CN109320472B - Preparation method of 3, 4-dichloro 5-cyanoisothiazole - Google Patents

Abstract

The invention provides a preparation method of 3, 4-dichloro-5-cyanoisothiazole, which takes a low-toxicity ferricyanide complex as an initial raw material to react with carbon disulfide and chlorine under the catalysis of a catalyst, and the purity of the obtained product can reach 98%. The invention avoids using virulent sodium cyanide, improves the safety of industrial production, and has the raw materials of conventional compounds and low price. The process is simple and suitable for large-scale production.

Description

Preparation method of 3, 4-dichloro 5-cyanoisothiazole

Technical Field

The invention belongs to the field of preparation of medicine and pesticide intermediates, and particularly relates to a preparation method of 3, 4-dichloro-5-cyanoisothiazole.

Background

Isotianil (Isotianil) is the first resistance-inducing fungicide used to control rice blast. 3, 4-dichloro-5-cyanoisothiazole is an important intermediate for the preparation of isotianil. German Bayer company DE2231097 (1972) used trichloroacetonitrile and sulfur to synthesize 3, 4-dichloro-5-cyanoisothiazole. In the same year, Bayer's DE2231098 patent uses a synthesis process in which dichlorofumaronitrile or tetrachlorosuccinonitrile is reacted with sulfur. Both of these patents have expired and used specific raw materials trichloroacetonitrile, dichlorofumaronitrile and tetrachlorosuccinonitrile. Later on in the Bayer application, DE102005031348, another process was disclosed for the preparation of 3, 4-dichloro-5-cyanoisothiazole from the more basic starting materials sodium cyanide, carbon disulfide and chlorine, by further hydrolysis under the action of sodium hydroxide to give 3, 4-dichloroisothiazole-5-carboxylic acid. The reaction formula is as follows:

the Hubei Chengyu pharmaceutical Co., Ltd patent CN102030718B optimizes the process based on the synthesis route of Bayer patent, and the process reduces the generation of impurities, improves the purity of the finished product, and reduces the amount of wastewater. The sodium cyanide process used above requires the use of a highly toxic raw material sodium cyanide. "Zhongmurazu, Xiu-kuan, and Aoshangshansu" of Nippon Ministry chemical industries, incorporated by Zhao chemical industries, 2017, in patent families WO2010126170, JP2010260805, WO2014054294 and WO2015151491 disclose a process for preparing a liquid crystal composition by reacting succinonitrile or its chloride, fumaronitrile or its chloride, maleonitrile or its chloride, or a mixture thereof with sulfur, or sulfur and chlorine, or disulfur dichloride in an aprotic polar solvent or without a solvent. The raw materials succinonitrile, fumaronitrile and maleonitrile and their chlorides used in the above fomentation process are still expensive. Andreas s.kalogirou et al (RSC Advances, 2014, 7735) synthesize substituted 1,2, 3-dithioazoles, and then react to synthesize isothiazole compounds. The reaction steps are long and the raw material sources are difficult.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a method for preparing 3, 4-dichloro-5-cyanoisothiazole, which has the advantages of low cost, safe raw materials and simple process.

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

a preparation method of 3, 4-dichloro-5-cyanoisothiazole is characterized in that a ferricyanide complex is used as an initial raw material and reacts with carbon disulfide and chlorine gas under the catalysis of a catalyst to prepare the 3, 4-dichloro-5-cyanoisothiazole.

In the above preparation method, the ferricyanide complex comprises ferricyanide complex and its aqueous compound, and is selected from one or more of potassium ferricyanide, sodium ferricyanide, potassium ferrocyanide and sodium ferrocyanide. Sodium ferrocyanide is preferred.

In the preparation method, the catalyst is one or more of copper salt, palladium salt and carbonate. Preferably, the copper salt is Cu (OAc)₂CuI, or Cu (BF)₄)₂The palladium salt is PdCl₂Or Pd (OAc)₂The carbonate is potassium carbonate or sodium carbonate.

In the preparation method, the molar amount of the catalyst is 0.1-10%, and more preferably 1-5% of the iron cyanide complex.

