CN104672114A - A preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid - Google Patents
A preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid Download PDFInfo
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- CN104672114A CN104672114A CN201310603545.7A CN201310603545A CN104672114A CN 104672114 A CN104672114 A CN 104672114A CN 201310603545 A CN201310603545 A CN 201310603545A CN 104672114 A CN104672114 A CN 104672114A
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Abstract
The invention relates to a preparing method of a medicine intermediate, and particularly relates to a preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid. The method includes performing sulfurization by adopting 2,4-dichlorobenzoic acid and chlorosulfonic acid as initial raw materials, sodium sulfate as a catalyst and NMP as a solvent; centrifuging to obtain 2,4-dichloro-5-carboxybenzenesulfonyl chloride; subjecting the 2,4-dichloro-5-carboxybenzenesulfonyl chloride to ammoniation with ammonia water; acidifying; washing with water to obtain a crude product of the 2,4-dichloro-5-sulfamoylbenzoic acid; purifying the crude product with ethanol; and recrystallizing to obtain a 2,4-dichloro-5-sulfamoylbenzoic acid product with high quality. The method is less in process steps, easily available in raw materials, low in pollution, high in product purity and low in cost, and is a green synthesis route.
Description
Technical field
The invention belongs to the preparation method of medicine intermediate, specifically the preparation method of the chloro-5-sulfonamide benzoic acid of a kind of 2,4-bis-.
Background technology
The chloro-5-sulfonamide benzoic acid of 2,4-bis-, English name Lasamide is the important intermediate of Furosemide.Furosemide, also claims furosemide, diuretic(s), is applicable to I and II hypertension, especially senile hypertension or concurrent heart failure person.Be used for the treatment of the peripheral edema caused by cardiac edema, renal edema, hepatic ascites, dysfunction or vascular disorder clinically, and the discharge of top urethral calculus can be impelled.Its diuretic properties is rapid, powerful, is used for the several cases that other hydragog(ue) are invalid.There is following problem in the method for the chloro-5-sulfonamide benzoic acid of synthesis 2,4-bis-traditional at present: 1. in reaction process due to the generation of side reaction, the by product brought makes synthesis yield decline; 2. in reaction process, use methyl-sulphoxide to make solvent, because solvent boiling point is lower, easy oxidized generation by product; 3. do refining solvent with acetone, bring harm to a line worker is healthy.
Summary of the invention
Object of the present invention is exactly the problems referred to above existed in the method for the chloro-5-sulfonamide benzoic acid of existing synthesis 2,4-bis-, provides a kind of preparation method of 2,4-bis-chloro-5-sulfonamide benzoic acids newly.
The preparation method of 2,4-bis-chloro-5-sulfonamide benzoic acids of the present invention, comprises the following steps:
(1) sulfonated: with 2,4 dichloro benzene formic acid and chlorsulfonic acid for raw material, sodium sulfate is as catalyzer; First add in reactor by N-Methyl pyrrolidone, then add 2,4 dichloro benzene formic acid and sodium sulfate, heating makes material be warming up to 145 DEG C, after material dissolves completely, starts to drip chlorsulfonic acid, dropwises rear insulation 5 hours;
(2) centrifugal: the complete material of reaction in step (1) is cooled to room temperature, centrifugal go out product, solvent recuperation, obtains the chloro-5-carboxylphenylsulphonyl chloride of intermediate 2,4-bis-;
(3) ammonification: ammoniacal liquor is put into ammoniation kettle, opens ammoniation kettle chuck, with cryosel cooling, treats that in still, ammonia temperature is down to 0 DEG C, in still, slowly adds the chloro-5-carboxylphenylsulphonyl chloride of 2,4-bis-, control temperature of reaction≤5 DEG C, react 2 hours;
(4) acidifying: obtain in product the hydrochloric acid conditioning solution pH value dripping 30% after reaction in step (3), control temperature of reaction≤10 DEG C in dropping process, stops dripping when system pH is 1 ~ 2;
(5) wash: by centrifugal for acidizing product after washing, be washed till when centrifugate pH value is 4 ~ 5 and terminate, obtain 2,4-bis-chloro-5-sulfonamide benzoic acid crude product;
(6) refining: chloro-for 2,4-bis-5-sulfonamide benzoic acid crude product and alcohol to be added in refining kettle, is warming up to 75 DEG C, after system is as clear as crystal, adds gac and carry out decolouring 1.5 hours; After decolouring, while hot by liquid suction filtration in crystallization kettle, centrifugal after crystallisation by cooling, dry, obtain the chloro-5-sulfonamide benzoic acid of 2,4-bis-.
