CN112624943A - Synthesis method of feloxicib intermediate - Google Patents
Synthesis method of feloxicib intermediate Download PDFInfo
- Publication number
- CN112624943A CN112624943A CN202011587581.5A CN202011587581A CN112624943A CN 112624943 A CN112624943 A CN 112624943A CN 202011587581 A CN202011587581 A CN 202011587581A CN 112624943 A CN112624943 A CN 112624943A
- Authority
- CN
- China
- Prior art keywords
- follows
- reacting
- formula
- hours
- reaction
- 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.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a synthetic method of a feloxicib intermediate. Comprises the steps of hydroxyl protection, acyl chloride preparation, Friedel-crafts acylation and further sulfination reaction. The raw materials of the 2-hydroxyisobutyric acid and the bromobenzene are cheap and easy to obtain, the whole process step is simple, the operation is simple, the amplification is easy, the yield is high, and the purity is good. The first three steps adopt a one-pot method for reaction, complex post-treatment and separation and purification are not needed, the next step of reaction is directly carried out, the operation process is greatly simplified, the production efficiency is improved, only one solvent is used, the use and recovery of various solvents and the generation of various waste water and waste gas are avoided, the production cost is greatly reduced, and the method has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of a feloxicib intermediate.
Background
The felocoxib (Firocoxib) 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 the synthesis of prostaglandin mediated by cyclooxygenase-2 (COX-2), so as to have the effects of relieving fever, easing pain and resisting inflammation. 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.
2-hydroxy-2-methyl-1- (4-methanesulfonylphenyl) propanone (formula V) is a key intermediate of feloxib and has the following structural formula:
the synthesis of the key intermediate mainly comprises the following methods:
the method comprises the following steps: synthetic routes reported in patent documents US5981576A, US6020343A, 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 normal hexane system to obtain a target compound C. The reaction formula is as follows:
the main disadvantages of the synthesis process are: (1) the initial raw material of the thiobenzol has unpleasant odor, is easy to burn and explode when meeting open fire and high heat, can cause pollution to the environment, and has great environmental protection pressure. (2) The hydroxylation reaction uses carbon tetrachloride, a class of solvents known to be carcinogenic and strongly suspected of being harmful to humans and the environment, which is detrimental to environmental and occupational health. (3) The diethyl ether and the normal hexane used in the crystallization solvent of the last step are extremely flammable and explosive solvents, and are not suitable for industrial production.
The second method comprises the following steps: a synthetic route 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 bromine to generate a compound B; then 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 C; oxidizing the compound C with an oxidant such as OXONE potassium hydrogen persulfate complex salt, extracting, separating, drying, and concentrating to obtain the target compound D. The reaction formula is as follows:
the main disadvantages of the synthesis process are: (1) as in the first process, the use of thiobenzol ether having an offensive odor as a starting material has a great pressure in environmental protection. (2) Bromine used in the bromination reaction has extremely strong toxicity and corrosiveness, and is very harmful to the environment and occupational health.
The third method comprises the following steps: a synthetic route reported in patent document CN 107686471B. P-bromophenylketone is taken as an initial raw material and is subjected to methylation reaction with a methylation reagent (methyl iodide or dimethyl sulfate) to produce a compound A; the compound A and sodium methylsulfinate are subjected to sulfonylation reaction to generate a compound B; and reacting the compound B with N-bromosuccinimide at the temperature of 80-120 ℃ for 10-14 h, extracting, separating, drying, concentrating, and crystallizing in a methyl tert-butyl ether/N-heptane mixed solvent system to obtain a target compound C. The reaction formula is as follows:
the main disadvantages of the synthesis process are: (1) the methylating agent methyl iodide or dimethyl sulfate used in the first step is very toxic, and methyl iodide is listed in the list of 3 carcinogens, and dimethyl sulfate is a tubular product. (2) According to the document "org. lett.,2015,17,876-879", it is known that dimethyl sulfoxide not only serves as a solvent in the third step reaction, but also provides an oxygen source for hydroxylation reaction, and the reaction with a brominated intermediate state produces dimethyl sulfide as a byproduct. Dimethyl sulfide is similar to dimethyl sulfide, has an unpleasant odor, is not environment-friendly, 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 80-120 ℃, and potential safety hazards exist. In addition, the crystallization solvent for this step is a methyl t-butyl ether/n-heptane system, and the solubility of compound C in both solvents is poor, and in particular, n-heptane is hardly soluble, so that it is difficult to improve the purity of the objective compound C by crystallization with the mixed solvent.
