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Preparation method of celecoxib

A technology of celecoxib and amides, applied in the field of new celecoxib preparation, can solve the problems of long reaction period, up to 24 hours, difficult to realize industrialization, etc., to achieve excellent product quality, reduce reaction time, avoid The effect of post-processing

Active Publication Date: 2014-02-12
北京京卫燕康药物研究所有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the following disadvantages: 1) From the technical point of view, the reaction process needs up to 24 hours of reflux reaction, and the reaction solvent needs to be distilled out earlier during post-treatment, after being neutralized by acid, extracted with ethyl acetate, and then dried Ethyl acetate was removed by distillation to obtain 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione
The disadvantages in the process are: a large amount of solvent is required, nearly 20 times; the reaction cycle is long, requiring 24 hours
The shortcoming of this technology is: produce 2~5wt.% regioisomerism and pyrazole hydrolyzate in the reaction process, need to purify repeatedly, and yield is low; The post-reaction treatment is complicated, needs to evaporate solvent first, then extracts with ethyl acetate , concentrated and recrystallized; the reaction requires a large amount of solvent, and the single-batch output of a 1000-liter reactor is only 3-5 kg, which is difficult to achieve industrialization
Process disadvantage is: when preparing 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione, there will be 2~5wt.% p-methylacetophenone reaction Endless
[0024] The defects in the above method make the industrialization of the process difficult, the yield is low, the energy consumption is large, and the production cost is high

Method used

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  • Preparation method of celecoxib
  • Preparation method of celecoxib
  • Preparation method of celecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Preparation of 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione:

[0066] Under nitrogen protection, 2.5 L of N,N-dimethylformamide and 162.5 g (3.0 mol) of sodium methoxide were added to a 5-liter reactor, and the temperature was lowered to 5-10°C. 335.0 g (2.5 mol) of p-methylacetophenone was added dropwise for 0.5 hours. After the dropwise addition, 390.5 g (0.3 mol) of ethyl trifluoroacetate was added dropwise for 0.5 hours, and the reaction was carried out at room temperature for 0.5 hours.

[0067] Pour this solution into 7500 mL of ice water and stir mechanically. Use 37% concentrated hydrochloric acid to adjust the pH value to 3-5, stir for 20 minutes, filter with suction, and dry to obtain light yellow solid 4,4,4-trifluoro-1-(4-methylphenyl)-1,3- Diacetyl 500.6g (2.17mol), yield 86.8%.

[0068] Synthesis of Celecoxib:

[0069] Add 4 L of N, N-dimethylformamide, 534.5 g (2.39 mol) of 4-(aminosulfonyl) phenylhydrazine hydrochloride, and 90 ml of 37% concent...

Embodiment 2

[0071] One-step synthesis of celecoxib:

[0072] Under a nitrogen atmosphere, 7.56 kg of N,N-dimethylformamide and 331.5 g (6.13 mol) of sodium methoxide were added to a 20-liter reactor, stirred mechanically, and cooled to 0-5°C. 685.5 g (5.11 mol) of p-methylacetophenone was added dropwise for 30 minutes, and stirring was continued for 10 minutes. 798.5 g (5.62 mol) of ethyl trifluoroacetate was added dropwise over 30 minutes. Continue the reaction at room temperature for 20 minutes, slowly add 720 ml of 37% concentrated hydrochloric acid, add 1.14 kg (5.11 mol) of 4-(aminosulfonyl)phenylhydrazine hydrochloride, and heat to 55°C for 4 hours. After cooling to room temperature, 11.5 kg of water was slowly added. Stir for 1.5 hours, filter, and dry to obtain 1.57 kg (4.12 mol) of celecoxib. Yield: 80.5%, purity 99.1%, 160-164°C.

Embodiment 3

[0074] Synthesis of celecoxib in two steps using N,N-dimethylacetamide as solvent

[0075] Preparation of 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione:

[0076] Under nitrogen protection, 250 mL of N,N-dimethylacetamide and 162.4 g (0.30 mol) of sodium methoxide were added to a 500 mL reaction kettle, and the temperature was lowered to 5-10°C. 335.3 g (0.25 mol) of p-methylacetophenone was added dropwise for 40 minutes. After the dropwise addition, 390.0 g (0.3 mol) of ethyl trifluoroacetate was added dropwise for 30 minutes, and the reaction was carried out at room temperature for 30 minutes.

[0077] Pour this solution into 750 mL of ice water and stir mechanically. Use 37% concentrated hydrochloric acid to adjust the pH value to 3-4, stir for 20 minutes, filter with suction, and dry to obtain light yellow solid 4,4,4-trifluoro-1-(4-methylphenyl)-1,3- Diacetyl 48.5g (0.21mol), yield 84.1%.

[0078] Synthesis of Celecoxib:

[0079] Add 400mL of N,N-dimethylacetamide...

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Abstract

The invention provides a preparation method of celecoxib. The preparation method provided by the invention can improve the yield and the purity and save the cost by using an amide solvent.

Description

technical field [0001] The invention relates to a new preparation method of Celecoxib. Background technique [0002] As we all know, celecoxib is a new type of non-steroidal anti-inflammatory drug and type II cyclooxyesterase (COX-2) inhibitor developed by Searle Company of the United States. Patent CN94194833.1 first disclosed its structure and anti-inflammatory effect. [0003] Celecoxib chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (CAS: 169590-42- 5) [0004] The structure of celecoxib is as follows: [0005] [0006] Celecoxib can be prepared by the following methods: [0007] [0008] Step 1: p-methylacetophenone and ethyl trifluoroacetate in methanol, tetrahydrofuran, methyl tert-butyl ether, isopropanol, or a mixture of these solvents, and react in the presence of a basic compound , to prepare 4,4,4-trifluoro-1-(4-methylphenyl)-1,3-butanedione: [0009] For example: [0010] Patent US6232472 describes that i...

Claims

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Application Information

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IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 王德平张盈盈郝磊戚强龙高大鹏
Owner 北京京卫燕康药物研究所有限公司
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