CN111170908B - Synthesis method of 2, 4-dimethyl-3-methylsulfonyl halogeno-benzene - Google Patents
Synthesis method of 2, 4-dimethyl-3-methylsulfonyl halogeno-benzene Download PDFInfo
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- CN111170908B CN111170908B CN202010024011.9A CN202010024011A CN111170908B CN 111170908 B CN111170908 B CN 111170908B CN 202010024011 A CN202010024011 A CN 202010024011A CN 111170908 B CN111170908 B CN 111170908B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
Abstract
The invention discloses a method for synthesizing 2, 4-dimethyl-3-methylsulfonyl halogenobenzene, which comprises the steps of firstly carrying out sulfhydrylation on 2, 6-dimethylaniline serving as a raw material in a system with tert-butyl nitrite and copper powder serving as catalysts by using dimethyldisulfide, finally carrying out oxidation by using peracetic acid, extracting reaction liquid by using dichloromethane after the reaction is finished, drying and spin-drying to obtain 2, 6-dimethylmethylsulfonyl benzene, adding a halogenating reagent into the obtained 2, 6-dimethylmethylsulfonyl benzene in a concentrated sulfuric acid system for reaction, adding water after the reaction is finished, filtering and drying to obtain the 2, 4-dimethyl-3-methylsulfonyl halogenobenzene. The raw materials are easy to obtain, the route is feasible, the operation is simple, the product purity is high, and the cost is low.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a synthetic method of 2, 4-dimethyl-3-methylsulfonyl halogenobenzene.
Background
The 2, 4-dimethyl-3-methylsulfonyl iodobenzene is a white powdery solid and is an important pesticide intermediate raw material, and the existing synthetic method of the 2, 4-dimethyl-3-methylsulfonyl halobenzene generally has the defects of complex operation process, low product purity, high cost and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for synthesizing 2, 4-dimethyl-3-methylsulfonyl halogenobenzene.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing 2, 4-dimethyl-3-methylsulfonyl halogenobenzene comprises the following steps:
s1, preparing 2, 6-dimethyl methyl mercapto benzene by using 2, 6-dimethyl aniline as a raw material:
2, 6-dimethylaniline is taken out and put into a reaction vessel, dimethyldisulfide and copper powder are added under stirring and heated; then, dropwise adding tert-butyl nitrite; monitoring by TLC, cooling the reaction solution, adding 40mL of dichloromethane, filtering, washing the filtrate with acid, dissolving flocculent copper salt in water, separating liquid to obtain an organic phase, washing the organic phase with water, drying the organic phase, and spin-drying to obtain solid 2, 6-dimethylmethylmercaptobenzene;
s2, oxidation:
taking solid 2, 6-dimethyl methylmercaptobenzene into a reaction bottle, adding dichloromethane, stirring and dissolving, dripping peroxyacetic acid aqueous solution at normal temperature, and monitoring by TLC (thin layer chromatography) until the raw materials disappear; adding dichloromethane and deionized water, separating in a separating funnel, extracting the water phase twice with dichloromethane, combining the organic phase, drying, and spin-drying to obtain solid 2, 6-dimethyl methylsulfonyl benzene;
s3, halo:
taking 2, 6-dimethylmethylsulfonylbenzene in a new reaction bottle, adding concentrated sulfuric acid, carrying out ice bath, adding a halogenating reagent for multiple times, stirring for 2 hours in ice bath, and then stirring at room temperature overnight; and monitoring by TLC, after the reaction is finished, adding deionized water into the reaction bottle, separating out a solid, and filtering to obtain a final product, namely 2, 4-dimethyl-3-methylsulfonyl iodobenzene.
Further, in step S1, the molar ratio of 2, 6-dimethylaniline to tert-butyl nitrite is 1: 2.25.
further, in step S1, the molar ratio of 2, 6-dimethylaniline to copper powder is 1: 0.75.
further, in step S1, the reaction temperature is 50 ℃ to 60 ℃, preferably 55 ℃.
Further, in step S2, the molar ratio of 2, 6-dimethylmethylmercaptobenzene to peroxyacetic acid is 1: 1.86.
further, in step S3, the molar ratio of the 2, 6-dimethylmethanesulfonylbenzene to the halogenating agent is 1: 1-1.3.
Further, in step S3, the temperature of the ice bath is-5 ℃ to 5 ℃.
The invention has the beneficial effects that: according to the method, 2, 6-dimethylaniline is used as a raw material, firstly, dimethyldisulfide is subjected to sulfhydrylation in a system with tert-butyl nitrite and copper powder as catalysts, finally, peroxyacetic acid is used for oxidation, after the reaction is finished, dichloromethane is used for extracting reaction liquid, drying and spin-drying are carried out to obtain 2, 6-dimethylmethylsulfonylbenzene, the obtained 2, 6-dimethylmethylsulfonylbenzene is added with a halogenating reagent in a concentrated sulfuric acid system for reaction, and after the reaction is finished, water is added, and filtration and drying are carried out to obtain the 2, 4-dimethyl-3-methylsulfonylbenzene halide. The raw materials are easy to obtain, the route is feasible, the operation is simple, the product purity is high, and the cost is low.
