CN109053505B - Synthesis method of important intermediate of feloxicib - Google Patents
Synthesis method of important intermediate of feloxicib Download PDFInfo
- Publication number
- CN109053505B CN109053505B CN201810876892.XA CN201810876892A CN109053505B CN 109053505 B CN109053505 B CN 109053505B CN 201810876892 A CN201810876892 A CN 201810876892A CN 109053505 B CN109053505 B CN 109053505B
- Authority
- CN
- China
- Prior art keywords
- reaction
- methylsulfonyl
- solvent
- felicoxib
- isobutyrophenone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of a felocoxib intermediate, which takes p-methylsulfonyl isobutyrophenone as a starting raw material and adopts a one-pot method, firstly generating a brominated intermediate in an NBS (N-bromosuccinimide) system, hydrolyzing to obtain a target compound [ 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one ], wherein the used materials are all environment-friendly materials, and do not generate environment-friendly byproducts, such as thioether compounds, simple operation, no potential safety hazard, mild reaction conditions, suitability for industrial production, less by-products, and a crystallization solvent is optimized for a target compound, so that a product with high yield and purity can be obtained, and the product can be directly used for preparing the felicoxib subsequently to obtain a high-purity final product, namely the felicoxib.
Description
Technical Field
The invention relates to the field of synthesis of medicinal chemistry, in particular to a synthesis method of an important intermediate of felicoxib.
Background
The feloxicib is an important non-steroidal anti-inflammatory veterinary drug, and mainly has the effect of blocking the conversion of arachidonic acid into prostaglandin by selectively inhibiting cyclooxygenase-2 (COX-2) mediated synthesis of the prostaglandin, so that the effects of antipyresis, analgesia and anti-inflammation are achieved. Compared with other non-steroidal anti-inflammatory veterinary drugs, the fenocoxib can efficiently and selectively inhibit COX-2, can be rapidly absorbed by the body, and has a remarkable curative effect on relieving osteoarthritis pain.
The compound 2-hydroxy-1- (4-methanesulfonyl-phenyl) -2-methyl-propan-1-one, of the formula:
is an important intermediate for synthesizing the veterinary drug felicoxib.
The following methods are reported for the synthesis of this intermediate:
the first method is a synthetic route of the felicoxib reported in patent documents US5981576, US6020343A and CN 1203066C. Taking the thiobenzol as an initial raw material, carrying out Friedel-crafts reaction with isobutyryl chloride to generate a compound A, hydroxylating the compound A to generate a compound B, oxidizing the compound B by an oxidant such as OXONE potassium hydrogen persulfate composite salt, and crystallizing in an ether and hexane system to obtain a target compound C, wherein the reaction formula is as follows:
the main disadvantages of the synthesis process are: 1. the use of the thiobenzol ether with an unpleasant odor as a starting material has great pressure on environmental protection. 2. The hydroxylation reaction uses carbon tetrachloride, which is a class of solvents known to be carcinogenic and harmful to both humans and the environment. 3. The diethyl ether and hexane used as crystallization solvents are extremely flammable and explosive solvents, and are not suitable for industrial production.
The second method is a synthetic route of feloxicib reported in patent document CN 104803956A. Taking the thiobenzol as an initial raw material, and carrying out Friedel-crafts reaction with isobutyryl chloride to generate a compound A; reacting the compound A with liquid bromine to generate a brominated intermediate, and hydrolyzing under the conditions that sodium hydroxide is used as alkali and tetrabutylammonium bromide is used as a phase transfer catalyst to obtain a compound B; and oxidizing the compound B with oxidant such as OXONE potassium hydrogen persulfate complex salt, extracting, separating, drying and concentrating to obtain the target compound C. The reaction formula is as follows:
the synthetic process has the following disadvantages: 1. the use of the thiobenzol ether with an unpleasant odor as a starting material has been under great pressure in the environmental protection. 2. The liquid bromine used in the bromination reaction has extremely strong toxicity and corrosivity, is extremely not beneficial to the environment and occupational health, and should be avoided as much as possible. 3. The synthesis process is to directly concentrate the extraction solvent under reduced pressure to obtain the target compound C, and a proper crystallization process is not available, so that the purity of the compound C cannot be ensured. The purity of the compound C as an important intermediate of the veterinary drug, namely the feloxicib, can directly influence the purity of the final product, namely the feloxicib.