The method four comprises the following steps: the synthesis method reported in patent document CN 109053505B. The method comprises the steps of taking p-methylsulfonyl isobutyrophenone as a starting material, reacting the p-methylsulfonyl isobutyrophenone with N-bromosuccinimide and a catalyst (thiourea or ammonium acetate) to obtain bromine, and hydrolyzing the bromine in an alkaline solution to obtain a target compound. The reaction formula is as follows:
the main disadvantages of the synthesis process are: the starting material has few suppliers of methanesulfonyl isobutyrophenone, is difficult to obtain, can only provide reagent products in small packages in the market at present, and is high in price (the scientific price of 8050/100mg in Beijing carbofuran), so that the cost is high and the industrial scale-up production cannot be carried out. If the raw material p-methylsulfonyl isobutyrophenone is synthesized by itself, the same disadvantages as in the third method are present.
Therefore, the synthesis method of the intermediate 2-hydroxy-2-methyl-1- (4-methylsulfonylphenyl) acetone of the floroxib, which has the advantages of cheap and easily obtained starting materials, safety, environmental protection, low cost and industrial production prospect, is provided, and has important significance.
Disclosure of Invention
The invention aims to provide a synthesis method of a felicoxib intermediate, which is safe, environment-friendly, low in cost and has an industrial production prospect.
The invention provides a synthesis method of a feloxicib intermediate, which is characterized by comprising the following steps:
(1) reacting 2-hydroxyisobutyric acid shown in the formula I with an alcoholic hydroxyl protecting reagent to obtain a compound shown in the formula II;
(2) reacting the compound shown in the formula II with an acylating reagent under the action of organic base to obtain a compound shown in a formula III;
(3) reacting the compound shown in the formula III with bromobenzene under the action of Lewis acid, and removing a protecting group to obtain a compound shown in a formula IV;
(4) reacting the compound shown in the formula IV obtained in the step (3) with sodium methanesulfinate under the action of a catalyst to obtain a feloxicib intermediate shown in the formula V;
the reaction route is as follows:
wherein R is an alcoholic hydroxyl protecting group selected from: 2-tetrahydropyranyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, triethylsilyl group, or trimethylsilyl group.
Further, the alcoholic hydroxyl protecting agent in step (1) is selected from: 3, 4-dihydro-2H-pyran, t-butyldimethylsilyl chloride, triisopropylsilyl, triethylsilyl or trimethylsilyl;
and/or the acylating agent of step (2) is selected from oxalyl chloride or thionyl chloride, preferably oxalyl chloride; the organic base is selected from: triethylamine, pyridine, imidazole, N-methylmorpholine or 4-dimethylaminopyridine, preferably triethylamine;
and/or the Lewis acid of step (3) is selected from: aluminum trichloride, zinc dichloride, ferric trichloride, boron trifluoride, titanium tetrachloride or stannic tetrachloride, preferably aluminum trichloride;
and/or the catalyst in the step (4) is cuprous halide and proline, preferably cuprous iodide and L-proline.
Further, the alcoholic hydroxyl protecting reagent in the step (1) is 3, 4-dihydro-2H-pyran; the reaction conditions in the step (1) are as follows: reacting for 1-3 hours at 20-30 ℃ under the action of a catalyst, preferably reacting for 2 hours at 25 ℃; the molar ratio of the 2-hydroxyisobutyric acid to the alcoholic hydroxyl protecting reagent to the catalyst is as follows: 1 (1-2) (0.01-0.03), preferably 1:1.2: 0.02; the catalyst is preferably pyridinium p-toluenesulfonate.