Detailed Description
The present invention will be further described below, and it should be noted that the present embodiment is based on the technical solution, and a detailed implementation manner and a specific operation process are provided, but the protection scope of the present invention is not limited to the present embodiment.
A method for synthesizing 2, 4-dimethyl-3-methylsulfonyl halogenobenzene comprises the following steps:
s1, preparing 2, 6-dimethyl methyl mercapto benzene by using 2, 6-dimethyl aniline as a raw material:
2, 6-dimethylaniline is taken out and put into a reaction vessel, dimethyldisulfide and copper powder are added under stirring and heated; then, dropwise adding tert-butyl nitrite; and monitoring by TLC (thin layer chromatography), cooling the reaction solution, adding dichloromethane, filtering, washing the filtrate with acid, dissolving flocculent copper salt in water, separating the solution to obtain an organic phase, washing the organic phase with water, drying the organic phase, and performing spin drying to obtain solid 2, 6-dimethylmethylmercaptobenzene.
The reaction equation is:
further, the molar ratio of the 2, 6-dimethylaniline to the tert-butyl nitrite is 1: 2.25;
further, the molar ratio of the 2, 6-dimethylaniline to the copper powder is 1: 0.75;
further, the molar ratio of 2, 6-dimethylaniline to dimethyldisulfide was 1: 9.04.
Further, the reaction temperature is 50 ℃ to 60 ℃, preferably 55 ℃.
Specifically, in this example, 1.21 g (10mmol) of 2, 6-dimethylaniline was taken in a three-necked flask, and 8mL (90.4mmol) of dimethyldisulfide and copper powder 480 were added under stirring and heated to 55 ℃; 1.545 g (15mmol) of tert-butyl nitrite is added dropwise, and the raw material is monitored to be remained in the reaction process, so 0.75 g (7.28mmol) of tert-butyl nitrite is added, and 2.259 g (22.5mmol) of tert-butyl nitrite is shared in the total process; and monitoring by TLC, cooling the reaction liquid, adding 40mL of dichloromethane, filtering, washing the filtrate with acid, dissolving flocculent copper salt in water, separating liquid to obtain an organic phase, washing the organic phase with water, drying the organic phase, and performing spin drying to obtain solid 2, 6-dimethylmethylmercaptobenzene with the yield of 57.3%.
S2, oxidation:
taking solid 2, 6-dimethyl methylmercaptobenzene into a reaction bottle, adding dichloromethane, stirring and dissolving, dripping peroxyacetic acid aqueous solution at normal temperature, and monitoring by TLC (thin layer chromatography) until the raw materials disappear; adding dichloromethane and deionized water, separating in a separating funnel, extracting the water phase twice with dichloromethane, combining the organic phase, drying and spin-drying to obtain solid 2, 6-dimethyl methylsulfonyl benzene.
The reaction equation is:
further, the molar ratio of the 2, 6-dimethyl methylmercaptobenzene to the peroxyacetic acid is 1: 1.86 of the total weight of the product;
further, the preparation process of the peroxyacetic acid comprises the following steps: adding 125 g of 30% hydrogen peroxide into 1-2 ml of concentrated sulfuric acid, stirring at normal temperature, dropwise adding 75 g of glacial acetic acid, and stirring for 12 hours.
In this example, specifically, 3.6836 g (20mmol) of solid 2, 6-dimethylmethylmercaptobenzene was put into a single-neck flask, 10mL of dichloromethane was added and stirred to dissolve, 2mol/L aqueous peroxyacetic acid solution was added dropwise at normal temperature, and TLC monitoring was carried out until the starting material disappeared, and the amount of the aqueous peroxyacetic acid solution was 18.6 mL; adding 20mL of dichloromethane and 10mL of deionized water, separating in a separating funnel, extracting the aqueous phase twice by using 10mL of dichloromethane, combining the organic phase, drying and spin-drying to obtain solid 2, 6-dimethyl methylsulfonylbenzene. The yield thereof was found to be 86.5%.
S3, halo:
taking 2, 6-dimethylmethylsulfonylbenzene in a new reaction bottle, adding concentrated sulfuric acid, carrying out ice bath, adding a halogenating reagent for multiple times, stirring for 2 hours in ice bath, and then stirring at room temperature overnight; and monitoring by TLC, after the reaction is finished, adding deionized water into the reaction bottle, separating out a solid, and filtering to obtain a final product, namely 2, 4-dimethyl-3-methylsulfonyl iodobenzene.
Further, the molar ratio of the 2, 6-dimethylmethanesulfonylbenzene to the halogenating agent is 1: 1-1.3, preferably 1: 1.2, 1:1.1 and 1: 1;
further, the temperature of the ice bath is-5 ℃ to 5 ℃.
