阅读说明：本技术 一种阿佐塞米中间体的合成方法 (Synthetic method of azosemide intermediate ) 是由 陆军 刘辉 刘明荣 于 2020-06-12 设计创作，主要内容包括：本发明公开了一种阿佐塞米中间体的合成方法,包括如下步骤：(1)催化磺化反应：将4-氯-2-氟苯甲酸与氯磺酸在催化剂的作用下进行催化磺化反应,生成4-氯-2-氟苯磺酰氯；(2)氨化反应；(3)酸化处理：将步骤(2)中氨化反应后的物质用酸液调节至pH值为酸性,然后抽滤、重结晶,干燥,得到所述4-氯-2-氟-5-氨磺酰苯甲酸。本发明一种阿佐塞米中间体的合成方法,通过在磺化体系引入催化剂,降低磺化温度,分阶段加热推动反应进行,从而抑制异构体杂质的产生,本发明反应条件温和,可制备高品质的产品,收率优良,生产工艺流程简单方便,安全可靠。(The invention discloses a synthetic method of an azosemide intermediate, which comprises the following steps: (1) catalyzing 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) performing ammoniation reaction; (3) acidifying: and (3) adjusting the substance subjected to the amination reaction in the step (2) to have an acidic pH value by using an acid solution, and then performing suction filtration, recrystallization and drying to obtain the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid. The synthetic method of the azosemide intermediate has the advantages that 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.)

1. The synthetic method of the azosemide intermediate is characterized by comprising the following steps:

(1) catalyzing 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: performing water extraction and sterilization on the reaction liquid obtained in the step (1), performing suction filtration to obtain a crude product of 4-chloro-2-fluorobenzenesulfonyl chloride, and performing an ammoniation reaction on the obtained crude product of 4-chloro-2-fluorobenzenesulfonyl chloride and an ammoniation reagent;

(3) acidifying: and (3) adjusting the substance subjected to the amination reaction in the step (2) to have an acidic pH value by using an acid solution, and then performing suction filtration, recrystallization and drying to obtain the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid.

2. The method for synthesizing the intermediate of the azosemide as claimed in claim 1, wherein in the step (1), the amount of the catalyst is 0-200 mol%.

3. The method of claim 2, wherein the catalyst is one or more of sodium chloride, potassium chloride, ammonium chloride, zinc chloride, copper chloride, ferric chloride, aluminum chloride, barium chloride, lithium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, ammonium sulfate, magnesium sulfate, copper sulfate, ferric sulfate, barium sulfate, sodium phosphate, or potassium phosphate.

4. The method for synthesizing the intermediate of azosemide according to claim 3, wherein the catalyst is sodium chloride, potassium chloride, lithium chloride or ammonium chloride.

5. The method for synthesizing the intermediate of azosemide as claimed in claim 1, wherein in step (1), the catalytic sulfonation reaction is performed in two stages, and the reaction temperature in the first stage is lower than that in the second stage.

6. The method for synthesizing the intermediate of the azosemide as claimed in claim 5, wherein the reaction temperature of the first stage is 80-110 ℃; the reaction temperature of the first stage is below 160 ℃.

7. The method for synthesizing the intermediate of azosemide according to claim 1, wherein the amount of the ammoniation reagent used in the step (2) is 100-500 mol%.

8. The method of claim 7, wherein the ammoniating agent is ammonia gas, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium sulfate, ammonium nitrate, or ammonium phosphate.

9. The method for synthesizing the azosemide intermediate as claimed in claim 1, wherein in the step (1), the chlorosulfonic acid is used in an amount of 200 to 600 mol%.

10. The method for synthesizing the intermediate of azosemide according to claim 1, wherein in the step (3), the pH value is less than or equal to 3.

Technical Field

The invention relates to the technical field of chemical production, in particular to a synthetic method of an azosemide intermediate, and specifically relates to a synthetic method.

Background

The azosemide is a novel benzenesulfonamide compound (patent: DE1815922A 1) developed by Deguoligmen company (Boehringer mameheim), belongs to loop diuretics, has diuretic effect mainly by inhibiting reabsorption of ascending sodium and chlorine of renal tubular loop, is clinically used for treating cardiac edema (congestive heart failure), renal edema and hepatic edema, is a long-acting diuretic, has basically equivalent oral effect to furosemide, but has lasting and mild effect; if the medicine is administrated intravenously, the diuretic effect is 5.5-8 times stronger than that of furosemide; the azosemide has obvious functions of reducing swelling and promoting urination, improving heart function and reducing ascites on heart, liver and kidney edema or ascites, and is an effective and well-tolerated treatment medicament.

An important intermediate in the synthesis of azosemide is 4-chloro-2-fluoro-5-sulfamoylbenzoic acid (Cas: 4793-22-0), and the synthesis of azosemide from 4-chloro-2-fluoro-5-sulfamoylbenzoic acid comprises the following steps:

therefore, the yield of the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid of the intermediate product and the quality, purity and the like directly influence the yield and quality of the final product, namely, the azosemide.

At present, 4-chloro-2-fluoro-5-sulfamoylbenzoic acid is synthesized by taking 4-chloro-2-fluorobenzoic acid as an initial raw material and performing sulfonation and ammoniation. The synthesis reaction is as follows:

Disclosure of Invention

The invention mainly solves the technical problem of providing a synthetic method of an azosemide intermediate, which can solve the problems existing in the existing synthetic method.

