CN101717359A

CN101717359A - Method for synthesizing indapamide

Info

Publication number: CN101717359A
Application number: CN200910012548A
Authority: CN
Inventors: 宋宇
Original assignee: Beijing Chengyu Pharmaceutical Co Ltd
Current assignee: Beijing Chengyu Pharmaceutical Co Ltd
Priority date: 2009-07-15
Filing date: 2009-07-15
Publication date: 2010-06-02
Anticipated expiration: 2029-07-15
Also published as: CN101717359B

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

The synthetic method of indapamide

Technical field

The invention belongs to medication chemistry products production field, particularly a kind of synthetic method of diuretic antihypertensive medicine indapamide.

Background technology

The chemistry of indapamide (Indapamide) is called 4-chloro-3-sulfamyl-N-(2; 3-dihydro-2-Methyl-1H-indole-1-yl) benzamide; be the diuretic antihypertensive medicine, be mainly used in light, moderate hypertension patient clinically, have strong drug action and the little characteristics of untoward reaction.

The structural formula of indapamide:

As existing preparation method; (US 5101040 at United States Patent (USP); US 5110946) in introduced under the triethylamine effect, 4-chloro-3-sulfamyl Benzoyl chloride and N-amido-2 methyl indole quinoline reactant salt prepares the process of indapamide, reaction yield is 80.5%.Because the less stable of 4-chloro-3-sulfamyl Benzoyl chloride causes reaction yield not high, its reaction principle is as follows:

Having introduced in Japanese Patent (JP54-30159) and having utilized 4-chloro-3-sulfamyl-N-(2-Methyl-1H-indole-1-yl) benzamide is raw material; under the platinum oxide effect, carry out catalytic hydrogenation; the process of preparation indapamide; yield is higher; but owing to used expensive platinum oxide; cause production cost too high, can't carry out large-scale production, its reaction principle is as follows:

In Chinese patent (CN 1927833), introduced under dehydrating condensation agent and triethylamine effect, the process of 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline hydrochloride prepared in reaction indapamide, reaction yield reaches 92.6%.But since dehydrating condensation agent N, N '-dicyclohexylcarbodiimide, N, N '-DIC price is more expensive, causes production cost higher, and its reaction principle is as follows:

As a kind of improved preparation method, in Chinese patent (CN 101029017), introduced under the triethylamine effect, the process of 4-chloro-3-sulfamyl Benzoyl chloride and N-amido-2 methyl indole quinoline prepared in reaction indapamide, reaction yield reaches 92%.But it is same because the use of 4-chloro-3-sulfamyl Benzoyl chloride causes the generation of many impurity in the reaction process.

Summary of the invention

The present invention be intended to overcome the deficiencies in the prior art part and provide a kind of high yield, easy and simple to handle, the indapamide synthetic method to be to satisfy requirement of massive production cheaply.

For achieving the above object, the present invention is achieved in that

A kind of synthetic method of indapamide; its concrete steps are: in inert solvent; with 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline analogue at chloro 1; under 3-dimethyl-2-climiqualine and the organic bases effect; under room temperature, react; purified processing promptly gets purpose product indapamide.

As a kind of preferred version, 4-chloro-3-sulfamoylbenzoic acid of the present invention and N-amido-2 methyl indole quinoline analogue is 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline or its corresponding salt.

As another kind of preferred version, 4-chloro-3-sulfamoylbenzoic acid of the present invention and N-amido-corresponding salt of 2 methyl indole quinoline is hydrochloride, hydrobromate, mesylate or p-methyl benzenesulfonic acid salt.

Further, organic bases of the present invention can be selected triethylamine, pyridine, 4-N, N-methylamino pyridine, N, the mixture of one or more in the methylphenylamine.

Further, 4-chloro-3-sulfamoylbenzoic acid of the present invention, N-amido-2 methyl indole quinoline or its corresponding salt and chloro 1, the mol ratio that 3-dimethyl-2-climiqualine carries out condensation reaction is 1: 1～2: 1～3.

In addition, the mol ratio of organic bases of the present invention and N-amido-2 methyl indole quinoline or its corresponding salt can be: 1: 1～3.

Secondly, inert solvent of the present invention is ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), methylene dichloride, 1, the mixture of one or more in 2-ethylene dichloride, the chloroform.