Further, the alcoholic hydroxyl group protecting agent in the step (1) is tert-butyldimethylsilyl chloride; the reaction conditions in the step (1) are as follows: reacting for 1-3 hours at 20-30 ℃ under the action of alkali, preferably for 2 hours at 25 ℃; the molar ratio of the 2-hydroxyisobutyric acid to the alcoholic hydroxyl protecting agent to the alkali is as follows: 1 (1-2) (0.01-0.03), preferably 1:1.2: 0.02; the base is selected from: triethylamine, pyridine, imidazole, N-methylmorpholine or 4-dimethylaminopyridine, preferably triethylamine.
Further, the reaction conditions in the step (2) are as follows: reacting at-5 ℃ for 0.5-1.5 hours, preferably at 0 ℃ for 1 hour; the molar ratio of the 2-hydroxybutyric acid in the step (1) to the acylating reagent and the catalyst in the step (2) is as follows: 1 (1-3) and (1-3), preferably 1:1.2: 1.2.
Further, the reaction conditions in the step (3) are as follows: reacting for 1-3 hours at 20-30 ℃, preferably for 2 hours at 25 ℃; the molar ratio of the 2-hydroxybutyric acid in the step (1) to the bromobenzene and the Lewis acid in the step (3) is as follows: 1 (1-2) and (2-3), preferably 1:1: 2; and/or the method for removing the protecting group is to stir for 20-40 min under the acidic condition, preferably for 30min under the acidic condition.
Further, the step (3) further comprises the following post-processing steps: separating to obtain water phase, extracting to obtain organic phase, washing the organic phase, and concentrating; preferably, the extraction is with dichloromethane and/or the washing is with water.
Further, the reaction conditions in the step (4) are as follows: reacting in an organic solvent at 90-110 ℃ for 18-30 hours under the protection of nitrogen, preferably at 100 ℃ for 24 hours; the organic solvent is preferably dimethyl sulfoxide; the mol ratio of the compound shown in the formula IV, the methane sodium methanesulfonate and the catalyst is as follows: 1 (1-3) (0.3-0.8), preferably 1:1.5: 0.3.
Further, the step (4) further comprises the following post-processing steps: quenching reaction, extracting to obtain organic phase, drying, filtering, concentrating the filtrate to obtain crude product, crystallizing, filtering and stoving.
Further, in the step (4), the quenching reaction is performed by adding water for 30min, and/or the extraction is performed by using ethyl acetate, and/or the drying is performed by adding anhydrous sodium sulfate, and/or the crystallization is performed by: adding isopropanol into the crude product, heating to 60 deg.C, adding n-hexane dropwise, naturally cooling to room temperature, and stirring for 30 min.
According to the method for preparing the feloxicib intermediate, the used raw materials, namely 2-hydroxyisobutyric acid and bromobenzene, are low in price and easy to obtain, the whole process step is simple, the operation is simple, the amplification is easy, the yield is high, the purity is good, and the method has a good industrial application prospect.
Moreover, the biggest bright point of the invention is that the first three steps of reactions are carried out by adopting a one-pot method. Namely: the reactions of the steps of hydroxyl protection, acyl chloride preparation, Friedel-crafts acylation reaction and the like do not need complex post-treatment, separation and purification, and are directly put into the next reaction, so that the operation process is greatly simplified, and the production efficiency is improved. And the one-pot method only uses one solvent, thereby avoiding the use and recovery of various solvents and the generation of various waste water and waste gas and greatly reducing the production cost.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a reaction scheme for the preparation of compounds of formula IV using 2-tetrahydropyranyl as a hydroxy protecting group.
FIG. 2 is a reaction scheme of tert-butyldimethylsilyl group as a protecting group for hydroxyl group to prepare the compound of formula IV.
FIG. 3 is the NMR spectrum of 2-hydroxy-2-methyl-1- (4-methylsulfonylphenyl) acetone, a compound of formula V, according to the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1 preparation of a Flerocoxib intermediate by the Process of the invention
1. Preparation of 2-hydroxy-2-methyl-1- (4-bromophenyl) acetone (formula IV)
(1) 2-tetrahydropyranyl as a hydroxy protecting group
The reaction scheme is shown in FIG. 1.
