CN109810031B - Preparation method of tilobaxib intermediate - Google Patents
Preparation method of tilobaxib intermediate Download PDFInfo
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Abstract
The invention relates to a preparation method of a tilapia intermediate, belonging to the technical field of pharmacy. The preparation method provided by the invention comprises the following steps: the target product is prepared by reacting a raw material with an acyl chloride reagent, then reacting with another raw material in the presence of alkali, and performing aftertreatment. The method provided by the invention has strong operability, and is beneficial to the operation and cost control of industrial mass production.
Description
Technical Field
The invention relates to a preparation method of a tilapia intermediate, belonging to the technical field of pharmacy.
Background
The tiloxicillin is a veterinary non-steroidal anti-inflammatory drug which can selectively inhibit the synthesis of prostaglandin mediated by cyclooxygenase-2, has the effects of relieving fever, easing pain and resisting inflammation, and can be used for treating various acute and chronic pains and inflammations.
In the prior art, sodium chloroacetate and cyclopropylmethanol are usually adopted to obtain acid under the action of sodium hydride, and then the acid reacts with sulfur compounds under the action of condensing agents to obtain a target intermediate or the obtained acid reacts with brominated sulfur compounds to obtain the target intermediate. Therefore, it is necessary to develop a safer and simpler method.
Disclosure of Invention
The present invention provides a process for preparing compound (I), an intermediate for the preparation of celecoxib.
A process for preparing compound (I), comprising: step b: after the compound (01) is reacted with an acyl chloride reagent, the obtained product is contacted with the compound (02), and the compound (I) is prepared through post-treatment after the reaction is completed in the presence of alkali, wherein the reaction formula is shown as follows:
in some embodiments, a method of preparing compound (I) comprises:
step a: the cyclopropyl methanol is contacted with the potassium tert-butoxide, then the obtained mixture is contacted with halide, after the reaction is completed, the compound (01) is obtained through post-treatment,
step b: after the compound (01) is reacted with an acyl chloride reagent, the obtained product is contacted with the compound (02), and the compound (I) is prepared through post-treatment after the reaction is completed in the presence of alkali, wherein the reaction formula is shown as follows:
in the above method, the acyl chloride reagent is thionyl chloride, oxalyl chloride, tebuconazole or a combination thereof. In some embodiments, the acid chloride reagent is thionyl chloride, which is more advantageous for reaction performance, control or handling. The halide is sodium chloroacetate, sodium bromoacetate, chloroacetic acid, bromoacetic acid, or a combination thereof. In some embodiments, the halide is sodium chloroacetate, which is more advantageous for reaction performance and handling.
In some embodiments, a method of preparing compound (I) comprises: step b: after the compound (01) is reacted with thionyl chloride, the obtained product is contacted with the compound (02), and the compound (I) is prepared through post-treatment after the reaction is completed in the presence of alkali, wherein the reaction formula is shown as follows:
in some embodiments, a method of preparing compound (I) comprises:
step a: the cyclopropyl methanol is contacted with the potassium tert-butoxide, then the obtained mixture is contacted with sodium chloroacetate, after the reaction is completed, the compound (01) is obtained through post treatment,
step b: after the compound (01) is reacted with thionyl chloride, the obtained product is contacted with the compound (02), and the compound (I) is prepared through post-treatment after the reaction is completed in the presence of alkali, wherein the reaction formula is shown as follows:
in another aspect, the present invention provides a method of preparing a celecoxib comprising: the compound (I) prepared by the method is subjected to cyclization reaction in toluene in the presence of 1, 8-diazabicyclo undec-7-ene (DBU) and isopropyl trifluoroacetate to obtain non-Luo Kao shake.
