A kind of preparation method of celecoxib

A technology of celecoxib and reaction temperature, applied in the direction of organic chemistry, can solve the problems of obvious amplification effect, low product yield, low productivity, etc., achieve easy post-treatment operation, mild reaction conditions, and avoid regioisomers The effect of generation of impurities

Active Publication Date: 2022-03-18
迪嘉药业集团股份有限公司
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  • Abstract
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Problems solved by technology

This route is also easy to produce isomer impurity B, and the amplification effect is obvious. With the enlargement of industrial batches, the content is getting higher and higher. The scale of 100 grams in the laboratory can reach about 0.2%, and the scale of more than ten kilograms in the pilot test can reach about 1%. , the scale of industrialized 100 kg can reach more than 3%, while the limit stipulated by the United States Pharmacopoeia is not higher than 0.10%, so the product needs to be refined many times to meet the requirements of the Pharmacopoeia, resulting in low product yield and low productivity

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  • A kind of preparation method of celecoxib
  • A kind of preparation method of celecoxib
  • A kind of preparation method of celecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] (1) Preparation of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride (VI)

[0040] Add 200 g (1.07 mol) of 4-hydrazinobenzenesulfonamide, 2 L of toluene, and dropwise 47.1 g (1.07 mol) of acetaldehyde into a 5 L reaction flask, and react at 20 °C for 4 h. Cool down to 0°C, add 165 g (1.07 mol) p-toluoyl chloride dropwise, and react at 20°C for 3 h. Cool down to 0°C, add 390 g (3.21 mol) of 30% hydrochloric acid ethanol, react at 0°C for 2 h, after the reaction is complete, concentrate under reduced pressure at 55°C to remove the solvent. Slurry with 1.6 L of methyl tert-butyl ether for 2 h, filter and dry to obtain 350 g of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride, yield 95.9%, HPLC purity 98.44%.

[0041] (2) Preparation of Celecoxib (I)

[0042] Add 100 g (0.89 mol) of 1,1,1-trifluoroacetone, 1.3 L of 80% aqueous ethanol to a 5 L reaction flask, add 320 g (0.94 mol) of 4-[1-(4-methylbenzoyl ) hydrazino]benzenesulfonamide hydr...

Embodiment 2

[0044] (1) Preparation of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride (VI)

[0045] Add 200 g (1.07 mol) of 4-hydrazinobenzenesulfonamide, 2 L of toluene, and 49.3 g (1.12 mol) of acetaldehyde into a 5 L reaction flask, and react at 70 °C for 2 h. Cool down to 0°C, add 173 g (1.12 mol) p-toluoyl chloride dropwise, and react at 30°C for 2.5 h. Cool down to 0°C, add 520 g (4.28 mol) of 30% hydrochloric acid ethanol, react at 0°C for 3 hours, after the reaction is complete, concentrate under reduced pressure at 55°C to remove the solvent. Slurry with 1.6 L of methyl tert-butyl ether for 2 h, filter and dry to obtain 351 g of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride, yield 96.1%, HPLC The purity is 99.08%.

[0046] (2) Preparation of Celecoxib (I)

[0047] Add 105 g (0.94 mol) 1,1,1-trifluoroacetone, 1.3 L isopropanol to a 5 L reaction flask, add 320 g (0.94 mol) 4-[1-(4-methylbenzoyl) Hydrazino]benzenesulfonamide hydrochloride, rea...

Embodiment 3

[0049](1) Preparation of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride (VI)

[0050] Add 200 g (1.07 mol) of 4-hydrazinobenzenesulfonamide and 2 L of 2-methyltetrahydrofuran into a 5 L reaction flask, add 56.4 g (1.28 mol) of acetaldehyde dropwise, and react at 50°C for 2.5 h. Cool down to 0°C, add 331 g (2.14 mol) p-toluoyl chloride dropwise, and react at 40°C for 2 h. Cool down to 20°C, add 650 g (5.35 mol) of 30% hydrochloric acid ethanol, react at 30°C for 1.5 h, after the reaction is complete, concentrate under reduced pressure at 55°C to remove the solvent. Slurry with 1.6 L of methyl tert-butyl ether for 2 h, filter and dry to obtain 342 g of 4-[1-(4-methylbenzoyl)hydrazino]benzenesulfonamide hydrochloride, yield 93.7%, HPLC The purity is 97.09%.

[0051] (2) Preparation of Celecoxib (I)

[0052] Add 114 g (1.02 mol) 1,1,1-trifluoroacetone, 1.2 L methanol to a 5 L reaction flask, add 290 g (0.85 mol) 4-[1-(4-methylbenzoyl)hydrazino] Benzenesulfona...

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Abstract

The invention relates to a preparation method of celecoxib, which belongs to the technical field of preparation methods of raw materials. The preparation method of celecoxib described in the present invention, at first described in formula II 4-hydrazinobenzenesulfonamide reacts with acetaldehyde, obtains the reaction liquid containing the compound of formula III; Then in the reaction liquid obtained in the first step, add formula The p-toluoyl chloride described in IV can obtain the reaction solution containing formula V; in the reaction solution obtained in the second step, add hydrochloric acid ethanol to obtain compound VI, and then form a plug with 1,1,1-trifluoroacetone ring closure Lecoxib. The change of the ring mode fundamentally avoids the formation of regioisomer impurities. This preparation method uses a one-pot reaction for upprotection, condensation, and deprotection. The reaction conditions are mild, the post-treatment is easy, and the total yield can reach 90%. The above is more suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of celecoxib, which belongs to the technical field of preparation methods of raw materials. Background technique [0002] Celecoxib (trade name: Celebrex, chemical name: 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1 H -pyrazol-1-yl]benzenesulfonamide) is a novel non-steroidal anti-inflammatory drug, its chemical structure is as follows formula I: [0003] . [0004] 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. It can be used to treat various acute and chronic arthritis and rheumatoid arthritis and other inflammatory diseases. Due to its wide application and large demand, various synthetic methods of celecoxib have been proposed at present, but most of them have the disadvantages of low yield, high impurity content, and unsuitability for large-scale industrial production. The literature repo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/12
CPCC07D231/12
Inventor 梁松军苗华明梁晓艳王宁宁李明叶毕可兴张启超刘东华
Owner 迪嘉药业集团股份有限公司
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