阅读说明：本技术 一种对乙酰氨基苯磺酰氯的制备方法 (Preparation method of p-acetamidobenzenesulfonyl chloride ) 是由 张金生 熊倩 蔡中文 廖德洁 于 2021-07-09 设计创作，主要内容包括：本发明提供了一种对乙酰氨基苯磺酰氯的制备方法。该方法以乙酰苯胺和氯磺酸为原料在催化剂存在下经磺化反应制得对乙酰氨基苯磺酸,再与氯代试剂进行氯化反应得到对乙酰氨基苯磺酰氯产品。本发明工艺简单,对设备无特殊要求,操作简便,三废较少,产品质量好,适于工业化生产。(The invention provides a preparation method of p-acetamido-benzenesulfonyl chloride. The method takes acetanilide and chlorosulfonic acid as raw materials to prepare p-acetamidobenzene sulfonic acid through sulfonation reaction in the presence of a catalyst, and then the p-acetamidobenzene sulfonic acid is subjected to chlorination reaction with a chlorination reagent to obtain a p-acetamidobenzene sulfonyl chloride product. The invention has simple process, no special requirement on equipment, simple and convenient operation, less three wastes and good product quality, and is suitable for industrial production.)

1. A preparation method of p-acetamido benzene sulfonyl chloride formula I is characterized in that acetanilide formula IV and chlorosulfonic acid type V are subjected to sulfonation reaction in the presence of a catalyst to prepare p-acetamido benzene sulfonic acid type II, and then the p-acetamido benzene sulfonyl chloride formula I is obtained by chlorination reaction with a chlorinated reagent formula III; the reaction formula is as follows:

2. the method of claim 1, wherein: the molar ratio of the acetanilide formula IV to the chlorosulfonic acid type V in the sulfonation reaction is 1: (1.0-1.1).

3. The method of claim 1, wherein: the catalyst for sulfonation reaction is ammonium sulfate or ammonium chloride.

4. The method of claim 1, wherein: the chlorinated reagent formula III adopts phosgene or bis (trichloromethyl) carbonate.

5. The method according to claims 1 and 4, characterized in that: the mol ratio of the p-acetamido benzene sulfonic acid II to the chloro reagent formula III carbonyl chloride in the chlorination reaction is 1: (1.0-2.0).

6. The method according to claims 1 and 4, characterized in that: the molar ratio of the p-acetamido benzene sulfonic acid II to the chloro reagent formula III bis (trichloromethyl) carbonate in the chlorination reaction is 1: (0.34-0.8).

7. The method of claim 1, wherein: the catalyst for the chlorination reaction is N, N-dimethylformamide or N, N-dimethylacetamide.

8. The method of claim 1, wherein: the reaction temperature of the chlorination reaction is 40-60 ℃.

Technical Field

The invention belongs to the technical field of preparation of intermediates of sulfonamides antibacterial drugs, and particularly relates to a preparation method of p-acetamidobenzenesulfonyl chloride.

Background

The p-acetamido-benzenesulfonyl chloride belongs to a key intermediate of sulfonamide antibacterial drugs, can also be used as an intermediate of disperse dyes, and has wide application. P-acetamidobenzenesulfonyl chloride, chemical name: 4-acetamidobenzenesulfonyl chloride, english name: N-Acetylsulfenilyl chloride with CAS registry number: 121-60-8, and the chemical structural formula is as follows:

the production of P-acetamidobenzenesulfonyl chloride currently adopts the traditional process (see the national pharmaceutical administration. national raw material medicine process compilation, P149-150): acetanilide and chlorosulfonic acid are subjected to sulfonation reaction to prepare p-acetaminophenylsulfonic acid, and the p-acetaminophenylsulfonic acid chloride is continuously subjected to chlorination reaction with excessive chlorosulfonic acid to obtain p-acetaminophenylsulfonyl chloride, wherein the main reaction formula is as follows:

the process has the following disadvantages: 1) in the chlorosulfonation reaction, because the sulfonation reagent and the chlorination reagent are chlorosulfonic acid, but the chlorination property of the chlorosulfonic acid is poor, the product yield is low, in order to obtain better economic yield, the chlorosulfonic acid far higher than the theoretical dosage needs to be adopted, so the dosage of the chlorosulfonic acid reaches more than 6 moles, the theoretical dosage only needs 2 moles, and more than 4 moles of chlorosulfonic acid raw materials do not participate in the reaction, therefore, in the post-treatment process, a large amount of sulfuric acid and hydrochloric acid can be generated, a large amount of high-concentration acid wastewater is formed, and more than ten tons of waste acid water are generated when one ton of sulfanilamide is produced according to calculation, so the method is difficult to treat, has serious environmental pollution, and directly influences the economic benefit of enterprises; 2) because the dosage of chlorosulfonic acid is greatly excessive, a small part of chlorosulfonic acid is also chlorinated at the meta position of a benzene ring in the chlorosulfonation reaction process to form meta-chlorine impurities, and the impurities are difficult to remove in subsequent reaction, refining and other processes, so that a final product still has large residues, and HPLC (high performance liquid chromatography) detection usually exceeds 0.2 percent, even exceeds 1.0 percent.

