Preparation method of sivelestat sodium hydrate intermediate

A technology of severestat sodium and intermediates, applied in the preparation of sulfonic acid amides, organic chemistry and other directions, can solve the problems of low industrial production safety factor, low iron powder reduction yield, easy poisoning of palladium carbon, etc. Synthetic process route, simple solvent recycling, mild reaction conditions

Inactive Publication Date: 2014-09-17
ANHUI HERYI CHEM
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  • Abstract
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Problems solved by technology

[0004] 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

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  • Preparation method of sivelestat sodium hydrate intermediate
  • Preparation method of sivelestat sodium hydrate intermediate
  • Preparation method of sivelestat sodium hydrate intermediate

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Embodiment 1

[0021] A kind of preparation method of sivelestat sodium intermediate that the embodiment of the present invention 1 proposes comprises the following steps:

[0022] 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 React for 1.8-2.5h; After the reaction is finished, let stand to separate the organic layer, the water layer is N-benzyloxycarbonylmethyl-2-aminobenzamide glycine solution, and adjust the pH value of the water layer with dilute alkali until PH=7. After stirring for a period of time, re-measure the pH value to remain unchanged,...

Embodiment 2

[0025] A kind of preparation method of sivelestat sodium intermediate that the embodiment of the present invention 2 proposes, comprises the steps:

[0026] S1. Put 50 grams of acid chloride, 500 ml of dichloromethane, 65 g of triethylamine, 35 g of glycine methyl ester hydrochloride, and an appropriate amount of amide catalyst into the reaction container in turn, and react at 28 ° C for 6 hours; after the reaction, pour the reaction product into In 300ml of hydrochloric acid with a mass fraction of 20wt%, stir and react at 25°C for 2h; let stand, separate the organic layer, the water layer is N-benzyloxycarbonylmethyl-2-aminobenzamide glycine solution, and the water layer is washed with dilute Adjust the pH value with alkali until PH = 7. After stirring for a period of time, re-measure the pH value to remain unchanged, filter out the light yellow solid, recrystallize with absolute ethanol after drying, and dry to obtain a off-white solid as N-benzyloxycarbonylmethyl Base-2-am...

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Abstract

The invention discloses a preparation method of a sivelestat sodium hydrate intermediate, 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 reaction vessel to react, pouring reaction products into dilute hydrochloric acid, standing and removing an organic layer, adjusting pH value of a water layer to neutral with diluted alkali, filtering, drying, recrystalizing, 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 the reaction vessel to react, and pouring reaction products into dilute hydrochloric acid to react so as to obtain the sivelestat sodium hydrate intermediate. By the preparation method of the sivelestat sodium hydrate intermediate, synthetic process route is greatly shortened. The preparation 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 intermediates, in particular to a preparation method of sivelestat sodium intermediates. Background technique [0002] Sivelestatsodium (Sivelestatsodium, 1 trade name: Elaspol), chemical name is N-[2-[4-(pivaloyloxy) benzenesulfonamide base] benzoyl] glycine sodium salt tetrahydrate, by Developed by Japan's Ono Pharmaceutical Co., Ltd. (Ono), it is currently the world's first marketed neutrophil elastase selective inhibitor [1], which is clinically used to treat acute lung injury caused by systemic inflammatory response syndrome [ 2]. The disease is also the main cause of death in the infectious atypical pneumonia (SARS). Existing technology is by using nitrobenzoyl chloride, amino acid as raw material, by amidation, then through the reduction of iron powder, acyl chloride, palladium carbon reduction hydrogenation, obtains sivelestat sodium intermediate, its process route for: [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/29C07C303/38
Inventor 董来山
Owner ANHUI HERYI CHEM
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