2-Hydroxyisobutyric acid (200g, 1.92mol) was dissolved in 2000ml of dichloromethane and 3, 4-dihydro-2H-pyran (193.8g, 2.30mol) and pyridinium p-toluenesulfonate (9.6g, 0.0384mol) were added and reacted at room temperature for 2H to give a solution of 2- (2-tetrahydropyran-oxy) -2-methylpropionic acid (formula II-1) in dichloromethane which was used directly for the next acid chloride formation reaction.
Cooling the solution to 0 ℃, adding triethylamine (232.7g, 2.30mol) and oxalyl chloride (291.9g, 2.30mol), keeping the temperature at 0 ℃ for reaction for 1h, filtering to remove triethylamine hydrochloride, obtaining a dichloromethane solution of 2- (2-tetrahydropyranyl-oxy) -2-methylpropanoyl chloride (formula III-1), and directly using the dichloromethane solution in the next Friedel-crafts reaction.
To the above solution were added aluminum trichloride (512.0g, 3.84mol) and bromobenzene (301.4g, 1.92mol) and reacted at room temperature for 2 h. The reaction was quenched by addition of 2N hydrochloric acid (3000ml) and stirred for 30min and deprotected, the layers were separated, the aqueous phase was extracted with dichloromethane (2000ml), the organic phases were combined and washed twice with tap water (1000 ml. times.2). The organic phase was concentrated to give 429.4g of 2-hydroxy-2-methyl-1-p-bromophenyl-acetone (formula IV) in 92% yield.
(2) Tert-butyl dimethyl silicon base as hydroxyl protecting group
The reaction scheme is shown in FIG. 2.
2-Hydroxyisobutyric acid (200g, 1.92mol) was dissolved in 2000ml of dichloromethane, and t-butyldimethylsilyl chloride (346.7g, 2.30mol) and triethylamine (291.4g, 2.88mol) were added thereto and reacted at room temperature for 2 hours. Triethylamine hydrochloride is filtered to remove triethylamine hydrochloride, and a dichloromethane solution of 2- (2-tert-butyldimethylsilyloxy) -2-methylpropanoic acid (formula II-2) is obtained and is directly used for the next step of acyl chloride synthesis reaction.
Cooling the solution to 0 ℃, adding triethylamine (232.7g, 2.30mol) and oxalyl chloride (291.9g, 2.30mol), keeping the temperature at 0 ℃ for reaction for 1h, filtering to remove triethylamine hydrochloride, obtaining a dichloromethane solution of 2- (2-tert-butyldimethylsilyloxy) -2-methylpropanoyl chloride (formula III-2), and directly using the dichloromethane solution in the next step of Friedel-crafts reaction.
To the above solution were added zinc dichloride (532.4g, 3.84mol) and bromobenzene (301.4g, 1.92mol) and reacted at room temperature for 3 h. The reaction was quenched by addition of 2N hydrochloric acid (3000ml) and stirred for 30min and deprotected, the layers were separated, the aqueous phase was extracted with dichloromethane (2000ml), the organic phases were combined and washed twice with tap water (1000 ml. times.2). The organic phase was concentrated to give 415.6g of 2-hydroxy-2-methyl-1-p-bromophenyl-acetone (formula IV) in 89% yield.
2. Preparation of 2-hydroxy-2-methyl-1- (4-methanesulfonylphenyl) propanone (formula V)
2-hydroxy-2-methyl-1-p-bromophenyl-acetone (100g, 0.411mol), sodium methylsulfinate (63.0g, 0.617mol), L-proline (9.5g, 0.0822mol) and dimethyl sulfoxide (1500ml) were charged into a reaction flask, nitrogen was passed through, and cuprous iodide (7.8g, 0.0411mol) was added. Heating to 100 ℃ under the protection of nitrogen and reacting for 24 hours. The temperature was reduced to room temperature, and the mixture was quenched by addition of 1500ml of water, extracted with ethyl acetate (1500ml), and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate and drying to obtain crude product. Adding isopropanol (200ml) into the crude product, heating to 60 ℃, dropwise adding n-hexane (400ml), naturally cooling to room temperature, stirring for 30min, filtering, and drying to obtain 86.7g of 2-hydroxy-2-methyl-1- (4-methylsulfonylphenyl) acetone (formula V), with yield of 87% and purity of 99.3%.
