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Method for preparing celecoxib by using one-pot method

A technology of celecoxib and p-methylacetophenone, which is applied in the field of medicine, can solve the problems of the price of the recrystallization mixed solution, the unqualified solvent residue of the product, and the difficulty in recycling, so as to reduce the amount of solvent used and the discharge of sewage. amount, reducing the effect of purification and treatment processes

Active Publication Date: 2018-09-21
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method of celecoxib as reported in the document [J Med Chem, 1997,40 (9): 1347-1365] adopts this method exactly, and the shortcoming of this method is: the yield is low, and the reaction time is longer; The body has not been separated and purified, and there are many impurities; there are cumbersome steps such as distillation, extraction, washing, and drying; there are recrystallization steps and the use of mixed solutions is expensive and difficult to recover
The disadvantage of this method is that the purity of the obtained product is low, the crystal form is relatively fine, and it is easy to agglomerate; the use of N,N-dimethylformamide as a solvent is more expensive, and the solvent has a high boiling point, which is difficult to recycle and easily cause Product solvent residue unqualified

Method used

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  • Method for preparing celecoxib by using one-pot method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 1) Preparation of Intermediate I

[0033] Add 34.6ml (291mmol) ethyl trifluoroacetate and 26.7ml (400mmol) ethylenediamine into a 1000ml three-necked flask, stir for 5-10 minutes, then add 30ml (224mmol) p-methylacetophenone, heat up to 60°C for reaction After 2.5 hours, the reaction of p-methylacetophenone was detected by TLC plate detection, and the intermediate DO was obtained.

[0034] 2) Preparation of celecoxib crude product

[0035] Add 500ml of methanol to the reaction solution in the previous step, add 50.1g (224mmol) of p-hydrazinobenzenesulfonamide hydrochloride, add concentrated hydrochloric acid (concentration: 37.5%) to adjust the pH value to 3.4, and heat the feed solution to 65°C for 3.5 Hours; after the reaction is complete, add 530ml of purified water, cool down to 20°C, keep warm for 1.5 hours to crystallize, and filter with suction. Obtain 77.65g of celecoxib crude product, the purity is 99.5%, and the yield is 90.9%.

[0036] 3) Preparation of Ce...

Embodiment 2

[0040] 1) Preparation of Intermediate I

[0041] Add 35.6ml (300mmol) ethyl trifluoroacetate and 27ml (405mmol) ethylenediamine into a 1000ml three-necked flask, stir for 5-10 minutes, then add 30ml (224mmol) p-methylacetophenone, and heat up to 65°C for reaction 2 Hours, then TLC spot plate detection p-methylacetophenone reaction is complete, obtains intermediate DO.

[0042] 2) Preparation of celecoxib crude product

[0043] Add 450ml of methanol to the reaction solution in the previous step, add 50.0g (223mmol) of p-hydrazinobenzenesulfonamide hydrochloride, add concentrated hydrochloric acid (concentration: 37.5%) to adjust the pH value to 3.3, and heat the feed solution to 60°C for reaction 4 After 1 hour, the reaction was completed, 500ml of purified water was added, the temperature was lowered to 20° C., crystallization was carried out after 1.5 hours of heat preservation, and suction filtration was performed. Obtain 76.8g of celecoxib crude product, the purity is 99....

Embodiment 3

[0048] 1) Preparation of Intermediate I

[0049] Add 340ml (286mmol) ethyl trifluoroacetate and 26.7ml (400mmol) ethylenediamine into a 1000ml three-necked flask, stir for 5-10 minutes, then add 30ml (224mmol) p-methylacetophenone, heat up to 60°C and react for 2.5 Hours, then TLC spot plate detection p-methylacetophenone reaction is complete, obtains intermediate DO.

[0050] 2) Preparation of celecoxib crude product

[0051] Add 500ml of isopropanol to the reaction solution in the previous step, add 49g (21.9mmol) p-hydrazinobenzenesulfonamide hydrochloride, add concentrated sulfuric acid (98%) to adjust the pH value to 3.4, and heat the feed solution to 65°C for 3.5 After 1 hour, the reaction was completed, 550ml of purified water was added, the temperature was lowered to 20°C, the temperature was maintained for 1.5 hours to crystallize, and suction filtration was performed. Obtained celecoxib crude product 75.5g, the purity is 99.5%, the yield is 88.4%.

[0052] 3) Prepar...

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Abstract

The invention discloses a method for preparing celecoxib by using a one-pot method. The method comprises the following steps: in the presence of ethidene diamine, mixing p-methylacetophenone and ethyltrifluoroacetate, and enabling the components to react completely at 40-80 DEG C without other solvent so as to obtain a reaction liquid of an intermediate DO; putting the reaction liquid into an alcohol solvent, further adding bihydrazino-benzsulfamide hydrochloride, further adding an organic acid to adjust the pH value to 3-6, controlling the temperature of a material liquid to 50-80 DEG C, andenabling the components to react completely; after the reaction is completed, adding water, cooling to 10-30 DEG C to separate out a crystal, and carrying out suction filtration so as to obtain a crude product of celecoxib; dissolving the crude product with methanol, dropping the material liquid into water, controlling the temperature of the material liquid to 40-50 DEG C in the dropping process,cooling to 10-30 DEG C to separate out a crystal after dropping is completed, and carrying out suction filtration, thereby obtaining a finished product of celecoxib. The total yield of the product prepared by using the method is greater than 85%, and HPLC (High Performance Liquid Chromatography) tests show that the purity of the product is greater than or equal to 99.90%.

Description

technical field [0001] The invention relates to a preparation method of celecoxib, belonging to the technical field of medicine. Background technique [0002] Celecoxib, chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; structural formula is as follows. Celecoxib is a new generation of non-steroidal anti-inflammatory analgesics, which inhibits prostaglandin production by selectively inhibiting cyclooxygenase-2 (COX-2) to achieve anti-inflammatory and analgesic effects. Since celecoxib does not inhibit the physiological enzyme cyclooxygenase-1 (COX-1), which has a protective effect on the gastrointestinal tract, its risk of gastrointestinal adverse reactions is significantly lower than that of traditional non-steroidal anti-inflammatory analgesics medicine. [0003] [0004] The preparation method of celecoxib is mainly to condense p-methyl acetophenone and trifluoroacetate via Claisen to obtain β-diketone intermediate, and then...

Claims

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Application Information

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IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 布彬彬张坤王仕川褚杰赵旭东李保勇
Owner 山东安信制药有限公司
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