CN115784947A - COX-II enzyme inhibitor celecoxib intermediate and synthesis method thereof - Google Patents
COX-II enzyme inhibitor celecoxib intermediate and synthesis method thereof Download PDFInfo
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Abstract
The invention discloses a COX-II enzyme inhibitor celecoxib intermediate and a synthesis method thereof, belonging to the technical field of chemical synthesis, wherein the intermediate 2a is obtained by the following steps: 4-sulfamide-phenylhydrazine is used as a raw material, an anhydrous organic solvent I is used as a medium, protonic acid is used as a catalyst, and the protonic acid reacts with 1-ethoxy-2,2,2-trifluoroethanol at the temperature of 40-60 ℃ for 4-5 hours under the protection of nitrogen gas to synthesize an intermediate 2a, wherein the protonic acid is glacial acetic acid or trifluoroacetic acid.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a COX-II enzyme inhibitor celecoxib intermediate and a synthesis method thereof.
Background
Celecoxib is a novel non-steroidal anti-inflammatory drug, a type II epoxylipase (COX 2) inhibitor, developed by hil (search) corporation of america. Can be used for treating various acute and chronic arthritis and rheumatoid arthritis. Due to wide application and large demand, various methods for synthesizing celecoxib have been proposed at present, and the literature reports that the main approaches are as follows: 1. the hydrazino benzene sulfonate and an olefin or alkyne compound are subjected to 1,3-dipolar ring reaction to synthesize celecoxib (Tetrahedron lett.2006,47, 7943-7946), and the method has the problems of difficult preparation of the hydrazino benzene sulfonate and poor selectivity in the reaction process and is not suitable for industrial amplification; 2. the direct condensation of 1,3 diketone compounds and 4-sulfamide-phenylhydrazine compounds is used for synthesizing celecoxib, and the method has the problem of selectivity (J.Med.chem.1997, 40, 1347-1365). In recent years, patent CN 110526868B discloses a preparation method of celecoxib, wherein 4 hydrazino benzene sulfonamide reacts with acetaldehyde, the acetaldehyde occupies hydrazino N-H of the 4 hydrazino benzene sulfonamide and then is added with a acyl chloride compound, then the acetaldehyde is removed, and cyclization is carried out to prepare the celecoxib.
Disclosure of Invention
In view of the above-mentioned technical deficiencies, it is an object of the present invention to provide a COX-II enzyme inhibitor celecoxib intermediate, wherein intermediate 2a is obtained by: 4-sulfamide-phenylhydrazine is used as a raw material, an anhydrous organic solvent I is used as a medium, protonic acid is used as a catalyst, and the protonic acid reacts with 1-ethoxy-2,2,2-trifluoroethanol at the temperature of 40-60 ℃ for 4-5 hours under the protection of nitrogen gas to synthesize an intermediate 2a, wherein the protonic acid is glacial acetic acid or trifluoroacetic acid.
Preferably, the reaction temperature is 40-50 ℃, and the organic solvent I is one or a mixture of tetrahydrofuran and dichloromethane.
Preferably, the molar ratio of the 4-sulfamide-phenylhydrazine, the 1-ethoxy-2,2,2-trifluoroethanol and the protonic acid is 1.
Preferably, the molecular structure of the intermediate 2a is as follows:
another object of the present invention is to provide a method for synthesizing celecoxib, a COX-II enzyme inhibitor, which is characterized by synthesizing celecoxib via intermediate 2 a.
