阅读说明：本技术 一种制备2-氨基-5-取代-1,3,4-噻二唑的方法 (Method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole ) 是由 刘玉婷 李洁 尹大伟 孙嘉希 于 2019-10-24 设计创作，主要内容包括：一种制备2-氨基-5-取代-1,3,4-噻二唑的方法。向反应容器中加入配方量的氯化胆碱和尿素,于80℃下搅拌得无色透明溶液即低共熔溶剂DES；冷至室温,然后加入配方量的羧酸及硫代氨基脲,缓慢升温,于80℃反应,TLC监测至反应结束；将反应混合液冷至室温,然后在冰浴冷却下向混合液中加入氨水调pH值为8～9,析出固体,抽滤,滤饼用冰水洗涤,干燥,即得2-氨基-5-取代-1,3,4-噻二唑。滤液回收得低共熔溶剂,可以重复使用。本发明方法操作简单、后处理简单、反应时间短、效率高、催化剂可回收利用、绿色环保、降低了成本、无需有机溶剂,是一种高效合成2-氨基-5-取代-1,3,4-噻二唑的方法。(A method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole. Adding choline chloride and urea in a formula amount into a reaction container, and stirring at 80 ℃ to obtain a colorless transparent solution, namely a eutectic solvent DES; cooling to room temperature, adding the carboxylic acid and the thiosemicarbazide according to the formula ratio, slowly heating, reacting at 80 ℃, and monitoring by TLC until the reaction is finished; and cooling the reaction mixed solution to room temperature, adding ammonia water into the mixed solution under ice-bath cooling to adjust the pH value to 8-9, separating out a solid, performing suction filtration, washing a filter cake with ice water, and drying to obtain the 2-amino-5-substituted-1, 3, 4-thiadiazole. The eutectic solvent is recovered from the filtrate and can be reused. The method has the advantages of simple operation, simple post-treatment, short reaction time, high efficiency, recyclable catalyst, environmental protection, reduced cost and no need of organic solvent, and is a method for efficiently synthesizing the 2-amino-5-substituted-1, 3, 4-thiadiazole.)

1. A method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole is characterized by comprising the following steps:

carboxylic acid and thiosemicarbazide react in choline chloride-urea eutectic solvent to obtain 2-amino-5-substituted-1, 3, 4-thiadiazole.

2. The method of claim 1, wherein the choline chloride has the formula:

3. the method of claim 1, wherein the carboxylic acid is a carboxylic acid comprising C₂～C₁₀Fatty acids of (A), phenoxyacetic acid, o-chlorophenoxyacetic acid, m-chlorophenoxyacetic acid, p-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, p-iodophenoxyacetic acid, p-bromophenoxyacetic acid, p-fluorophenoxyacetic acid, 2-nitrophenoxyacetic acid, p-methoxyphenoxyacetic acid, α -naphthyloxyacetic acid, β -naphthyloxyacetic acid, m-methylbenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, o-methoxybenzoic acid, m-methoxybenzoic acid, p-aminobenzoic acid, o-aminobenzoic acid, m-aminobenzoic acid, 2-fluorobenzoic acid, 2, 4-dichlorobenzoic acid, o-chlorobenzoic acid, 3, 5-dinitrobenzoic acid, p-chlorobenzoic acid, p-bromobenzoic acid, m-bromobenzoic acid, p-nitrobenzoic acid, isonicotinic acidBenzoic acid.

4. The method of claim 1, wherein the ratio of carboxylic acid: the mol ratio of the thiosemicarbazide is 1: 1.1-1.5.

5. The method as claimed in claim 1, wherein the choline chloride and the urea are dissolved by heating in a molar ratio of 1: 1-4 to obtain the choline chloride-urea eutectic solvent.

6. The method of claim 1, comprising the steps of:

1) choline chloride Amol and urea Bmol with the formula amount are added into a reaction vessel, and are stirred at the temperature of 80 ℃ to obtain colorless transparent solution, namely eutectic solvent;

2) cooling the reaction system to room temperature, adding carboxylic acid Cmol and thiosemicarbazide Dmol according to the formula ratio, slowly heating, reacting at 80 ℃, monitoring by TLC (thin layer chromatography) until the reaction is complete, wherein a developing agent of the TLC is a mixed solution of ethyl acetate and petroleum ether with the volume ratio of 1: 3;

3) and cooling the reaction mixed solution to room temperature, then adding ammonia water into the mixed solution under ice bath cooling to adjust the pH value to 8-9, separating out a solid, performing suction filtration, washing a filter cake with ice water, and drying to obtain the 2-amino-5-substituted-1, 3, 4-thiadiazole. Recovering the filtrate to obtain a eutectic solvent which can be repeatedly used; a: b: c: d is 1 to (1 to 4) to 1 to (1.1 to 1.5).

