DK162642B - PROCEDURE FOR THE PREPARATION OF THIOTETRONIC ACID - Google Patents

Abstract

1. Process for preparing thiotetronic acid, characterized in that 4-chloro-4-chloromethyloxetane-2-one is directly reacted with hydrogen sulfide in the presence of an amine to thiotetronic acid or prior to the isolation of the thiotetronic acid the reaction mixture is reacted with ketene and the reaction product is reacted with a mineral acid to obtain the thiotetronic acid.

Description

in

DK 162642 B

The present invention relates to a particular process for the preparation of thiotetronic acid of the formula HO -------------

Thiotetronic acid has significant uses as an intermediate for the preparation of (±) thiolactomycin, which is a broad-spectrum antibiotic, cf. Tetrahedron Letters, Vol. 25, No. 46, 5243-5246, 1984.

From E. Benary, Chem. Berichte 46, 2 103 (1913), it is known to prepare thiotetronic acid from acetylthioglycoyl chloride by reaction with sodium malone ester and subsequent cyclization and treatment with water.

D.B. Macierewicz, Rocz. Chem. 47, 1735 (1973) carried out the reaction of E. Benary, thereby producing thiotetronic acid in a yield of 30.3%, based on the acetylthioglycoyl chloride used.

Another possibility is the synthesis according to J.Z. Mortensen et al., Tetrahedron 27, 3839 (1971). From 2,4-dibromothiophene, over three steps are prepared by reaction with butyl lithium and t-butyl perbenzoate thiotetronic acid in a yield of 46.2%.

In all these known methods, the yields are far too modest for a technical method.

Furthermore, the known processes are disadvantageous in that they are cumbersome, the starting materials are expensive and the reagents used are difficult to handle.

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It is therefore the object of the present invention to provide a process for producing thiotetronic acid which is distinguished by high yields and high purity of the thiotetronic acid, favorable starting materials and simple process execution.

This is achieved by the process of the invention by reacting 4-chloro-4-chloromethyloxetan-2-one with. form one

HNC / H

C1 / \

Noo H2CC1 xcr 10 with dihydrogen sulfide in the presence of ammonia, guanidine or an amine, and then the reaction mixture is reacted with the ketone and then the reaction product formed is reacted with a mineral acid to thiotetronic acid.

4-Chloro-4-chloromethyloxetan-2-one can be prepared in a simple manner according to the process set forth in the specification of European Patent Application No. 60,808 and can be used in the process of the invention after a flash distillation.

The dihydrogen sulfide is suitably used in gaseous form.

As suitable amines, primary, secondary or tertiary amines are advantageously used. It is particularly advantageous to use tertiary amines, e.g. triethylamine.

It is convenient to carry out the reaction in a solvent. As solvents, those which are inert to the reactive starting material such as halogenated hydrocarbons, ethers or carboxylic acid esters are used. As examples of useful solvents,

DK 162642 B

Detergents may be mentioned methylene chloride, chloroform, ether solvents such as tetrahydrofuran, or ethyl acetate. However, it is particularly preferred to use tetrahydrofuran.

The starting materials are suitably used in a molar ratio of 4-chloro-4-chloromethyloxetan-2-one to dihydrogen sulfide as well as amine or guanidine or ammonia of from 1: 2: 2 to 1: 4: 3, preferably from 1: 2.5: 2 to 1: 3.5: 2.5.

Preferably, temperatures are operated from 0 ° C to -40 ° C, especially from -10 ° C to -25 ° C.

The reaction is conveniently carried out in such a way that the solution of the starting material is saturated with dihydrogen sulfide, to which ammonia, guanidine or the amine is added over a period of 30-120 minutes.

After the addition of ammonia, guanidine or the amine, the reaction mixture is reacted with the ketene at temperatures of conveniently -10 ° C to 5 ° C, preferably at 0 ° C.

The chain is suitably used in amounts of 2-4 moles, preferably 2.5-3.5 moles, per mole. mole of 4-chloro-4-chloromethyl-oxetan-2-one.

In this reaction, the novel compound 2,4-diacetoxythiophene of formula CH-c-O -, - is formed. 0 25 3 ^ A_0 -! - CH3

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This compound can be simply distilled purified.

By treating the 2,4-diacetoxythiophene with a non-oxidizing inorganic mineral acid, pure thiotetric acid is obtained.

Suitably, hydrochloric or sulfuric acid, preferably hydrochloric acid, is used in aqueous solution at a concentration of 10-30%.

The reaction temperature is conveniently between 0 ° C and 30 ° C / preferably at 15-25 ° C.

The reaction time can be 2-5 hours.

After evaporation, preferably in high vacuum, a virtually colorless crystalline thiotetronic acid is obtained in high yield with a purity of more than 96%.

The process according to the invention is further illustrated in the following example.

Example 15.5 g (0.091 mol) of 4-chloro-4-chloromethyloxetan-2-one in 300 ml of tetrahydrofuran is cooled to -20 ° C and the solution 20 is saturated with gaseous dihydrogen sulfide. Then a solution of 20.2 g (0.2 mole) of triethylamine in 100 ml of tetrahydrofuran is added dropwise at -15 ° C. The reaction solution is evaporated to a volume of 50 ml, at which point 0.3 mol of chain 25 is added to this solution at one hour. Then, the reaction solution is allowed to warm to room temperature and the solvent is distilled off in a rotary evaporator. The residue is subjected to high vacuum distillation. 13.7 g of 2,4-di-acetoxythiophene are obtained with a purity of 95.6%, KP 0.25 = 105 ° C, which corresponds to 13.1 g of 100% product (yield 65.2% ).

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Spectroscopic Data 1-H NMR (300 MHz, CDCL 3): δ = 2.24 (s, 3H), 2.30 (s, 3H), 6.57 (d, J = 2.5 Hz, 1H), 6.61 (d, 1H) 5 MS (70eV) m / z = 200 (M +, 3), 158 (M + -CH 2 = C = 0.10), 116 (M + -2 CH 2 -C = 0.35) 43 (100).

To 1.81 g are added 3.5 g of 20% hydrochloric acid and the mixture is stirred for 3 hours at room temperature. First, an emulsion is formed which, after an hour, forms a clear solution. This colored solution is evaporated in high vacuum.

1.0 g of practically colorless crystalline product are obtained with m.p. 119-121 ° C. (Purity of HPLC: 96.1%).

This corresponds to 0.96 g of 100% thiotetronic acid, which in turn corresponds to a yield of 96%.

Claims (8)

A process for preparing thiotetronic acid of formula HO. ...... J = ° 5 s characterized in that 4-chloro-4-chloromethyloxetan-2-one of the formula V Cl / X> o ° H 2 and then the reaction mixture is reacted with the ketene and the reaction product formed is reacted with mineral acid to form thiotetronic acid. Process according to claim 1, characterized in that the amine is a primary, secondary or tertiary amine. Process according to claims 1 and 2, characterized in that the amine is a tertiary amine. Process according to claims 1-3, characterized in that the reaction is carried out in an inert solvent part. DK 162642 B Process according to claims 1-4, characterized in that the molar ratio of the starting compounds 4-chloro-4-chloromethyloxetan-2-one to dihydrogen sulfide and the amine, guanidine or ammonia is from 1: 2: 2 to 1: 4: 3. Process according to claims 1-5, characterized in that temperatures between 0 ° C and -40 ° C are used. Process according to claims 1-6, characterized in that the chain is used in an amount of 2-4 moles per ml. mole of 4-chloro-4-chloromethyloxetan-2-one. Process according to claims 1-7, characterized in that non-oxidizing mineral acid is used as mineral acid.