Preferably, the method comprises the following steps:
s1, dissolving 4-sulfamide-phenylhydrazine in an anhydrous organic solvent I, adding protonic acid, filling nitrogen as protective gas, dissolving 1-ethoxy-2,2,2-trifluoroethanol in the organic solvent I, dropwise adding a reaction system, reacting for 4-5 hours at 40-60 ℃ to obtain an intermediate 2a, wherein the protonic acid is glacial acetic acid or trifluoroacetic acid, and the molar ratio of the 4-sulfamide-phenylhydrazine, 1-ethoxy-2,2,2-trifluoroethanol to the protonic acid is 1.05-1.1;
s2, adding secondary amine and an organic solvent II into a reaction kettle at room temperature, adding a dehydrating agent, 4-methylacetophenone and 1, 10-phenanthroline, heating to reflux, and reacting for 1-2 hours to obtain a reaction solution I, wherein the molar ratio of the secondary amine to the dehydrating agent to the 4-methylacetophenone to the 1, 10-phenanthroline is as follows: 1.1-1.15;
s3: cooling the reaction liquid I to room temperature, dissolving the intermediate 2a obtained in the step S1 by using an anhydrous organic solvent II, slowly dropwise adding the solution into the reaction liquid II cooled to room temperature, simultaneously adding copper salt serving as a catalyst, and continuously stirring for 5 minutes after the dropwise adding is finished to obtain the reaction liquid II with celecoxib 3ab as a main component, wherein the molar ratio of the intermediate 2a to the copper salt to the acetophenone is 0.95-1.
Preferably, the reaction temperature in the step S1 is 40-50 ℃, and the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.
Preferably, the organic solvent I is one or a mixture of tetrahydrofuran and dichloromethane.
Preferably, the secondary amine is one or more of morpholine, piperidine and pyrrolidine; the organic solvent II is one or a mixture of toluene, benzene and xylene.
Preferably, the copper salt is one of copper bis (8-hydroxyquinoline), copper acetoacetate, copper bis (trifluoromethanesulfonyl) imide and copper trifluoromethanesulfonate.
The invention has the beneficial effects that: 1. according to the invention, through condition screening, the hydrazinobenzenesulfonic acid compound is directly prepared from 4-sulfamide-phenylhydrazine and 1-ethoxy-2,2,2-trifluoroethanol, so that the reaction selectivity is improved; 2. the intermediate 2a is synthesized firstly, and then the target compound celecoxib is synthesized through a one-pot two-step method, so that no additional reagent is required to be introduced in the whole reaction process, the reaction selectivity is improved, the reaction steps are shortened, the synthesis efficiency is improved, various raw materials are effectively utilized, the raw material utilization efficiency is improved, and the green chemistry concept is met; 3. the celecoxib is synthesized through the intermediate 2a, the condition is mild, and the operation is simple.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
s1, adding 1g of 4-sulfamide-phenylhydrazine into a three-necked bottle, adding anhydrous tetrahydrofuran as a solvent, stirring to form a uniform solution, dropwise adding about 0.1g of glacial acetic acid, filling nitrogen to form a nitrogen protection atmosphere, dissolving 0.85g of 1-ethoxy-2,2,2-trifluoroethanol into the anhydrous tetrahydrofuran, dropwise adding into a reaction system under the protection of the nitrogen atmosphere, reacting for 4 hours at the temperature of 45 ℃, cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, diluting and dissolving residues with diethyl ether, washing an organic phase with 0.5mol/L hydrochloric acid and saturated saline water in sequence, drying the organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to recover diethyl ether, and obtaining intermediates 2a,1.38g, GC-MS QP 2010, found [ M + H, and]+：C 8 H 9 F 3 N 3 O 2 S+268.0359。
s2, adding 0.49g of morpholine into a round-bottomed bottle, adding anhydrous toluene to dissolve, adding 0.68g of anhydrous magnesium sulfate, 0.69g of 4-methylacetophenone and 0.06g of 1, 10-phenanthroline, and refluxing for 1 hour;
s3, reducing the reaction system to room temperature, dissolving the residue 2a obtained in the step S1 in anhydrous toluene, slowly dropwise adding the anhydrous toluene into the reaction system, simultaneously adding 0.11g of copper trifluoromethanesulfonate into the reaction system as a catalyst, and continuously stirring for 5 minutes after dropwise adding is finished; after the reaction is finished, adding hydrochloric acid, stirring for 1 hour, standing for layering, removing a water phase, sequentially washing the organic phase with water, drying the organic phase with anhydrous magnesium sulfate, concentrating to remove the solvent, dissolving the residue with ethyl acetate, then adding n-hexane/heptane (the v/v of the ethyl acetate/n-hexane is about 1:2) until the solid is completely separated out, filtering the solvent to obtain a crude product 3ab, and using isopropanol/water v/v =1:1 to obtain the product, 3ab 1.54g and white solid, DSC =159.7-162.1 ℃ and the total yield is 71%.
