CN100422146C - Synthesis method of indapamide - Google Patents
Synthesis method of indapamide Download PDFInfo
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- CN100422146C CN100422146C CNB2006100159225A CN200610015922A CN100422146C CN 100422146 C CN100422146 C CN 100422146C CN B2006100159225 A CNB2006100159225 A CN B2006100159225A CN 200610015922 A CN200610015922 A CN 200610015922A CN 100422146 C CN100422146 C CN 100422146C
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- indapamide
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- methyl indoline
- indoline hydrochloride
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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
The present invention relates to a kind of synthetic method of indapamide, belong to pharmaceutical chemistry technical field.
Background technology
The synthetic method of using at present more general preparation indapamide is to be starting raw material with 4-chloro-3-sulfonamido-phenylformic acid, earlier carry out chloride and prepare 4-chloro-3-sulfonamido Benzoyl chloride with sulfur oxychloride, and then with 4-chloro-3-sulfonamido Benzoyl chloride and 2 methyl indole quinoline hydrochloride condensation prepared indapamide.
The operational path of general synthetic indapamide is at present:
This method has following main drawback:
One, in acyl chloride reaction, use a large amount of sulfur oxychlorides, sulfur oxychloride belongs to hazardous chemical, easily emit a large amount of hydrogenchloride and sulfur dioxide gas with wet air and water, and very exothermic, easily set off an explosion, and environment and equipment are had severe corrosive, and safety coefficient is low.
Two, when 4-chloro-3-sulfonamido Benzoyl chloride and N-amido-condensation of 2 methyl indole quinoline hydrochloride, require reaction definitely anhydrous, for guaranteed reagent,G.R. anhydrous, must dewater with sodium Metal 99.5 before use, distillation so easily causes security incident, makes troubles to production operation.
Three, the less stable of chemical intermediate 4-chloro-3-sulfonamido Benzoyl chloride is met wet easily decomposition, and had pungency, and is serious to equipment corrosion when dry, is difficult for storing.
Four, the production cycle long, yield is not high.
Summary of the invention
The objective of the invention is to overcome the deficiency on the prior art, provide a route short, cost is low, and the yield height is easy to control, the synthetic route of safe indapamide.
The present invention is achieved by following technical solution, and synthesis step comprises:
1) N-amino-2-methyl indoline hydrochloride is dissolved in the aprotic organic solvent and under agitation drips triethylamine;
2) add 4-chloro-3-sulfonamido-phenylformic acid and dehydrating condensation agent;
3) obtain the indapamide crude product after 2.0～20 hours at 0～20 ℃ of following low-temp reaction;
4) with Virahol-crystal's system, obtain the indapamide product.
Described aprotic organic solvent can be methylene dichloride, chloroform, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate or their mixture; Described dehydrating condensation agent is N, N '-dicyclohexylcarbodiimide or N, N '-DIC.
The consumption of each raw material of the present invention is: the mass ratio of N-amino-2-methyl indoline hydrochloride and aprotic organic solvent is 1: 10～30; The mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 0.9～1.5; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 0.9～1.5; The mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 0.9～1.5.
In order to obtain better effect, preferred: the mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 1～1.5; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 0.9～1.2; The mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 1～1.5.
More preferably, the mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 1.2; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 1, and the mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 1.
Preferable reaction temperature is 10 ℃, and the reaction times is 5 hours.
Reaction process of the present invention is as follows:
Advantage of the present invention and characteristics are:
1) saves the sulfur oxychloride acyl chloride reaction, improved security.
2) pollution and corrodibility have been reduced to environment and equipment.
3) cost reduces.
4) yield can improve more than ten percentage points than the traditional technology yield.
Specific implementation method
Further specify the present invention below in conjunction with embodiment, but do not limit the present invention.
Embodiment 1
Add the 200ml tetrahydrofuran (THF) in reaction flask, 9.3gN-amino-2-methyl indoline hydrochloride stirs and drips the 8.5ml triethylamine down, be cooled to 10 ℃, add N, N '-dicyclohexylcarbodiimide 10.8g and 4-chloro-3-sulfonamido-phenylformic acid 11.0g, control reaction temperature is at 10 ℃, 10 hours reaction times, after reaction finishes, the filtering insolubles, tetrahydrofuran (THF) in the evaporate to dryness filtrate, add Virahol-aqueous solution and carry out recrystallization, obtain indapamide 16.5g, yield 90.4%.
Embodiment 2
Add the 260ml tetrahydrofuran (THF) in reaction flask, 11.0gN-amino-2-methyl indoline hydrochloride stirs and drips the 9.2ml triethylamine down, be cooled to 10 ℃, add N, N '-DIC 7.0g and 4-chloro-3-sulfonamido-phenylformic acid 14.0g, control reaction temperature is at 5 ℃, 20 hours reaction times, after reaction finishes, the filtering insolubles, tetrahydrofuran (THF) in the evaporate to dryness filtrate, add Virahol-aqueous solution and carry out recrystallization, obtain indapamide 16.9g, yield 92.6%.
Embodiment 3
Add the 100ml methylene dichloride in reaction flask, 9.3gN-amino-2-methyl indoline hydrochloride stirs and drips the 8.0ml triethylamine down, be cooled to 10 ℃, add N, N '-dicyclohexylcarbodiimide 10g, control reaction temperature is at 4.0 ℃, 4 hours reaction times, after reaction finishes, the filtering insolubles, methylene dichloride in the evaporate to dryness filtrate, add Virahol-aqueous solution and carry out recrystallization, obtain indapamide 15.1g, yield 83.4%.
