CN108558759B - Method for preparing celecoxib by one-pot method - Google Patents
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Abstract
The invention discloses a method for preparing celecoxib by a one-pot method. The method comprises the following steps: in the presence of ethylenediamine, mixing p-methylacetophenone and ethyl trifluoroacetate, reacting at 40-80 ℃ without other solvents until the reaction is complete to obtain a reaction solution of an intermediate DO; adding an alcohol solvent into the reaction liquid, adding p-hydrazino benzene sulfonamide hydrochloride, adding an inorganic acid to adjust the pH value to 3-6, and controlling the temperature of the feed liquid to be 50-80 ℃ to react until the reaction is complete; after the reaction is finished, adding water, cooling to 10-30 ℃ for crystallization, and performing suction filtration to obtain a celecoxib crude product; dissolving the crude product with methanol, then dropwise adding the feed liquid into water, controlling the temperature of the feed liquid to be 40-50 ℃ in the dropwise adding process, cooling to 10-30 ℃ after dropwise adding is finished, crystallizing, and carrying out suction filtration to obtain a celecoxib finished product. The total yield of the product prepared by the method is more than 85 percent, and the purity is more than or equal to 99.90 percent through HPLC detection.
Description
Technical Field
The invention relates to a preparation method of celecoxib, and belongs to the technical field of medicines.
Background
Celecoxib, chemical name: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide; the structural formula is as follows. Celecoxib is a new-generation non-steroidal anti-inflammatory analgesic, and achieves the effects of resisting inflammation and relieving pain by selectively inhibiting cyclooxygenase-2 (COX-2) to inhibit the generation of prostaglandin. Since celecoxib does not inhibit cyclooxygenase-1 (COX-1), a physiological enzyme with gastrointestinal tract protection, the risk of gastrointestinal adverse reactions of the celecoxib is obviously lower than that of the traditional non-steroidal anti-inflammatory analgesics.
The celecoxib preparation method is mainly characterized by that p-methylacetophenone and trifluoroacetate are undergone the process of Claisen condensation to obtain β -diketone intermediate, then said intermediate and p-hydrazino benzenesulfonyl amine hydrochloride are cyclized to obtain celecoxib, and its chemical reaction formula is shown in the specification, for example, the preparation method of celecoxib reported in the document [ J Med Chem, 1997,40 (9): 1347-1365] adopts said method, and said method has the defects of low yield, long reaction time, and its impurity content is large, and its intermediate has no need of separation and purification, and has the complex steps of distillation, extraction, washing and drying, etc., and its recrystallization step and mixed solution are expensive and difficult to recover.
Chinese patent CN103570622A discloses a method for preparing celecoxib, which uses N, N-dimethylformamide as a solvent, wherein methyl acetophenone and ethyl trifluoroacetate react to generate a β -diketone intermediate under the action of sodium methoxide, and the intermediate reacts with p-hydrazino benzene sulfonamide hydrochloride in the N, N-dimethylformamide to form celecoxib, wherein the chemical equation is shown as follows.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a method for preparing celecoxib by a one-pot method. In the method, the intermediate DO is prepared by using the ethylenediamine with weak alkalinity to replace the conventional strong bases such as sodium alkoxide and the like, and a solvent is not required, so that the reaction is more moderate, and the byproducts are less; the refining adopts a reverse dripping mode to drip the feed liquid into water, and the impurity removal effect is better than that of forward addition; the method of 'one-pot boiling' is adopted, the purification and treatment processes of intermediate links are reduced, and the process operation is simplified. The total yield of the product prepared by the method is more than 85 percent, and the purity is more than or equal to 99.90 percent through HPLC detection.
The technical scheme of the invention is as follows: the method for preparing celecoxib by a one-pot method is characterized by comprising the following steps of:
1) in the presence of ethylenediamine, mixing p-methylacetophenone and ethyl trifluoroacetate, reacting at 40-80 ℃ without other solvents until the reaction is complete to obtain a reaction solution of an intermediate DO;
2) adding an alcohol solvent into the reaction liquid, adding p-hydrazino benzene sulfonamide hydrochloride, adding an inorganic acid to adjust the pH value to 3-6, and controlling the temperature of the feed liquid to be 50-80 ℃ to react until the reaction is complete; after the reaction is finished, adding water, cooling to 10-30 ℃ for crystallization, and performing suction filtration to obtain a celecoxib crude product;
3) dissolving the crude celecoxib product in methanol, then dropwise adding the feed liquid into water, controlling the temperature of the feed liquid to be 40-50 ℃ in the dropwise adding process, cooling to 10-30 ℃ after dropwise adding, crystallizing, and carrying out suction filtration to obtain a celecoxib finished product.
