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Synthetic method of Azosemide intermediate

A synthesis method and technology of azosemide are applied in the preparation of sulfonic acid, the preparation of sulfonic acid amides, organic chemistry, etc., and can solve the problem of reducing the yield and purity of 4-chloro-2-fluoro-5-sulfamoylbenzoic acid, affecting the Product purity and yield, easy hydrolysis of sulfonyl chloride, etc., to achieve the effect of simple and convenient production process, excellent yield, and inhibition of isomer impurities

Active Publication Date: 2020-09-22
SUZHOU HUADAO BIOLOGICAL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the prior art, the synthesis of 4-chloro-2-fluoro-5-sulfamoylbenzoic acid is slightly reported in the literature, and "Research on Azosemide Synthesis Technology" briefly introduces the synthesis of azosemide with 2 -Fluoro-4-chloro-benzoic acid and chlorosulfonic acid are prepared by sulfonation and ammoniation to prepare 2-fluoro-4-chloro-5-amiodoylbenzoic acid. The preparation process will make 2-fluoro-4-chloro-benzene Formic acid directly reacts with chlorosulfonic acid, and the yield of the 2-fluoro-4-chloro-5-amiodoylbenzoic acid that the reaction generates is low, only 51.1%, and the purity is also low, and this is due to the formation of Impurities such as by-products are removed, which affects the purity and yield of the product
In addition, the ammoniation reaction in the prior art uses ammonia as a reagent, and the sulfonyl chloride is easily hydrolyzed in the ammoniation process, which also reduces the output and purity of 4-chloro-2-fluoro-5-sulfamoylbenzoic acid

Method used

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  • Synthetic method of Azosemide intermediate
  • Synthetic method of Azosemide intermediate
  • Synthetic method of Azosemide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 120 milliliters of chlorosulfonic acid and 25 grams of sodium chloride to the reaction flask, raise the temperature to 100°C, add 50 grams of 4-chloro-2-fluorobenzoic acid in batches, react at 100°C for another 1 hour, and then raise the temperature to 120 ℃ reaction for 5 hours, to achieve staged heating to promote the reaction, thereby effectively inhibiting the generation of isomer impurities. After the reaction, the reaction solution was cooled to room temperature, slowly poured onto crushed ice, stirred sufficiently, then filtered with suction, and the obtained filter cake was washed with ice water.

[0036] Cool 500ml of isopropanol to 0°C, feed 25g of ammonia gas, control the temperature below 10°C, add the above-mentioned filter cake in batches, naturally raise the temperature and stir overnight; then concentrate to remove isopropanol, add 200ml of water Stir for 1 hour, acidify with hydrochloric acid until the pH is 2-3, cool and crystallize, filter with su...

Embodiment 2

[0038] Add 120 ml of chlorosulfonic acid and 30 g of ammonium chloride to the reaction flask, add 50 g of 4-chloro-2-fluorobenzoic acid in batches, then raise the temperature to 100°C for 1 hour, then raise the temperature to 160°C for 1 hour , to achieve staged heating to promote the reaction, thereby effectively inhibiting the generation of isomer impurities. After the reaction, cool the reaction liquid with ice salt, control the temperature below 20°C, slowly add 500 ml of cold water dropwise to extract the reaction, filter with suction, and wash the obtained filter cake with ice water.

[0039] Add 120 grams of ammonium carbonate to the obtained filter cake, grind continuously for 2 hours, leave it overnight, add 200 milliliters of water and stir, acidify with hydrochloric acid until the pH is 2 to 3, cool and crystallize, suction filter, wash with water, and the volume ratio of the solid used is The 10:1 ethanol-water mixture was recrystallized twice, and dried to obtain ...

Embodiment 3

[0041] Add 150 ml of chlorosulfonic acid and 20 g of lithium chloride to the reaction flask, raise the temperature to 80°C, add 50 g of 4-chloro-2-fluorobenzoic acid in batches, raise the temperature to 100°C for 1 hour, and then raise the temperature to 120°C After 5 hours of reaction, staged heating is realized to promote the reaction, thereby effectively suppressing the generation of isomer impurities. After the reaction, the reaction solution was cooled to room temperature, slowly poured onto crushed ice, stirred fully, then filtered with suction, and the obtained filter cake was washed with ice water.

[0042]Grind the filter cake and 85 grams of ammonium chloride evenly, gradually add solid sodium carbonate in small batches for full grinding, and wait until the system does not emit carbon dioxide gas and the system is alkaline, and continue the grinding reaction for 1 hour. Add 250 ml of water and stir, acidify with hydrochloric acid until the pH value is 2-3, cool and c...

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Abstract

The invention discloses a synthesis method of an azeosemide intermediate, wherein the synthesis method comprises the following steps: (1) catalytic sulfonation reaction: carrying out catalytic sulfonation reaction on 4-chloro-2-fluorobenzoic acid and chlorosulfonic acid under the action of a catalyst to generate 4-chloro-2-fluorobenzenesulfonyl chloride; (2) ammoniation reaction; and (3) acidification treatment: adjusting the pH value of the substance subjected to the ammonification reaction in the step (2) to be acidic by using an acid solution, and then carrying out suction filtration, recrystallization and drying to obtain the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid. According to the synthesis method of the azeosemide intermediate, the catalyst is introduced into a sulfonation system,the sulfonation temperature is reduced, and the reaction is promoted by heating in stages, so that the generation of isomer impurities is inhibited, the reaction conditions are mild, a high-quality product can be prepared, the yield is excellent, the production process flow is simple and convenient, and safety and reliability are realized.

Description

technical field [0001] The invention relates to the technical field of chemical production, in particular to a synthesis method of an azosemide intermediate, in particular to a synthesis method. Background technique [0002] Azosemide is a new type of benzenesulfonamide compound (patent: DE1815922A1) developed by Boehringer Mamnheim, Germany. It belongs to the loop diuretic, mainly by inhibiting the reabsorption of sodium and chloride in the ascending branch of the loop of the kidney. It produces diuretic effect and is clinically used to treat cardiac edema (congestive heart failure), renal edema and hepatic edema. It is a long-acting diuretic, and its oral effect is basically equivalent to furosemide, but it is more effective The effect is slow but long-lasting and gentle; if administered intravenously, the diuretic effect is 5.5-8 times stronger than furosemide; azosemide can significantly reduce swelling and diuresis, improve heart function, It reduces the effect of asci...

Claims

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Application Information

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IPC IPC(8): C07C303/38C07C311/16
CPCC07C303/38C07C303/08C07C311/16C07C309/86
Inventor 陆军刘辉刘明荣
Owner SUZHOU HUADAO BIOLOGICAL PHARMA
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