Recently, some researchers have made some improvements on the traditional process, such as taking thionyl chloride as a chlorination reagent or adding phosphorus pentachloride in the chlorination reaction process, but the dosage of the chlorination reagent is still large, and the product yield is low. The impurity content of the product is high, and the waste acid liquor is not reduced fundamentally.

Therefore, the development of a new synthesis process route of p-acetamido-benzenesulfonyl chloride with high quality, high yield, low three wastes and low cost is very necessary.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for preparing p-acetamido-benzenesulfonyl chloride, which solves the defects of quality problem, process yield, three-waste treatment, high cost and the like.

1. A preparation method of p-acetamido benzene sulfonyl chloride formula I is characterized in that acetanilide formula IV and chlorosulfonic acid type V are subjected to sulfonation reaction in the presence of a catalyst to prepare p-acetamido benzene sulfonic acid type II, and then the p-acetamido benzene sulfonyl chloride formula I is obtained by chlorination reaction with a chlorinated reagent formula III; the reaction formula is as follows:

2. the method of claim 1, wherein: the molar ratio of the acetanilide formula IV to the chlorosulfonic acid type V in the sulfonation reaction is 1: (1.0-1.1).

3. The method of claim 1, wherein: the catalyst for the sulfonation reaction is ammonium sulfate or ammonium sulfate.

4. The method of claim 1, wherein: the chlorinated reagent formula III adopts phosgene (phosgene for short) or bis (trichloromethyl) carbonate (triphosgene for short).

5. The method according to claims 1 and 4, characterized in that: in the chlorination reaction, the molar ratio of the p-acetamido benzene sulfonic acid II to the chloro reagent formula III carbonyl chloride (phosgene for short) is 1: (1.0-2.0).

6. The method according to claims 1 and 4, characterized in that: in the chlorination reaction, the molar ratio of the p-acetamido benzene sulfonic acid II to the chloro reagent III bis (trichloromethyl) carbonate (triphosgene) is 1: (0.34-0.8).

7. The method of claim 1, wherein: the catalyst of the chlorination reaction is N, N-dimethylformamide (DMF for short) or N, N-dimethylacetamide (DMA for short).

8. The method of claim 1, wherein: the reaction temperature of the chlorination reaction is 40-60 ℃.

The invention has the following advantages:

1. compared with the prior art, the p-acetamido-benzenesulfonyl chloride prepared by the preparation method has high yield, and the molar yield can reach 88.0-95.0%.

2. The p-acetamido-benzenesulfonyl chloride prepared by the preparation method reduces the generation of m-chlorine impurities because no large excess chlorosulfonic acid is used, and the final product contains few m-chlorine impurities, and meanwhile, the purity of the product is over 99.0 percent, and other impurities are less than 0.1 percent.

3. Compared with the method in the prior art, the preparation method of the invention avoids the generation of a large amount of waste acid water because the dosage of chlorosulfonic acid is the theoretical dosage, and the water content of the waste acid is less than 10 percent of the original process, thereby fundamentally solving the problem of environmental protection treatment from the source.

4. Compared with the method in the prior art, the chlorinated reagent is replaced by phosgene or bis (trichloromethyl) carbonate from the original chlorosulfonic acid, only hydrogen chloride gas and carbon dioxide gas are generated in the reaction, the hydrogen chloride gas can be absorbed by water to prepare hydrochloric acid, and the carbon dioxide can be directly discharged, so that the method is relatively easy in environmental protection treatment, and the pressure of the environmental protection treatment is greatly reduced.

5. Compared with the method in the prior art, the preparation method has simple process operation, has no special requirements on production equipment, reduces the corrosion degree of the equipment, and is suitable for industrial production.

The raw material acetanilide used in the invention is easy to obtain, and can also be prepared by a method disclosed by the prior literature (written by fan Nengyan. organic synthesis case P183), and the specific process is as follows: the method is characterized in that aniline is used as a raw material and is subjected to acetylation reaction with acetic anhydride to obtain acetanilide, and the reaction formula is as follows:

the raw material chlorosulfonic acid used in the invention is easy to obtain, and the chloro reagent phosgene (short for phosgene) or bis (trichloromethyl) carbonate (short for triphosgene) used in the invention is also easy to purchase.

The preparation process of the present invention is further illustrated and explained by the examples, but the scope of the present invention is not limited thereto.

Detailed Description

EXAMPLE 1 preparation of Paracetamidobenzene sulfonic acid type II

Respectively adding 62.2g (0.46mol) of acetanilide IV and 3.0g of ammonium sulfate into a reaction bottle, cooling to 0-5 ℃, adding 53.6g (0.46mol) of chlorosulfonic acid V, heating to 40-50 ℃, stirring and reacting for 2 hours, generating hydrogen chloride gas in the reaction process, cooling after the reaction is finished, filtering to obtain 98.2g of white solid p-acetamidobenzene sulfonic acid II, wherein the yield is 99.2%.