The reaction route is as follows:
wherein the content of the first and second substances,
in the step 1), the molar ratio of p-methylacetophenone to ethyl trifluoroacetate to ethylenediamine is 1: (1-5): (1-3), preferably 1: (1.2-1.5): (1.5-2.0).
The reaction temperature in step 1) is preferably 55 to 65 ℃ and the reaction time is preferably 2 to 3 hours.
The alcohol solvent in step 2) may be methanol, ethanol, isopropanol, etc., preferably methanol.
The inorganic acid for adjusting the pH in step 2) is a conventional inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, and the pH of the feed solution is preferably adjusted to 3.0 to 3.5.
The reaction temperature of the step 2) is preferably 60 ℃ to 65 ℃, and the reaction time is preferably 3 to 4 hours.
Step 2), the molar ratio of the p-hydrazinylbenzenesulfonamide hydrochloride to the p-methylacetophenone is 0.95-1.1: 1, preferably 1: 1. the volume ratio of the alcohol solvent to the p-methylacetophenone is 10-20: 1, preferably 13 to 17: 1.
compared with the prior art, the invention has the advantages that:
1. solvent is not needed in the preparation of the intermediate DO, the ethylene diamine with weak alkalinity is used for replacing the common alkali such as sodium alkoxide and the like, the reaction is more moderate, and the byproducts are less;
2. the feed liquid is dripped into water in a reverse dripping mode for refining, so that the impurity removal effect is better than that of forward addition, and the product quality is more stable;
3. the method of 'one-pot boiling' is adopted, the purification and treatment processes of intermediate links are reduced, the process operation is simplified, the solvent usage amount and the sewage discharge amount are reduced, the production cost is reduced, the energy conservation and consumption reduction are realized, and the influence on the environment is reduced.
4. The total yield of the product prepared by the process is more than 85 percent, and the purity is more than or equal to 99.90 percent through HPLC detection. The method has the advantages of simple operation, high yield and high purity, and is beneficial to industrial large-scale production.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It should be understood that the processing equipment or devices not specifically mentioned in the following examples are conventional in the art; all pressure values and ranges refer to absolute pressures.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
Example 1
1) Preparation of intermediate I
34.6ml (291mmol) of ethyl trifluoroacetate and 26.7ml (400mmol) of ethylenediamine are added into a 1000ml three-neck flask, the mixture is stirred for 5 to 10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 60 ℃ for reaction for 2.5 hours, and then the TLC point plate detects that the p-methylacetophenone is completely reacted to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 500ml of methanol into the reaction liquid in the previous step, adding 50.1g (224mmol) of p-hydrazino benzene sulfonamide hydrochloride, adding concentrated hydrochloric acid (the concentration is 37.5 percent) to adjust the pH value to be 3.4, heating the material liquid to 65 ℃, and carrying out heat preservation reaction for 3.5 hours; and (3) after the reaction is finished, adding 530ml of purified water, cooling to 20 ℃, preserving the temperature for 1.5 hours, crystallizing, and filtering. 77.65g of crude celecoxib is obtained, the purity is 99.5%, and the yield is 90.9%.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-neck flask, adding 250ml of methanol, stirring, heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, and filtering; adding 300ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolorized feed liquid into the water, controlling the temperature of the feed liquid at 43.5 ℃ in the dropwise adding process, cooling to 25.6 ℃ for crystallization, keeping the temperature for 1.5 hours, and performing suction filtration to obtain 38.1g of celecoxib, wherein the purity is 99.96%, and the yield is 95.2%.
The overall yield was 86.5%.
Example 2
1) Preparation of intermediate I
35.6ml (300mmol) of ethyl trifluoroacetate and 27ml (405mmol) of ethylenediamine are added into a 1000ml three-neck flask, stirred for 5-10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 65 ℃ for reaction for 2 hours, and then the TLC point plate detection shows that the p-methylacetophenone completely reacts to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 450ml of methanol into the reaction liquid in the previous step, adding 50.0g (223mmol) of p-hydrazinobenzenesulfonamide hydrochloride, adding concentrated hydrochloric acid (the concentration is 37.5%) to adjust the pH value to 3.3, heating the material liquid to 60 ℃, preserving heat for reaction for 4 hours, adding 500ml of purified water after the reaction is finished, cooling to 20 ℃, preserving heat for 1.5 hours, crystallizing, and filtering. 76.8g of crude celecoxib product is obtained, the purity is 99.6 percent, and the yield is 89.9 percent.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-necked bottle, adding 250ml of methanol, stirring and heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, filtering, adding 330ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolored feed liquid into water, controlling the temperature of the feed liquid at 43.0 ℃ in the dropwise adding process, cooling to 25.0 ℃ for crystallization, keeping the temperature for 2 hours, and then carrying out suction filtration to obtain 38.5g of celecoxib with the purity of 99.95% and the yield of 96.4%.