Hinge structure of the present invention has the following advantages:
1., with the catalyzer of anhydrous sodium sulphate as sulfonation reaction, the sulfate ion concentration in reaction system well prevents the generation of side reaction after improving.
2. use NMP(N-methyl-2-pyrrolidone) as the solvent of sulfonation reaction, relative conventional solvent DMSO (methyl-sulphoxide) boiling point is higher, structure is relatively more stable, avoids the oxidized yield that causes of solvent in reaction again and reduces, the trouble that by product increases.
3. use alcohol as refining solvent, do refining solvent relative in prior synthesizing method with acetone, namely meet the demand of occupational health aspect, post, add safety coefficient, well control production cost again.
The present invention is according to China's industrial production actual demand, devise a kind of with 2,4-dichlorobenzoic acid, NMP, anhydrous sodium sulphate, chlorsulfonic acid, ammoniacal liquor are the synthetic method of starting raw material, have that raw material is easy to get, technique is simplified, it is low to pollute, product purity is high, the advantage such as with low cost is the operational path of an environmental protection.
Embodiment
Embodiment 1
The preparation method of 2,4-bis-chloro-5-sulfonamide benzoic acids of the present invention, comprises the following steps:
(1) sulfonated: with 2,4 dichloro benzene formic acid and chlorsulfonic acid for raw material, sodium sulfate is as catalyzer; First add in reactor by N-Methyl pyrrolidone, then add 2,4 dichloro benzene formic acid and sodium sulfate, heating makes material be warming up to 145 DEG C, after material dissolves completely, starts to drip chlorsulfonic acid, dropwises rear insulation 5 hours;
(2) centrifugal: the complete material of reaction in step (1) is cooled to room temperature, centrifugal go out product, solvent recuperation, obtains the chloro-5-carboxylphenylsulphonyl chloride of intermediate 2,4-bis-;
(3) ammonification: ammoniacal liquor is put into ammoniation kettle, opens ammoniation kettle chuck, with cryosel cooling, treats that in still, ammonia temperature is down to 0 DEG C, in still, slowly adds the chloro-5-carboxylphenylsulphonyl chloride of 2,4-bis-, control temperature of reaction≤5 DEG C, react 2 hours;
(4) acidifying: obtain in product the hydrochloric acid conditioning solution pH value dripping 30% after reaction in step (3), control temperature of reaction≤10 DEG C in dropping process, stops dripping when system pH is 1 ~ 2;
(5) wash: by centrifugal for acidizing product after washing, be washed till when centrifugate pH value is 4 ~ 5 and terminate, obtain 2,4-bis-chloro-5-sulfonamide benzoic acid crude product;
(6) refining: chloro-for 2,4-bis-5-sulfonamide benzoic acid crude product and alcohol to be added in refining kettle, is warming up to 75 DEG C, after system is as clear as crystal, adds gac and carry out decolouring 1.5 hours; After decolouring, while hot by liquid suction filtration in crystallization kettle, centrifugal after crystallisation by cooling, dry, obtain the chloro-5-sulfonamide benzoic acid of 2,4-bis-.
