Synthesis of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide

A technology of trifluoromethyl and methylphenyl, applied in the field of synthesis of 4-[5--3--1-hydrogen-pyrazol-1-yl]benzenesulfonamide, can solve the problem of reducing the incidence of adverse reactions and other problems, to achieve the effects of easy crystallization conditions, complete crystallization, and high yield

Inactive Publication Date: 2017-08-04
FUJIAN FUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Celecoxib is as effective as traditional NSAIDs in treating osteoarthritis (OA), but with a lower incidence of adverse reactions

Method used

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  • Synthesis of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide
  • Synthesis of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide
  • Synthesis of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthetic method of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-pyrazol-1-yl]benzenesulfonamide comprises the following steps:

[0030] 1) Add 100ml of n-hexane, 10g of o-methyl acetophenone, 6.2g of sodium methoxide to a 250mL three-necked flask in sequence, stir at 25°C for 20 minutes, then cool down to 5°C in an ice-water bath, add 13.3g of ethyl trifluoroacetate dropwise, After the dropwise addition, the ice-water bath was removed, and the temperature was gradually raised to 60°C for reflux reaction for 3 hours. The mixture of ethyl acetate and petroleum ether with a volume ratio of 1:10 was used as the developer, and TLC was monitored until the reaction was completed;

[0031] After the reaction stopped, pour the reaction solution into a beaker, add purified water, add 6M hydrochloric acid under stirring to adjust the pH value to 3, separate the liquid, wash the organic layer with water, dry with anhydrous magnesium sulfate, filter, and rotary evaporate...

Embodiment 2

[0038] The synthetic method of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-pyrazol-1-yl]benzenesulfonamide comprises the following steps:

[0039] 1) Add 100ml of petroleum ether, 10g of o-methyl acetophenone, and 15ml of lithium diisopropylamide to a 250mL three-necked flask, stir at 20°C for 30 minutes, then cool down to 10°C in an ice-water bath, and add ethyl trifluoroacetate dropwise 13.3g, remove the ice-water bath after the dropwise addition, gradually raise the temperature to 55°C and reflux for 3.5h, use a mixture of ethyl acetate and petroleum ether with a volume ratio of 1:10 as the developer, and monitor by TLC until the end of the reaction;

[0040] After the reaction stopped, pour the reaction solution into a beaker, add purified water, add 6M hydrochloric acid under stirring to adjust the pH value to 1, separate the liquid, wash the organic layer with water, dry with anhydrous magnesium sulfate, filter, and rotary evaporate to obtain the intermediate;

...

Embodiment 3

[0044] A synthetic method of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl]benzenesulfonamide, comprising the following steps:

[0045] 1) Add 100ml of dichloromethane, 10g of o-tolyl acetophenone, 20ml of DBU successively to the 250mL there-necked flask, stir at 25°C for 20 minutes, then cool down to 0°C in an ice-water bath, add dropwise 13.3g of ethyl trifluoroacetate, dropwise After the completion, the ice-water bath was removed, and the temperature was gradually raised to 65° C. and refluxed for 2.5 hours. The mixture of ethyl acetate and petroleum ether with a volume ratio of 1:10 was used as the developing solvent, and TLC was monitored until the reaction was completed;

[0046] After the reaction was stopped, the reaction solution was poured into a beaker, purified water was added, 6M hydrochloric acid was added under stirring to adjust the pH to 2, the layers were separated, the organic layer was washed with water, dried over anhydrous magnesium sulfate,...

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Abstract

The invention discloses a synthesis method of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide. The synthesis method comprises the following steps: with methyl acetophenone as a starting raw material, under a strong alkaline condition, in a non-polar organic solvent, dropwise adding ethyl trifluoroacetate, heating for reacting, adjusting the pH of a reaction solution to 1-3 by using acid, drying and performing rotary evaporation to obtain an intermediate, then in the presence of a mixed solvent, performing a reaction on the intermediate and p-sulfonamidophenylhydrazine hydrochloride to produce a crude product, and recrystallizing the crude product by using an organic solvent to obtain the 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide with high purity. The 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide is a common impurity in the production process of celecoxib, and the 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydro-pyrazol-1-yl] benzenesulfonamide is used as a reference substance, is included in the quality standard and can be used for analyzing various impurities in the celecoxib and the celecoxib purity.

Description

technical field [0001] The invention belongs to the field of fine organic synthesis, in particular to a synthetic method of 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-pyrazol-1-yl]benzenesulfonamide . Background technique [0002] In 1999, celecoxib, the first COX-2 selective inhibitor, came out. It has been proved by a large number of clinical data that it can significantly reduce the gastrointestinal damage caused by traditional NSAIDs. Studies have shown that its inhibitory effect on selective COX-2 is 375 times stronger than that on COX-1. The efficacy of celecoxib for osteoarthritis (OA) is comparable to that of traditional NSAIDs, but the incidence of adverse reactions is reduced. It has been hailed as a "milestone breakthrough" because it reduces the gastrointestinal damage caused by traditional anti-inflammatory and analgesic drugs in the past. [0003] In 2007, celecoxib was approved for low back pain, frozen shoulder and tenosynovitis. Celecoxib is in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12
Inventor 林敏
Owner FUJIAN FUKANG PHARMA
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