The overall yield was 86.6%.
Example 3
1) Preparation of intermediate I
340ml (286mmol) of ethyl trifluoroacetate and 26.7ml (400mmol) of ethylenediamine are added into a 1000ml three-neck flask, the mixture is stirred for 5 to 10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 60 ℃ for reaction for 2.5 hours, and then the TLC point plate detects that the p-methylacetophenone completely reacts to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 500ml of isopropanol into the reaction liquid in the previous step, adding 49g (21.9mmol) of p-hydrazino benzene sulfonamide hydrochloride, adding concentrated sulfuric acid (98%) to adjust the pH value to 3.4, heating the feed liquid to 65 ℃, preserving heat for reaction for 3.5 hours, adding 550ml of purified water after the reaction is finished, cooling to 20 ℃, preserving heat for 1.5 hours, crystallizing, and filtering. 75.5g of crude celecoxib with the purity of 99.5 percent and the yield of 88.4 percent is obtained.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-necked bottle, adding 250ml of methanol, stirring and heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, filtering, adding 300ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolored feed liquid into water, controlling the temperature of the feed liquid at 45.6 ℃ in the dropwise adding process, cooling to 25.6 ℃ for crystallization, keeping the temperature for 1.5 hours, and then carrying out suction filtration to obtain 38.7g of celecoxib with the purity of 99.97% and the yield of 96.8%.
The overall yield was 85.5%.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the methods and compositions set forth herein, as well as variations of the methods and compositions of the present invention, will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.
Claims (7)
1. A method for preparing celecoxib by a one-pot method is characterized by comprising the following steps:
1) in the presence of ethylenediamine, mixing p-methylacetophenone with ethyl trifluoroacetate, reacting for 2-3 hours at 55-65 ℃ without other solvents to obtain a reaction solution containing an intermediate DO;
2) adding an alcohol solvent into the reaction liquid, adding p-hydrazino benzene sulfonamide hydrochloride, adding an inorganic acid to adjust the pH value to 3-6, and controlling the temperature of the feed liquid to be 60-65 ℃ to react for 3-4 hours; after the reaction is finished, adding water, cooling to 10-30 ℃ for crystallization, and performing suction filtration to obtain a celecoxib crude product;
wherein intermediate DO is
；
Dissolving the crude celecoxib product obtained in the step 2) in methanol, then dropwise adding the feed liquid into water, controlling the temperature of the feed liquid to be 40-50 ℃ in the dropwise adding process, cooling to 10-30 ℃ after dropwise adding is finished, crystallizing, and carrying out suction filtration to obtain a celecoxib finished product.
2. The method for preparing celecoxib in one-pot according to claim 1, wherein the molar ratio of p-methylacetophenone to ethyl trifluoroacetate and ethylenediamine in step 1) is 1: (1-5): (1-3).
3. The method for preparing celecoxib in one-pot according to claim 2, wherein the molar ratio of p-methylacetophenone to ethyl trifluoroacetate and ethylenediamine in step 1) is 1: (1.2-1.5): (1.5-2.0).
4. The method for preparing celecoxib in one pot according to claim 1, wherein the alcoholic solvent in step 2) is methanol, ethanol or isopropanol.
5. The process of claim 1, wherein the inorganic acid used to adjust the pH in step 2) is hydrochloric acid, sulfuric acid, or phosphoric acid.
6. The method for preparing celecoxib according to any one of claims 1-5, wherein the molar ratio of the added amount of the hydrazinobenzenesulfonamide hydrochloride to the p-methylacetophenone in the step 2) is 0.95-1.1: 1.
7. the method for preparing celecoxib according to any one of claims 1-5, wherein the volume ratio of the addition amount of the alcohol solvent in the step 2) to the p-methylacetophenone is 10-20: 1.
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| CN110698404A (en) * | 2019-11-26 | 2020-01-17 | 安徽恒星制药有限公司 | Preparation method of high-purity celecoxib |
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