The inventor finds through research that in the step a, potassium tert-butoxide is used instead of sodium hydride as alkali, so that the safety risk of the amplified production is greatly reduced, the reaction is safe and controllable, and the operation is easy; however, at the same time, a tertiary butyl impurity A is produced, and the resultant compound (01) contains the tertiary butyl impurity A, which adversely affects the subsequent reaction steps. Further research has found that a small amount of tertiary butyl impurity A generated in the step a can be continuously reacted with the compound (02) in the reaction process of the compound (02) and the compound (01) in the step B to generate corresponding tertiary butyl impurity B, and most of the impurity A can be removed through post-treatment in the step B; in the step B, the compound (01) is reacted with an acyl chloride reagent such as thionyl chloride and the like, and then reacted with the compound (02) by using the acyl chloride reagent such as thionyl chloride and the like, so that the operation is simplified, the compound (I) is easy to obtain, simultaneously, a small amount of impurities B can be controlled to be generated, and part of tert-butyl impurities B can be removed by post-treatment, so that the compound (I) is simply prepared, and the tert-butyl impurities B in the prepared compound (I) are less. In the reaction for preparing the end product, the tert-butyl impurity B may react to form impurity C. In the invention, by controlling the reaction conditions of the step a and the step B, a compound (I) product containing a small amount of impurity B can be obtained, and when the compound (I) containing a small amount of impurity B is used for preparing the celecoxib, the content of tert-butyl impurity C in the prepared celecoxib can reach the requirement (namely, the impurity content is lower than 0.1%). Although tert-butyl impurities are generated in the previous step, the method has no influence on the final product of non-Luo Kao shake, improves the safety of the whole process, simplifies the operation, and can ensure the yield and better control the cost. Tert-butyl impurity A, impurity B, impurity C structure as follows:
in the invention, a small amount of residual tert-butyl impurity B and corresponding impurity C generated by the residual tert-butyl impurity B can be controlled and/or removed in the process of preparing the tilmicoxib, so that the impurity in the final product of the tilmicoxib meets the quality requirement of less than 0.1 percent.
In some embodiments, contacting the cyclopropylmethanol with potassium tert-butoxide comprises: potassium tert-butoxide, an organic solvent and cyclopropylmethanol are mixed, optionally under an inert gas atmosphere, and the mixture is then controlled at a certain temperature for a certain time, optionally the mixture is cooled to a certain temperature, to obtain a mixture. The organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether, or a combination thereof. The dosage of the organic solvent is 5mL-50mL for each gram of cyclopropylmethanol.
The inert gas is a gas which does not react with the reaction materials.
In some embodiments, in step a, the resulting mixture is contacted with sodium chloroacetate and reacted at 0 ℃ to 60 ℃ for 5 hours to 50 hours, with the reaction being complete. In some embodiments, in step a, the resulting mixture is contacted with sodium chloroacetate and reacted at 20 ℃ to 60 ℃ for 10 hours to 50 hours, with the reaction being complete. In some embodiments, in step a, the resulting mixture is contacted with sodium chloroacetate and reacted at 30 ℃ to 60 ℃ for 10 hours to 30 hours, with the reaction being complete. In some embodiments, in step a, the resulting mixture is contacted with sodium chloroacetate and reacted at 30 ℃ to 60 ℃ for 15 hours to 30 hours, with the reaction being complete.
In step a, the molar ratio of the cyclopropyl methanol to the halide is 1:1-1:3. In some embodiments, the molar ratio of cyclopropylmethanol to halide is 1:1 to 1:2.2, which is more advantageous for reaction performance and control.
In the step a, the molar ratio of the cyclopropyl methanol to the potassium tert-butoxide is 1:1-1:5. In some embodiments, the molar ratio of cyclopropylmethanol to potassium tert-butoxide is from 1:1 to 1:3. In some embodiments, the molar ratio of cyclopropylmethanol to potassium tert-butoxide is 1:1.2 to 1:3, which is more advantageous for reaction performance and control.
In some embodiments, in step a, the molar ratio of cyclopropylmethanol to sodium chloroacetate is 1:1 to 1:3. In some embodiments, the molar ratio of cyclopropylmethanol to sodium chloroacetate is 1:1 to 1:2.2, which is more advantageous for reaction performance and control.