In order to solve the technical problems, the invention adopts a technical scheme that: the synthesis method of the azosemide intermediate is provided, and comprises the following steps:

(1) catalyzing 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: performing water extraction and sterilization on the reaction liquid obtained in the step (1), performing suction filtration to obtain a crude product of 4-chloro-2-fluorobenzenesulfonyl chloride, and performing an ammoniation reaction on the obtained crude product of 4-chloro-2-fluorobenzenesulfonyl chloride and an ammoniation reagent;

(3) acidifying: and (3) adjusting the substance subjected to the amination reaction in the step (2) to have an acidic pH value by using an acid solution, and then performing suction filtration, recrystallization and drying to obtain the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid.

In a preferred embodiment of the present invention, in the step (1), the catalyst is used in an amount of 0 to 200 mol%.

In a preferred embodiment of the present invention, the catalyst is one or more of sodium chloride, potassium chloride, ammonium chloride, zinc chloride, copper chloride, ferric chloride, aluminum chloride, barium chloride, lithium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, ammonium sulfate, magnesium sulfate, copper sulfate, ferric sulfate, barium sulfate, sodium phosphate or potassium phosphate.

In a preferred embodiment of the invention, the catalyst is sodium chloride, potassium chloride, lithium chloride or ammonium chloride.

In a preferred embodiment of the present invention, in the step (1), the catalytic sulfonation reaction is carried out in two stages, and the reaction temperature in the first stage is lower than that in the second stage.

In a preferred embodiment of the present invention, the reaction temperature of the first stage is 80 to 110 ℃; the reaction temperature of the first stage is below 160 ℃.

In a preferred embodiment of the present invention, in the step (2), the amount of the ammoniation agent is 100 to 500 mol%.

In a preferred embodiment of the invention, the ammoniating agent is ammonia, ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium sulfate, ammonium nitrate or ammonium phosphate.

In a preferred embodiment of the present invention, in the step (1), the chlorosulfonic acid is used in an amount of 200 to 600 mol%.

In a preferred embodiment of the present invention, in the step (3), the pH is 3 or less.

The invention has the beneficial effects that: the synthetic method of the azosemide intermediate has the advantages that 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.

Drawings

FIG. 1 is a mass spectrometric detection profile of 4-chloro-2-fluoro-5-sulfamoylbenzoic acid prepared by the synthetic method of an azosemide intermediate of the present invention.

Detailed Description

The following detailed description of the preferred embodiments of the present invention, taken in conjunction with the accompanying drawings, will make the advantages and features of the invention easier to understand by those skilled in the art, and thus will clearly and clearly define the scope of the invention.

Referring to fig. 1, an embodiment of the present invention includes:

the invention discloses a synthesis method of an azosemide intermediate, which comprises the step of carrying out sulfonation reaction on 4-chloro-2-fluorobenzoic acid serving as a raw material and 200-600 mol% of chlorosulfonic acid under the action of 0-200 mol% of a catalyst to generate 4-chloro-2-fluorobenzenesulfonyl chloride. The catalyst is one or more of sodium chloride, potassium chloride, ammonium chloride, zinc chloride, copper chloride, ferric chloride, aluminum chloride, barium chloride, lithium chloride, magnesium chloride, calcium chloride, sodium sulfate, potassium sulfate, ammonium sulfate, magnesium sulfate, copper sulfate, ferric sulfate, barium sulfate, sodium phosphate or potassium phosphate.

By introducing the catalyst into the sulfonation system, the sulfonation temperature can be reduced to 80-160 ℃, and staged heating is realized to promote the reaction, so that the generation of isomer impurities is effectively inhibited, and the quantity and the quality of a target product are improved; in addition, the reaction condition is mild, and the preparation of high-quality products is facilitated.

And cooling the reaction liquid obtained by the catalytic sulfonation reaction, performing water extraction, performing suction filtration to obtain a crude product of 4-chloro-2-fluorobenzenesulfonyl chloride, and performing an amination reaction on the obtained crude product of 4-chloro-2-fluorobenzenesulfonyl chloride and 100-500 mol% of an ammoniation reagent.

The ammoniation reagent is ammonia gas, so that the introduction of water caused by using ammonia water can be avoided, the hydrolysis of 4-chloro-2-fluorobenzenesulfonyl chloride is reduced, and the reaction yield can be improved.

The ammoniation reagent can also be solid ammoniation reagents such as ammonium carbonate, ammonium bicarbonate, ammonium chloride, ammonium sulfate, ammonium nitrate or ammonium phosphate and the like, and the solid ammoniation reagents and the 4-chloro-2-fluorobenzenesulfonyl chloride crude product are subjected to solid-phase ammoniation reaction. In the ammonification process, measures such as reaction temperature reduction, solid-phase ammonification reaction and the like are adopted, so that the hydrolysis of the 4-chloro-2-fluorobenzenesulfonyl chloride is reduced, and the reaction yield can be improved.

And (3) adjusting the pH value of the material after the ammoniation reaction to 2-3 by using acid liquor, and then performing suction filtration, recrystallization and drying to obtain the 4-chloro-2-fluoro-5-sulfamoylbenzoic acid.