Novel method for synthesizing thiotriazinone (TTZ) by using mixed solvent

Abstract

The invention relates to a novel method for synthesizing thiotriazinone (TTZ) by using a mixed solvent. The synthetic process comprises the following steps: performing cyclization reaction on 2-methylthiosemicarbazide, the mixed solvent, diethyl oxalate and sodium methylate at 0-45 DEG C to generate triazine ring sodium salt, and acidifying through hydrochloric acid to obtain thiotriazinone. Due to the use of the mixed solvent, the system viscosity of the synthetic process is greatly improved, the TTZ cyclization yield is increased to be more than 90% (by 2-methylthiosemicarbazide), and the content of a byproduct-1-methyl-5-sulfydryl-1,2,4-triazole-3-methyl carboxylate is less than 0.002%, namely less than 20ppm.

Description

Technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to the synthesis of a pharmaceutical intermediate, in particular to a new method for synthesizing a triazine ring using a mixed solvent. Background technique [0002] Triazine ring (TTZ) is a key intermediate for the synthesis of ceftriaxone sodium. After 7-ACT is synthesized with 7-ACA, ceftriaxone sodium can be synthesized with DAMA, so it is an important intermediate for the production of ceftriaxone sodium. Plays a key role in the production of ceftriaxone sodium. Ceftriaxone sodium, also known as ceftriaxone, is a landmark third-generation cephalosporin antibiotic (trade name Rochephen) developed by Roche in Switzerland. It was first marketed in Switzerland in 1982 and was the first semi-synthetic Broad-spectrum long-acting cephalosporins are mainly used for infections caused by sensitive bacteria, such as respiratory infections (especially pneumonia), ear, nose and throat...

AI Technical Summary

Problems solved by technology

[0007] 1. Synthetic route 1, the route of the process of intramolecular cyclization is more complicated, especially the preparation of raw material methylmalonyl chloride is complicated, the yield is low (about 80%), and it is a highly active acid chloride intermediate, It is inconvenient to operate, and at the same time it must be purified by ion exchange resin, the process is complex, the cost is high, it is not suitable for industrial production, and has no practical production significance

[0008] 2. Synthetic route 2, the intermolecular cyclization process requires a large amount of solvent system to complete the second step of the cyclization process. At the same time, the traditional reaction process uses a single solvent system, resulting in a very viscous system and uneven local concentration. , in the presence of local excess base, the by-product 1-methyl-5-mercapto-1,2,4-triazole-3-carboxylic acid methyl ester is generated, resulting in low cyclization yield

At the same time, the by-product is difficult to remove in the subsequent separation process and becomes an important impurity that affects product quality.