Method three is a synthetic route of feloxicib reported in patent document CN 107686471A. Taking p-bromophenylketone as an initial raw material, and carrying out methylation reaction with methyl iodide to produce a compound a; then the compound a and sodium methylsulfinate are subjected to sulfonylation reaction to generate a compound b; finally, taking DMSO (dimethyl sulfoxide) as a solvent, adding NBS (N-bromosuccinimide) into the compound b, and reacting for 10-14 h at 80-100 ℃. And then extracting, separating, drying, concentrating, and crystallizing in a methyl tert-butyl ether/n-heptane mixed solvent system to obtain the target compound C. The reaction formula is as follows:
the formation mechanism of compound C in the third step of the synthesis process is shown in the document "org.lett., 2015,17,876-879" as follows:
wherein dimethyl sulfoxide is used as a solvent in the reaction process, and also provides an oxygen source for hydroxylation reaction, and the oxygen source reacts with a bromination intermediate state to generate a byproduct dimethyl sulfide. Dimethyl sulfide is similar to dimethyl sulfide in that it has an unpleasant odor and is not environmentally friendly. And dimethyl sulfide has a flash point of-38 ℃, and is extremely easy to burn and explode under high temperature. The process needs to react for 10-14 hours at 80-100 ℃, and potential safety hazards exist.
Meanwhile, dimethyl sulfide is also a reagent with strong nucleophilicity, and can generate side reaction with a brominated intermediate state under the step time high-temperature reaction, so that the purity of the compound C is influenced. The crystallization solvent of this process is a methyl tert-butyl ether/n-heptane system, whereas compound C has poor solubility in both solvents, especially n-heptane, which is almost insoluble. Therefore, it is difficult to increase the purity of compound C by crystallization using the mixed solvent.
Therefore, there is still a need in the art for a safe and environmentally friendly synthetic method capable of purifying target compound C to ensure the purity of the important intermediates of felicoxib and to support the high purity of felicoxib.
Disclosure of Invention
The invention aims to provide a synthetic method which is simple to operate, low in production cost, safe and environment-friendly, has the function of purifying important intermediates of the felicoxib, and is suitable for industrial production.
The invention provides a synthesis method of an important intermediate of felicoxib, namely 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one, which comprises the following steps:
(1) mixing p-methylsulfonyl isobutyrophenone, N-bromosuccinimide, a catalyst and a reaction solvent, heating to 60-80 ℃ for reaction, and cooling to room temperature after the reaction is finished to obtain a mixed solution;
(2) adding an alkali aqueous solution into the mixed solution, reacting at room temperature, adding an organic solvent and water after the reaction is finished, extracting, drying, filtering, and concentrating under reduced pressure to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one.
The reaction formula is as follows:
and (2) adopting a one-pot reaction, directly using the mixed solution containing the compound II obtained in the step (1) for the next reaction, without separating and purifying the intermediate II, and having simple operation and high yield. And the adopted raw materials are simple and easy to obtain, the method is environment-friendly, and thioether byproducts with bad smell and influence on the environment are not generated in the reaction.
Further, the reaction solvent in step (1) is selected from acetonitrile, ethyl acetate or isopropyl acetate, preferably acetonitrile or ethyl acetate.
Further, the mass-to-volume ratio (g/mL) of the methanesulfonylisobutyrophenone to the reaction solvent in the step (1) is 1:3 to 6.
Further, in the step (1), the catalyst is selected from thiourea, ammonium acetate or p-toluenesulfonic acid, and is preferably thiourea or ammonium acetate.