1HNMR(400MHz,CDCl3)：δ1.62(6H，s)，δ3.09(3H，s)，δ3.35(1H，s)，δ8.02-8.05(2H，m)，δ8.18-8.21(2H，m)。
LCMS:m/z 243.1[M+H]+.
In conclusion, the invention provides a preparation method of the feloxib intermediate 2-hydroxy-2-methyl-1- (4-methylsulfonylphenyl) acetone, which has high yield and high purity. The raw materials of the 2-hydroxyisobutyric acid and bromobenzene are cheap and easy to obtain, and the whole process has simple steps, simple operation and easy amplification. The first three steps of reactions are carried out by adopting a one-pot method, complex post-treatment and separation and purification are not needed, and the reaction is directly put into the next step of reaction, so that the operation process is greatly simplified, and the production efficiency is improved. And the one-pot method only uses one solvent, avoids the use and recovery of various solvents and the generation of various waste water and waste gas, greatly reduces the production cost and has good industrial application prospect.
Claims (10)
1. A method for synthesizing a feloxib intermediate, comprising the steps of:
(1) reacting 2-hydroxyisobutyric acid shown in the formula I with an alcoholic hydroxyl protecting reagent to obtain a compound shown in the formula II;
(2) reacting the compound shown in the formula II with an acylating reagent under the action of organic base to obtain a compound shown in a formula III;
(3) reacting the compound shown in the formula III with bromobenzene under the action of Lewis acid, and removing a protecting group to obtain a compound shown in a formula IV;
(4) reacting the compound shown in the formula IV obtained in the step (3) with sodium methanesulfinate under the action of a catalyst to obtain a feloxicib intermediate shown in the formula V;
the reaction route is as follows:
wherein R is an alcoholic hydroxyl protecting group selected from: 2-tetrahydropyranyl group, tert-butyldimethylsilyl group, triisopropylsilyl group, triethylsilyl group, or trimethylsilyl group.
2. The method of synthesis according to claim 1, wherein the alcoholic hydroxyl protecting reagent of step (1) is selected from the group consisting of: 3, 4-dihydro-2H-pyran, t-butyldimethylsilyl chloride, triisopropylsilyl, triethylsilyl or trimethylsilyl;
and/or the acylating agent of step (2) is selected from oxalyl chloride or thionyl chloride, preferably oxalyl chloride; the organic base is selected from: triethylamine, pyridine, imidazole, N-methylmorpholine or 4-dimethylaminopyridine, preferably triethylamine;
and/or the Lewis acid of step (3) is selected from: aluminum trichloride, zinc dichloride, ferric trichloride, boron trifluoride, titanium tetrachloride or stannic tetrachloride, preferably aluminum trichloride;
and/or the catalyst in the step (4) is cuprous halide and proline, preferably cuprous iodide and L-proline.
3. The synthetic method of claim 1 or 2 wherein the alcoholic hydroxyl protecting reagent of step (1) is 3, 4-dihydro-2H-pyran; the reaction conditions in the step (1) are as follows: reacting for 1-3 hours at 20-30 ℃ under the action of a catalyst, preferably reacting for 2 hours at 25 ℃; the molar ratio of the 2-hydroxyisobutyric acid to the alcoholic hydroxyl protecting reagent to the catalyst is as follows: 1 (1-2) (0.01-0.03), preferably 1:1.2: 0.02; the catalyst is preferably pyridinium p-toluenesulfonate.
