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Method for preparing Parecoxib

A technology of parecoxib and compounds, applied in the field of pharmaceutical chemical synthesis, can solve problems such as increased cost, increased reaction steps, and expensive reagents, and achieves the effects of low cost, mild reaction conditions, and easy operation

Active Publication Date: 2016-07-27
SHANGHAI DINGYA PHARM CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The disadvantage of this method is that the reagents used are more expensive, and the multi-step reaction uses strong corrosive reagents, such as chlorosulfonic acid, thionyl chloride, and propionic acid, which have high requirements for equipment and production personnel, which is not conducive to industrial production.
[0010] This method increases carbonyl (C=O) and amino (NH 2 ) protection and deprotection steps increase the reaction steps and increase the cost

Method used

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  • Method for preparing Parecoxib
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  • Method for preparing Parecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of embodiment one 4-(2-oxo-2-phenylethyl) benzenesulfonic acid amine (compound of formula 2)

[0028] .

[0029] Add 9.8g of 1,2-benzophenone (compound of formula 1) and 100mL of dichloromethane into a three-necked round-bottomed flask, stir to dissolve, then cool down to -10°C, then slowly add 58.3g of chlorosulfonic acid under nitrogen protection , the temperature is maintained at -5 ° C ~ 0 ° C, after the addition, continue to stir at room temperature for 1 hour, and then heat to reflux for 5 hours, cool the reaction solution to room temperature, slowly drop it into the ice-water mixture under stirring conditions In the middle, stand to separate and separate, collect the organic phase, extract the water phase with dichloromethane (70mL×3), combine the organic phase, dry and concentrate, then add 150mL of ammonia water, continue to stir for 3 hours, concentrate to remove water, and use 30mL of solid Virahol washing, then with Virahol: water: methyl ...

Embodiment 2

[0031] The preparation of embodiment two [4-(2-oxo-2-phenylethyl) benzenesulfonyl] propanamide (formula 3 compound)

[0032] .

[0033] Add 8.25 g of 4-(2-oxo-2-phenylethyl)benzenesulfonic acid amine (compound of formula 2), 33 mL of propionic anhydride, 3.94 g of triethylamine, and 4-dimethylaminopyridine into a 500 mL three-neck round bottom flask 0.08g and THF 100mL, stirred and refluxed for 5 hours, after cooling, added 50mL saturated aqueous solution of sodium bicarbonate to the mixed solution, allowed to stand for layers, washed the organic phase with saturated brine, stood for layers, collected the organic phase, and dried it Concentrate, solid ethyl acetate: sherwood oil is a mixed solvent of 1:3 and is stirred and beaten for 30 minutes, filters, filter cake is washed with ethyl acetate: sherwood oil is a mixed solvent of 1:3, and dry filter cake obtains white solid 6.95g , yield 70%.

[0034] 1 H-NMR (400MHz, CD 3 OD-d 4 ):7.84-7.69(m,4H),7.61-7.38(m,5H),4.26(s...

Embodiment 3

[0035] The preparation of embodiment three [4-(2-oxo-2-phenylethyl-1-acetyl) benzenesulfonyl] propanamide (formula 4 compound)

[0036] .

[0037] Add 5 g of [4-(2-oxo-2-phenylethyl)benzenesulfonyl] propionamide to 30 mL of pyridine, slowly add 1.4 g of acetyl chloride dropwise under ice bath, and continue stirring at room temperature after the dropwise addition is complete Reaction, after the TLC method is used to detect that the reaction is complete, add 10mL water to the mixed solution, let it stand and filter, and the filter cake is washed with 30mL water, ethyl acetate: petroleum ether as a mixed solvent of 1:6, and dried to obtain a light yellow solid Powder 4.2g, yield 75%.

[0038] 1 H-NMR (400MHz, CD 3 OD-d 4 ):7.91-7.79(m,4H),7.63-7.46(m,5H),4.78(s,1H),2.37(m,2H),2.26(s,3H),1.14(m,3H).

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Abstract

The invention relates to a method for preparing Parecoxib, and belongs to the synthesis field of pharmaceutical chemistry. 1,2-diphenyl-ethanone is used as an starting raw material, a reaction is carried out between the starting raw material and chlorosulfonic acid / ammonia-water, in order to prepare 4-(2-oxo-2-phenethyl)benzenesulfonamide, and an acylation reaction is carried out for 4-(2-oxo-2-phenethyl)benzenesulfonamide, and finally hydroxylamine hydrochloride is used for preparing Parecoxib by condensation and cyclization. Compared with the prior art, the method has the advantages of mild reaction conditions, short synthetic route, simple operation, and low cost.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing parecoxib. Background technique [0002] Parecoxib is the first specific cyclooxygenase-2 (COX-2) inhibitor developed by Pharmacia that can be administered intravenously and intramuscularly. It was launched in the UK in 2002, and its chemical name is N-[[4 -(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propionamide, chemical structure with formula express: [0003] . [0004] According to comprehensive literature reports, the current synthetic methods of parecoxib can be divided into three categories according to the different starting materials: respectively using 1,2-benzophenone or 1-phenyl-2-acetone as starting materials to prepare Parecoxib; or use 1-acetophenone oxime as a raw material to prepare Parecoxib by butt condensation. [0005] With 1,2-benzophenone as the starting material, as the synthetic route reported in CN102329...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
Inventor 不公告发明人
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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