/g, with volume ratio normal heptane：Ethyl acetate is 10：1~ 5：1 eluent elution, collects the eluent of impure B, is concentrated to give white solid.
  6. 6. the synthetic method of the gout suppressant Febustat intermediate impurities as described in claim 1 or 4, it is characterised in that：Will Gained concentration oily liquids is isolated and purified, and obtained concentration oily liquids is specially mixed (silica gel 200 with silica gel Mesh), the mass ratio of silica gel and crude product is 1~3g/g, adds after dichloromethane mixes and is concentrated into condenser pipe there is no drop drop Under, column chromatography for separation, quality and the crude product quality ratio of lower berth silica gel are 5~10g/g, with volume ratio normal heptane：Ethyl acetate is 10：1~5：1 eluent elution, collects the eluent of impurity B, is concentrated to give white solid impurity B.
  7. 7. a kind of synthesis described in claim 1 obtain gout suppressant Febustat intermediate impurities as system of identification for anti-pain Application in expelling wind drug Fei Busi.
CN201711444700.XA 2017-12-27 2017-12-27 A kind of synthetic method of gout suppressant Febustat intermediate impurities and its application for synthesizing impurity Withdrawn CN108033929A (en)

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Publication number Priority date Publication date Assignee Title
CN111875557A (en) * 2020-08-19 2020-11-03 南通大学 Thiazole derivative and synthesis method thereof
CN111875557B (en) * 2020-08-19 2023-06-02 南通大学 Thiazole derivative and synthesis method thereof

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Application publication date: 20180515