4. The synthetic method of claim 1 or 2 wherein the alcoholic hydroxyl protecting agent of step (1) is tert-butyldimethylsilyl chloride; the reaction conditions in the step (1) are as follows: reacting for 1-3 hours at 20-30 ℃ under the action of alkali, preferably for 2 hours at 25 ℃; the molar ratio of the 2-hydroxyisobutyric acid to the alcoholic hydroxyl protecting agent to the alkali is as follows: 1 (1-2) (0.01-0.03), preferably 1:1.2: 0.02; the base is selected from: triethylamine, pyridine, imidazole, N-methylmorpholine or 4-dimethylaminopyridine, preferably triethylamine.
5. The synthesis method according to claim 1 or 2, wherein the reaction conditions in step (2) are as follows: reacting at-5 ℃ for 0.5-1.5 hours, preferably at 0 ℃ for 1 hour; the molar ratio of the 2-hydroxybutyric acid in the step (1) to the acylating reagent and the catalyst in the step (2) is as follows: 1 (1-3) and (1-3), preferably 1:1.2: 1.2.
6. The synthesis method according to claim 1, wherein the reaction conditions in step (3) are as follows: reacting for 1-3 hours at 20-30 ℃, preferably for 2 hours at 25 ℃; the molar ratio of the 2-hydroxybutyric acid in the step (1) to the bromobenzene and the Lewis acid in the step (3) is as follows: 1 (1-2) and (2-3), preferably 1:1: 2; and/or the method for removing the protecting group is to stir for 20-40 min under the acidic condition, preferably for 30min under the acidic condition.
7. The synthesis method according to claim 1, wherein the step (3) further comprises the following post-treatment steps: separating to obtain water phase, extracting to obtain organic phase, washing the organic phase, and concentrating; preferably, the extraction is with dichloromethane and/or the washing is with water.
8. The synthesis method according to claim 1, wherein the reaction conditions in step (4) are as follows: reacting in an organic solvent at 90-110 ℃ for 18-30 hours under the protection of nitrogen, preferably at 100 ℃ for 24 hours; the organic solvent is preferably dimethyl sulfoxide; the mol ratio of the compound shown in the formula IV, the methane sodium methanesulfonate and the catalyst is as follows: 1 (1-3) (0.3-0.8), preferably 1:1.5: 0.3.
9. The synthesis method according to claim 1, wherein the step (4) further comprises the following post-treatment steps: quenching reaction, extracting to obtain organic phase, drying, filtering, concentrating the filtrate to obtain crude product, crystallizing, filtering and stoving.
10. The synthesis process according to claim 9, wherein the quenching reaction is water addition for 30min, and/or the extraction is extraction with ethyl acetate, and/or the drying is drying with anhydrous sodium sulfate, and/or the crystallization is: adding isopropanol into the crude product, heating to 60 deg.C, adding n-hexane dropwise, naturally cooling to room temperature, and stirring for 30 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011587581.5A CN112624943B (en) | 2020-12-28 | 2020-12-28 | Synthesis method of feloxicib intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011587581.5A CN112624943B (en) | 2020-12-28 | 2020-12-28 | Synthesis method of feloxicib intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112624943A true CN112624943A (en) | 2021-04-09 |
| CN112624943B CN112624943B (en) | 2022-07-01 |
Family
ID=75285877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011587581.5A Active CN112624943B (en) | 2020-12-28 | 2020-12-28 | Synthesis method of feloxicib intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112624943B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5604260A (en) * | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
| 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 |
| CN107778204A (en) * | 2017-10-26 | 2018-03-09 | 扬州天和药业有限公司 | A kind of preparation method of Fei Luokao former times intermediate |
| CN109053505A (en) * | 2018-08-03 | 2018-12-21 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times important intermediate |