7. The method as claimed in claim 6, wherein the ammonia water in step 3) is a 10% ammonia water solution.

8. The 2-amino-5-substituted-1, 3, 4-thiadiazoles prepared according to the process of any one of claims 1 to 7, wherein the structural formula is:

r is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, phenoxymethylene, o-chlorophenoxymethylene, m-chlorophenoxymethylene, p-chlorophenoxymethylene, 2, 4-dichlorophenoxymethylene, p-iodophenoxymethylene, p-bromophenoxymethylene, p-fluorophenoxymethylene, 2-nitrophenoxymethylene, p-methoxyphenoxymethylene, alpha-naphthyloxymethylene, beta-naphthyloxymethylene, phenyl, m-methylphenyl, o-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-aminophenyl, o-aminophenyl, 2-fluorophenyl, 2, 4-dichlorophenyl, o-chlorophenyl, 3, 5-dinitrophenyl, p-chlorophenyl, p-bromophenyl, m-bromophenyl, p-nitrophenyl, 4-pyridyl, O-bromophenyl or p-fluorophenyl.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole.

Background

The 1,3, 4-thiadiazole compounds are five-membered heterocyclic compounds containing S, N heteroatoms, and mainly exist in the form of derivatives after the hydrogen on the 2, 5 positions is substituted. Because the active substituent groups on the 2 and 5 positions can react with a plurality of compounds, the compounds are often used as important intermediates in organic synthesis and pharmaceutical chemistry.

1,3, 4-thiadiazole compounds are widely used in the fields of medicine, agriculture, industry and the like, and particularly in the field of medicine, have antiviral, antibacterial, anxiolytic, antidepressant, stress-suppressing, blood pressure-lowering, anticancer and other activities. Conventionally, studies on the synthesis and activity of 1,3, 4-thiadiazole compounds have been attracting attention.

In 2011, the substituted benzoic acid and the thiosemicarbazide are adopted as reaction raw materials, phosphorus oxychloride is used as a catalyst, and a series of 2-amino-5-phenyl-1, 3, 4-thiadiazole derivatives are synthesized, but the phosphorus oxychloride test is high in toxicity, the reaction process is complex, the reaction time is long, and the operation is inconvenient.

Disclosure of Invention

The invention aims to provide a method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole, which has the advantages of simple operation, no need of organic solvent, short reaction time, simple post-treatment, high yield and high purity.

In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:

1) adding choline chloride (Amol) and urea (Bmol) with the formula amount into a reaction vessel, and stirring at 80 ℃ until the choline chloride (Amol) and the urea are completely dissolved to obtain a eutectic solvent;

2) cooling the reaction system to room temperature, adding carboxylic acid (Cmol) and thiosemicarbazide (Dmol) according to the formula ratio, slowly heating, reacting at 80 ℃, and monitoring by TLC until the reaction is finished;

3) and cooling the reaction mixed solution to room temperature, then adding ammonia water into the mixed solution under ice bath cooling to adjust the pH value to 8-9, separating out a solid, performing suction filtration, washing a filter cake with ice water, and drying to obtain the 2-amino-5-substituted-1, 3, 4-thiadiazole. And recovering the filtrate to obtain the eutectic solvent.

The structural formula of the choline chloride is as follows:

the structural formula of the urea is as follows:

in the step, choline chloride: urea: carboxylic acid: the mol ratio of the thiosemicarbazide is 1: 1 to 4: 1: 1.1 to 1.5

The choline chloride and the urea are stirred at the temperature of 80 ℃ until being completely dissolved to obtain the eutectic solvent which is used as both the solvent and the catalyst.

Said carboxylic acid comprising C₂～C₁₀The fatty acid, phenoxyacetic acid, o-chlorophenoxyacetic acid, m-chlorophenoxyacetic acid, p-chlorophenoxyacetic acid, 2, 4-dichlorophenoxyacetic acid, p-iodophenoxyacetic acid, p-bromophenoxyacetic acid, p-fluorophenoxyacetic acid, 2-nitrophenoxyacetic acid, p-methoxyphenoxyacetic acid, α -naphthyloxyacetic acid, β -naphthyloxyacetic acid, m-methylbenzoic acid, o-methylbenzoic acid, p-methylbenzoic acid, o-methoxybenzoic acid, m-methoxybenzoic acid, p-aminobenzoic acid, o-aminobenzoic acid, m-aminobenzoic acid, 2-fluorobenzoic acid, 2, 4-dichlorobenzoic acid, o-chlorobenzoic acid, 3, 5-dinitrobenzoic acid, p-chlorobenzoic acid, p-bromobenzoic acid, m-bromobenzoic acid, p-nitrobenzoic acid, isonicotinic acid, o-bromob.