Further, the molar ratio of the mesyl isobutyrophenone to the catalyst in the step (1) is 1:0.1 to 0.5.
Further, the molar ratio of the methanesulfonylisobutyrophenone to the N-bromosuccinimide in the step (1) is: 1:1.2-2.0.
Further, the aqueous alkali solution of step (2) is selected from an aqueous potassium carbonate solution, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.
Further, the preparation method also comprises a recrystallization step, and the recrystallization solvent is selected from methyl tert-butyl ether, isopropanol, isopropyl acetate, ethyl acetate/methyl tert-butyl ether mixed solvent or isopropyl acetate/methyl tert-butyl ether mixed solvent. The purity of the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one is greatly improved by screening the recrystallization solvent.
The invention also provides application of the preparation method in preparing the feloxicib.
The methods of the present application are also applicable to compounds
Wherein R1 is Ar group, R2 is straight-chain or branched Cn alkane group, and R3 is hydrogen or straight-chain or branched Cn alkane group, such as compounds IV and V.
The important intermediate of the feloxicib prepared by the embodiment of the invention has the following advantages:
(1) the invention takes p-methylsulfonyl isobutyrophenone as an initial raw material, adopts a one-pot method, firstly generates a brominated intermediate under an NBS (N-bromosuccinimide) system, and then hydrolyzes to obtain a target compound [ 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one ], wherein the used materials are environment-friendly materials, and can not generate environment-friendly byproducts, such as thioether compounds.
(2) The method has the advantages of simple operation, no potential safety hazard, mild reaction conditions and suitability for industrial production.
(3) The method has few byproducts, optimizes the crystallization solvent aiming at the target compound, can obtain a product with high yield and purity, and can be directly used for preparing the felicoxib subsequently to obtain a high-purity final product, namely the felicoxib.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
The structure of the compound was determined by nuclear magnetic resonance (1H NMR) or MS.
The NMR spectrometer (1H NMR) was Bruker AVANCE-400, the NMR (1H NMR) shifts () are given in parts per million (ppm), the measurement solvent was DMSO-d6, the internal standard was Tetramethylsilane (TMS), and the chemical shifts were given in 10-6 (ppm).
The term "room temperature" according to the present invention means a temperature between 10 and 25 ℃.
The invention will be further illustrated with reference to the following specific examples:
example 1 preparation of important intermediates of felicoxib:
mixing p-methylsulfonyl isobutyrophenone (10.0g, 1.0eq) with 50mL of acetonitrile, adding N-bromosuccinimide (11.8g, 1.5eq) and thiourea (1.0g, 0.3eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of sodium hydroxide (5.0g) and water (25.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, evaporating a filtrate under reduced pressure to remove a solvent, then adding 20mL of isopropanol, heating to 70 ℃, dissolving, cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.18g, light brown solid, yield 85.7%, HPLC purity 98.1%).
The characterization results of the important intermediates of felicoxib provided in this example are as follows:
1HNMR(CDCl3)1.61(6H，s)，3.09(3H，s)，3.32(1H，br)，8.02-8.00(2H，m)，8.22-8.19(2H，m)
LC-MS: the molecular weight of the intermediate is 242.29, the mass spectrum gives the [ M + H ] + -peak, the M/z is 243.2, which accords with the molecular weight.
Example 2 preparation of important intermediates of felocoxib:
mixing the p-methylsulfonyl isobutyrophenone (30.0g, 1.0eq) with 90mL of acetonitrile, adding N-bromosuccinimide (37.8g, 1.6eq) and thiourea (2.0g, 0.2eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of sodium hydroxide (15.0g) and water (75.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, evaporating a filtrate under reduced pressure to remove a solvent, then adding 45mL of isopropyl acetate, heating to 75 ℃, dissolving, cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (28.0g, light brown solid, yield 87.2%, HPLC purity 98.8%).
