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New synthetic method of sivelestat sodium hydrate

A newly synthesized technology of sivelestat sodium, which is applied in the preparation of sulfonic acid amide and organic chemistry, can solve the problems of low iron powder reduction yield, low safety factor of industrial production, easy poisoning of palladium carbon, etc. The effect of simple recycling, shortened synthesis process route, and mild reaction conditions

Active Publication Date: 2014-09-17
ANHUI HERYI CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the above-mentioned technical process of preparing sivelestat sodium salt, its process route is long, the reduction yield of iron powder is low, palladium carbon reduction hydrogenation reduction is not easy to operate, and palladium carbon is easy to poison and lose activity and is expensive, hydrogenation There is pressure in reduction, and the safety factor of industrial production is low

Method used

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  • New synthetic method of sivelestat sodium hydrate

Examples

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Embodiment 1

[0020] A kind of new synthetic method of sivelestat sodium that the embodiment of the present invention 1 proposes, comprises the following steps:

[0021] Take 1 mol of acid chloride (acyl chloride is obtained by reacting with thionyl chloride after acylation with amino benzoic acid as raw material), 500 ml of non-polar organic solvent, 1.0-3.0 mol of alkali acid-binding agent, glycine methyl ester hydrochloride Put 1.0-2.0mol and appropriate amount of amide catalyst into the reaction container in turn, and react at 25-30°C for 5-7h; pour the reaction product into 300ml of hydrochloric acid with a mass fraction of 18-20wt%, and stir at 20-30°C Reaction 1.8-2.5h;

[0022] After the reaction, the organic layer was separated by standing, the water layer was N-benzyloxycarbonylmethyl-2-aminobenzamide glycine solution, the pH value of the water layer was adjusted with dilute alkali until pH=7±0.1, after stirring for a period of time The pH value of the re-measurement remains unch...

Embodiment 2

[0026] A kind of new synthetic method of sivelestat sodium that the embodiment of the present invention 2 proposes, comprises the following steps:

[0027] S1. Put 50 grams of acid chloride (8), 500 ml of dichloromethane, 65 g of triethylamine, 35 g of glycine methyl ester hydrochloride (9), and an appropriate amount of amide catalyst into the reaction vessel in turn, and react at 28° C. for 6 hours; the reaction ends Finally, pour the reaction product into 300ml of hydrochloric acid with a mass fraction of 20wt%, and stir and react at 25°C for 2h; let it stand, and separate the organic layer, and the water layer is N-benzyloxycarbonylmethyl-2-aminobenzamide glycine (10) solution, the pH value of the water layer is adjusted with dilute alkali until pH = 7 ± 0.1, and after stirring for a period of time, the pH value of the retest remains unchanged, and the light yellow solid is filtered out, recrystallized with absolute ethanol after drying, and dried The off-white solid obtain...

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Abstract

The invention discloses a new synthetic method of sivelestat sodium hydrate, comprising the following steps: successively pouring acyl chloride, a nonpolar organic solvent, an alkaline acid-binding agent, glycine methyl ester hydrochloride and an amide-type catalyst into a reactor so as to react, pouring reaction products into diluted hydrochloric acid, removing an organic layer, adjusting pH of a water layer to neutral with diluted alkali, filtering, drying, recystalizing, drying to obtain N-benzoyloxycarbonylmethyl-2-aminobenzamideglycine; successively pouring N-benzoyloxycarbonylmethyl-2-aminobenzamideglycine, 4-pivaloyloxybenzenesulfonyl choride, the nonpolar organic solvent, the alkaline acid-binding agent and the amide-type catalyst into a reaction vessel to react, pouring reaction products into diluted hydrochloric acid, standing and removing an organic layer, pouring sodium hydroxide into a water layer, cooling reaction products after the end of the reaction, filtering out crystals, dissolving and decolouring to obtain sivelestat sodium hydrate. By the new synthetic method of sivelestat sodium hydrate, synthetic process route is greatly shortened. The synthetic method is easy to operate. Reaction conditions are mild, and industrial production safety coefficient is raised.

Description

technical field [0001] The invention relates to the technical field of sivelestat sodium, in particular to a new synthesis method of sivelestat sodium. Background technique [0002] Sivelestatsodium (Sivelestatsodium, trade name Elaspol), the chemical name is N-[2-[4-(pivaloyloxy) benzenesulfonamide base] benzoyl] glycine sodium salt tetrahydrate, produced by Japan Ono It was developed by Pharmaceutical Co., Ltd. (Ono) and first launched in Japan in April 2002. It is currently the world's first marketed selective inhibitor of neutrophil elastase. Sivelestat sodium is clinically used in the treatment of acute lung injury caused by systemic inflammatory response syndrome, which is also the main cause of final death in infectious atypical pneumonia (SARS). [0003] In the current process, using nitrobenzoyl chloride (1) and glycine benzyl ester p-toluenesulfonate (2) as raw materials, N-benzyloxymethyl-2-nitrobenzyl is obtained by amidation reaction Amide (3) is reduced by ir...

Claims

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Application Information

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IPC IPC(8): C07C311/29C07C303/40C07C303/38
Inventor 董来山
Owner ANHUI HERYI CHEM
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