In the technology of the synthetic indapamide of the present invention; adopt chloro 1,3-dimethyl-2-climiqualine directly reacts 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline or its corresponding salt as the condensing agent of reaction; avoided the first formation acyl chlorides technological process of condensation again; use cheap effective dehydrating condensation agent simultaneously, make good reaction selectivity, the yield height; easy and simple to handle; safe and reliable, reduced production cost, be fit to large-scale production.

The purity height of target product indapamide of the present invention can satisfy the requirement of field of medicaments.

The invention will be further described below in conjunction with embodiment.Protection scope of the present invention not only is confined to the statement of following content.

Embodiment

The present invention adopts chloro 1; 3-dimethyl-2-climiqualine prepares indapamide as condensing agent; its concrete scheme is: in inert solvent; with 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline or its corresponding salt at chloro 1; under 3-dimethyl-2-climiqualine and the organic bases effect; react under room temperature, purified processing promptly gets purpose product indapamide.

In the above-mentioned method for preparing indapamide, 4-chloro-3-sulfamoylbenzoic acid, N-amido-2 methyl indole quinoline or its corresponding salt and chloro 1, the mol ratio that 3-dimethyl-2-climiqualine carries out condensation reaction is: 1: 1～2: 1～3; Be preferably 1: 1～1.5: 1～1.5;

Organic bases is triethylamine, pyridine, 4-N, N-methylamino pyridine, N, and the mixture of one or more in the methylphenylamine is preferably triethylamine, pyridine;

The inert solvent that reaction is selected is ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), methylene dichloride, 1, and the mixture of one or more in 2-ethylene dichloride, the chloroform is preferably ethyl acetate, tetrahydrofuran (THF), 1, the 2-ethylene dichloride.

The condensing agent chloro 1 that the present invention relates to, 3-dimethyl-2-climiqualine, can by be easy to get 1,3-dimethyl-2-imidazolone is a raw material, makes by following chemical principle:

Reference example

Chloro 1, the preparation of 3-dimethyl-2-climiqualine

In three mouthfuls of reaction flasks of 1000mL, add 1,3-dimethyl-2-imidazolone (34.2 grams, 0.3 mole), tetracol phenixin (400 milliliters) stirs the carbon tetrachloride solution that slowly drips solid phosgene down and (contains solid phosgene 30 grams, 0.1 mole, 100 milliliters in tetracol phenixin), reaction mixture keeps below 5 ℃, vigorous stirring 0.5 hour, and room temperature reaction is after 1 hour, be warming up to 50 ℃, kept 4 hours.The question response product is cooled to room temperature, and filtration, a small amount of tetracol phenixin washing obtain lily crystalline product chloro 1,3-dimethyl-2-climiqualine 49 grams, yield 96.6%, fusing point: 85～86 ℃.

Embodiment 1

In the 1000mL reaction flask, add ethyl acetate (300 milliliters), N-amido-2 methyl indole quinoline (14.8 grams; 0.1 mole); 4-chloro-3-sulfamoylbenzoic acid (23.6 grams, 0.1 mole), chloro 1; 3-dimethyl-2-climiqualine (11.4 grams; 0.1 mole), stirred 30 minutes down, splash into triethylamine (10.1 grams in 15 ℃; 0.1 mole), again in room temperature reaction 12 hours.Add entry (60 milliliters), filter, drying obtains the indapamide crude product.By Virahol-water recrystallization, obtain white crystalline product 32.7 grams, yield 89.4%, HPLC purity 99.67%, fusing point: 165～167 ℃, its infrared absorption spectrum is consistent with nucleus magnetic resonance absorption spectrum and bibliographical information.

Embodiment 2

In the 1000mL reaction flask, add tetrahydrofuran (THF) (400 milliliters), N-amido-2 methyl indole quinoline hydrochloride (18.5 grams; 0.1 mole); 4-chloro-3-sulfamoylbenzoic acid (28.3 grams, 0.12 mole), chloro 1; 3-dimethyl-2-climiqualine (14.8 grams; 0.13 mole), stirred 30 minutes down, splash into pyridine (11.8 grams in 10 ℃; 0.15 mole), again in room temperature reaction 16 hours.Add entry (80 milliliters), filter, drying obtains the indapamide crude product.By ethyl alcohol recrystallization, obtain white crystalline product 34 grams, yield 93.1%, HPLC purity 99.72%, fusing point: 165～167 ℃.

