IE58781B1 - Thiophenone derivatives and a process for the preparation thereof - Google Patents

Abstract

1. Thiophenone derivatives of the general formula see diagramm : EP0203495,P4,F1 wherein R is a C1 -C8 -alkoxy carbonyl group, which is unsubstituted or substituted with C1 -C4 -alkyl group(s), halogen-(C1 -C4 )-alkyl group(s) or halogen atom(s), a benzyloxycarbonyl group, which is unsubstituted or substituted with halogen atom(s), nitro group(s) or (C1 -C4 )-alkyl group(s), or a p-toluene sulfonyl group.

Description

The present invention is concerned with new thiophenone derivatives, which can easily be converted into thiotetronic acid, and with a process for the preparation thereof.

Thiotetronic acid itself is of importance as an intermediate for the preparation of (+)-thiolactomycin, an antibiotic with a wide spectrum of activity (see Tetrahedron Letters, 2.5, (46), 5243-5246/1984).

It is known (see E. Benary, Chem. Berichte, 46, 2103/1913) to prepare thiotetronic acid starting from acetylthioglycolyl chloride by reaction with sodium malonic ester and subsequent ring closure and water f treatment.

D.B. Macierewicz (Rocz. chem., 47, 1735/1973) reinvestigated the reaction of E. Benary and thereby obtained thiotetronic acid in a yield of 30.3%, referred to the acetylthioglycolyl chloride used.

Another possibility is provided by the synthesis of J.Z. Mortensen et al. (Tetrahedron, 27 , 3839/1971). Starting from 2,4-dibromothiophene, they obtained, via 3 stages, by reaction with butyl lithium and tert.-butyl perbenzoate, thiotetronic acid in a yield of 46.2%.

In the case of these previously known syntheses, not only are the yields modest but the educts and reagents used scarcely provide an economic technical process.

A further problem is the preparation of a qualitatively very valuable product since thiotetronic acid readily forms a dimeric condensation product not only in the case of recrystallisation but also in aqueous solutions with the splitting off of water.

Therefore, it is an object of the present invention to find an alternative thiotetronic acid precursor which is technically simple to prepare and 20 can be isolated from the reaction mixture, is obtained in high purity and can easily be converted into thiotetronic acid.

Thus, according to the present invention, there are provided new thiophenone derivatives of the general formula:4 wherein R is a C^-Cg-alkoxycarbonyl group, which is unsubstituted or substituted with Cj-C^-alkyl group(s), halogen(Ci"c4)alkyl group(s) or halogen atom(s), a benzyloxycarbonyl group, which is unsubstituted or substituted with halogen atom(s), nitro group(s) or (C^-C^)-alkyl group(s), or a p-toluenesulfonyl group.

The present invention also provides a process for preparing these new thiophenone derivatives, wherein 4-chloro-4-chlororoethyloxetan-2-one is reacted with hydrogen sulphide in the presence of a base and the intermediate-formed thiotetronic acid is reacted with a chloroformic acid ester of the general formula C1-C00R, in which R is as defined above, or ^-toluenesulphonic acid chloride to give the desired end product. 4-Chloro-4-chloromethyloxetan-2-one can be prepared in a simple manner according to European Patent Specification No. 0,060,608 and, after a flash distillation, used for the reaction according to the present invention.

The hydrogen sulphide is preferably used in gaseous form.

The base used is preferably a primary, secondary or tertiary amine, ammonia or guanidine, the tertiary amines, for example triethylamine, being especially advantageously used.

It is also preferable to carry out the reaction in a solvent, use thereby being made of a solvent which is inert towards the educts, for example a halogenated hydrocarbon, an ether or a carboxylic acid ester. Thus, for example, there can be used methylene chloride, chloroform or an ethereal solvent, such as tetrahydrofuran. However, ethyl acetate and tetrahydrofuran are especially preferred.

The educts are preferably used in a mole ratio 10 of 4-chloro-4-chloromethyloxetan-2-one to hydrogen sulphide to amine to chloroformic aid ester/jj-toluenesulphonic acid chloride of 1:1:2.8:0.8 to 1:3:4:1 and preferably of 1:2:2.8:0.8 to 1:3:3.0:1.

It is preferred to operate at a temperature of 15 from -40 to +20°C. and especially of from -20 to -10°C It is preferable to dissolve the 4-chloro-4chloromethyloxetan-2-one in an inert solvent, to saturate the solution with hydrogen sulphide and subsequently to add the amine over the course of 30 to 120 minutes.

After the addition of the amine, without having to separate off the intermediate formed thiotetronic acid, the reaction with the chloroformic acid ester or with the £>-toluenesulphonic acid chloride can be carried out directly in the solution to give the thio6 phenone derivatives according to the present invention.

