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Preparation method of imrecoxib, and preparation method of imrecoxib intermediate

A compound and condensing agent technology, applied in the field of preparation of Erecoxib and its intermediates, can solve problems such as strong irritation, low yield, physical health of production personnel and environmental damage, and achieve improved yield and post-processing simple effect

Active Publication Date: 2018-01-16
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In these two patent documents, the acylation step is completed using acid chloride, not only the yield is low, but the preparation of acid chloride inevitably uses SOCl 2 , the reagent is highly irritating and has caused serious damage to the health of production personnel and the environment

Method used

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  • Preparation method of imrecoxib, and preparation method of imrecoxib intermediate
  • Preparation method of imrecoxib, and preparation method of imrecoxib intermediate
  • Preparation method of imrecoxib, and preparation method of imrecoxib intermediate

Examples

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Effect test

Embodiment 1

[0031] Example 1: Preparation of the compound N-n-propyl-N-[2-hydroxyl-2-(4'-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (III)

[0032] 1) Using SOCl 2 preparation

[0033] Add 10g (0.067mol) p-methylphenylacetic acid and 40ml SOCl in a 100ml three-necked bottle 2 Heating to reflux for 1.5h, distilling off SOCl 2 , add 50ml tetrahydrofuran, obtain the tetrahydrofuran solution of p-methylphenylacetyl chloride, add dropwise the solution of 17.21g (0.067mol) N-n-propyl-beta-hydroxyl-4-methylsulfonylphenylethylamine dissolved in tetrahydrofuran and 16ml of pyridine, continue to react for 1h, the reaction is complete, evaporate the solvent, and dissolve the residue in 50ml of dichloromethane, wash with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine respectively, and dry with anhydrous sodium sulfate, concentrate under reduced pressure and evaporate The solvent was removed to obtain 15.9 g of compound (III), with a yield of 61% and a purit...

Embodiment 2

[0039] Embodiment 2: Preparation of Erecoxib

[0040] Step 1): Preparation of N-n-propyl-β-hydroxyl-4-methylsulfonylphenethylamine (IV)

[0041] Put 10.0kg of compound (V) and 236kg of anhydrous methanol into a 500L reactor, heat to dissolve and cool to below 5°C, add 1.0kg of neutral alumina (100-200 mesh), continue to slowly add 29.6 kg n-propylamine, seal the reaction kettle, pass through frozen brine and keep stirring at 0-10°C for 5 days, after the reaction is complete, filter, evaporate the reaction solution under reduced pressure to obtain 13kg of light yellow solid, add 32kg of dichloromethane to dissolve, and continue to add 88kg Ethyl acetate / petroleum ether mixture (ethyl acetate / petroleum ether=1:2), let stand, filter, and dry to obtain 9.4kg of compound (IV), with a yield of 72%.

[0042] Compound (IV): 1 H NMR (CDCl 3 )δ (ppm): 7.92 (d, 2H, ArH); 7.59 (d, 2H, ArH); 4.77 (dd, 1H, CH); 3.05 (s, 3H, CH 3 SO 2 ); 2.97 (dd, 1H, CH 2 ); 2.63 (dd, 1H, CH 2 ); 2.6...

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PUM

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Abstract

The invention relates to a preparation method of imrecoxib, and a preparation method of an imrecoxib intermediate. The preparation method of the imrecoxib intermediate remarkably improves the yield ofthe intermediate (III). The preparation method of the imrecoxib is characterized in that p-methylsulfonylstyrene oxide used as an initial raw material undergoes nucleophilic ring opening, acylation,oxidation and cyclization to obtain the final product N-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydropyrrol-2-one. The method has the advantages of short route, simplicity in operation, and suitableness for industrial amplified production.

Description

technical field [0001] The invention relates to a preparation method of Erecoxib and its intermediate. Background technique [0002] Erecoxib, chemical name: (N-n-propyl-3-(4-methylphenyl)-4-(4-methylsulfonylphenyl)-2,5-dihydropyrrol-2-one ), the structure is as shown in formula (I): [0003] [0004] As a highly selective COX-2 inhibitor, Erecoxib mainly inhibits COX-2, thereby inhibiting the production of inflammatory prostaglandins and inhibiting inflammation. Because it less inhibits COX-1, it rarely affects physiological protection functions . [0005] Regarding the preparation method of Erecoxib, two routes are disclosed in CN1134413C, the first one: using 4-methyl styrene oxide as raw material, through at least four steps of nucleophilic ring opening, acylation, oxidation and cyclization. Erecoxib is obtained, the second article: using 4-methylsulfonyl styrene oxide as the starting material, the steps of nucleophilic ring opening, acylation, oxidation and cycliz...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C317/32C07D207/38
Inventor 武乖利边林张全良
Owner JIANGSU HENGRUI MEDICINE CO LTD
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