EXAMPLE 2 preparation of Paracetamidobenzene sulfonic acid type II

202.7g (1.50mol) of acetanilide IV and 6.0g of ammonium sulfate are respectively added into a reaction bottle, cooled to 0-5 ℃, added with 209.7g (1.8mol) of chlorosulfonic acid V, heated to 35-45 ℃, stirred and reacted for 2 hours, hydrogen chloride gas is generated in the reaction process, and after the reaction is finished, the mixture is cooled and filtered to obtain 319.0g of white solid p-acetamidobenzene sulfonic acid II with the yield of 98.8 percent.

EXAMPLE 3 preparation of Acetaminophenylsulfonyl chloride of formula I

Respectively adding 271.2g of dichloromethane, 90.4g (0.42mol) of p-acetamidobenzene sulfonic acid II and 3.1g of N, N-dimethylformamide (DMF for short) into a reaction bottle, dropwise adding a dichloromethane solution of carbonyl chloride (45.5 g (0.46mol) of carbonyl chloride is introduced into 45.5g of dichloromethane in advance), heating to 38-45 ℃ for reaction for 2 hours after dropwise adding, generating hydrogen chloride and carbon dioxide gas in the reaction process, cooling to 0-10 ℃, and filtering to obtain 90.8g of p-acetamidobenzene sulfonic acid chloride formula I with the yield of 92.5%.

EXAMPLE 4 preparation of Acetaminophenylsulfonyl chloride of formula I

241.4g of trichloromethane, 53.8g (0.0.25mol) of p-acetamidobenzene sulfonic acid II and 2.5g of N, N-Dimethylacetamide (DMA) are respectively added into a reaction bottle, trichloromethane solution of phosgene (37.6 g (0.38mol) of phosgene is dripped into the trichloromethane, the temperature is raised to 38-45 ℃ after the trichloromethane is dripped for reaction for 2 hours, hydrogen chloride and carbon dioxide gas are generated in the reaction process, the reaction temperature is cooled to 0-10 ℃, and the p-acetamidobenzene sulfonic acid chloride formula I is obtained by filtration, wherein the yield is 94.3%.

EXAMPLE 5 preparation of Acetaminophenylsulfonyl chloride of formula I

Separately, 29.7g (0.10mol) of bis (trichloromethyl) carbonate and 29.7g of chloroform were put into a reaction flask and dissolved by stirring for further use.

Adding 180.9g of trichloromethane, 60.3g (0.28mol) of p-acetamidobenzene sulfonic acid II and 1.8g of N, N-Dimethylformamide (DMF) into another reaction bottle respectively, dropwise adding a dichloromethane solution of bis (trichloromethyl) carbonate, heating to 38-45 ℃ after dropwise adding, reacting for 2 hours, generating hydrogen chloride and carbon dioxide gas in the reaction process, cooling to 0-10 ℃, and filtering to obtain 62.5g of p-acetamidobenzene sulfonic acid chloride formula I, wherein the yield is 95.5%.

EXAMPLE 6 preparation of Acetaminophenylsulfonyl chloride of formula I

89.0g (0.30mol) of bis (trichloromethyl) carbonate and 89.0g of carbon tetrachloride are respectively added into a reaction bottle and stirred to be dissolved for standby.

75.7g (0.56mol) of acetanilide IV and 3.0g of ammonium chloride are respectively added into another reaction bottle, cooled to 0-5 ℃, added with 65.3g (0.56mol) of chlorosulfonic acid III, heated to 40-50 ℃, stirred and reacted for 2 hours, hydrogen chloride gas is generated in the reaction process, and after the reaction is finished, the mixture is cooled and directly subjected to the next reaction.

Adding 262g of carbon tetrachloride and 2.0g of N, N-dimethylformamide (DMF for short) into the reaction system, dripping carbon tetrachloride solution of bis (trichloromethyl) carbonate, heating to 38-45 ℃ after dripping, reacting for 2 hours, generating hydrogen chloride and carbon dioxide gas in the reaction process, cooling to 0-10 ℃, and filtering to obtain 123.0g of p-acetamidobenzenesulfonyl chloride formula I, wherein the yield is 94.0 percent

EXAMPLE 7 preparation of Acetaminophenylsulfonyl chloride of formula I (comparative experiment)

(see the State administration of medicine, national Assembly of bulk drugs, P149-150)

40.0g (0.30mol) of acetanilide formula IV is uniformly added with 210.4g (1.81mol) of chlorosulfonic acid at the temperature of 20 ℃, after standing for 8 hours at 48 ℃, drinking water is added to decompose excessive chlorosulfonic acid at the temperature of below about 20 ℃, the temperature is not more than 28 ℃, the mixture is cooled, filtered, and a filter cake is washed until the pH value is 3-4, so that 57.8g of p-acetaminophenylsulfonyl chloride formula I is obtained, and the yield is 82.5%.

The foregoing has been a detailed description of the invention, including preferred embodiments thereof. It will be appreciated that those skilled in the art, on consideration of the present disclosure, may make modifications and/or improvements within the spirit and scope of the present invention as defined by the appended claims, which modifications and enhancements are also considered to fall within the scope of the present invention.