Method for synthesizing indapamide

A technology for the synthesis of indapamide and its synthesis method, which is applied in the field of synthesis of the diuretic and antihypertensive drug indapamide, achieving the effects of high yield, good reaction selectivity, and reduced production cost

Active Publication Date: 2012-09-05
BEIJING CHENGYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But also due to the use of 4-chloro-3-sulfamoylbenzoyl chloride, many impurities are produced in the reaction process

Method used

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  • Method for synthesizing indapamide
  • Method for synthesizing indapamide
  • Method for synthesizing indapamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] In a 1000mL reaction flask, add ethyl acetate (300ml), N-amino-2-methylindoline (14.8g, 0.1mol), 4-chloro-3-sulfamoylbenzoic acid (23.6g, 0.1 mol), chlorinated 1,3-dimethyl-2-chloroimidazoline (11.4 grams, 0.1 mol), stirred at 15°C for 30 minutes, added dropwise triethylamine (10.1 grams, 0.1 mol), and then React at room temperature for 12 hours. Water (60 mL) was added, filtered and dried to give crude indapamide. Through isopropanol-water recrystallization, 32.7 g of a white crystalline product was obtained with a yield of 89.4%, an HPLC purity of 99.67%, and a melting point of 165-167°C. The infrared absorption spectrum and nuclear magnetic resonance absorption spectrum were consistent with those reported in literature.

Embodiment 2

[0036] In a 1000mL reaction flask, add tetrahydrofuran (400ml), N-amino-2-methylindoline hydrochloride (18.5g, 0.1mol), 4-chloro-3-sulfamoylbenzoic acid (28.3g , 0.12 mol), chlorinated 1,3-dimethyl-2-chloroimidazoline (14.8 g, 0.13 mol), stirred at 10°C for 30 minutes, added dropwise to pyridine (11.8 g, 0.15 mol), and then at room temperature React for 16 hours. Water (80 mL) was added, filtered and dried to give crude indapamide. Through ethanol recrystallization, 34 grams of white crystalline product was obtained, with a yield of 93.1%, an HPLC purity of 99.72%, and a melting point of 165-167°C.

Embodiment 3

[0038] In a 1000mL reaction flask, add 1,2-dichloroethane (300ml), N-amino-2-methylindoline methanesulfonate (24.4g, 0.1mol), 4-chloro-3- Sulfamoylbenzoic acid (28.3 grams, 0.12 moles), chlorinated 1,3-dimethyl-2-chloroimidazoline (14.8 grams, 0.13 moles), was stirred at 15°C for 30 minutes, and triethylamine ( 15.2 g, 0.15 mol), and reacted at room temperature for 15 hours. Water (100 mL) was added, filtered and dried to give crude indapamide. Through ethanol recrystallization, 32.4 g of white crystalline product was obtained, with a yield of 88.5%, an HPLC purity of 99.69%, and a melting point of 165-167°C.

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Abstract

The invention discloses a method for preparing indapamide from chloro-1,3-dimethyl-2-climiqualine as a condensing agent, comprising the following concrete steps of: under the action of a condensing agent of chloro-1,3-dimethyl-2-climiqualine and organic base, reacting 4-chloro-3-sulfamoylbenzoic acid with N-amido-2-methylene indoline or corresponding salts thereof in inert solvent at room temperature and carrying out purification treatment to obtain a target product of the indapamide, wherein the corresponding salts of the 4-chloro-3-sulfamoylbenzoic acid and the N-amido-2-methylene indoline are hydrochloride, hydrobromide, mesylate or paraaminomethyl benzene sulfonate. The invention has the advantages of high yield in the technological process, low cost and simple and convenient operation, and can meet the requirement of large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical and chemical product production, in particular to a method for synthesizing diuretic and antihypertensive drug indapamide. Background technique [0002] The chemical name of Indapamide is 4-chloro-3-sulfamoyl-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide, which is Diuretic and antihypertensive drugs are mainly used clinically for patients with mild to moderate hypertension, and have the characteristics of strong drug efficacy and small adverse reactions. [0003] The structural formula of indapamide: [0004] [0005] As an existing preparation method, in U.S. Patent (US 5101040, US 5110946), it is introduced that under the action of triethylamine, 4-chloro-3-sulfamoylbenzoyl chloride and N-amino-2-methylindole In the process of preparing indapamide by reaction of phylloline salt, the reaction yield is 80.5%. Due to the poor stability of 4-chloro-3-sulfamoylbenzoyl chloride, the reaction yiel...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08A61K31/404A61P7/10A61P9/12
Inventor 宋宇
Owner BEIJING CHENGYU PHARMA
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