Example 2:
s1, adding 5g of 4-sulfamide-phenylhydrazine into a three-necked bottle, adding anhydrous tetrahydrofuran as a solvent, stirring to form a uniform solution, dropwise adding about 0.4g of glacial acetic acid, filling nitrogen to form a nitrogen protective atmosphere, dissolving 4.04g of 1-ethoxy-2,2,2-trifluoroethanol into the anhydrous tetrahydrofuran, dropwise adding into a reaction system under the protection of the nitrogen atmosphere, reacting for 4 hours at the temperature of 50 ℃, cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, diluting and dissolving residues with diethyl ether, washing an organic phase with 0.5mol/L hydrochloric acid and saturated saline water in sequence, drying the organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to recover diethyl ether to obtain an intermediate 2a and 6.42g;
s2, adding 2.42g of morpholine into a round-bottomed bottle, adding anhydrous toluene to dissolve, adding 3.35g of anhydrous magnesium sulfate, 3.39g of 4-methylacetophenone and 0.23g of 1, 10-phenanthroline, and refluxing for 2 hours;
s3, reducing the reaction system to room temperature, dissolving the residue 2a obtained in the step S1 in anhydrous toluene, slowly dropwise adding the anhydrous toluene into the reaction system, simultaneously adding 0.41g of copper acetoacetate serving as a catalyst into the reaction system, and continuously stirring for 5 minutes after dropwise adding is finished; after the reaction is finished, adding hydrochloric acid, stirring for 1.5 hours, standing for layering, removing a water phase, sequentially washing an organic phase with water, drying the organic phase with anhydrous magnesium sulfate, concentrating to remove the solvent, dissolving the residue with ethyl acetate, then adding n-hexane/heptane (the v/v of the ethyl acetate/n-hexane is about 1:2) until the solid is completely separated out, filtering the solvent to obtain a crude product 3ab, and using isopropanol/water v/v =1:1 to obtain the product 3ab 8.29g, white solid with the total yield of 81 percent.
Example 3:
s1, adding 5g of 4-sulfamide-phenylhydrazine into a three-necked bottle, adding anhydrous tetrahydrofuran as a solvent, stirring to form a uniform solution, dropwise adding about 0.48g of glacial acetic acid, filling nitrogen to form a nitrogen protection atmosphere, dissolving 4.23g of 1-ethoxy-2,2,2-trifluoroethanol into the anhydrous tetrahydrofuran, dropwise adding into a reaction system under the protection of the nitrogen atmosphere, reacting for 4 hours at the temperature of 45 ℃ in the final mixed system, cooling the reaction liquid to room temperature, removing the solvent under reduced pressure, diluting and dissolving residues with diethyl ether, washing an organic phase with 0.5mol/L hydrochloric acid and saturated saline water in sequence, drying the organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to recover diethyl ether, and obtaining an intermediate 2a and 6.64g;
s2, adding 2.50g of morpholine into a round-bottomed bottle, adding anhydrous toluene to dissolve, adding 4.08g of anhydrous sodium sulfate, 3.50g of 4-methylacetophenone and 0.38g of 1, 10-phenanthroline, and refluxing for 2 hours;
s3, reducing the reaction system to room temperature, dissolving the residue 2a obtained in the step S1 in anhydrous toluene, slowly dropwise adding the anhydrous toluene into the reaction system, simultaneously adding 0.67g of copper acetoacetate serving as a catalyst into the reaction system, and continuously stirring for 5 minutes after dropwise adding is finished; after the reaction is finished, adding hydrochloric acid, stirring for 1.5 hours, standing for layering, removing a water phase, washing an organic phase with water, drying the organic phase with anhydrous magnesium sulfate, concentrating to remove the solvent, dissolving the residue with ethyl acetate, adding n-hexane/heptane (the v/v of the ethyl acetate/n-hexane is about 1:2) until the solid is completely separated out, filtering the solvent to obtain a crude product 3ab, and adding isopropanol/water v/v =1:1 to obtain the product, 3ab 8.08g and white solid with the total yield of 79 percent.