Claims (1)
- The preparation method of the chloro-5-sulfonamide benzoic acid of 1.2,4-bis-, is characterized in that comprising the following steps:(1) sulfonated: with 2,4 dichloro benzene formic acid and chlorsulfonic acid for raw material, sodium sulfate is as catalyzer; First add in reactor by N-Methyl pyrrolidone, then add 2,4 dichloro benzene formic acid and sodium sulfate, heating makes material be warming up to 145 DEG C, after material dissolves completely, starts to drip chlorsulfonic acid, dropwises rear insulation 5 hours;(2) centrifugal: the complete material of reaction in step (1) is cooled to room temperature, centrifugal go out product, solvent recuperation, obtains the chloro-5-carboxylphenylsulphonyl chloride of intermediate 2,4-bis-;(3) ammonification: ammoniacal liquor is put into ammoniation kettle, opens ammoniation kettle chuck, with cryosel cooling, treats that in still, ammonia temperature is down to 0 DEG C, in still, slowly adds the chloro-5-carboxylphenylsulphonyl chloride of 2,4-bis-, control temperature of reaction≤5 DEG C, react 2 hours;(4) acidifying: obtain in product the hydrochloric acid conditioning solution pH value dripping 30% after reaction in step (3), control temperature of reaction≤10 DEG C in dropping process, stops dripping when system pH is 1 ~ 2;(5) wash: by centrifugal for acidizing product after washing, be washed till when centrifugate pH value is 4 ~ 5 and terminate, obtain 2,4-bis-chloro-5-sulfonamide benzoic acid crude product;(6) refining: chloro-for 2,4-bis-5-sulfonamide benzoic acid crude product and alcohol to be added in refining kettle, is warming up to 75 DEG C, after system is as clear as crystal, adds gac and carry out decolouring 1.5 hours; After decolouring, while hot by liquid suction filtration in crystallization kettle, centrifugal after crystallisation by cooling, dry, obtain the chloro-5-sulfonamide benzoic acid of 2,4-bis-.
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| CN201310603545.7A CN104672114A (en) | 2013-11-26 | 2013-11-26 | A preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid |
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| CN201310603545.7A CN104672114A (en) | 2013-11-26 | 2013-11-26 | A preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108117500A (en) * | 2017-11-24 | 2018-06-05 | 江苏慈星药业有限公司 | It is a kind of to reduce the method that aminating reaction technique generates waste water abraum salt in ammonia sulphur methyl esters production process |
| CN108752242A (en) * | 2018-06-28 | 2018-11-06 | 金华双宏化工有限公司 | For the method for sulfonating of low cloud density aromatic hydrocarbons |
| CN112094209A (en) * | 2020-09-17 | 2020-12-18 | 山东阳谷华泰化工股份有限公司 | Method for preparing scorch retarder N-phenyl-N-trichloromethylthio benzene sulfonamide |
-
2013
- 2013-11-26 CN CN201310603545.7A patent/CN104672114A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108117500A (en) * | 2017-11-24 | 2018-06-05 | 江苏慈星药业有限公司 | It is a kind of to reduce the method that aminating reaction technique generates waste water abraum salt in ammonia sulphur methyl esters production process |
| CN108117500B (en) * | 2017-11-24 | 2020-08-18 | 江苏慈星药业有限公司 | Method for reducing waste water and waste salt generated in amination process in production process of methyl sulfamate |
| CN108752242A (en) * | 2018-06-28 | 2018-11-06 | 金华双宏化工有限公司 | For the method for sulfonating of low cloud density aromatic hydrocarbons |
| CN108752242B (en) * | 2018-06-28 | 2021-01-01 | 金华双宏化工有限公司 | Sulfonation method for low electron cloud density aromatic hydrocarbon |
| CN112094209A (en) * | 2020-09-17 | 2020-12-18 | 山东阳谷华泰化工股份有限公司 | Method for preparing scorch retarder N-phenyl-N-trichloromethylthio benzene sulfonamide |
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Application publication date: 20150603 |