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The preparation method of parecoxib

A technology of parecoxib and its compound, which is 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 simple operation, mild reaction conditions, and low cost

Active Publication Date: 2018-12-11
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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  • The preparation method of parecoxib
  • The preparation method of parecoxib
  • The preparation method of parecoxib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Preparation of 4-(2-oxo-2-phenylethyl)amine benzenesulfonate (compound of formula 2)

[0028] .

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

Embodiment 2

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

[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, 4-dimethyl Aminopyridine 0.08 g and tetrahydrofuran 100 mL, stirred and refluxed for 5 hours, after cooling, added 50 mL of saturated aqueous solution of sodium bicarbonate to the mixture, allowed to stand for layers, the organic phase was washed with saturated brine, stood for layers, and collected the organic phase , it is dried and concentrated, and the solid is ethyl acetate: sherwood oil is a 1:3 mixed solvent for stirring and beating for 30 minutes, filters, and the filter cake is washed with ethyl acetate: a 1:3 mixed solvent of sherwood oil, and the dried filter cake obtains White solid 6.95 g, 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(...

Embodiment 3

[0035] Example 3 Preparation of [4-(2-oxo-2-phenethyl-1-acetyl)benzenesulfonyl]propanamide (compound of formula 4)

[0036]

[0037] Add 5 g of [4-(2-oxo-2-phenylethyl)benzenesulfonyl]propanamide into 30 mL of pyridine, slowly add 1.4 g of acetyl chloride dropwise under ice-cooling, Continue to stir the reaction, after the TLC method is used to detect that the reaction is complete, add 10 mL of water to the mixed solution, let it stand and filter, the filter cake is successively washed with 30 mL of water, ethyl acetate: petroleum ether as a mixed solvent of 1:6, and dried. 4.2 g of light yellow solid powder was obtained with a yield of 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 Patents(China)
IPC IPC(8): C07D261/08
Inventor 不公告发明人
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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