Example 4:
s1, adding 5g of 4-sulfamide-phenylhydrazine into a three-necked bottle, adding anhydrous dichloromethane serving as a solvent, stirring to form a uniform solution, dropwise adding about 0.48g of glacial acetic acid, filling nitrogen to form a nitrogen protection atmosphere, dissolving 4.04g of 1-ethoxy-2,2,2-trifluoroethanol into the anhydrous dichloromethane, dropwise adding into a reaction system under the protection of the nitrogen atmosphere, reacting for 4 hours at the temperature of 40 ℃ in the final mixed system, cooling the reaction liquid to room temperature after the reaction is finished, removing the solvent under reduced pressure, diluting and dissolving residues with diethyl ether, washing an organic phase with 0.5mol/L hydrochloric acid and saturated saline water in sequence, drying the organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure and recovering the diethyl ether to obtain an intermediate 2a,6.49g;
s2, adding 2.50g of piperidine into a round-bottomed bottle, adding anhydrous toluene to dissolve, adding 4.18g of anhydrous sodium sulfate, 3.43g of 4-methylacetophenone and 0.37g of 1, 10-phenanthroline, and refluxing for 2 hours;
s3, reducing the reaction system to room temperature, dissolving the residue 2a obtained in the step S1 in anhydrous toluene, slowly dropwise adding the anhydrous toluene into the reaction system, simultaneously adding 0.74g of copper trifluoromethanesulfonate into the reaction system as a catalyst, and continuously stirring for 5 minutes after dropwise adding is finished; after the reaction is finished, adding hydrochloric acid, stirring for 1.5 hours, standing for layering, removing a water phase, washing an organic phase with water, drying the organic phase with anhydrous magnesium sulfate, concentrating to remove the solvent, dissolving the residue with ethyl acetate, adding n-hexane/heptane (the v/v of the ethyl acetate/n-hexane is about 1:2) until the solid is completely separated out, filtering the solvent to obtain a crude product 3ab, and adding isopropanol/water v/v =1:1 to obtain the product, 3ab 7.88g and a white solid with the total yield of 77 percent.
Example 5:
s1, adding 5g of 4-sulfamide-phenylhydrazine into a three-necked bottle, adding anhydrous tetrahydrofuran as a solvent, stirring to form a uniform solution, dropwise adding about 0.67g of trifluoroacetic acid, filling nitrogen to form a nitrogen protection atmosphere, dissolving 4.15g of 1-ethoxy-2,2,2-trifluoroethanol into the anhydrous tetrahydrofuran, dropwise adding into a reaction system under the protection of the nitrogen atmosphere, reacting for 4 hours at the temperature of 40 ℃ in the final mixed system, cooling the reaction solution to room temperature, removing the solvent under reduced pressure, diluting and dissolving residues with diethyl ether, washing an organic phase with 0.5mol/L hydrochloric acid and saturated saline water in sequence, drying the organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to recover diethyl ether, and obtaining an intermediate 2a and 6.77g;
s2, adding 2.50g of morpholine into a round-bottomed bottle, adding anhydrous toluene to dissolve, adding 3.45g of anhydrous magnesium sulfate, 3.50g of 4-methylacetophenone and 047g of 1, 10-phenanthroline, and refluxing for 2 hours;
s3, reducing the reaction system to room temperature, dissolving the residue 2a obtained in the step S1 in anhydrous toluene, slowly dropwise adding the anhydrous toluene into the reaction system, simultaneously adding 0.95g of copper trifluoromethanesulfonate into the reaction system as a catalyst, and continuously stirring for 5 minutes after dropwise adding is finished; after the reaction is finished, adding hydrochloric acid, stirring for 1.5 hours, standing for layering, removing a water phase, washing an organic phase with water, drying the organic phase with anhydrous magnesium sulfate, concentrating to remove the solvent, dissolving the residue with ethyl acetate, adding n-hexane/heptane (the v/v of the ethyl acetate/n-hexane is about 1:2) until the solid is completely separated out, filtering the solvent to obtain a crude product 3ab, and adding isopropanol/water v/v =1:1 to obtain the product, 3ab 8.60g and white solid with the total yield of 84 percent.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A COX-II enzyme inhibitor celecoxib intermediate, wherein said intermediate 2a is obtained by: 4-sulfamide-phenylhydrazine is used as a raw material, an anhydrous organic solvent I is used as a medium, protonic acid is used as a catalyst, and the protonic acid reacts with 1-ethoxy-2,2,2-trifluoroethanol at the temperature of 40-60 ℃ for 4-5 hours under the protection of nitrogen gas to synthesize an intermediate 2a, wherein the protonic acid is glacial acetic acid or trifluoroacetic acid.