In some embodiments, in step a, the post-processing comprises: controlling the temperature of the reaction liquid to be 0-5 ℃, adding hydrochloric acid to adjust the pH to 1-2, then using sodium hydroxide to adjust the pH to 9-10, adding water, stirring, standing, and separating liquid; the aqueous phase is washed with methylene chloride, the pH of the resulting aqueous phase is adjusted to 1-3 with hydrochloric acid, and then extracted with methylene chloride to obtain a methylene chloride solution containing the compound (01), and the obtained methylene chloride solution containing the compound (01) may be dried with anhydrous sodium sulfate as necessary. The solvent is removed from the methylene chloride solution containing the compound (01) to obtain the compound (01).
In the step b, the methylene chloride solution containing the compound (01) obtained in the step a may be used, or the methylene chloride solution containing the compound (01) obtained in the step a may be used to remove the solvent.
In some embodiments, in step b, a mixture of compound (01) and a reaction solvent, optionally with a catalytic amount of N, N-Dimethylformamide (DMF), is reacted with an acid chloride reagent for 0.1 hour to 10 hours to obtain a mixture; then the obtained mixture is contacted with the compound (02) and alkali, a catalyst is optionally added, the reaction is carried out at the temperature of 0-40 ℃, and the compound (I) is obtained after the reaction is completed and the post-treatment is carried out. In some embodiments, compound (02) and base, optionally a catalyst, are dissolved in a reaction solvent and then mixed with the reaction system. In the step b, the reaction solvent may be dichloromethane, DMF, DMSO, or the like. In some embodiments, in step b, the reaction solvent is methylene chloride, facilitating the reaction and handling.
In some embodiments, in step b, a mixture of compound (01) and dichloromethane, optionally with a catalytic amount of N, N-Dimethylformamide (DMF), is reacted with thionyl chloride for 0.1 hour to 10 hours to obtain a mixture; then the obtained mixture is contacted with the compound (02) and alkali, a catalyst is optionally added, the reaction is carried out at the temperature of 0-40 ℃, and the compound (I) is obtained after the reaction is completed and the post-treatment is carried out. In some embodiments, compound (02) and base, optionally a catalyst, are dissolved in methylene chloride and then mixed with the reaction system.
In step b, the base is a base which can react with hydrogen chloride, hydrogen bromide, such as triethylamine, N-diisopropylethylamine, etc. The molar ratio of the alkali to the compound (02) is 1:1-1:5. In some embodiments, the base is triethylamine.
In step b, the catalyst may be 4-Dimethylaminopyridine (DMAP).
In the above method, the molar ratio of the acid chloride reagent to the compound (02) is 1:1 to 5:1.
The molar ratio of the compound (01) to the compound (02) is 1:1-5:1. In some embodiments, the molar ratio of compound (01) to compound (02) is from 1.2:1 to 3.6:1, which is more advantageous for reaction performance and control.
In some embodiments, the molar ratio of thionyl chloride to compound (02) is 1:1 to 5:1.
In step b, each gram of compound (01) may be dissolved in 3mL-15mL of methylene chloride.
In step b, the post-processing includes: and optionally adding dichloromethane into the reaction solution, adding water for washing, and removing the solvent from the obtained organic phase to obtain a crude product of the compound (I). Crystallizing the crude product with ethanol to obtain a compound (I) product; the ethanol dosage is 3mL-30mL for each gram of the compound (02). In some embodiments, the crude product is mixed with ethanol and then heated to reflux to completely dissolve the solid, the insoluble material is removed by filtration if necessary, then the heating is stopped, cooled to room temperature, stirred for 0.5 to 10 hours, the solid is isolated, the solid obtained is washed with ethanol, and then the solvent in the solid obtained is removed to give the compound (I) product.
Detailed Description
In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the invention, g: g; mL: milliliters; c: degrees celsius; h: hours; min: and (3) minutes.
In the present invention, the complete or stop reaction means that the remaining amount of the reaction raw material is not more than 2% of the fed amount or theoretical yield or not more than 1% of the fed amount or theoretical yield or not more than 0.5% of the fed amount or theoretical yield.
In the invention, room temperature refers to the ambient temperature, and the temperature range is 15-35 ℃ or 20-30 ℃ or 22-28 ℃ of the temperature.