The preparation method specifically comprises the following steps:

(1) suspending the iron cyanide complex and the catalyst in an aprotic polar solvent, dropwise adding carbon disulfide under the cooling of a water bath, controlling the temperature to be 20-30 ℃, stirring for 1 hour, heating to 40-140 ℃, and continuing to react for 5-70 hours;

(2) the reaction chlorine is introduced into the reaction in two portions: cooling the reaction solution, introducing part of the chlorine gas with the reaction amount at the temperature of 20-30 ℃, stirring for 1 hour at the temperature of 40-100 ℃, and then introducing the rest of the chlorine gas with the reaction amount again;

(3) and after the chlorine is introduced, continuously reacting for 2-3 hours at the temperature of 60-120 ℃ to obtain the 3, 4-dichloro-5-cyanoisothiazole.

In the preparation method, the aprotic polar solvent in the step (1) is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and hexamethylphosphoric triamide.

The step (1) is preferably carried out by heating to the temperature of 50-120 ℃ for 7-50 hours, and more preferably heating to the temperature of 60-110 ℃ for reaction for 10-25 hours.

In the above preparation method, the step (3) is followed by a step of separating and purifying the product.

One specific example of operation is as follows:

nitrogen was introduced to drive off excess chlorine. Recovering solvent from the reaction solution by reduced pressure distillation, extracting the residue with ethyl acetate, refluxing, cooling, filtering, recovering extractant from the obtained filtrate by reduced pressure, cooling, and crystallizing to obtain the product. And adding water into the mother liquor after crystallization for steam distillation, cooling the distillate for crystallization, and filtering to obtain the rest part of the product. The purity of all products reaches more than 98 percent.

The invention has the beneficial effects that: compared with the prior art, the invention has the following advantages:

1. the iron cyanide complex with low price and high safety is selected as the starting raw material, so that the use of virulent sodium cyanide is avoided, and the safety of industrial production is improved;

2. the invention uses catalyst to improve the reaction efficiency, the yield reaches 50-60%, and the product purity is more than 98%.

3. The raw materials are all conventional compounds, and the price is low;

4. the process is simple and suitable for large-scale production.

Detailed Description

The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

Example 1

Adding 250ml of dimethylformamide into a 500ml reaction bottle, adding 30.4g (100mmol) of sodium ferrocyanide and 0.2g (1mmol) of CuI under stirring, cooling in a water bath, dropwise adding 48.0g (630mmol) of carbon disulfide, and controlling the temperature to be 20-30 ℃. After stirring at room temperature for 1 hour, the reaction was continued for 15 hours while warming to 110 ℃. Then cooling to 20 ℃, introducing part of chlorine at the temperature of 20-30 ℃, stirring for 1 hour at 50 ℃, and introducing the rest part of chlorine. And after the chlorine is introduced, continuously reacting for 2-3 hours at 60 ℃. Nitrogen was introduced to drive off excess chlorine. And distilling under reduced pressure to recover about 220g of dimethylformamide, refluxing and extracting the residue with 200g of ethyl acetate, cooling the extracting solution, filtering, removing filter residues, recovering ethyl acetate from the filtrate under reduced pressure to dryness, cooling, crystallizing, filtering and airing to obtain 23g of brown solid. And adding water into the mother liquor after crystallization for steam distillation until no product is brought out, cooling the distillate, performing suction filtration, and drying to obtain 4g of white solid, wherein the total amount of the product is 27g, the yield is 50.3%, and the purity of all the products is more than 98%.

Example 2

Into a 500ml reaction flask was charged 250ml of dimethylformamide, and 36.85g (100mmol) of potassium ferrocyanide and Cu (BF) were added with stirring₄)₂0.5g (2.1mmol), cooling in water bath, dropping 48.0g (630mmol) of carbon disulfide, and controlling the temperature at 20-30 ℃. After stirring at room temperature for 1 hour, the reaction was continued for 20 hours while warming to 90 ℃. Then cooling to 20 ℃, introducing part of chlorine at the temperature of 20-30 ℃, stirring for 1 hour at 50 ℃, and introducing the rest part of chlorine. And after the chlorine is introduced, continuously reacting for 2-3 hours at 75 ℃. Nitrogen was introduced to drive off excess chlorine. And distilling under reduced pressure to recover about 220g of dimethylformamide, refluxing and extracting the residue with 200g of ethyl acetate, cooling the extracting solution, filtering, removing filter residues, recovering ethyl acetate from the filtrate under reduced pressure to dryness, cooling, crystallizing, filtering and airing to obtain 25g of brown solid. And adding water into the mother liquor after crystallization for steam distillation until no product is brought out, cooling the distillate, performing suction filtration, and drying to obtain 4g of white solid, wherein the total amount of the product is 29g, the yield is 54.0%, and the purity of all the products is more than 98%.