Example 3 preparation of important intermediates of felicoxib:
mixing the p-methylsulfonyl isobutyrophenone (30.0g, 1.0eq) with 150mL of acetonitrile, adding N-bromosuccinimide (37.8g, 1.6eq) and ammonium acetate (2.0g, 0.2eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of potassium hydroxide (21.0g) and water (105.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, evaporating a filtrate under reduced pressure to remove a solvent, then adding 45mL of isopropyl acetate, heating to 75 ℃, dissolving, cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (27.4g, light brown solid, yield 85.3%, HPLC purity 98.5%).
Example 4 preparation of important intermediates of felicoxib:
mixing p-methylsulfonyl isobutyrophenone (10.0g, 1.0eq) with 50mL of ethyl acetate, adding N-bromosuccinimide (9.4g, 1.2eq) and thiourea (1.7g, 0.5eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of sodium carbonate (10.0g) and water (50.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, evaporating a filtrate under reduced pressure to remove a solvent, then adding 10mL of isopropyl acetate, heating to 75 ℃, dissolving, cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (28.0g, light brown solid, yield 85.7%, HPLC purity 97.3%).
Example 5 preparation of important intermediates of felicoxib:
mixing p-methylsulfonyl isobutyrophenone (10.0g, 1.0eq) with 60mL of acetonitrile, adding N-bromosuccinimide (15.7g, 2.0eq) and thiourea (0.34g, 0.1eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of potassium carbonate (10.0g) and water (50.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, evaporating a filtrate under reduced pressure to remove a solvent, then adding 15mL of isopropyl acetate, heating to 75 ℃, dissolving, cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.1g, light brown solid, yield 85.0%, HPLC purity 97.2%).
Example 6 preparation of important intermediates of felicoxib:
mixing the p-methylsulfonyl isobutyrophenone (50.0g, 1.0eq) with 250mL of acetonitrile, adding N-bromosuccinimide (62.9g, 1.6eq) and ammonium acetate (3.4g, 0.2eq), heating to 60-80 ℃ under stirring, and carrying out heat preservation reaction for 1-2 h until the reaction is complete. And cooling to room temperature, slowly adding the prepared solution of sodium hydroxide (20.0g) and water (100.0g), and continuously stirring at room temperature for 10-12 h to complete hydrolysis reaction. Adding ethyl acetate and water, extracting, separating liquid, drying an organic phase by using anhydrous sodium sulfate, uniformly dividing a filtrate into five parts by mass after filtering, and testing different crystallization solvents respectively:
and (3) taking the first filtrate, evaporating the solvent under reduced pressure, adding 10mL of isopropyl acetate, heating to 75 ℃, dissolving, cooling at a constant speed, crystallizing, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.45g, light brown solid, 88.3% yield, 97.7% HPLC purity).
And (3) taking the second filtrate, evaporating the solvent under reduced pressure, adding 15mL of methyl tert-butyl ether, heating to 55 ℃, dissolving and clearing, then cooling at constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.63g, light brown solid, 89.9% yield, 96.5% HPLC purity).
And (3) taking the third filtrate, evaporating the solvent under reduced pressure, adding 15mL of methyl tert-butyl ether and 5mL of ethyl acetate, heating to 60 ℃, dissolving and clearing, then cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.20g, light brown solid, yield 85.9%, HPLC purity 97.4%).
And (3) taking the fourth filtrate, evaporating the solvent under reduced pressure, adding 15mL of methyl tert-butyl ether and 5mL of isopropyl acetate, heating to 60 ℃, dissolving and clearing, then cooling at a constant speed for crystallization, filtering, and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one. (9.31g, light brown solid, yield 87.0%, HPLC purity 96.9%).
And taking the fifth filtrate, evaporating the solvent under reduced pressure, adding 10mL of ethyl acetate, heating to 70 ℃, and dropwise adding 5mL of n-heptane at a constant speed. Then cooling at constant speed for crystallization, filtering and drying to obtain the 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propane-1-ketone. (9.46g, light brown solid, 88.4% yield, 92.6% HPLC purity).