2. The intermediate of celecoxib as a COX-II enzyme inhibitor of claim 1 wherein the reaction temperature is 40 ℃ to 50 ℃, the organic solvent I is tetrahydrofuran, or mixtures of one or both of methylene chloride.
3. The COX-II enzyme inhibitor celecoxib intermediate of claim 1 wherein the molar ratio of 4-sulfonamido-phenylhydrazine, 1-ethoxy-2,2,2-trifluoroethanol and protonic acid is 1.05 to 1.1.
4. The COX-II enzyme inhibitor celecoxib intermediate of any one of claims 1-3, wherein the intermediate 2a has the molecular structure:
5. a process for the synthesis of celecoxib as a COX-II enzyme inhibitor, wherein celecoxib is synthesized via intermediate 2a according to any one of claims 1 to 3.
6. The method of synthesizing celecoxib according to claim 5 comprising the steps of:
s1, dissolving 4-sulfamide-phenylhydrazine in an anhydrous organic solvent I, adding protonic acid, filling nitrogen as protective gas, dissolving 1-ethoxy-2,2,2-trifluoroethanol in the organic solvent I, dropwise adding a reaction system, reacting for 4-5 hours at 40-60 ℃ to obtain an intermediate 2a, wherein the protonic acid is glacial acetic acid or trifluoroacetic acid, and the molar ratio of the 4-sulfamide-phenylhydrazine, 1-ethoxy-2,2,2-trifluoroethanol to the protonic acid is 1.05-1.1;
s2, adding secondary amine and an organic solvent II into a reaction kettle at room temperature, adding a dehydrating agent, 4-methylacetophenone and 1, 10-phenanthroline, heating to reflux, and reacting for 1-2 hours to obtain a reaction solution I, wherein the molar ratio of the secondary amine to the dehydrating agent to the 4-methylacetophenone to the 1, 10-phenanthroline is as follows: 1.1-1.15;
s3: cooling the reaction liquid I to room temperature, dissolving the intermediate 2a obtained in the step S1 by using an anhydrous organic solvent II, slowly dropwise adding the solution into the reaction liquid II cooled to the room temperature, simultaneously adding copper salt serving as a catalyst, and continuously stirring for 5 minutes after the dropwise adding is finished to obtain the reaction liquid II with celecoxib as a main component, wherein the molar ratio of the intermediate 2a to the copper salt to the acetophenone is 0.95-1.
7. The method for synthesizing celecoxib according to claim 6, wherein the reaction temperature in the step S1 is 40-50 ℃, and the dehydrating agent is anhydrous magnesium sulfate or anhydrous sodium sulfate.
8. The method of claim 6, wherein the organic solvent I is one or a mixture of tetrahydrofuran and dichloromethane.
9. The method of claim 6, wherein the secondary amine is one or more of morpholine, piperidine, and pyrrolidine; the organic solvent II is one or a mixture of toluene, benzene and xylene.
10. The method of claim 6, wherein the copper salt is one of copper bis (8-hydroxyquinoline), copper acetoacetate, copper bis (trifluoromethanesulfonyl) imide, and copper trifluoromethanesulfonate.
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