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Preparation method of furosemide

A technology of furosemide and sulfonamidobenzoic acid, which is applied in the field of drug synthesis, can solve the problems of equipment corrosion by chlorosulfonic acid, large proportion of furfuramide, low total yield, etc., and achieves shortened heating time and short reaction steps. , The effect of good product quality

Active Publication Date: 2016-11-16
NORTHEAST PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has a long route and a low total yield of 14%-19.2%. In the last step, the condensation reaction yield of 2,4-dichloro-5-sulfonamidobenzoic acid and furfuryl amine is only 40%, and the ratio of furfuryl amine is large. high cost
The concentrated hydrochloric acid used in the diazotization process and the chlorosulfonic acid used in the chlorosulfonation process corrode equipment and seriously pollute the environment

Method used

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  • Preparation method of furosemide
  • Preparation method of furosemide
  • Preparation method of furosemide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The influence of different alkalis and dosages on the reaction yield:

[0026] Add 200ml of absolute ethanol and alkali to a 500mL four-necked bottle with a thermometer. The selection of the alkali is shown in Table 1. After stirring and dissolving, add 27g (0.1mol) of 2,4-dichloro-5-sulfonamidobenzene formic acid, heated to 40°C and stirred for 2 hours. The reaction solution was lowered to 20-30°C and stirred for 0.5 hours, filtered, washed with 30ml of absolute ethanol, and dried to obtain 2,4-dichloro-5-sulfonamidobenzoic acid sodium salt.

[0027] Add 29.2g (0.1mol) sodium 2,4-dichloro-5-sulfonamidobenzoate, 5ml ethylene glycol, 30g (0.3mol) furfurylamine into a 100ml four-necked bottle, heat to 130-135°C and stir for 3 hours . After the reaction is completed, the solvent and furfurylamine are distilled off under reduced pressure, the reaction solution is poured into a 500ml beaker, 200ml of isopropanol is added, stirred for 30 minutes, crystallized at 0-5°C for 5...

Embodiment 2

[0032] The influence of adopting different solvents on the reaction yield:

[0033] Add 200ml of absolute ethanol and 7.14g (0.105mol) of sodium ethylate to a 500mL four-necked bottle with a thermometer, add 27g (0.1mol) of 2,4-dichloro-5-sulfonamidobenzoic acid after stirring and dissolving, and heat up The reaction was stirred at 40°C for 2 hours. The reaction solution was lowered to 20-30° C. and stirred for 0.5 hours, filtered, washed with 30 ml of absolute ethanol, and dried to obtain 2,4-dichloro-5-sulfonamidobenzoic acid sodium salt with a yield of 100%.

[0034] Add 29.2g (0.1mol) 29.2g (0.1mol) sodium 4-dichloro-5-sulfonamidobenzoate in the 100ml four-necked bottle, 5ml solvent, 30g (0.3mol) furfurylamine, the selection situation of described solvent sees Table 2, heat Stir at 130-135°C for 3 hours. After the reaction was completed, the solvent and furfurylamine were distilled off under reduced pressure, the reaction solution was poured into a 500ml beaker, 200ml of...

Embodiment 3

[0039] Adopt the influence of different isopropanol consumptions on reaction yield:

[0040] Add 200ml of absolute ethanol and 7.14g (0.105mol) of sodium ethylate to a 500mL four-necked bottle with a thermometer, add 27g (0.1mol) of 2,4-dichloro-5-sulfonamidobenzoic acid after stirring and dissolving, and heat up The reaction was stirred at 40°C for 2 hours. The reaction solution was lowered to 20-30°C and stirred for 0.5 hours, filtered, washed with 30ml of absolute ethanol, and dried to obtain 2,4-dichloro-5-sulfonamidobenzoic acid sodium salt.

[0041] Add 29.2g (0.1mol) sodium 2,4-dichloro-5-sulfonamidobenzoate, 5ml ethylene glycol, 30g (0.3mol) furfurylamine into a 100ml four-necked bottle, heat to 130-135°C and stir for 3 hours . After the reaction is complete, distill off the solvent and furfurylamine under reduced pressure, pour the reaction solution into a 500ml beaker, add a certain amount of isopropanol, see Table 3 for the amount of isopropanol, stir for 30 minut...

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Abstract

The invention provides a preparation method of furosemide and relates to the technical field of pharmaceutical synthesis. The preparation method comprises the following steps: (1) 2,4-dichloro-5-sulfamoylbenzoic acid and alkali are subjected to a reaction in presence of an organic solvent, a reaction liquid is obtained and subjected to aftertreatment, and sodium 2,4-dichloro-5-sulfamoylbenzoic acid is obtained; (2) sodium 2,4-dichloro-5-sulfamoylbenzoic acid and furfurylamine are subjected to a reaction in presence of an organic solvent, furfurylamine and the solvent are recovered through reduced pressure distillation after the reaction, a reaction liquid is obtained and mixed with isopropyl alcohol, a mixture is stirred, crystallized and filtered, and sodium furosemide is obtained; (3) sodium furosemide is subjected to water dissolution, activated carbon decoloration and glacial acetic acid acidification, and a finished furosemide product is obtained. The preparation method has the advantages that raw materials are cheap and available, the cost is low, short time is consumed, reaction steps are short, operation is simple, product quality is good, yield is high, solvents can be recycled and reused, environmental pollution is small and the like, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing high-yield and high-quality furosemide in the technical field of drug synthesis. Background technique [0002] Furosemide is a diuretic developed by former Sidhurst in 1963, also known as furosemide, which is clinically used to treat peripheral edema caused by cardiac edema, renal edema, liver cirrhosis ascites, dysfunction or vascular disorder. Edema, and can promote the discharge of upper urethral stones. Its diuretic effect is rapid and powerful, and it is mostly used in severe cases where other diuretics are ineffective. [0003] In the synthesis of furosemide, at present, there are literatures reporting its synthesis method, but there are certain defects. [0004] In German patents DE1806581, DE1220436 and DE1213846: Furosemide is obtained by reacting 2-fluoro-4-chloro-5-sulfonamidobenzoic acid series compounds and furfurylamine as raw materials. The reaction conditions of this kind of process rout...

Claims

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Application Information

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IPC IPC(8): C07D307/52
CPCC07D307/52
Inventor 王卓杨亚圣刘九知沈思思张晓研
Owner NORTHEAST PHARMA GRP
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