Example 1
Potassium tert-butoxide (t-BuOK, 11.6 g) was mixed with tetrahydrofuran (150 mL), and cyclopropylmethanol (5.0 g) was slowly added under nitrogen, and after the addition was completed, the mixture was heated to 50℃and stirred for 1 hour, and then cooled to room temperature; sodium chloroacetate (9.7 g) was added at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes, and then heated to 40℃and stirred for reaction for 40 hours.
Cooling the obtained reaction liquid to 0-5 ℃, slowly dropwise adding concentrated hydrochloric acid, regulating the pH value to 1, then regulating the pH value to 9-10 by using 10% sodium hydroxide aqueous solution (mass fraction), adding water (100 mL), fully stirring, standing, separating liquid, adding water, stirring until white insoluble solid exists in the water phase, dissolving, washing by using dichloromethane (80 mL multiplied by 2), cooling the water phase to 0 ℃, regulating the pH value to 1-3 by using 3mol/L hydrochloric acid aqueous solution, controlling the temperature to be lower than 10 ℃ in the process of regulating the pH value, extracting by using dichloromethane (100 mL multiplied by 3), merging organic phases, and drying by using anhydrous sodium sulfate; the organic phase was evaporated to dryness under reduced pressure to give compound (01): 8.08g of pale yellow oil, and 16.72% of tert-butyl impurity A.
Example 2
Potassium tert-butoxide (t-BuOK, 24.12 g) was mixed with tetrahydrofuran (150 mL), and cyclopropylmethanol (5.0 g) was slowly added under nitrogen, and after the addition was completed, the mixture was heated to 50℃and stirred for 1 hour, and then cooled to room temperature; sodium chloroacetate (12.10 g) was added at room temperature, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes, and then heated to 40℃and stirred for reaction for 40 hours.
Cooling the obtained reaction liquid to 0-5 ℃, slowly dropwise adding concentrated hydrochloric acid, regulating the pH value to 1, then regulating the pH value to 9-10 by using 10% sodium hydroxide aqueous solution (mass fraction), adding water (100 mL), fully stirring, standing, separating liquid, adding water, stirring until white insoluble solid exists in the water phase, dissolving, washing by using dichloromethane (80 mL multiplied by 2), cooling the water phase to 0 ℃, regulating the pH value to 1-3 by using 3mol/L hydrochloric acid aqueous solution, controlling the temperature to be lower than 10 ℃ in the process of regulating the pH value, extracting by using dichloromethane (100 mL multiplied by 3), merging organic phases, and drying by using anhydrous sodium sulfate; the organic phase was evaporated to dryness under reduced pressure to give compound (01): 8.11g of pale yellow oil and 15.48% of tert-butyl impurity A.
Example 3
Compound (01) (3.75 g, t-butyl impurity a content 16.72%) was dissolved in methylene chloride (25 mL), N-dimethylformamide (227 mg) was added, thionyl chloride (1.7 mL) was slowly added at room temperature, and after the addition was completed, the reaction was stirred at room temperature for 6 hours to obtain a mixture; the resulting mixture was then mixed with a solution of compound (02) (4.84 g), DMAP (733 mg) and triethylamine (4.05 g) in dichloromethane (25 mL) at room temperature, and the reaction was stirred at room temperature for 8 hours. The reaction mixture was washed with water (25 mL. Times.2), separated, and the organic phase was evaporated to dryness under reduced pressure at 45℃to give a crude tan solid. Absolute ethyl alcohol (40 mL) is added into the obtained solid crude product, heating reflux is carried out to enable the solid crude product to be completely dissolved, then natural cooling is carried out to room temperature, stirring is carried out for 12 hours, suction filtration is carried out, the solid is washed by absolute ethyl alcohol (3 mL multiplied by 3), drying is carried out for 8 hours at 50 ℃ to obtain the compound (I): 6.03g of an off-white solid, having a tert-butyl impurity B content of 0.51%, was not detected.
