阅读说明：本技术 一种抗病毒药物中间体4-氨基-3-硝基苯磺酰胺的合成方法 (Synthesis method of antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide ) 是由 赵小林 崔家乙 汪金柱 沈在明 任勇杰 于 2020-12-24 设计创作，主要内容包括：本发明一种抗病毒药物中间体4-氨基-3-硝基苯磺酰胺的合成方法,以4-氟-3-硝基苯磺酰氯为主要原料,以乙腈为溶剂,室温环境下,经氨水胺化,一步法合成目标产物4-氨基-3-硝基苯磺酰胺,中间体经氨水低温胺化后,得目标产品；本发明工艺原料简单易得,操作简单方便,合成条件较温和,具有良好的社会和经济效益。(The invention relates to a method for synthesizing an antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide, which takes 4-fluoro-3-nitrobenzenesulfonyl chloride as a main raw material and acetonitrile as a solvent, synthesizes a target product 4-amino-3-nitrobenzenesulfonamide by an ammonia water amination one-step method under a room temperature environment, and obtains a target product after the intermediate is aminated by the ammonia water at a low temperature; the invention has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild synthesis conditions and good social and economic benefits.)

1. A synthetic method of an antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide is characterized by comprising the following steps:

(1) mixing acetonitrile and 4-fluoro-3-nitrobenzenesulfonyl chloride, cooling to 10 ℃ in an ice water bath, then dropwise adding ammonia water, keeping the temperature below 30 ℃, and reacting for 4-8 hours to obtain a reaction solution;

(2) adding dichloromethane into the reaction liquid in the step (1), stirring for 30-60min, standing for layering, collecting an organic layer, concentrating under reduced pressure at 40-50 ℃ to obtain a crude product, and pulping the crude product with ethanol to obtain 4-amino-3-nitrobenzenesulfonamide;

2. the method for synthesizing the antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide according to claim 1, wherein the mass ratio of acetonitrile to 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 3-5: 1.

3. The method for synthesizing the antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide according to claim 1, wherein the concentration of the ammonia water in the step (1) is 28%, and the mass ratio of the ammonia water to the 4-fluoro-3-nitrobenzenesulfonyl chloride is 2-2.2: 1.

4. The method for synthesizing the antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide according to claim 1, wherein the mass ratio of dichloromethane in the step (2) to 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 3-5: 1.

5. The method for synthesizing 4-amino-3-nitrobenzenesulfonamide as an antiviral drug intermediate according to claim 1, wherein the mass ratio of ethanol in the step (2) to 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 0.5-1: 1.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of an antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide.

Background

All diseases such as new coronary pneumonia, SARS, Ebola and the like which cause disastrous cost to human beings are caused by virus infection. Meanwhile, viral infection can cause various other diseases, which seriously endanger human health and life. Therefore, the development and research of antiviral drugs are an important part of the medical history of human beings. 4-amino-3-nitrobenzenesulfonamide is an important intermediate of GDC of a novel antiviral drug and plays an important role in a synthetic route of the GDC. Few literature reports exist on the synthesis of 4-amino-3-nitrobenzenesulfonamide. Synthesizing a target product 4-amino-3-nitrobenzenesulfonamide by using 4-fluoro-3-nitrobenzenesulfonyl chloride as a main raw material and acetonitrile as a solvent through ammonia water amination at room temperature; the process has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild synthesis conditions and good social and economic benefits.

Disclosure of Invention

In order to solve the problems, the invention discloses a synthetic method of an antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide, which has the advantages of simple and easily obtained raw materials, simple and convenient operation, easy control of reaction and simple post-treatment.

In order to achieve the purpose, the invention provides the following technical scheme:

a synthetic method of an antiviral drug intermediate 4-amino-3-nitrobenzenesulfonamide is characterized by comprising the following steps:

(1) mixing acetonitrile and 4-fluoro-3-nitrobenzenesulfonyl chloride, cooling to 10 ℃ in an ice water bath, then dropwise adding ammonia water, keeping the temperature at 30 DEG C

Reacting for 4-8h to obtain a reaction solution;

(2) adding dichloromethane into the reaction liquid in the step (1), stirring for 30-60min, standing for layering, collecting an organic layer, concentrating under reduced pressure at 40-50 ℃ to obtain a crude product, and pulping the crude product with ethanol to obtain 4-amino-3-nitrobenzenesulfonamide;

further, the mass ratio of the acetonitrile to the 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 3-5: 1.

Further, the concentration of the ammonia water in the step (1) is 28%, and the mass ratio of the ammonia water to the 4-fluoro-3-nitrobenzenesulfonyl chloride is 2-2.2: 1.

Further, the mass ratio of the dichloromethane in the step (2) to the 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 3-5: 1.

Further, the mass ratio of the ethanol in the step (2) to the 4-fluoro-3-nitrobenzenesulfonyl chloride in the step (1) is 0.5-1: 1.

Compared with the prior art, the invention has the following advantages and beneficial effects:

the method takes 4-fluoro-3-nitrobenzene sulfonyl chloride as a main raw material and acetonitrile as a solvent, and synthesizes a target product, namely 4-amino-3-nitrobenzene sulfonamide through ammonia water amination in a one-step method under a room temperature environment; the 4-fluoro-3-nitrobenzenesulfonyl chloride is aminated by ammonia water at low temperature to obtain a target product; the process has the advantages of simple and easily obtained raw materials, easily controlled reaction, simple and convenient operation, mild synthesis conditions, simple post-treatment and good social and economic benefits.

Detailed Description

The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.

Example 1

2kg of acetonitrile and 240g of 4-fluoro-3-nitrobenzenesulfonyl chloride are sequentially added into a 5L reaction bottle, and the temperature is reduced to 10 ℃ in an ice water bath. And (3) taking 500g of 28% ammonia water, slowly dropwise adding the ammonia water into the reaction solution, and keeping the temperature below 30 ℃. After dripping, keeping the temperature for reaction for 4 hours; adding 2kg of dichloromethane into the reaction solution, and stirring for 30 min; separating liquid and collecting an organic layer; concentrating the organic phase at 40-50 deg.C under reduced pressure to obtain crude product; the crude product is pulped by 150g of ethanol to obtain 190g of product, the yield is 87.5 percent, and the purity is 98 percent.

Example 2

40kg of acetonitrile and 9.6kg of 4-fluoro-3-nitrobenzenesulfonyl chloride are sequentially added into a 100L reaction kettle, and the temperature is reduced to 10 ℃ in an ice water bath. 20kg of 28% ammonia water is slowly dripped into the reaction solution, and the temperature is kept below 30 ℃. After dripping, keeping the temperature and reacting for 8 hours; adding 40kg of dichloromethane into the reaction solution, and stirring for 1 h; separating liquid and collecting an organic layer; concentrating the organic phase at 40-50 deg.C under reduced pressure to obtain crude product; the crude product is pulped by 6kg of ethanol to obtain 7.96kg of product, the yield is 91.47 percent, and the purity is 98 percent.

The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.