Comparative example 1 was prepared according to the method disclosed in example 10 of chinese patent CN 107686471A.
B1(40.0g, 1.0eq) was dissolved in 200mL of dimethyl sulfoxide, and N-bromosuccinimide (6.3g, 0.2eq) was added. The temperature is increased to 100 ℃ for reaction for 12 h. Cooling to room temperature after complete reaction, adding ethyl acetate and water for extraction, drying an organic phase, evaporating under reduced pressure to remove a solvent, and crystallizing by using methyl tert-butyl ether-n-heptane to obtain a compound C, namely: 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone, (35.4g, 82.7% yield, as a pale yellow solid, 92.1% purity).
From the above experiments, it can be seen that the preparation method of 2-hydroxy-2-methyl- (4-methylsulfonyl) phenyl-1-propanone provided in examples 1-6 of the present invention has a yield slightly higher than that of comparative example 1, a purity significantly higher than that of comparative example 1, and the preparation method of the present invention does not generate by-products having an influence on the environment of the unpleasant-smelling thioethers, and comparative example 1 generates the unpleasant-smelling dimethyl sulfide.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A method for synthesizing important intermediates of felicoxib comprises the following steps:
(1) mixing p-methylsulfonyl isobutyrophenone, N-bromosuccinimide, a catalyst and a reaction solvent, heating to 60-80 ℃ for reaction, and cooling to room temperature after the reaction is finished to obtain a mixed solution; the reaction solvent is ethyl acetate or acetonitrile; the catalyst is selected from thiourea or ammonium acetate; the mass-volume ratio g/mL of the p-methylsulfonyl isobutyrophenone to the reaction solvent is 1: 3-6; the molar ratio of the p-methylsulfonyl isobutyrophenone to the catalyst is 1: 0.1-0.5; the molar ratio of the p-methylsulfonyl isobutyrophenone to the N-bromosuccinimide is as follows: 1: 1.2-2.0;
(2) adding an alkali aqueous solution into the mixed solution, reacting at room temperature, adding an organic solvent and water after the reaction is finished, extracting, drying, filtering, and concentrating under reduced pressure to obtain 2-hydroxy-1- (4-methylsulfonyl-phenyl) -2-methyl-propan-1-one;
the reaction formula is as follows:
2. the method for synthesizing important intermediates of felicoxib according to claim 1, wherein the aqueous base solution of step (2) is selected from an aqueous potassium carbonate solution, an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.
3. The method for synthesizing important intermediates of felicoxib according to claim 1, further comprising a recrystallization step, wherein the recrystallization solvent is selected from methyl tert-butyl ether, isopropanol, isopropyl acetate, a mixed solvent of ethyl acetate and methyl tert-butyl ether, or a mixed solvent of isopropyl acetate and methyl tert-butyl ether.
