Synthesis of 1-substituted-5-sulfhydryl-tetrazole compounds or its salt

Abstract

The present invention relates to a synthesis method of a 1-substitution-5-sulfhydryl-tetrazole compound or salt, and a synthesis method thereof. The synthesis method comprises the following steps: a primary amidogen compound (RNH2) and carbon bisulfide react in an alcohol-water mixed solvent under the condition with a tertiary amine catalyst to form dithio-amidogen ammonium formate salt; the dithio-amidogen ammonium formate salt reacts with an alkylated reagent to form sulfome amidogen dithio-formiate; substituted sulfome amidogen dithio-formiate, a sodium salt thereof or a sylvine thereof reacts with sodium azide to generate the 1-substitution-5-sulfhydryl-tetrazole. The present invention has the advantages that the whole yield rate of the three steps is more than 80 percent, the operation is simple, the cost is low, the pollution is greatly reduced, and the application scope is wide.

Description

Technical field: [0001] The invention relates to a preparation method of 1-substituted-5-mercapto-tetrazolium compounds or salts thereof. Background of the invention: [0002] 1-substituted-5-mercapto-tetrazolium compounds, such as 1-sulfomethyl-5-mercapto-tetrazolium disodium salt, 1-acetoxy-5-mercapto-tetrazolium and its disodium salt, 1-Hydroxyethyl-5-mercapto-tetrazolium and its sodium salt, 1-(N,N-dimethylaminoethyl)-5-mercapto-tetrazolium and its sodium salt, 1-phenyl -5-Mercapto-tetrazolium, etc. are important pharmaceutical intermediates, used in the synthesis of cephalosporins and other pharmaceuticals. [0003] When the 1-position substituent in the 1-substituted-5-mercapto-tetrazolium compound is an inert group such as an alkyl group, an aryl group, etc., the usual synthetic method is that the corresponding amino compound and carbon disulfide are under alkaline conditions The following reaction generates the corresponding dithiocarbamate, which is then reacted w...

AI Technical Summary

Problems solved by technology

However, for hydroxyethyl, carboxyethyl, sulfomethyl, and other hydroxyalkyl, carboxyalkyl, sulfonic acid alkyl, substituted aminoalkyl, phosphate alkylamine and other amino compounds, the corresponding isothio Cyanate is either unstable or difficult to separate from the reaction system, so it cannot be prepared by this method

Even for amine compounds that can generate stable isothiocyanate, the above method also has the disadvantage of low yield of isothiocyanate

Chinese patent CN1562980A introduces a method of forming 5-benzylthiotetrazolium through the reaction of phenylbenzyl thiocyanate and sodium azide and then sequentially introducing 1-position substituents and metal sodium reduction to remove the 5-position benzyl group, but Sodium and liquid ammonia are used in the operation, which is difficult to operate

[0005] 3 provides a kind of dipotassium sulfomethylaminodithioformate formed by aminomethanesulfonic acid and carbon disulfide in the presence of potassium hydroxide, and then reacts with methyl iodide to generate methyl sulfomethylaminodithioformate Potassium salt, the latter is cyclized with sodium azide to form a tetrazole ring preparation method, but wherein methyl iodide is used as an alkylation raw material, and the cost is very high

The common disadvantage of these two methods is that the reaction of primary amine and carbon disulfide to form sulfomethylaminodithioformic acid dipotassium salt under potassium hydroxide conditions is easy to form side reactions such as foul-smelling sulfides, resulting in low yield and serious damage. Environmental pollution, the product enters the product in the form of potassium salt, which needs to be treated by ion exchange resin, which is time-consuming

And the overall yield of above two kinds of methods gained is all very low (less than 35%)

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