CN101717359B

CN101717359B - Method for synthesizing indapamide

Info

Publication number: CN101717359B
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: 2012-09-05
Anticipated expiration: 2029-07-15
Also published as: CN101717359A

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 compound method of indapamide

Technical field

The invention belongs to medication chemistry products production field, particularly a kind of compound 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) BM; 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 USP; US 5110946) in introduced under the triethylamine effect, 4-chloro-3-sulfamyl Benzoyl chloride 99min. 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 99min. causes reaction yield not high, its reaction principle is following:

In Japanese Patent (JP54-30159), having introduced and having utilized 4-chloro-3-sulfamyl-N-(2-Methyl-1H-indole-1-yl) BM 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 following:

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 '-NSC 57182, N, N '-DIC price is more expensive, causes production cost higher, and its reaction principle is following:

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 99min. 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 99min. causes the generation of many impurity in the reaction process.

Summary of the invention

The present invention be intended to overcome the weak point of prior art and provide a kind of high yield, easy and simple to handle, the indapamide compound 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 compound method of indapamide; Its concrete steps are: in inert solvent; 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, are reacted under room temperature; Purified processing promptly gets purpose product indapamide.

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

Further, organic bases according to the 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 according to the 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 according to the invention and N-amido-2 methyl indole quinoline or its corresponding salt can be: 1: 1～3.

Secondly, inert solvent according to the invention is ETHYLE ACETATE, propyl acetate, butylacetate, 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 is as the condensing agent of reaction; 4-chloro-3-sulfamoylbenzoic acid and N-amido-2 methyl indole quinoline or its corresponding salt are directly reacted, avoided the first formation acyl chlorides technological process of condensation again, use cheap effective dehydrating condensation agent simultaneously; Make good reaction selectivity, yield is high, and is easy and simple to handle; Safe and reliable, reduced production cost, be fit to large-scale production.

The purity of title product indapamide of the present invention is high, can satisfy the requirement of field of medicaments.

Below in conjunction with embodiment the present invention is described further.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, and 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; Under room temperature, react, 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 ETHYLE ACETATE, propyl acetate, butylacetate, THF, methylene dichloride, 1, and the mixture of one or more in 2-ethylene dichloride, the chloroform is preferably ETHYLE ACETATE, 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; Behind the room temperature reaction 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 ETHYLE 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 in 15 ℃; Splash into triethylamine (10.1 gram, 0.1 mole), again in room temperature reaction 12 hours.Add entry (60 milliliters), filter, drying obtains the indapamide bullion.Through 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 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 in 10 ℃; Splash into pyridine (11.8 gram, 0.15 mole), again in room temperature reaction 16 hours.Add entry (80 milliliters), filter, drying obtains the indapamide bullion.Through 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 bullion.Through 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 ETHYLE 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 in 15 ℃; Splash into pyridine (9.5 gram, 0.12 mole), again in room temperature reaction 20 hours.Add entry (150 milliliters), filter, drying obtains the indapamide bullion.Through 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 should be appreciated that still and can make amendment or be equal to replacement the present invention, to reach identical technique effect; As long as satisfy the use needs, all within protection scope of the present invention.

Claims

1. the compound method of an indapamide; It is characterized in that: in inert solvent; 4-chloro-3-sulfamoylbenzoic acid and N-amino-2-methyl indoline analogue at chloro 1, under 3-dimethyl--2-climiqualine and the organic bases effect, are reacted under room temperature; Purified processing promptly gets purpose product indapamide; Said N-amino-2-methyl indoline analogue is N-amino-2-methyl indoline or its corresponding salt.

2. the compound method of indapamide according to claim 1, it is characterized in that: the corresponding salt of said N-amino-2-methyl indoline is hydrochloride, hydrobromate, mesylate or p-methyl benzenesulfonic acid salt.

3. the compound method of indapamide according to claim 1 and 2, it is characterized in that: said organic bases is a kind of or its mixture in triethylamine or the pyridine.

4. the compound method of indapamide according to claim 3; It is characterized in that: said 4-chloro-3-sulfamoylbenzoic acid, N-amino-2-methyl indoline 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.

5. the compound method of indapamide according to claim 4, it is characterized in that: the mol ratio of said organic bases and N-amino-2-methyl indoline or its corresponding salt is 1: 1～3.

6. the compound method of indapamide according to claim 3; It is characterized in that: said inert solvent is ETHYLE ACETATE, propyl acetate, butylacetate, THF, methylene dichloride, 1, the mixture of one or more in 2-ethylene dichloride, the chloroform.

7. the compound method of indapamide according to claim 4; It is characterized in that: said inert solvent is ETHYLE ACETATE, propyl acetate, butylacetate, THF, methylene dichloride, 1, the mixture of one or more in 2-ethylene dichloride, the chloroform.