Synthesis method of indapamide

A technology of indapamide and its synthesis method, which is applied in the field of medicine and chemical industry, can solve problems such as inconvenient production operation, safety accidents, and long production cycle, and achieve the effects of reducing pollution and corrosion, improving safety, and reducing costs

Active Publication Date: 2007-03-14
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. In the acyl chloride reaction, a large amount of thionyl chloride is used. Thionyl chloride is a dangerous chemical. It is easy to release a large amount of hydrogen chloride and sulfur dioxide gas when it is mixed with moist air and water, and it is violently exothermic, which is easy to cause an explosion and is harmful to The environment and equipment are highly corrosive, and the safety factor is low
[0007] 2. When 4-chloro-3-sulfonylaminobenzoyl chloride is condensed with N-amino-2-methylindoline hydrochloride, the reaction is required to be absolutely anhydrous. In order to ensure that the reagent is anhydrous, it must be used before use Metal sodium is dehydrated and distilled, so it is easy to cause safety accidents and bring inconvenience to production operations
[0008] 3. The chemical intermediate 4-chloro-3-sulfonylaminobenzoyl chloride has poor stability, is easy to decompose when wet, and is irritating. When it is dry, it will seriously corrode the equipment and is not easy to store
[0009] 4. The production cycle is long and the yield is not high

Method used

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  • Synthesis method of indapamide
  • Synthesis method of indapamide

Examples

Experimental program
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Embodiment 1

[0031] Add 200ml tetrahydrofuran and 9.3g N-amino-2-methylindoline hydrochloride to the reaction flask, add 8.5ml triethylamine dropwise under stirring, cool to 10°C, add N,N'-dicyclohexyl carbon Diimine 10.8g and 4-chloro-3-sulfonylamino-benzoic acid 11.0g, the reaction temperature was controlled at 10°C, and the reaction time was 10 hours. After the reaction was completed, the insoluble matter was filtered off, the tetrahydrofuran in the filtrate was evaporated to dryness, and Isopropanol-water solution was recrystallized to obtain 16.5 g of indapamide, yield 90.4%.

Embodiment 2

[0033] Add 260ml tetrahydrofuran and 11.0g N-amino-2-methylindoline hydrochloride to the reaction flask, add 9.2ml triethylamine dropwise under stirring, cool to 10°C, add N,N'-diisopropyl 7.0 g of carbodiimide and 14.0 g of 4-chloro-3-sulfonylamino-benzoic acid, the reaction temperature was controlled at 5 ° C, and the reaction time was 20 hours. After the reaction was completed, the insoluble matter was filtered off, and the tetrahydrofuran in the filtrate was evaporated to dryness. Isopropanol-water solution was added for recrystallization to obtain 16.9 g of indapamide, yield 92.6%.

Embodiment 3

[0035] Add 100ml of dichloromethane and 9.3g of N-amino-2-methylindoline hydrochloride to the reaction flask, add 8.0ml of triethylamine dropwise under stirring, cool to 10°C, add N,N'-bicyclic Hexylcarbodiimide 10g, control the reaction temperature at 4.0°C, and the reaction time is 4 hours. After the reaction is completed, filter out the insoluble matter, evaporate the dichloromethane in the filtrate to dryness, add isopropanol-water solution for recrystallization, and obtain Inda Peramide 15.1g, yield 83.4%.

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Abstract

The present invention relates to Indapamide synthesizing process. The synthesis process includes the following steps: dissolving N-amido-2-methyl indoline hydrochloride in non-protonic organic solvent, and dropping triethylamine via stirring; the subsequent adding 4-chloro-3-sulphonylamino -benzoic acid and dewatering condensing agent and reaction at 0-20 deg.c for 2.0-20 hr to obtain coarse Indapamide product; and final refining in isopropanol-water to obtain Indapamide product. Compared with traditional process, the present invention has raised safety, less pollution and corrosion to environment and apparatus, lowered cost and raised yield.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a synthesis method of indapamide. Background technique [0002] The more common synthetic method for preparing indapamide is to use 4-chloro-3-sulfonylamino-benzoic acid as starting material, and first carry out acyl chloride with thionyl chloride to prepare 4-chloro-3-sulfonyl Aminobenzoyl chloride, followed by condensation of 4-chloro-3-sulfonamidobenzoyl chloride with 2-methylindoline hydrochloride to prepare indapamide. [0003] The current general synthetic route of indapamide is: [0004] [0005] This method has the following main disadvantages: [0006] 1. In the acyl chloride reaction, a large amount of thionyl chloride is used. Thionyl chloride is a dangerous chemical. It is easy to release a large amount of hydrogen chloride and sulfur dioxide gas when it is mixed with moist air and water, and it is violently exothermic, which is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08
Inventor 姜根华霍志甲王丽红张瑜
Owner TIANJIN LISHENG PHARM CO LTD
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