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Preparation method of celecoxib

A technology of celecoxib and sodium alkoxide, which is applied in the field of medicine, can solve problems such as unqualified solvent residues in products, expensive mixed solutions, and long reaction times, and achieve safe and environmentally friendly synthesis processes, broad market prospects, and economic benefits. good effect

Inactive Publication Date: 2014-12-03
QILU TIANHE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this method are: low yield and long reaction time; because the intermediates are not separated and purified, there are more 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 expensive. Difficult to recycle
The disadvantage is that the obtained product has low purity, fine crystal form, and is easy to agglomerate; using N,N-dimethylformamide as a solvent is more expensive, the solvent has a high boiling point, it is difficult to recycle, and it is easy to cause solvent residue in the product unqualified

Method used

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  • Preparation method of celecoxib
  • Preparation method of celecoxib

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Add 150ml of ethanol, 40ml (336mmol) of ethyl trifluoroacetate, 18.1g (336mmol) of sodium methoxide into a 1000ml three-neck flask, stir for 5-10 minutes, and then add 30ml (224mmol) of p-methylacetophenone. Raise the temperature to 50°C and react for 1 hour, then p-methylacetophenone was completely reacted by TLC spotting, cooled to room temperature, added 450ml of petroleum ether for crystallization, and obtained 54.0g of a white solid with a purity of 99.1% and a yield of 95.6%.

[0029] In a 1000ml three-necked flask, add 80ml of ethyl acetate and 210ml of isopropanol, 33g (131mmol) of intermediate 1, add 15.8ml of concentrated hydrochloric acid (concentration 37.5%) and stir, then add 29.3g (131mmol) of hydrazinobenzenesulfonamide salt acid salt, heated to 70°C for 1 hour reaction, and then HPLC detected that intermediate 1 was completely reacted, cooled to room temperature, added 500ml of purified water for crystallization, and obtained 44.9g of crude celecoxib wit...

Embodiment 2

[0032] Add 150ml tetrahydrofuran, 40ml (336mmol) ethyl trifluoroacetate, 18.1g (336mmol) sodium methoxide into a 1000ml three-neck flask, stir for 5-10 minutes, then add 30ml (224mmol) p-methylacetophenone. Raise the temperature to 50°C and react for 1 hour, then p-methylacetophenone was completely reacted by TLC spotting, cooled to room temperature, added 480ml of petroleum ether for crystallization, and obtained 46.7g of a white solid with a purity of 99.3% and a yield of 93.5%.

[0033] In a 1000ml three-necked flask, add 80ml of ethyl acetate and 200ml of isopropanol, 33g (131mmol) of intermediate 1, add 16.0ml of concentrated hydrochloric acid (concentration 37.5%) and stir, then add 29.3g (131mmol) of hydrazinobenzenesulfonamide salt After heating up to 60°C to react for 1 hour, the reaction of intermediate 1 was detected by HPLC. After cooling down to room temperature, 530ml of purified water was added for crystallization to obtain 53.1g of crude celecoxib with a yield o...

Embodiment 3

[0036] Add 150ml isopropanol, 40ml (336mmol) ethyl trifluoroacetate, 18.1g (336mmol) sodium methoxide into a 1000ml three-neck flask, stir for 5-10 minutes, then add 30ml (224mmol) p-methylacetophenone. Raise the temperature to 40°C and react for 1 hour, then p-methylacetophenone was completely reacted by TLC spotting, cooled to room temperature, added 390ml of petroleum ether for crystallization, and obtained 53.5g of a white solid with a purity of 99.5% and a yield of 94.8%.

[0037] In a 1000ml three-necked flask, add 80ml of ethyl acetate and 220ml of isopropanol, 33g (131mmol) of intermediate 1, add 15.5ml of concentrated hydrochloric acid (concentration 37.5%) and stir, then add 29.3g (131mmol) of hydrazinobenzenesulfonamide salt acid salt, heated to 60°C for 1 hour reaction, and then HPLC detected that intermediate 1 was completely reacted, cooled to room temperature, added 520ml of purified water for crystallization, and obtained 45.5g of crude celecoxib with a yield of...

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Abstract

The invention discloses a preparation method of celecoxib. The method comprises the steps of adding ethyl trifluoroacetate and sodium alcoholate in an organic solvent, adding p-methylacetophenone to carry out reaction at 40-50 DEG C for 1-2h and adding petroleum ether to carry out devitrification after the reaction so as to obtain a midbody 1; mixing the midbody 1 with ethyl acetate and isopropyl alcohol, adding hydrochloric acid and sulfonamidophenylhydrazine hydrochloride, controlling the temperature within 50-80 DEG C to carry out reaction for 1-2h and adding water to carry out devitrification after the reaction so as to obtain crude celecoxib; and adding the crude celecoxib in ethyl alcohol to carry out heating dissolution, adding activated carbon to carry out decoloration, cooling to 10-30 DEG C and adding water to carry out devitrification so as to obtain the finished product celecoxib. The preparation method has the advantages of mild reaction conditions, high yield, good purity, simplicity in operation and environment friendliness, has a more secure and environment-friendly synthesis process and wide market prospect and economic benefit.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a new preparation method of celecoxib. Background technique [0002] 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] Celecoxib, trade name: Celebrex; chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide ( CAS: 169590-42-5); the structural formula is as follows: [0004] [0005] The synthesis method of celecoxib is mainly to condense p-methylacetophenone and trifluoroaceta...

Claims

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Application Information

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IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 吴兆申李卓华吴柯张兆珍董廷华于志海左景冉李法东
Owner QILU TIANHE PHARMA
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