The reflux process in the step 2) is monitored by TLC, and the complete reaction of the raw materials is indicated when the raw material point of the carboxylic acid disappears; the developing solvent of the TLC is a mixed solvent of ethyl acetate and petroleum ether with the volume ratio of 1: 3.

The ammonia water in the step 3) is 10% ammonia water solution.

The substituent of the 2-amino-5-substituted-1, 3, 4-thiadiazole comprises methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, phenoxy methylene, o-chlorophenoxymethylene, m-chlorophenoxymethylene, p-chlorophenoxymethylene, 2, 4-dichlorophenoxy methylene, p-iodophenoxy methylene, p-bromophenoxy methylene, p-fluorophenoxy methylene, 2-nitrophenoxy methylene, p-methoxyphenoxy methylene, alpha-naphthoxy methylene, beta-naphthoxy methylene, phenyl, m-methylphenyl, o-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-aminophenyl, o-aminophenyl, m-aminophenyl, 2-fluorophenyl, 2, 4-dichlorophenyl, o-chlorophenyl and 3, 5-dinitrophenyl, p-chlorophenyl, p-bromophenyl, m-bromophenyl, p-nitrophenyl, 4-pyridyl, o-bromophenyl or p-fluorophenyl.

The reaction mechanism of the invention is as follows: the eutectic solvent is obtained by stirring choline chloride and urea at 80 ℃ until the choline chloride and the urea are completely dissolved, and is used for catalyzing the reaction of carboxylic acid and thiosemicarbazide to prepare 2-amino-5-substituted-1, 3, 4-thiadiazole.

The structural formula of the 2-amino-5-substituted-1, 3, 4-thiadiazole compound is as follows:

compared with the prior art, the invention has the following advantages:

firstly, the method comprises the following steps: the method of the invention has simple operation and simple post-treatment;

secondly, the method comprises the following steps: the reaction time is short, and the efficiency is high;

thirdly, the method comprises the following steps: the catalyst can be recycled, and the cost is reduced;

fourthly: the catalyst is more green and environment-friendly;

fifth, the method comprises the following steps: no organic solvent is required.

Drawings

FIG. 1 is an infrared spectrum of 2-amino-5-methyl-1, 3, 4-thiadiazole;

FIG. 2 is an infrared spectrum of 2-amino-5- (4-pyridyl) -1,3, 4-thiadiazole;

FIG. 3 is an infrared spectrum of 2-amino-5-phenyl-1, 3, 4-thiadiazole;

FIG. 4 is an infrared spectrum of 2-amino-5-mercapto-1, 3, 4-thiadiazole;

FIG. 5 is an infrared spectrum of 2-amino-5-o-iodophenyl-1, 3, 4-thiadiazole.

Detailed Description

The invention relates to a method for preparing 2-amino-5-substituted-1, 3, 4-thiadiazole, which comprises the steps of firstly obtaining eutectic solvent by choline chloride and urea, then adding carboxylic acid and thiosemicarbazide into a reactor to prepare the 2-amino-5-substituted-1, 3, 4-thiadiazole, wherein the reaction formula is as follows:

wherein R is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, phenoxymethylene, o-chlorophenoxymethylene, m-chlorophenoxymethylene, p-chlorophenoxymethylene, 2, 4-dichlorophenoxymethylene, p-iodophenoxymethylene, p-bromophenoxymethylene, p-fluorophenoxymethylene, 2-nitrophenoxymethylene, p-methoxyphenoxymethylene, α -naphthyloxymethylene, β -naphthyloxymethylene, phenyl, m-methylphenyl, o-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-aminophenyl, o-aminophenyl, 2-fluorophenyl, 2, 4-dichlorophenyl, o-chlorophenyl, 3, 5-dinitrophenyl, p-chlorophenyl, p-bromophenyl, m-bromophenyl, p-nitrophenyl, 4-pyridyl, O-bromophenyl or p-fluorophenyl.

The present invention will be described in further detail with reference to specific examples thereof, but the embodiments of the present invention are not limited thereto.