JPS5812275B2 - 1- Thikane -1H- Tetrazole -5- Thioluruino Seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention provides novel 1-monosubstituted -IH-tetrazole-5-
There are seven methods related to the production of thiols, and the outline thereof is as follows.

(In the formula, R means a hydroxyalkyl group and R means an alkoxycarbonylalkyl group, respectively.) The method of the present invention is carried out by reacting a reactive derivative of hydroxyalkyl-substituted dithiocarbamic acid (I) with an azilating agent. be exposed.

The reactive derivative of hydroxyalkyl-substituted dithiocarbamic acid (I) used in this invention is, for example, hydroxyalkyl-substituted dithiocarbamic acid (I) obtained by reacting hydroxyalkylamine with carbon disulfide in the presence of a base.
The salt of (2) can be prepared by subsequently converting the salt into its reactive derivative by a conventional method, and the reactive derivative of alkoxy-alponylalkyl-substituted dithiocarbamic acid (I)' can also be prepared in the same manner.

The hydroxyalkyl-substituted dithiocarbamic acids used in this invention are represented by the above general formula (I), and more specifically, include methyl, ethyl, probyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc. It means a compound in which R is a hydroxyalkyl group in which the alkyl group is substituted with a hydroxy group.

These reactive derivatives of hydroxyanolekyl-substituted dithiocarbamic acid (I) include methyl ester, ethyl ester, furoyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, pentyl ester, hexyl ester, Esters such as benzyl ester, phenacyl ester, and phenethyl ester are used.

Examples of the azide agent in the present invention include metal azides such as lithium azide, sodium azide, and potassium azide, and organic ammonium azides such as tetramethylguanidium azide.

The reaction of this invention is usually carried out in a solvent.

Examples of the solvent include acetone, dimethylformamide, dioxane, methanol, ethanol, dimethyl sulfoxide, etc., as well as general organic solvents and water that do not adversely affect this reaction, but highly polar solvents are preferred.

Among these, hydrophilic solvents can be used in combination with water.

Although the reaction temperature is not particularly limited, the reaction is usually carried out with or under heating in many cases.

The target product (II) obtained by this reaction is isolated and collected by a conventional method.

Further, the target product (n) can also be obtained by the following method.

That is, the target compound (IF) can also be obtained by first reacting a reactive derivative of alkoxylponylalkyl-substituted dithiocarbamic acid (I)' with an azilating agent, and then subjecting the obtained compound (■)' to a reduction reaction. can be obtained.

The alkoxy group substituted dithiocarbamic acid in this reaction is represented by the above general formula (I)', but more specifically, the alkyl group as exemplified in the explanation of the above hydroxyalkyl substituted dithiocarbamate (I) The hydrogen atom at any position in is an alkoxy group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary ptoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. It means a compound having as R' an alkoxycarbonyl alkyl group substituted with a carbonyl group.

Examples of the reactive derivatives of these alkoxycarbonylalkyl-substituted dithiocarbamic acids (I)' include the same reactive derivatives as those exemplified above as the reactive derivatives of the hydroxyalkyl-substituted dithiocarbamic acids (I).

The reaction and conditions for the reaction between the reactive derivative of the alkoxyalkyl-substituted dithiocarbamic acid (I)' and the azilating agent are as follows: The reaction conditions for the reaction are applied as is.

Next, methods such as chemical reduction, catalytic reduction, electrolytic reduction, etc. are adopted as the reduction reaction of the obtained compound (■)′.
Specific examples include methods using a combination of sodium metal and alcohol, methods using lithium aluminum hydride and sodium borohydride, and catalytic reduction using Adkins catalysts such as copper chromite and zinc chromite. .

These reduction reactions are usually performed in a solvent. Examples of the solvent include water, general organic solvents that do not adversely affect this reaction, such as chloroform, methylene chloride, methanol, ethanol, dimethylformamide, tetrahydrofuran, and mixed solvents thereof.

Although the reaction temperature is not particularly limited, the reaction is often carried out at room temperature or under heating.

These reaction solvents and reaction temperatures are appropriately selected according to the compound (■)' and the reduction method employed.

The target compound (■) thus obtained is isolated and collected by a conventional method.

The 1-monosubstituted -IH-tetrazole-5-thiols (n) thus obtained can be converted into desired salts such as sodium salts and potassium salts by conventional methods.

The 1-monosubstituted -IH-tetrazole-5-thiols (■) obtained by the method of this invention are all new compounds, and are useful as intermediates for the synthesis of cephalosporanic acid derivatives having these as substituents at the 3-position. .

Next, the method of the present invention will be explained using examples.

Example I N-(2-hydroxyethyl)dithiocarbamic acid methyl ester 3.7t, sodium azide 2.4v, water 2
A mixture of 0 ml and 20 ml of dioxane is heated under reflux for 4 hours.

Dioxane is distilled off from the reaction solution under reduced pressure, and the remaining solution is washed with ether.

This was adjusted to pH 1 with 10% hydrochloric acid, and then extracted with ethyl acetate.

After concentrating this under reduced pressure, the oily residue was purified by silica gel column chromatography.
0.175' of 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol at ~137°C is obtained.

Ultraviolet absorption spectrum Ethanol λmax 248 mμ λ pH 6.4 Phosphate buffer 226 mμ maX Example 2 (1) N--[-}oxycarbonylmethylcythiocarbamate methyl ester 9.72, sodium azide 3
．． 3? , a solution consisting of 50 ml of water and 5 or 1 l of dioxane is heated under reflux for 3 hours.

Dioxane is distilled off from the reaction solution under reduced pressure, and the remaining solution is washed with ethyl acetate.

After adjusting the pH to 1 with 10% hydrochloric acid, the mixture was extracted twice with 100ml of chloroform and 10 times with 5oWLl.

After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.28r of 2-(5-mercapto-IH-tetrazol-1-yl)acetic acid ethyl ester.

Infrared absorption spectrum (cm'): 1,750 ma
190 drops of ethyl acetate are dissolved in a mixture of 1 ml of water and 9 ml of methanol, 760 drops of sodium borohydride are added, and the mixture is stirred at room temperature for 2 hours.

After adding 5 ml of water to the reaction solution, methanol was distilled off under reduced pressure.

Wash the residual liquid once with Ete/1/101117,
After adjusting the pH to 4 with % hydrochloric acid, extract 5 times with 15 #l/ethyl acetate.

After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1-(2-hydroxyethyl)-1H-tetrazole-5-thiol with a mp of 135 to 137°C.
Obtain Il9.

Claims (1)

[Scope of Claims] 1. A reactive derivative of a hydroxyalkyl-substituted dithiocarbamic acid represented by the general formula R-NHCSSH (wherein R means a hydroxyalkyl group) is reacted with an azidizing agent to form a compound of the general formula ( A method for producing 1-mono-substituted 1-IH-tetrazole-5-thiols, characterized in that 1-mono-substituted 1-IH-tetrazole-5-thiols are obtained. 2 A reactive derivative of an alkoxycarbonylalkyl-substituted dithiocarbamic acid represented by the general formula R'-NHCSSH (in the formula, R' means an alkoxycarbonylalkyl group) is reacted with an azilating agent to form a general compound (in the formula, R' has the same meaning as before) to obtain a compound represented by the following formula, which is then subjected to a reduction reaction to obtain a 1-monosubstituted -IH-tetrazole represented by the general formula (wherein R represents a hydroxyalkyl group). -1 Monosubstituted -1H-tetrazole- characterized by obtaining -5 monothiols
Method for producing 5-thiols.