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

A technology of mixed solvents and triazine rings, applied in the field of chemical synthesis, can solve the problems of system viscosity, complex preparation, uneven local concentration, etc., and achieve the effect of improving the viscosity of the system

Active Publication Date: 2014-12-03
SHANDONG HUIHAI PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 re

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add 2-methylthiosemicarbazide, mixed solvent, diethyl oxalate, and sodium methoxide to the reaction kettle at a mass ratio of 1:10:4:10. The mixed solvent is a mixture of methanol and DMSO. The mass of methanol and DMSO The ratio is 1:3, and the cyclization reaction is carried out at 0-45°C. After the reaction is completed, it is acidified with hydrochloric acid. The amount of hydrochloric acid is 30% of the amount of 2-methylthiosemicarbazide, then filtered and dried to obtain the triazine ring. The yield is 91.6%, {calculation formula=M(triazine ring) / [M(methylthiosemicarbazide)*159.17 / 105.16]}, by-product content (HPLC) 0.0005% (5ppm).

Embodiment 2

[0025] Add 2-methylthiosemicarbazide, mixed solvent, diethyl oxalate, and sodium methoxide to the reaction kettle at a mass ratio of 1:20:3:6. The mixed solvent is a mixture of ethanol and NMP. The mass of ethanol and NMP The ratio is 1:0.75, and the cyclization reaction is carried out at 0-45°C. After the reaction is completed, it is acidified with hydrochloric acid. The amount of hydrochloric acid is 40% of the amount of 2-methylthiosemicarbazide, then filtered and dried to obtain the triazine ring. The yield is 90.5%, {calculation formula=M(triazine ring) / [M(methylthiosemicarbazide)*159.17 / 105.16]}, by-product content (HPLC) 0.0008% (8ppm).

Embodiment 3

[0027] Add 2-methylthiosemicarbazide, mixed solvent, diethyl oxalate, and sodium methoxide to the reaction kettle at a mass ratio of 1:15:5:15. The mixed solvent is a mixture of methanol and DMF. The mass of methanol and DMF The ratio is 1:2, and the cyclization reaction is carried out at 0-45°C. After the reaction is completed, it is acidified with hydrochloric acid. The amount of hydrochloric acid is 50% of the amount of 2-methylthiosemicarbazide, then filtered and dried to obtain the triazine ring. The yield is 90.8%, {calculation formula=M(triazine ring) / [M(methylthiosemicarbazide)*159.17 / 105.16]}, by-product content (HPLC) 0.0011% (11ppm).

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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...

Claims

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Application Information

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IPC IPC(8): C07D253/075
CPCC07D253/075
Inventor 牟应科姜福元孙成斌郭刚魏成飞
Owner SHANDONG HUIHAI PHARMA & CHEM
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