The isolation of the thiophene derivatives can take place in a simple manner by extraction or recrystallisation.

In this way, there can be achieved yields greater than 70%, with contents of much greater than 90% and, in certain cases, of greater than 99%.

The reaction of the thiophene derivatives to give thiotetronic acids is carried out under basic conditions, preferably in the presence of an aliphatic amine or of ammonia.

After appropriate working up, there can be obtained a qualitatively very valuable thiotetronic acid with a content of greater than 95%.

Especially preferred compounds according to the present invention, which fulfil the initially mentioned advantages to the highest degree, include 4-(ethoxycarbonyloxy)-thiophen-2(5H)-one and 4-(methoxycarbonyl oxy )- thi ophen- 2 ( 5H)-one.

The following Examples are given for the purpose of illustrating the present invention:Example 1.

A solution of 15.9 g. (0.1 mole) 4-chloro-4chloromethyloxetan-2-one in 300 ml. tetrahydrofuran was cooled to -20°C. and saturated with gaseous hydrogen sulphide. Subsequently, 20.4 g. (0.2 mole) triethylamine were added dropwise thereto, with vigorous stirring, within the course of 1 hour. The reaction mixture was allowed to warm up to ambient temperature, then stirred for 1 hour, precipitated salt was filtered off and the solvent was evaporated off to one half on a rotary evaporator.

This solution was mixed with 9.8 g. (0.09 mole) ethyl chloroformate, cooled to 0°C. and mixed dropwise with 9.1 g. (0.09 mole) triethylamine. The precipitated salt was filtered off with suction and the reaction solution was evaporated on a rotary evaporator. The residue was boiled with 400 ml. petroleum ether and the solution was decanted off and cooled to -20°C.

The precipitated crystals were filtered off with suction.

There were obtained 15.0 g. of 4-(ethoxycarbonyl oxy)-thiophen-2(5H)-one in the form of beige coloured crystals (m.p. 52 - 54°C.) with a content of 99.2% (GC). This corresponded to 14.9 g. of 100% product or to a yield of 79.1%, referred to the oxetanone used. 1H-NMR spectrum (CDCl^, 300 mHz) 6.42 (t, J3 5 = 1.3 Hz, IH) 4.29 (q. J = 7.1 Hz, 2H) 4.02 (d, J3 5 = 1.3 Hz, 2H) 1.33 (t, J = 7.1 Hz, 3H).

Example 2.

Analogously to Example 1 but using 8.50 g. (0.09 mole) methyl chloroformate instead of ethyl chloroformate, there were obtained 13.8 g. (79.2%, referred to the oxetanone used) 4-(methoxycarbonyloxy)thiophen-2(5H)-one. The beige coloured product had a melting range of 64 - 66°C. and a content, according to GC, of 92.1%. 1H-NMR spectrum (CDC1.J, 300 MHz) ξ = 6.49 (t, J3 5 = 1.3 Hz, lH) 4.05 (d, J 5 » 1.3 Hz, 2H) 3.96 (s, 3H) Example 3.

A solution of 16.3 g. (0.1 mole) 4-chloro-4chloromethyloxetan-2-one in 300 ml. tetrahydrofuran was cooled to -20°c. and saturated with gaseous hydrogen sulphide. Subsequently, 20.4 g. (0.2 mole) triethylamine were added dropwise thereto, with vigorous stirring, in the course of 1 hour. The reaction solution was allowed to warm up to ambient temperature, further stirred for 1 hour, precipitated salt was filtered off and the solvent was evaporated to one half on a rotary evaporator. This solution was mixed with 19.1 g. (0.1 mole) £>-tol uene sulphonic acid chloride, cooled to 0°C. and mixed dropwise with .2 g. (0.1 mole) triethylamine. The precipitated salt was filtered off and the reaction solution was evaporated on a rotary evaporator. The residue was washed with 50 ml. methanol. There were obtained 19.8 g. of 4-(£-toluenesulphonyloxy)-thiophen-2(5H)-one as a TLC-pure product; m.p. 139 - 14O°C. This corresponded to a yield of 73.3%, referred to the oxetanone used. spectrum ( 300 MHz, CDC1 3) = 7.86 (d, J = 8.8 Hz, 2H) 7.43 (d, J = 8.8 Hz, 2H) 6.13 (t, J = 1.2 Hz, IH) 3.96 (d, J = 1.3 Hz, IH) 2.50 (s, 3H) Example 4.