Example 3

Into a 500ml reaction flask was added 250ml of dimethylformamide, and 36.85g (100mmol) of potassium ferrocyanide and PdCl were added with stirring₂0.3g (1.7mmol), cooling in water bath, dropping 48.0g (630mmol) of carbon disulfide, and controlling the temperature at 20-30 ℃. After stirring at room temperature for 1 hour, the reaction was continued for 20 hours while the temperature was raised to 100 ℃. Then cooling to 20 ℃, introducing part of chlorine at the temperature of 20-30 ℃, stirring for 1 hour at 50 ℃, and introducing the rest part of chlorine. And after the chlorine is introduced, continuously reacting for 2-3 hours at 85 ℃. Nitrogen was introduced to drive off excess chlorine. And distilling under reduced pressure to recover about 220g of dimethylformamide, refluxing and extracting the residue with 200g of ethyl acetate, cooling the extracting solution, filtering, removing filter residues, recovering ethyl acetate from the filtrate under reduced pressure to dryness, cooling, crystallizing, filtering and airing to obtain 26g of brown solid. And adding water into the mother liquor after crystallization for steam distillation until no product is brought out, cooling the distillate, performing suction filtration, and drying to obtain 4g of white solid, wherein the total amount of the product is 30g, the yield is 55.9%, and the purity of all the products is more than 98%.

Comparative examples

Adding 250ml of dimethylformamide into a 500ml reaction bottle, adding 30.4g (100mmol) of sodium ferrocyanide while stirring, cooling in a water bath, dropwise adding 48.0g (630mmol) of carbon disulfide, and controlling the temperature to be 20-30 ℃. After stirring at room temperature for 1 hour, the reaction was continued for 15 hours while warming to 110 ℃. Then cooling to 20 ℃, introducing part of chlorine at the temperature of 20-30 ℃, stirring for 1 hour at 50 ℃, and introducing the rest part of chlorine. And after the chlorine is introduced, continuously reacting for 2-3 hours at 60 ℃. Nitrogen was introduced to drive off excess chlorine. And distilling under reduced pressure to recover about 220g of dimethylformamide, refluxing and extracting the residue with 200g of ethyl acetate, cooling the extracting solution, filtering, removing filter residues, recovering ethyl acetate from the filtrate under reduced pressure to dryness, cooling, crystallizing, filtering and airing to obtain 11g of brown solid. And adding water into the mother liquor after crystallization for steam distillation until no product is brought out, cooling the distillate, performing suction filtration, and drying to obtain 3g of white solid, wherein the total amount of the product is 14g, the yield is 26.1%, and the purity of all the products is more than 98%. It can be seen that under the condition of lacking catalyst, the product yield is obviously reduced, and the requirement of industrial production is not met.

Claims (6)

1. A preparation method of 3, 4-dichloro-5-cyanoisothiazole is characterized in that a ferricyanide complex is used as an initial raw material and reacts with carbon disulfide and chlorine gas under the catalysis of a catalyst to prepare the 3, 4-dichloro-5-cyanoisothiazole, the ferricyanide complex is sodium ferrocyanide and/or potassium ferrocyanide, and the catalyst is CuI and Cu (BF)₄)₂、PdCl₂One or more of them.

2. The method of claim 1, wherein the molar amount of the catalyst is 0.1% to 10% of the iron cyanide complex.

3. The preparation method of claim 2, wherein the molar amount of the catalyst is 1% to 5% of the ferricyanide complex.

4. The method according to any one of claims 1 to 3, comprising in particular the steps of:

(1) suspending the iron cyanide complex and a catalyst in an aprotic polar solvent, dropwise adding carbon disulfide under the cooling of a water bath, controlling the temperature to be 20-30 ℃, stirring for 1 hour, heating to 40-140 ℃, and continuing to react for 5-70 hours;

(2) the reaction chlorine is introduced into the reaction in two portions: cooling the reaction solution, introducing part of the chlorine gas with the reaction amount at the temperature of 20-30 ℃, stirring at the temperature of 40-100 ℃ for 1 hour, and then introducing the rest of the chlorine gas with the reaction amount again;

(3) and after the chlorine is introduced, continuously reacting for 2-3 hours at the temperature of 60-120 ℃ to obtain the 3, 4-dichloro-5-cyanoisothiazole.

5. The preparation method according to claim 4, wherein the temperature in the step (1) is raised to 60 ℃ to 110 ℃ for reaction for 10 hours to 25 hours.

6. The method according to claim 4, wherein the step (3) is followed by a step of separating and purifying the product.