Specifically, in this example, 1.84 g (10mmol) of 2, 6-dimethylmethylsulfonylbenzene was put into a single-neck bottle, 20mL of concentrated sulfuric acid was added, the mixture was cooled to 5 ℃ or below in ice, 2.25 g (10mmol) of NIS was added in small amounts, the mixture was stirred for 2 hours in ice bath, and then the mixture was stirred at room temperature overnight; and monitoring by TLC, after the reaction is finished, adding 20mL of deionized water into a reaction bottle, separating out a solid, and filtering to obtain a final product, namely 2, 4-dimethyl-3-methylsulfonyl iodobenzene. The yield was 81.6%.
Further, the molar ratio of the 2, 6-dimethylmethanesulfonylbenzene to the NIS may be further selected to be 1: 1-1.3, more preferably 1: 1.2, 1:1.1 and 1:1.
Various corresponding changes and modifications can be made by those skilled in the art based on the above technical solutions and concepts, and all such changes and modifications should be included in the protection scope of the present invention.
Claims (8)
1. A method for synthesizing 2, 4-dimethyl-3-methylsulfonyl halogenobenzene is characterized by comprising the following steps:
s1, preparing 2, 6-dimethyl methyl mercapto benzene by using 2, 6-dimethyl aniline as a raw material:
2, 6-dimethylaniline is taken out and put into a reaction vessel, dimethyldisulfide and copper powder are added under stirring and heated; then, dropwise adding tert-butyl nitrite; monitoring by TLC, cooling the reaction solution, adding 40ml of dichloromethane, filtering, washing the filtrate with acid, dissolving flocculent copper salt in water, separating liquid to obtain an organic phase, washing the organic phase with water, drying the organic phase, and spin-drying to obtain solid 2, 6-dimethylmethylmercaptobenzene;
s2, oxidation:
taking solid 2, 6-dimethyl methylmercaptobenzene into a reaction bottle, adding dichloromethane, stirring and dissolving, dripping peroxyacetic acid aqueous solution at normal temperature, and monitoring by TLC (thin layer chromatography) until the raw materials disappear; adding dichloromethane and deionized water, separating in a separating funnel, extracting the water phase twice with dichloromethane, combining the organic phases, drying, and spin-drying to obtain solid 2, 6-dimethylmethylsulfonylbenzene;
s3, halo:
taking 2, 6-dimethylmethylsulfonylbenzene in a new reaction bottle, adding concentrated sulfuric acid, carrying out ice bath, adding a halogenating reagent for multiple times, stirring for 2 hours in ice bath, and then stirring at room temperature overnight; and monitoring by TLC, after the reaction is finished, adding deionized water into the reaction bottle, separating out a solid, and filtering to obtain a final product, namely 2, 4-dimethyl-3-methylsulfonyl iodobenzene.
2. The method of claim 1, wherein in step S1, the molar ratio of 2, 6-dimethylaniline to tert-butyl nitrite is 1: 2.25.
3. the method of claim 1, wherein in step S1, the molar ratio of 2, 6-dimethylaniline to copper powder is 1: 0.75.
4. the method of claim 1, wherein the reaction temperature is 50-60 ℃ in step S1.
5. The method of claim 4, wherein the reaction temperature in step S1 is 55 ℃.
6. The method of claim 1, wherein in step S2, the molar ratio of 2, 6-dimethylmethylmercaptobenzene to peroxyacetic acid is 1: 1.86.
7. the method of claim 1, wherein in step S3, the molar ratio of the 2, 6-dimethylmethanesulfonylbenzene to the halogenating agent is 1: 1-1.3.
8. The method of claim 1, wherein the temperature of the ice bath is-5 ℃ to 5 ℃ in step S3.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5189224A (en) * | 1990-10-19 | 1993-02-23 | Nissan Chemical Industries Ltd. | Method for preparing 4-alkylsulfonyl-2-chloro-m-xylene |
| CN1443156A (en) * | 2000-07-17 | 2003-09-17 | 巴斯福股份公司 | Preparation of 4-thioalkylbromobenzene derivatives |
| CN104086466A (en) * | 2014-07-03 | 2014-10-08 | 倍合德华强(连云港)医药化工科技有限公司 | Preparation method of 2-chloro-4-methylsulfonylbenzoic acid |
| CN104169286A (en) * | 2012-03-06 | 2014-11-26 | 辉瑞大药厂 | Macrocyclic derivatives for the treatment of proliferative diseases |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5189224A (en) * | 1990-10-19 | 1993-02-23 | Nissan Chemical Industries Ltd. | Method for preparing 4-alkylsulfonyl-2-chloro-m-xylene |
| CN1443156A (en) * | 2000-07-17 | 2003-09-17 | 巴斯福股份公司 | Preparation of 4-thioalkylbromobenzene derivatives |
| CN104169286A (en) * | 2012-03-06 | 2014-11-26 | 辉瑞大药厂 | Macrocyclic derivatives for the treatment of proliferative diseases |
| CN104086466A (en) * | 2014-07-03 | 2014-10-08 | 倍合德华强(连云港)医药化工科技有限公司 | Preparation method of 2-chloro-4-methylsulfonylbenzoic acid |
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