Preparation method of 4-methylthiazole-5-ethyl formate

Abstract

The invention discloses a preparation method of 4-methylthiazole-5-ethyl formate and relates to the technical field of organic synthesis. In the method, glycol dimethyl ether is employed as a reaction solvent and ethyl-2-chloroacetoacetate, phosphorous sulfide and formamide are employed as reaction raw materials. The method includes the following steps: dissolving the phosphorous sulfide in the glycol dimethyl ether, adding the formamide dropwisely, performing a reaction for 2-3 h, adding the ethyl-2-chloroacetoacetate dropwisely, heating the mixture to 60 DEG C and carrying out a reaction for 4-8 h, cooling the reaction product after the reaction is finished, filtering the reaction product to obtain a solid, adding the solid to water, regulating the pH value to 7-8 under a low temperature with sodium hydroxide, and filtering the solid to obtain the 4-methylthiazole-5-ethyl formate. The preparation method is carried out through a one-pot method to obtain the target product, thereby omitting a purifying step in the process. The preparation method is more than 95% in molar yield of the product, is 99% in product purity and is suitable for large-scale production.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing ethyl 4-methylthiazole-5-carboxylate. Background technique: [0002] Ethyl 4-methylthiazole-5-carboxylate is an intermediate of the drug febuxostat for the treatment of gout. At this stage, the main methods for preparing ethyl 4-methylthiazole-5-carboxylate are as follows: [0003] 1. Patent WO2006 / 108701, using ethyl 2-mercapto-4-methylthiazole-5-carboxylate as raw material, oxidizing with hydrogen peroxide in hydrochloric acid, to prepare ethyl 4-methylthiazole-5-carboxylate, post-treatment Ether solvent extraction and silica gel column chromatography are used to obtain pure products with a molar yield of 23.6%. This process has the following defects: the raw material 2-mercapto-4-methylthiazole-5-carboxylic acid ethyl ester has no commercial raw material supply, and the price It is expensive and costly; the post-reaction treatment adopts solvent ext...

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Problems solved by technology

[0003] 1. Patent WO2006 / 108701, using ethyl 2-mercapto-4-methylthiazole-5-carboxylate as raw material, oxidizing with hydrogen peroxide in hydrochloric acid to prepare ethyl 4-methylthiazole-5-carboxylate, post-treatment Adopt the technology of ether solvent extraction and silica gel column chromatography to obtain pure product, molar yield 23.6%, this technology has following defect: raw material 2-mercapto-4-methylthiazole-5-ethyl carboxylate does not have commercial raw material supply, price Expensive and high cost; solvent extraction is used for post-reaction treatment, which does not conform to the concept of green chemistry; silica gel column chromatography is used for product purification, which cannot be industrially produced on a large scale; product yield is too low

[0004] 2. Literature [Tetrahedron, Vol.69, 2013, p4436-4444], using ethyl 2-amino-4-methylthiazole-5-carboxylate as raw material, in phosphoric acid, using diazotization process to prepare 4- Methylthiazole-5-ethyl carboxylate, post-treatment adopts dichloromethane solvent extraction and silica gel column chromatography to obtain pure product, molar yield 59%, this process has the following defects: raw material 2-amino-4-methanol There is no commercial supply of ethyl thiazole-5-carboxylate, and the price is expensive; the post-reaction treatment adopts solvent extraction, which does not conform to the concept of green chemistry; the product purification adopts silica gel column chromatography, which cannot be industrially produced on a large scale; the product yield is too high Low

[0005] 3. Patent US2002 / 68729, using ethyl 2-chloroacetoacetate and thioformamide as raw materials, heating to 110°C in magnesium carbonate and dioxane solvent to prepare 4-methylthiazole-5-carboxylic acid Ethyl ester, post-treatment adopts ether solvent extraction and silica gel column chromatography to obtain pure product, the molar yield is 17%. This process has the following defects: the raw material thioformamide is highly toxic, and it is dangerous to purchase and transport in large quantities , not suitable for large-scale production; the post-reaction treatment uses solvent extraction, which does not conform to the concept of green chemistry; the product purification adopts silica gel column chromatography, which cannot be industrially produced on a large scale; the product yield is too low, only 17%

[0006] 4. Patent CN200610098646, in "Preparation of 4-methylthiazole-5-carboxamide" on page 38 of the description, involves the synthesis method of ethyl 4-methylthiazole-5-carboxylate, using 2-chloroacetoacetic acid Ethyl ester and thioformamide are used as raw materials, in an ethanol solvent, refluxed for 8 hours to prepare ethyl 4-methylthiazole-5-carboxylate, extracted with ethyl acetate solvent, dried, and concentrated to obtain a crude product without purification For subsequent reaction steps, this process has the following problems: the raw material thioformamide is highly toxic, and it is dangerous to purchase and transport in large quantities, and is not suitable for large-scale production; the post-reaction treatment uses solvent extraction, which does not conform to the concept of green chemistry; the crude product The product is a red oily liquid, obviously the purity is not too high; and the synthesis yield of ethyl 4-methylthiazole-5-carboxylate is not mentioned in this patent