Example 4
Compound (01) (10.01 g, t-butyl impurity a content 16.41%) was dissolved in methylene chloride (25 mL), N-dimethylformamide (227 mg) was added, thionyl chloride (4.5 mL) was slowly added at room temperature, and after the addition was completed, the reaction was stirred at room temperature for 6 hours to obtain a mixture; the resulting mixture was then mixed with a solution of compound (02) (4.84 g), DMAP (733 mg) and triethylamine (10.81 g) in methylene chloride (35 mL) at room temperature, and the reaction was stirred at room temperature for 8 hours. The reaction mixture was washed with water (30 mL. Times.2), separated, and the organic phase was evaporated to dryness under reduced pressure at 45℃to give a crude tan solid. Absolute ethyl alcohol (40 mL) is added into the obtained solid crude product, heating reflux is carried out to enable the solid crude product to be completely dissolved, then natural cooling is carried out to room temperature, stirring is carried out for 12 hours, suction filtration is carried out, the solid is washed by absolute ethyl alcohol (3 mL multiplied by 3), drying is carried out for 8 hours at 50 ℃ to obtain the compound (I): 6.10g of an off-white solid, having a tert-butyl impurity B content of 0.40%, was not detected.
Example 5
Compound (01) enriched in tert-butyl impurity a (5.20 g, tert-butyl impurity a content 44%) was dissolved in dichloromethane (25 mL), DMF (10 drops) was added, cooled to 0 ℃, thionyl chloride (2.9 mL) was added, and after the addition was completed, the reaction was stirred at room temperature for 6 hours; the resultant mixture was mixed with compound (02) (4.84 g), DMAP (733 mg), triethylamine (6.07 g) and methylene chloride (25 mL), and reacted at room temperature with stirring for 12 hours (the reaction solution was sampled and examined, a large amount of compound (02) was found to remain, and the impurity B content was 1.80%). Dichloromethane (100 mL) was added to the reaction solution, extracted with water (75 ml×2), the solution was separated, and the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying to give a brown oil.
The brown oily matter is added into absolute ethyl alcohol (40 mL), heated and refluxed to be completely dissolved, then the heating is stopped, the temperature is naturally reduced to room temperature, the mixture is stirred for 12 hours, the mixture is filtered, the solid is washed by absolute ethyl alcohol (3 mL multiplied by 3), and the obtained solid is dried at 50 ℃ to obtain a compound (I): 2.34g of a white solid, having a content of 0.35% of tert-butyl impurity B, was detected. The mother liquor after post-treatment contains raw materials, namely tertiary butyl impurity A and tertiary butyl impurity B.
Example 6
Compound (I) (6.26 g, enriched in tert-butyl impurity B, content 11.75%) was dissolved in toluene (31 mL), DBU (8.06 g) and isopropyl trifluoroacetate (4.41 g) were added, and the mixture was heated to 95℃and reacted with stirring for 12 hours (the reaction solution was sampled and examined, tert-butyl impurity C content 6.75%). Stopping heating, naturally cooling the reaction solution to room temperature, distilling under reduced pressure until no fraction flows out, slowly dripping water (31 mL), slowly precipitating solid, stirring at room temperature for 2h after dripping, suction filtering, washing the filter cake with water (10 mL×2), and detecting to obtain solid wet product, wherein the content of tert-butyl impurity C is 2.63%.
The solid wet product was added to absolute ethanol (18 mL), heated to complete dissolution, then the heating was stopped, cooled naturally to room temperature, stirred for 12 hours, suction filtered, and the solid was washed with ethanol (3 mL. Times.2). The resulting solid was dried at 50℃to give non-Luo Kaoxi as a white solid, 4.78g and a t-butyl impurity C content of 0.06%.
Example 7
Compound (I) (4.40 g, t-butyl impurity B content 0.42%) was dissolved in toluene (22 mL), DBU (5.66 g) and isopropyl trifluoroacetate (3.10 g) were added, and the mixture was heated to 95 ℃ and reacted with stirring for 12 hours (the reaction solution was sampled and examined, t-butyl impurity C content 0.11%). Stopping heating, naturally cooling the reaction solution to room temperature, distilling under reduced pressure until no fraction flows out, slowly dripping water (22 mL), slowly precipitating solid, stirring at room temperature for 2h after dripping, suction filtering, washing the filter cake with water (20 mL), and suction drying to obtain a solid wet product, and detecting, wherein the content of tert-butyl impurity C is 0.09%.