Embodiment 3

In the 1000mL reaction flask, add 1,2-ethylene dichloride (300 milliliters); N-amido-2 methyl indole quinoline mesylate (24.4 grams, 0.1 mole), 4-chloro-3-sulfamoylbenzoic acid (28.3 grams; 0.12 mole); chloro 1,3-dimethyl-2-climiqualine (14.8 grams, 0.13 mole); stirred 30 minutes down in 15 ℃; splash into triethylamine (15.2 gram, 0.15 mole), again in room temperature reaction 15 hours.Add entry (100 milliliters), filter, drying obtains the indapamide crude product.By ethyl alcohol recrystallization, obtain white crystalline product 32.4 grams, yield 88.5%, HPLC purity 99.69%, fusing point: 165～167 ℃.

Embodiment 4

In the 1000mL reaction flask, add ethyl acetate (300 milliliters), N-amido-2 methyl indole quinoline p-methyl benzenesulfonic acid salt (32 grams; 0.1 mole); 4-chloro-3-sulfamoylbenzoic acid (28.3 grams, 0.12 mole), chloro 1; 3-dimethyl-2-climiqualine (17.1 grams; 0.15 mole), stirred 30 minutes down, splash into pyridine (9.5 grams in 15 ℃; 0.12 mole), again in room temperature reaction 20 hours.Add entry (150 milliliters), filter, drying obtains the indapamide crude product.By Virahol-water recrystallization, obtain white crystalline product 31.5 grams, yield 86.3%, HPLC purity 99.57%, fusing point: 165～167 ℃.

Be with being appreciated that, more than about specific descriptions of the present invention, only be used to the present invention is described and be not to be subject to the described technical scheme of the embodiment of the invention, those of ordinary skill in the art is to be understood that, still can make amendment or be equal to replacement the present invention, to reach identical technique effect; Use needs as long as satisfy, all within protection scope of the present invention.

Claims

1. the synthetic method of an indapamide; it is characterized in that: in inert solvent; with 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline analogue at chloro 1; under 3-dimethyl-2-climiqualine and the organic bases effect; under room temperature, react; purified processing promptly gets purpose product indapamide.

2. the synthetic method of indapamide according to claim 1, it is characterized in that: described 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline analogue is 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline or its corresponding salt.

3. the synthetic method of indapamide according to claim 2, it is characterized in that: described 4-chloro-3-sulfamoylbenzoic acid and N-amido-corresponding salt of 2 methyl indole quinoline is hydrochloride, hydrobromate, mesylate or p-methyl benzenesulfonic acid salt.

4. according to the synthetic method of arbitrary described indapamide of claim 1～3, it is characterized in that: described organic bases is triethylamine, pyridine, 4-N, N-methylamino pyridine, N, the mixture of one or more in the methylphenylamine.

5. according to the synthetic method of claim 2 or 3 described indapamides; it is characterized in that: described 4-chloro-3-sulfamoylbenzoic acid, N-amido-2 methyl indole quinoline or its corresponding salt and chloro 1, the mol ratio that 3-dimethyl-2-climiqualine carries out condensation reaction is 1: 1～2: 1～3.

6. the synthetic method of indapamide according to claim 5, it is characterized in that: the mol ratio of described organic bases and N-amido-2 methyl indole quinoline or its corresponding salt is: 1: 1～3.

7. the synthetic method of indapamide according to claim 4, it is characterized in that: described inert solvent is ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), methylene dichloride, 1, the mixture of one or more in 2-ethylene dichloride, the chloroform.

8. the synthetic method of indapamide according to claim 5, it is characterized in that: described inert solvent is ethyl acetate, propyl acetate, butylacetate, tetrahydrofuran (THF), methylene dichloride, 1, the mixture of one or more in 2-ethylene dichloride, the chloroform.

9. the synthetic method of indapamide according to claim 5, it is characterized in that: described organic bases is triethylamine, pyridine, 4-N, N-methylamino pyridine, N, the mixture of one or more in the methylphenylamine.