| CN109810031A (en) * | 2017-11-21 | 2019-05-28 | 乳源瑶族自治县东阳光生物科技有限公司 | The preparation method of Fei Luokao former times intermediate |
| 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 |
-
2020
- 2020-12-28 CN CN202011587581.5A patent/CN112624943B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5604260A (en) * | 1992-12-11 | 1997-02-18 | Merck Frosst Canada Inc. | 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2 |
| CN104803956A (en) * | 2015-03-06 | 2015-07-29 | 江苏天和制药有限公司 | Synthesis method of firocoxib |
| 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 |
| CN107778204A (en) * | 2017-10-26 | 2018-03-09 | 扬州天和药业有限公司 | A kind of preparation method of Fei Luokao former times intermediate |
| CN109810031A (en) * | 2017-11-21 | 2019-05-28 | 乳源瑶族自治县东阳光生物科技有限公司 | The preparation method of Fei Luokao former times intermediate |
| CN109053505A (en) * | 2018-08-03 | 2018-12-21 | 四川青木制药有限公司 | A kind of synthetic method of Fei Luokao former times important intermediate |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112624943B (en) | 2022-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107686471B (en) | Synthesis method of feloxicib and intermediate thereof | |
| JP5468145B2 (en) | Method for preparing rosuvastatin calcium intermediate | |
| CZ301809B6 (en) | Process for preparing 2-halobenzoic acids and derivatives thereof | |
| Wang et al. | A general method for synthesis of Se-trifluoromethyl esters through Iron-catalyzed trifluoromethylselenolation of acid chlorides | |
| CN109053505B (en) | Synthesis method of important intermediate of feloxicib | |
| CN112979497A (en) | Method for preparing 2-iodoaryl ether based on o-haloiodobenzene without catalyst | |
| CN113024372A (en) | Synthetic method of 2-chloro-3-fluoro-4-trifluoromethyl benzoyl chloride | |
| CN112624943B (en) | Synthesis method of feloxicib intermediate | |
| JP2000034239A (en) | Production of trifluoromethylated aromatic compound | |
| CN106518822A (en) | Synthetic method of strigolactone (+/-)-GR24 and 4-substituted (+/-)-GR24 | |
| CN110407830B (en) | Method for synthesizing N-arylphenothiazine compound | |
| Marshall et al. | The synthesis of substituted phenols from pyranone precursors | |
| Koyanagi et al. | A new synthetic route to 2‐substituted naphtho [2, 3‐b] furan‐4, 9‐dione2‐Substituted Naphtho [2, 3‐b] furan‐4, 9‐dione | |
| CN108727323B (en) | Method for catalytically synthesizing trifluoromethyl substituted homoisoflavone compound by using N-heterocyclic carbene | |
| WO2003095424A1 (en) | Process for producing shogaol and intermediates for the synthesis thereof | |
| CN110256451A (en) | A kind of synthetic method of benzofuran simultaneously [2,3-b] quinoline | |
| EP3640235B1 (en) | Process for the preparation of cyclic peri-succinoylacenaphthene and related 1,4-diketo compounds | |
| CN116253623B (en) | Direct cross-coupling method of aryl fluorine sulfate and aryl bromine | |
| CN108358761B (en) | Salvianolic acid A intermediate and preparation method thereof | |
| CN116813508A (en) | Method for synthesizing 5-halogeno-2-methylbenzoic acid with high selectivity | |
| CN108164431B (en) | 2-hydroxy-5- (2,3,5, 6-tetrafluoro-4-trifluoromethyl benzylamino) benzoic acid and preparation method thereof | |
| KR100570279B1 (en) | Intermediates of coenzyme qn and process for the preparation thereof | |
| CN113387850A (en) | Preparation method of eribulin intermediate | |
| Argüello et al. | Reaction of 1-substituted 2, 2-dimethyl-3-phenylpropane with t-BuOK in DMSO. An unexpected formation of a cyclopropane ring | |
| CN116947864A (en) | Synthesis method of 6-substituted indolinone compound |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230915 Address after: No.13, Yulan Road, Yaogu, Western New Area, Meishan Economic Development Zone, Sichuan Province, 620000 Patentee after: Sichuan Inodabo Pharmaceutical Technology Co.,Ltd. Address before: No.88, Keyuan South Road, fengjiawan Industrial Park, high tech Zone, Chengdu, Sichuan 610000 Patentee before: CHENGDU D-INNOVATION PHARMACEUTICAL CO.,LTD. |