DE2652121A1 - (1,3,4)-Thiadiazole-(5)-thiols prodn. - from dithiocarbazate salts and amidines, useful as antibiotic intermediates - Google Patents

Abstract

Prepn. of thiadiazole-5-thiols of formula (I) comprises reacting a salt of dithiocarbazic acid (III) NH2.NH.CS.SH with an amidine R-C(=NH)-NH2 or its salt. In the formula, R=H, 1-4C alkyl, 7-8C aralkyl or 6-7C aryl. (I) is then liberated from the salt formed by treatment with acid. (I), esp. where R=CH3, are intermediates for pharmaceuticals such as the antibiotic cephazolin. Better yields and product purity than known methods.

Description

Process for the production of 1,3,4-

Thiadiazole-5-thiols The invention relates to a process for the preparation of 1,3,4-thiadiazole-5-thiols of the general formula I. wherein R denotes hydrogen, alkyl with 1-4 carbon atoms, aralkyl with 7-8 carbon atoms or aryl with 6-7 carbon atoms.

The production of some of these compounds is known per se, e.g. from German Offenlegungsschrift 21 62 324 and 23 43 825. Thereafter, 1, 3,4-thiadiazole-5-thiols substituted in the 2-position are obtained by a Salt of dithiocarbazic acid (H2N-NH-CS-SH) with a corresponding orthoester, Imino ether, thioic acid ester or thioamide, or by adding a salt of a dithiocarbazic acid of the general formula R1-CO-NH-NH-CS-SH (III), in which R1 is H or lower alkyl means reacting with an acid The known procedures have several disadvantages.

So partly leave the yields too wiuaschell, partly is the quality of the products obtained is unsatisfactory.

The invention was based on the object of a new method of production of the compounds of the formula to find that these disadvantages are not or only to a lesser extent Owns dimensions. This task was accomplished by providing the one described below Procedure solved.

It has been found that salts of 1,3,4-thiadiazole-5-thiols of the formula I can be obtained easily, in high yields and with excellent purity, by adding a salt of dithiocarbazic acid with an amidine of the general formula II, in which R has the meaning given above, or (preferably) a salt thereof implements. From the salts obtained in this way, the free thiols can be acidified in Freedom to be set.

This process is based on a novel chemical reaction, which has no parallel in the known literature. Although it is known to be amidines to react with hydrazines to open-chain amidrazones. However, so far there is no procedure known, according to which 1,3,4-thiadiazoles can be obtained from amidines.

The reaction also does not take place via a salt of an N-acyldithiocarbazic acid (analogous to III) as an intermediate.

That can. be shown, for example, that according to the invention Process the ring system of the thiadiazole already in the alkaline reaction solution (pHiO) Can be detected by UV spectroscopy or thin-layer chromatography. Under the same reaction conditions become the connections of formula III not yet cyclized; with these the ring closure only takes place through Treating with a strong acid, for example by reacting with concentrated Sulfuric acid.

The invention relates to a process for the preparation of the 1,3,4-thiadiazole-5-thiols that of the formula I, characterized in that a salt of dithiocarbazic acid is used reacted with an amidine of the formula II or a salt thereof and then the compound of formula I from its salt thus obtained with an acid in freedom puts.

In the formulas I and II, the radical R preferably denotes a methyl group.

The alkali metal salts can preferably be used as salts of dithiocarbazic acid the sodium or potassium salt, the salts with ammonia, hydrazine or primary, secondary or tertiary aliphatic amines, such as methylamine, dimethylamine or trimethylamine, Ethylamine, diethylamine or triethylamine, propylamine, dipropylamine or tripropylamine, Methylethylamine, diethylpropylamine or dimethylisopropylamine, or with heterocyclic Amines, such as pyridine, α-, ß- or -picoline, pyrrolidine, N-methylpyrrolidine, Imidazolidine, piperidine, N-methylpiperidine or piperazine can be used.

Suitable salts of the amidines of the formula II are preferably the hydrohalides, especially the hydrochlorides, but also e.g. the sulfates, nitrates, perchlorates, also sulphonic acid salts, e.g. benzene sulphonates, fatty acid salts e.g. acetates.

The inventive:% tJ wn5f can in the presence or absence of a inert solvent can be carried out. The preferred solvent is water. Examples of other solvents that can be used are alcohols such as methanol, ethanol, Isopropanol; Glycols and glycol ethers such as methyl glycol, diglyme; Amides such as dimethylformamide, Sulfoxides such as dimethyl sulfoxide; Sulfolane; Ethers such as tetrahydrofuran or dioxane; Amines, e.g. the above-mentioned organic bases such as pyridine; Hydrazine; Ammonia; CS2 or mixtures of the solvents mentioned with one another, especially the Mixtures with water. The reaction temperature is not critical; preferably will the reaction at temperatures between Oo and the boiling point of the solvent used, in particular made between about 50 and about 1000. The pH of the reaction mixture is preferably between about 7 and about 12; the best yields will be at pH values between 9 and 11 are obtained, especially at around pH 10. However, it is also possible, the implementation in the weakly acidic range at pH values between about 3 and 7, e.g. in aqueous acetic acid (pH 4). However, then sink mostly the yields.

The conversion of the salt obtained into the free thiol of the formula I is expediently carried out with a strong acid such as hydrochloric acid or sulfuric acid.

The compounds of formula I obtained, especially the preferred one 2-Methyl-1,3,4-thiadiazole-5-thiol are valuable intermediate products for the production of drugs such as cefazolin. Their implementation on such antibiotics can after methods known from the literature take place.

Example 49.2 g of potassium dithiocarbazinate monohydrate and 41 are dissolved g of acetamidine hydrochloride in 300 ml of water with stirring, heated to 700 for 5 hours and cools down to around 200. The reaction solution (pH10) is with hydrochloric acid to about pH 1.5 acidified and stirred at 200 for a further 10 minutes. The obtained is filtered 2-methyl-1,3,4-thiadiazole-5-thiol, washed with water and dried under reduced pressure Pressure at 500. F. 182 - 1840, analogously from the hydrochlorides of formamidine, Propionamidine, butyramidine, isobutyramidine, isovaleramidine, trimethylacetamidine, Benzamidine or phenylacetamidine: 1,3,4-thiadiazol-5-thiol, F. 1430 2-ethyl-1, 3,4-thiadiazol-5-thiol, F. 760 2-n-propyl-1,3,4-thiadiazole-5-thiol, F. 50-510 2-isopropyl-1,3,4-thiadiazole-5-thiol, F. 43-450 2-isobutyl-1,3,4-thiadiazole-5-thiol, F. 58-600 2-tert.-butyl-1,3,4-thiadiazole-5-thiol, F. 119 - 1200 2-Phenyl-1, 3,4-thiadiazole-5-thiol, F. 210-2120 2-Benzyl-1,3,4-thiadiazole-5-thiol, F. 116-1170

Claims (1)

A process for the preparation of 1,3,4-thiadiazoi - = - thiols of the general formula I. wherein R denotes hydrogen, alkyl with 1-4 carbon atoms, aralkyl with 7-8 carbon atoms or aryl with 6-7 carbon atoms, characterized in that a salt of dithiocarbazic acid with an amidine of the general formula II in which R has the meaning given above or reacts a salt thereof and then liberates the compound of the general formula I from its salt thus obtained with an acid. Sub-claim method according to claim, characterized in that that the starting material of the general formula II acetamidine or one of its salts, preferably acetamidinium chloride is used.