Analogously to Example 1 but using 12.3 g. (0.09 mole) butyl chloroformate instead of ethyl chloroformate, there was obtained a yield of 75.7%, referred to the oxetanone used, of 4-(n-butyloxycarbonyloxy)-thiophen2(5H)-one in the form of pale brownish coloured crystals: m.p. 28 - 29°C.

^H-NMR spectrum (CDCl^, 300 MHz) δ = 6.48 (t, J_ c = 1.2 Hz, IH) j. □ 4.30 (t, J = 6.9 Hz, 2H) 4.09 (d, J3 5 = 1.2 Hz, 2H) 1.73 (m, 2H) 1.44 (m, 2H) 0.98 (t, J = 7.2 Hz, 3H) Example 5.

Analogously to Example 1 but using 15.3 g. (0.09 mole) benzyl chloroformate instead of ethyl chloroformate, there was obtained a yield of 74.1%, referred to the oxetanone used, of 4-(benzyloxycarbonyloxy)thiophen-2(5H)-one in the form of beige coloured crystals: m.p. 82 - 83°C. 1H-NMR spectrum (CDCl^, 300 MHz) S = 7.41 (S, 5H) 6.49 (t, J. _ = 1.2 Hz, IH) .28 (S, 2H) 4.07 (d, J3 5 = 1.2 HZ, 2H) 1 Example 6. 3.8 g. (0.02 mole) 4-(ethoxycarbonyloxy)thiophen-2(5H)-one were dissolved in 25 ml. tetrahydrofuran and cooled to -1O°C. A solution of 2.9 g. (0.04 mole) diethylamine in 35 ml. tetrahydrofuran was added thereto. The precipitated solid (diethylammonium salt of thiotetronic acid) was filtered off with suction, then taken up in 20 ml. water and acidified with concentrated hydrochloric acid to pH 1 - 2, while stirring.

The precipitated thiotetronic acid was extracted with 100 ml. ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and the solvent subsequently evaporated off on a rotary evaporator. The residue was dried in a high vacuum. There were obtained 2.0 g. thiotetronic acid as an almost white, microcrystalline product with a content of 96.9% (titration o with sodium hydroxide solution); m.p. 120 - 122 C.

This corresponded to 1.9 g. of 100% product or to a yield of 83.6%, referred to the 4-(ethoxycarbonyloxy)thiophen-2(5H)-one used.

Claims (13)

1. A thiophenone derivative of the general formula wherein R is a C^-Cg-alkoxycarbonyl group, which is unsub5 stituted or substituted with C^-C^-alkyl group(s), halogen(C 1 -C 4 )-alkyl group(s) or halogen atom(s), a benzyloxycarbonyl group, which is unsubstituted or substituted with halogen atom(s), nitro group(s) or (C^-C^-alkyl group(s) , or a p-tolu enesulfonyl group. 0

2. 4-(Bthoxycarbonyloxy)-thiophen-2(5H)-one of the formula:0 H 5 C 2 OCO

3. 4-(Methoxycarbonyloxy)-thiophen-2(5H)-one of the formula:** II HgCOCO

4. a process for the preparation of a thiophenone derivative according to claim 1, which comprises reacting 4chloro-4-chloromethyloxetan-2-one with hydrogen sulphide in the presence of a base and reacting the 20 intermediate formed thiotetronic acid with a chloroformic acid ester of the general formula Cl-COOR, in which R is as defined in Claim 1, or £-toluenesulphonic acid chloride to give the desired end product. 1 3

5. A process according to claim 4, wherein the base used is a primary, secondary or tertiary amine, ammonia or guanidine.

6. A process according to claim 5, wherein the base 5 used is a tertiary amine.

7. A process according to any of claims 4 to 6, wherein the reaction is carried out in an inert solvent.

8. A process according to any of claims 4 to 7 , wherein 10 the molar educt ratio of chloroformic acid ester/ £-toluenesulphonyl chloride to amine to 4-chloro-4chloromethyloxetan-2-one is 0.8:2.8:1.0 to 1.0:4.0:1.0.

9. . A process according to any of claims 4 to 8, wherein the molar educt ratio of hydrogen sulphide to 4-chloro 15 4-chloromethyloxetan-2-one is 1:1 to 1:3.

10. A process according to any of claims 4 to 9, wherein the reaction is carried out in the temperature range of from -40 to +20°C.

11. A process according to claim 4 for the preparation 20 of a thiophenone derivative according to any of claims 1 to 3, substantially as hereinbefore described and exemplified. i 1 4

12. A thiophenone derivative according to any of claims 1 to 3, whenever prepared by the process * according to any of claims 4 to 11. r

13. Use of a thiophenone derivative according to any of 5 , claims 1 to 3 and 12, for the preparation of thiotetronic acid.