Synthetic method of 2-thiopheneacetic acid

Abstract

The invention relates to a synthetic method of 2-thiopheneacetic acid, and the synthetic method comprises the following steps: adding thiophene, methylbenzene and aluminium chloride anhydrous into a reaction container, dropping methyl chloroacetate while heating to 50-60 DEG C, and performing heat preservation after dropping; after cooling a reaction liquid to room temperature, pouring proper ice water and hydrochloric acid, layering, extracting the water layer by using proper methylbenzene, drying the organic layer by using anhydrous sodium sulphate, filtering, and concentrating a filtrate and alkaline liquor to be dry so as to obtain 2-thiophene methyl acetate; adding a sodium hydroxide aqueous solution and 2-thiophene methyl acetate into the reaction container, heating to 70-80 DEG C, performing heat preservation for 2-3 hours, cooling to room temperature after performing heat preservation, adjusting ph to 0.5 by using concentrated hydrochloric acid, cooling to 0-10 DEG C, performing heat preservation for 1-2 hours, filtering, and drying the filter cake to obtain 2-thiopheneacetic acid. The synthetic method of 2-thiopheneacetic acid disclosed by the invention has the advantages of being short in process route, cheap and easily available in raw materials, high in yield, good in product quality and suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate 2-thiopheneacetic acid, belonging to the technical fields of medicine and chemical industry. Background technique [0002] 2-thiopheneacetic acid is an important raw material for the preparation of 2-thiophene acetyl chloride, and is widely used in the pharmaceutical industry. Improve the antibacterial activity of the drug. [0003] There are many synthetic methods reported for 2-thiopheneacetic acid, all of which use thiophene as a raw material and adopt a multi-step synthesis process to finally obtain the product. But the most important are the following methods: [0004] 1. Using thiophene as a raw material, acetylate it under a catalyst to obtain 2-acetylthiophene, then react with ethanol, sulfur, and ammonia water under pressure to obtain 2-thiopheneacetamide, and then hydrolyze to obtain 2-thiopheneacetic acid. The process of preparing 2-thiopheneacetamide from 2-ac...

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Problems solved by technology

[0004] 1. Using thiophene as a raw material, acetylate it under a catalyst to obtain 2-acetylthiophene, then react with ethanol, sulfur, and ammonia water under pressure to obtain 2-thiopheneacetamide, and then hydrolyze to obtain 2-thiopheneacetic acid. The process of preparing 2-thiopheneacetamide from 2-acetylthiophene needs to be carried out under high and low conditions, and the amount of sulfur is too large, and the product yield is low

[0005] 2. Using thiophene as a raw material, react under phosphorus oxychloride and N,N-dimethylformamide to obtain 2-thiophene carboxaldehyde, then react with sodium cyanide, and hydrogenate the obtained product to obtain 2-thiophene acetonitrile, and then The product is obtained by hydrolysis. This method has a long route, requires the use of highly toxic sodium cyanide, and requires the use of a large amount of platinum catalyst, which is not suitable for industrial production in terms of safety and economy.

[0006] 3. Use thiophene as raw material to obtain 2-chloromethylthiophene through chloromethylation reaction, and then pressurize with carbon monoxide, methanol, and potassium hydroxide under the catalysis of cobalt salt to generate 2-thiophene acetate, and then obtain 2-thiophene acetate through hydrolysis - Thiophene acetic acid, the 2-chloromethylthiophene obtained in this method is a kind of tear gas substance, and it is unstable, it cannot be left for a long time, and there is a danger of explosion

[0007] 4. Use thiophene to obtain 2-acetylthiophene through acetylation, and then catalyze the corresponding imine with C4-C8 aliphatic primary amine or cyclic amine at 120°C, and then combine the imine with excess sulfur at a temperature not higher than 100 Reaction in an organic solvent at ℃ to obtain 2-thiophenesulfamide, and then hydrolysis and acidification to obtain 2-thiopheneacetic acid. This method has complicated reaction steps, difficult separation of intermediate products, low yield of target compound, and is not suitable for industrial production.

[0008] 5. Using thiophene as a raw material, react with glyoxylic acid, and then reduce to obtain 2-thiopheneacetic acid. This method is simple in process, but the glyoxylic acid used needs to be dehydrated, which is costly, and the excess red phosphorus is not explained.

[0009] 6. Using thiophene as raw material, 2-acetylthiophene is obtained through acetylation, then oxidized to obtain 2-thiophene glyoxylic acid, and then reduced with hydrazine hydrate to obtain 2-thiopheneacetic acid. The process route is relatively short, but 2-acetylthiophene is oxidized to obtain 2-thiophene glyoxylic acid yield is low, only 86.5%