4. Use of the preparation method according to any one of claims 1 to 3 for the synthesis of feloxib.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810876892.XA CN109053505B (en) | 2018-08-03 | 2018-08-03 | Synthesis method of important intermediate of feloxicib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810876892.XA CN109053505B (en) | 2018-08-03 | 2018-08-03 | Synthesis method of important intermediate of feloxicib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109053505A CN109053505A (en) | 2018-12-21 |
| CN109053505B true CN109053505B (en) | 2020-08-11 |
Family
ID=64833149
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810876892.XA Active CN109053505B (en) | 2018-08-03 | 2018-08-03 | Synthesis method of important intermediate of feloxicib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109053505B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110452198B (en) * | 2019-09-03 | 2021-03-26 | 山东鲁抗舍里乐药业有限公司 | Preparation method of feloxicib |
| 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 |
| CN112500321A (en) * | 2020-09-25 | 2021-03-16 | 安徽省公众检验研究院有限公司 | Preparation method of feloxicib key intermediate |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
| CN106349285A (en) * | 2016-08-29 | 2017-01-25 | 天津久日新材料股份有限公司 | Hydroxyl-containing acyl phosphine oxides and their preparation and application |
| CN107686471A (en) * | 2017-09-28 | 2018-02-13 | 四川青木制药有限公司 | A kind of Fei Luokao former times and its synthetic method of intermediate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030225098A1 (en) * | 2002-03-21 | 2003-12-04 | Hirst Gavin C. | Kinase inhibitors |
| US9950999B2 (en) * | 2016-08-12 | 2018-04-24 | International Business Machines Corporation | Non-ionic low diffusing photo-acid generators |
-
2018
- 2018-08-03 CN CN201810876892.XA patent/CN109053505B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020343A (en) * | 1995-10-13 | 2000-02-01 | Merck Frosst Canada, Inc. | (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
| CN106349285A (en) * | 2016-08-29 | 2017-01-25 | 天津久日新材料股份有限公司 | Hydroxyl-containing acyl phosphine oxides and their preparation and application |
| CN107686471A (en) * | 2017-09-28 | 2018-02-13 | 四川青木制药有限公司 | A kind of Fei Luokao former times and its synthetic method of intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Regioselective monobromination of aromatics via a halogen bond acceptor-donor interaction of catalytic thioamide and N-bromosuccinimide;Bovonsombat, Pakorn等;《Tetrahedron》;20171231;第73卷(第46期);第6564-6572页 * |
| Studies on novel synthetic methodologies. Part 116. A facile nuclear bromination of phenols and anilines using NBS in the presence of ammonium acetate as a catalyst;Das, Biswanath 等;《Journal of Molecular Catalysis A: Chemical》;20071231;第267卷;第30-33页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109053505A (en) | 2018-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109053505B (en) | Synthesis method of important intermediate of feloxicib | |
| CN107686471B (en) | Synthesis method of feloxicib and intermediate thereof | |
| US10259789B2 (en) | Process for the preparation of 4-alkoxy-3-acetoxypicolinic acids | |
| EP1845084B1 (en) | Process for producing (z)-1-phenyl-1-(n,n-diethylaminocarbonyl)idomethylcyclopropane | |
| MXPA04008109A (en) | Method for preparing benzisoxazole methane sulfonyl chloride and its amidation to form zonisamide. | |
| RU2744834C2 (en) | Method for producing 4-alkoxy-3-hydroxypicolinic acids | |
| JP2022034093A (en) | Method of producing alkane iodide derivative | |
| CN111170837B (en) | Synthesis method of methyl ketone compound | |
| TWI403504B (en) | Method for producing 2-haloimidazole compound | |
| CN113045424A (en) | Synthetic method of 2- (5-fluoro-2-nitrophenoxy) acetate compound | |
| JP4138067B2 (en) | Method for producing methine derivative | |
| US8586792B2 (en) | Process for the preparation of 4-iodo-3-nitrobenzamide | |
| TWI733749B (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
| CN112624943B (en) | Synthesis method of feloxicib intermediate | |
| KR100856133B1 (en) | Improved process for preparing atorvastatin | |
| SU978724A3 (en) | Method of producing 1-(2,6-dimethylphenoxy)-2-azide-propane | |
| CN116535327A (en) | Method for improving stability of aromatic difluoromethyl compound in preparation and use | |
| JP5000031B2 (en) | Method for producing aromatic-o-dialdehyde compound | |
| KR100195888B1 (en) | Process for producing d,l-3-methyl-cyclopentadecan-1-one | |
| JP2009527511A (en) | Process for the preparation of 3,4-disubstituted phenylacetic acids and novel intermediates | |
| JP2001509501A (en) | Method for producing 2-alkylthiobenzoic acid derivative | |
| WO2022219485A1 (en) | A scalable process for the preparation of substantially pure glycine tert-butyl ester and its salt thereof | |
| JP2646294B2 (en) | Nitrile production method | |
| JPH06135937A (en) | Production of 5,5-disubstituted hydantoin | |
| KR100466693B1 (en) | A preparing process of phenoxyacetamide derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |