DK162641B - 4-SUBSTITUTED THIOPHEN-2 (5H) -ON DERIVATIVES AND PROCEDURES FOR PREPARING 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

in

DK 162641 B

The invention relates to novel 4-substituted thiophen-2 (5H) -one derivatives of formula I which can be readily converted to thiotetronic acid and a process 5 for the preparation of the 4-substituted thiophen-2 (5H) -one derivatives.

Thiotetronic acid itself has significant potential uses as an intermediate for the preparation of (± Jthiolactomycin, which is a broad-spectrum antibiotic, cf. Tetrahedron Letters, Vol. by reaction with sodium malon ester and subsequent cyclization and treatment with water, cf. E. Benary, Chem. Berichte 46, 2103 (1913) .This reaction has been further developed such that thiotetronic acid can be prepared in a yield of 30.3%. , calculated on the acetylthioglycoyl chloride used, cf. DB Macierewicz, Rocz, Chem. 47, 1735 (1973). Further, it is known to produce thiotetronic acid in 46.2% yield from 2,4-dibromothiophene by reaction. over 3 steps with butyl lithium and t-butyl perbenzoate, cf. JZ Mortensen et al, Tetrahedron 27, 3839 (1971).

In these known processes, not only are the yields too small, but also the starting materials used and reagents used are hindering the way of an economical technical process.

Another problem consists in the preparation of a qualitatively valuable product, since thiotetronic acid forms, both in recrystallization and in aqueous solutions, a 30 dimer condensation product during water decomposition.

It is the object of the present invention to provide an alternative intermediate for thiotetronic acid, which intermediate can be prepared technically in a simple manner, isolated from the reaction mixture in

DK 162641 B

2 high purity and converted to thiotetronic acid in a simple manner.

This is achieved with the novel 4-substituted thiophene-2 (5H) -one derivatives of the invention, which are peculiar in that they have the general formula ROv._ \ J = ° 1 wherein R is a C (1- 8) -alkoxycarbonyl group, a benzyloxycarbonyl group or a p-toluenesulfonyl group.

The process of the invention for the preparation of the 4-substituted thiophen-2 (5H) -one derivatives of general formula I is characterized in that 4-chloro-4-chloromethyl-oxetan-2-one of the formula

HV-H

Cl / X

is reacted with dihydrogen sulfide in the presence of a base, and the intermediately formed thiotetronic acid of formula HO______ \ J = ° is reacted with a chloroformic acid ester of formula C1C00R wherein R is as defined above or by

DK 162641 B

3 p-toluenesulfonic acid chloride.

4-Chloro-4-chloromethyloxetane ~ 2-one can be prepared in a simple manner, as described in European patent application no.

No. 5,60,808, and can be used in the instant reaction after a flash distillation.

The dihydrogen sulfide is suitably used in gaseous form.

Examples of suitable bases include primary, secondary or tertiary amines, ammonia or guanidine.

Particularly advantageous amines are the tertiary amines, e.g. triethylamine. Chloric formic acid C (1-8) alkyl or benzyl ester is suitably used. For the preparation of preferred thiophenone derivatives, the chloroformic acid C (1-2) alkyl esters are used.

Furthermore, it is appropriate to carry out the reaction in solvents. Solvents which are inert to the starting material used, such as halogenated hydrocarbons, ethers or carboxylic acid esters, may be used. As examples of useful solvents 20 may be mentioned methylene chloride, chloroform and ether solvents such as tetrahydrofuran. It is particularly preferred to use tetrahydrofuran or ethyl acetate.

The starting materials are suitably used in the molar ratio of 4-chloro-4-chloromethyloxetan-2-one to dihydrogen sulfide 25 to base for chloroformic acid ester / p-toluenesulfonic acid chloride of 1: 1: 2.8: 0.8 to 1: 3: 4: 1, preferably from 1: 2: 2.8: 0.8 to 1: 3: 3.0: 1.

It is preferred to operate at temperatures from -40 ° C to 20 ° C, especially between -20 ° C and -10 ° C.

In an appropriate embodiment of the method

DK 162641 B

4, a solution of 4-chloro-4-chloromethyloxetan-2-one is added in an inert solvent with dihydrogen sulfide and the base is added over 30-120 minutes.

After the amine addition, the intermediate thiotetronic acid formed without isolation can be reacted directly in solution with chloroformic acid ester or p-toluenesulfonic acid chloride to the thiophenone derivatives of the invention.

The isolation of the thiophenone derivatives of formula I can be accomplished simply by extraction or by recrystallization. In this way, yields of more than 70% can be obtained in a purity of at least 90%, in some cases more than 99%.

The reaction of the thiophenone derivatives of formula I to 15 thiotetronic acid is carried out in a basic environment, conveniently in the presence of an aliphatic amine or NH 3. After proper work-up, a qualitatively valuable thiotetronic acid with a purity greater than 95% can be obtained.

Particularly preferred compounds which provide particularly high benefits to the aforementioned advantages may be mentioned 4- (ethoxy-carbonyloxy) -thiophen-2 (5H) -one and 4- (methoxycarbonyloxy) -thiophen-2 (5H) -one.

The invention is further illustrated in the following Examples 1-5. The preparation of thiotetronic acid from a 4-substituted thiophene-2 (5H) -one derivative is illustrated in Example 6.

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Example 1 5

A solution of 15.9 g (0.1 mole) of 4-chloro-4-chloromethyloxetan-2-one in 300 ml of tetrahydrofuran is cooled to -20 ° C and the solution is saturated with gaseous dihydrogen sulfide. Thereafter, 20.4 g (0.2 mole) of triethylamine are added dropwise with vigorous stirring over one hour. The reaction solution is allowed to warm to room temperature, stirred for one hour, then the precipitated salt is filtered off and the solvent is evaporated on a rotary evaporator to half the volume. To this solution is added 9.8 g (0.09 mole) of chloroformic acid ethyl ester, then the mixture is cooled to 0 ° C and 9.1 g (0.09 mole) of triethyl, amine are added dropwise. The precipitated salt is filtered off and the reaction solution is evaporated on a rotary evaporator. The residue is boiled with 400 ml of petroleum ether, the solution is decanted and cooled to -20 ° C. The precipitated crystals are isolated by suction filtration. 15.0 g of 4- (ethoxycarbonyloxy) -thiophen-2 (5H) -one are obtained in the form of beige crystals, m.p. 52-54 ° C and a purity of 99.2% (GC). This corresponds to 20 to 14.9 g of 100% pure product or a yield of 79.1%, calculated on the oxetanone used.

1 H NMR Spectrum (CDCl 3, 300 MHz) β = 6.42 (t, J 3 = 1.3 Hz, 1H) 4.29 (q, J = 7.1 Hz, 2H) 4.02 (d = 1.3 Hz, 2H) 1.33 (t, J = 7.1 Hz, 3H)

Example 2

By analogy to the procedure described in Example 1, however, using 8.50 g (0.09 mol) of chloroformic acid methyl ester instead of chloroformic acid ethyl ester, 4- (methoxycarbonyloxy) -thiophen-2 (5H) -one is prepared in a yield of 13.8 g = 79.2%, based on the oxetanone used. The beige colored product has a melting range of 64-66 ° C and a purity determined by gas chromatography of 92.1%.

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1 H NMR Spectrum (CDCl3, 300 MHz) δ δ 6.49 (tf J3 = 1.3 Hz, 1H) 4.05 (d, J3 = 1.3 Hz, 2H) 3.96 (s, 3H) Example 3

A solution of 16.3 g (0.1 mole) of 4-chloro-4-chloromethyl-oxetan-2-one in 300 ml of tetrahydrofuran is cooled to -20 ° C and the solution is saturated with gaseous dihydrogen sulfide.

Thereafter, 20.4 g (0.2 mole) of triethylamine are added dropwise with vigorous stirring for 10 hours. The reaction solution is allowed to warm to room temperature, then stirred for one hour, the separated salt is filtered off and the solvent is evaporated on a half-volume rotary evaporator. To this solution is added 19.1 g (0.1 mole) of p-toluenesulfonic acid chloride, the mixture is cooled to 0 ° C and 10.2 g (0.1 mole) of triethylamine are added dropwise. The separated salt is filtered off and the reaction solution is evaporated on a rotary evaporator. The residue is washed with 50 ml of methanol. 19.8 g of 4- (p-toluenesulfonyloxy) -thiophen-2 (5H) -one are obtained. as a thin layer chromatographically pure product with m.p. 139-140 ° C. This corresponds to a yield of 73.3%, based on the oxetanone used.

1 H NMR Spectrum (300 MHz, CDCl 3) δ = 7.86 (d, J = 8.8 Hz, 2H) 7.43 (d, J = 8.8 Hz, 2H) 6.13 (t, J = 1.2 Hz, 1H) 3.96 (d, J = 1.2 Hz, 1H) 2.50 (s, 3H)

Example 4

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7

By analogy to the procedure described in Example 1, however, using 12.3 g (0.09 mol) of chloromyric acid butyl ester instead of 4- (n-butyloxycarbonyloxy) -thiophene-2 (5H) -one, in a yield of 75.7%, based on oxetanone used, in the form of slightly brownish crystals, mp 28-29 ° C.

1 H NMR spectrum (CDCl3, 300 MHz) δ = 6.48 (t, J, c = 1.2 Hz, 1H)

3 f D

4.30 (t, J = 6.9 Hz, 2H) 4.09 (d, J = c = 1.2 Hz, 2H) 3/0 1.73 (m, 2H) 1.44 (m, 2H) ) 0.98 (t, J = 7.2 Hz, 3H) Example 5

Analogous to the procedure described in Example 1, although 15.3 g (0.09 mole) of chloroformic acid benzyl ester is used in place of chloroformic acid ethyl ester, 4- (benzyloxycarbonyloxy) -thiophen-2 (5H) -one is prepared in a yield of 74.1%, based on oxetanone used, in the form of beige crystals with m.p. 82-83 ° C.

1 H NMR Spectrum (CDCl3, 300 MHz) δ = 7.41 (S, 5H) 6.49 (t, J 3 = 1.2 Hz, 1H) 5.28 (s, 2H) 4.07 ( d, J0 c = 1.2 Hz, 2H) 3/0

Example 6

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Dissolve 3/8 g (0/02 mol) of 4- (ethoxycarbonyloxy) -thiophen-2 (5H) -one in 25 ml of tetrahydrofuran and cool the solution to -10 ° C. To this solution is added a solution of 2.9 g (0.04 mole) of diethylamine in 35 ml of tetrahydrofuran.

The separated solid is aspirated (diethylammonium salt of thiotetronic acid) and taken up in 20 ml of water. The mixture is acidified with stirring with concentrated hydrochloric acid to pH 1-2. The precipitated thiotetronic acid is extracted with 100 ml of ethyl acetate. The organic phase is dried over Na 2 SO 4 and the solvent is evaporated on a rotary evaporator. The residue is dried in high vacuum. 2.0 g of thiotetronic acid is obtained as an almost white microcrystalline lens product, m.p. 120-122 ° C with a purity of 96.9% (NaOH titration). This corresponds to 1.9 g of 100% pure product or a yield of 83.6%, based on the 4- (ethoxycarbonyloxy) -thiophen-2 (5H) -one used.

Claims (9)

Compound according to claim 1, characterized in that it is 4- (ethoxycarbonyloxy) -thiophene-2 (5H) -one of the formula O II ο2η5οοο Compound according to claim 1, characterized in that it is 4- (methoxycarbonyloxy) -thiophen-2 (5H) -one of the formula 0 (CH 2 OCC) J 7 === 1 J = o Process for the preparation of 4-substituted thiophen-2 (5H) -one derivatives according to claim 1, characterized in that 4-chloro-4-chloromethyloxetan-2-one of the formula DK 162641 B HV / H C1 yx xy> is reacted with dihydrogen sulfide in the presence of a base, and the intermediately formed thiotetronic acid of formula H0 - r ~ 5 X ^ = ° X is reacted with a chloroformic acid ester of formula C1C00R, wherein R is as defined in claim 1 meaning, or with p-toluenesulfonic acid chloride. Process according to claim 4, characterized in that primary, secondary or tertiary amines, ammonia or guanidine are used as bases. Process according to claims 4 and 5, characterized in that tertiary amines are used as bases. Process according to claims 4-6, characterized in that the reaction is carried out in inert solvents. Process according to claims 4-7, characterized in that the molar ratio of the starting materials chloromyric acid ester / p-toluenesulfonyl chloride, base and 4-chloro-4-chloro-methyloxetan-2-one is 0.8: 2.8: 1. 0 to 1.0: 4.0: 1.0. Process according to claims 4-8, characterized in that the molar ratio of dihydrogen sulfide to 4-chloro-4-chloromethyloxetan-2-one is 1: 1 to 1: 3. Process according to claims 4-7, characterized in that it is operated in a temperature range from -40 ° C to 20 ° C.