Embodiment 4
Add the 200ml methylene dichloride in reaction flask, 9.3g (0.05mol) N-amino-2-methyl indoline hydrochloride stirs and drips the 8.5ml triethylamine down, be cooled to 10 ℃, add N, N '-DIC 7.0g, control reaction temperature is at 15 ℃, 10 hours reaction times, after reaction finishes, the filtering insolubles, methylene dichloride in the evaporate to dryness filtrate, add Virahol-aqueous solution and carry out recrystallization, obtain indapamide 16.4g, yield 89.9%.
Embodiment 5
Add the 200ml ethyl acetate in reaction flask, 9.3g N-amino-2-methyl indoline hydrochloride stirs and drips the 8.5ml triethylamine down, be cooled to 10 ℃, add N, N '-DIC 7.0g, control reaction temperature is at 10 ℃, 3 hours reaction times, after reaction finishes, the filtering insolubles, tetrahydrofuran (THF) in the evaporate to dryness filtrate, add Virahol-aqueous solution and carry out recrystallization, obtain indapamide 12.5g, yield 68.4%.
Claims (5)
1. the synthetic method of an indapamide, it is characterized in that: synthesis step comprises:
1) N-amino-2-methyl indoline hydrochloride is dissolved in the aprotic organic solvent and under agitation drips triethylamine;
2) add 4-chloro-3-sulfonamido-phenylformic acid and dehydrating condensation agent;
Described dehydrating condensation agent is N, N '-dicyclohexylcarbodiimide or N, N '-DIC.
3) obtain the indapamide crude product after 2.0～20 hours at 0～20 ℃ of following low-temp reaction;
4) with Virahol-crystal's system, obtain the indapamide product;
There is following proportionlity in above-mentioned each storeroom:
The mass ratio of N-amino-2-methyl indoline hydrochloride and aprotic organic solvent is 1: 10～30; The mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 0.9～1.5; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 0.9～1.5; The mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 0.9～1.5.
2. according to the synthetic method of the described indapamide of claim 1, it is characterized in that: aprotic organic solvent is methylene dichloride, chloroform, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate or their mixture.
3. according to the synthetic method of the described indapamide of claim 1, it is characterized in that: the mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 1～1.5; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 0.9～1.2; The mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 1～1.5.
4. according to the synthetic method of the described indapamide of claim 1, it is characterized in that: the mass ratio of N-amino-2-methyl indoline hydrochloride and triethylamine is 1: 1.2; The mass ratio of 4-chloro-3-sulfonamido-phenylformic acid and N-amino-2-methyl indoline hydrochloride is 1: 1; The mass ratio of N-amino-2-methyl indoline hydrochloride and dehydrating condensation agent is 1: 1.
5. according to the synthetic method of the described indapamide of claim 1, it is characterized in that: temperature of reaction is 10 ℃, and the reaction times is 5 hours.
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| CNB2006100159225A CN100422146C (en) | 2006-09-25 | 2006-09-25 | Synthesis method of indapamide |
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| CNB2006100159225A CN100422146C (en) | 2006-09-25 | 2006-09-25 | Synthesis method of indapamide |
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| CN1927833A CN1927833A (en) | 2007-03-14 |
| CN100422146C true CN100422146C (en) | 2008-10-01 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101717359B (en) * | 2009-07-15 | 2012-09-05 | 北京成宇药业有限公司 | Method for synthesizing indapamide |
| CN106316916A (en) * | 2015-06-29 | 2017-01-11 | 天津市亨必达化学合成物有限公司 | Purification method of indapamide |
| CN105418479A (en) * | 2015-11-18 | 2016-03-23 | 天津市亨必达化学合成物有限公司 | Indapamide synthetic method |
| CN111175388B (en) * | 2019-11-18 | 2022-12-06 | 远大医药（中国）有限公司 | Method for determining DCC content in indapamide bulk drug |
| CN112142643A (en) * | 2020-10-10 | 2020-12-29 | 天津和治药业集团有限公司 | Synthetic method of indapamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068239A2 (en) * | 1981-06-16 | 1983-01-05 | MITSUI TOATSU CHEMICALS, Inc. | Sulfamoylbenzoic acid derivatives and pharmaceutical compositions comprising same |
| EP0462017A1 (en) * | 1990-06-14 | 1991-12-18 | Adir Et Compagnie | Process for the industrial preparation of 3-sulfamoyl-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide from 2,3-dihydro-2-methyl-1H-indole and hydroxylamine-O-sulfonic acid |
| EP0462016A1 (en) * | 1990-06-14 | 1991-12-18 | Adir Et Compagnie | Process for the industrial preparation of 4-chloro-3-sulfamoyl-N-(2,3-dihydro-2-methyl-1H-indol-1-yl) benzamide |
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2006
- 2006-09-25 CN CNB2006100159225A patent/CN100422146C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068239A2 (en) * | 1981-06-16 | 1983-01-05 | MITSUI TOATSU CHEMICALS, Inc. | Sulfamoylbenzoic acid derivatives and pharmaceutical compositions comprising same |
| EP0462017A1 (en) * | 1990-06-14 | 1991-12-18 | Adir Et Compagnie | Process for the industrial preparation of 3-sulfamoyl-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide from 2,3-dihydro-2-methyl-1H-indole and hydroxylamine-O-sulfonic acid |
| EP0462016A1 (en) * | 1990-06-14 | 1991-12-18 | Adir Et Compagnie | Process for the industrial preparation of 4-chloro-3-sulfamoyl-N-(2,3-dihydro-2-methyl-1H-indol-1-yl) benzamide |
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