Adding the solid wet product into absolute ethanol (12 mL), heating to dissolve completely, stopping heating, naturally cooling to room temperature, stirring for 10 hours, transferring to-5-0deg.C, stirring for 1 hr, suction filtering, and washing the solid with ethanol (3 mL). The resulting solid was dried under vacuum at 60℃for 12h to give non-Luo Kaoxi as a white solid, 3.72g, with no detectable tert-butyl impurities A, B and C.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (7)
1. A process for preparing compound (I), comprising: step a: the cyclopropyl methanol is contacted with potassium tert-butoxide, then the obtained mixture is contacted with halide, and after the reaction is completed, the compound (01) is obtained through post-treatment; the reaction formula is shown as follows:
wherein the halide is sodium chloroacetate;
step b: the compound (01) is reacted with acyl chloride reagent for 0.1 to 10 hours under the condition of adding catalytic amount of N, N-dimethylformamide, the obtained product is contacted with the compound (02), the compound (I) is prepared after the reaction is completed by post-treatment under the condition of existence of alkali, optional addition of catalyst and reaction at 0 to 40 ℃; the reaction formula is shown as follows:
wherein the molar ratio of the N, N-dimethylformamide to the compound (2) is as follows: 1:6.45, wherein the acyl chloride reagent is thionyl chloride.
2. The method of claim 1, wherein the post-processing comprises: washing the reaction solution with water, and removing the solvent from the obtained organic phase to obtain a crude product of the compound (I); crystallizing the crude product with ethanol to obtain a compound (I) product; the ethanol dosage is 3mL-30mL for each gram of the compound (02).
3. The process according to claim 1, wherein the molar ratio of compound (01) to compound (02) is from 1:1 to 5:1.
4. The process according to claim 1, wherein the molar ratio of thionyl chloride to compound (02) is from 1:1 to 5:1.
5. The process according to claim 2, wherein in step a, potassium tert-butoxide, an organic solvent and cyclopropylmethanol are mixed, optionally under an inert gas atmosphere, and the mixture is then controlled at a certain temperature for a certain time, optionally the mixture is cooled to a certain temperature, resulting in a mixture.
6. The process according to claim 2, wherein in step a the resulting mixture is contacted with a halide and reacted at 0 ℃ to 60 ℃ for 5 hours to 50 hours.
7. The process according to claim 2, wherein in step a the molar ratio of cyclopropylmethanol to potassium tert-butoxide is from 1:1 to 1:5.
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| CN110452199B (en) * | 2019-09-03 | 2021-03-30 | 山东鲁抗舍里乐药业有限公司 | Preparation method of feloxicib |
| CN112624943B (en) * | 2020-12-28 | 2022-07-01 | 成都伊诺达博医药科技有限公司 | Synthesis method of feloxicib intermediate |
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| TW200505446A (en) * | 2003-01-17 | 2005-02-16 | Fuj Isawa Pharmaceutical Co Ltd | Inhibitor of cox |
| EP2066659B1 (en) * | 2006-09-29 | 2013-08-28 | Grünenthal GmbH | Substituted sulfonamide derivatives |
| US8207335B2 (en) * | 2009-02-13 | 2012-06-26 | Boehringer Ingelheim International Gmbh | Process for making certain compounds having B1 antagonistic activity |
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| US5981576A (en) * | 1995-10-13 | 1999-11-09 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| CN105859664A (en) * | 2016-05-03 | 2016-08-17 | 中国药科大学 | Firocoxib preparation method |
| WO2018109781A1 (en) * | 2016-12-13 | 2018-06-21 | Sequent Scientific Limited | A process for the preparation of firocoxib |
| CN110105314A (en) * | 2019-06-02 | 2019-08-09 | 江苏君若医药有限公司 | One method for preparing Fei Luokao former times |
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