DE1193050B - Process for the preparation of isothiazoles - Google Patents

Description

Process for the preparation of isothiazoles The so far in the literature mononuclear isothiazoles described have functional groups such as hydroxy, Alkoxy or amino groups, in the 4- or 5-position.

It has now been found that new isothiazoles of the general formula can be obtained in which R1 is a hydroxy, alkoxy or amino group and R2 is an alkyl or aryl group, if one can produce compounds of the general formula wherein R3 is a carbamide, carbiminoalkyl ester, or amidine group, treated with an approximately equimolar amount of bromine in a solvent.

Suitable solvents are those which are used under the reaction conditions are inert to bromine, preferably alcohols, esters, e.g. B. ethyl acetate, and especially Pyridine. With the known sensitivity of thioketones to oxidizing agents the clear reaction according to the invention could not be expected.

The compounds of the general formula used as starting materials II, in which R3 is a carbamide or carbaminoalkyl ester group, is not obtained in appropriately claimed from the corresponding acylacetamides or acylacetimidoesters by reaction with hydrogen sulfide in the presence of hydrogen chloride and under Exclusion of water according to the in "Journal of Indian chemical Society (, Vol. 10, 1933, P. 71 for the preparation of the thioketone corresponding to the acetoacetic ester Way of working. The starting compounds of the general formula II, wherein R3 is a Amidine group is obtained in a manner not claimed from the corresponding Thioacylacetimidoesters by reaction with ammonia.

The new isothiazoles of the general formula I are valuable starting materials for the production of dyes or drugs. By reacting with bromine in one Mixture of glacial acetic acid and water can put the process products in the 4-position brominate.

(Protection is not sought for this process.) Example 1 a) 15.2 g (0.15 mol) of acetylacetamide are dissolved in 400 ml of methanol, which at -6 "C with saturated dry hydrogen chloride and then 30 minutes with dry hydrogen sulfide was treated, entered with stirring. You then lead a vigorous 6 hours Stream hydrogen sulfide through at -6 to 0 ° C using a frit. Thioacetylamide hydrochloride begins as soon as the hydrogen sulfide is introduced to crystallize. Complete separation is achieved after the reaction has ended cooled to -20 "C.

The isolated, colorless hydrochloride is washed with absolute ether. The yield of thioacetylacetamide hydrochloride is 21.6 g (94% of theory). For further purification, the salt is dissolved in cold, absolute methanol, with ether added until turbid and cooled to 5 ° C. Colorless needles are obtained from Decomposition point 109 "C. The compound can only work with the complete exclusion of moisture be kept. b) 15.4 g (0.1 g-mol) of this thioacetylacetamide hydrochloride are suspended in 70 ml of absolute ethyl acetate and added dropwise at 20 ° C a solution of 16 g (0.2 gram atom) of bromine in 100 ml of absolute ethyl acetate was added. Half of the bromine solution is quickly decolorized. If you continue to drop it, it will remain get the bromine color. It is stirred vigorously for a further 24 hours, then the hydrobromide separated from the still bromine-containing solvent together with residues of disulfide and treated with 200 ml of water.

After filtering off the insoluble disulfide (1.3 g), the aqueous Phase extracted in the perforator with ether. Remains after evaporation of the ether a slightly brownish crystals (9.8 g, 850 / o of theory), which from 200 ml Ligroin (boiling point 60 to 95 "C) is recrystallized.

The 3-hydroxy-5-methylisothiazole falls in colorless prisms of melting point 96 "C at that in water and most organic solvents are readily soluble. The methanolic solution turns blood red with iron (III) chloride.

Example 2 a) 9.78 g (60 milimoles) of benzoylacetamide are in 500 ml Methanol, which is saturated with dry hydrogen chloride in the cold and then Was treated with dry hydrogen sulfide for 30 minutes, dissolved. It still will A vigorous stream of hydrogen sulfide passed 6 hours at -6 to 0 ° C and the batch was left to stand for 12 hours at room temperature. Then the Solution medium evaporated. It leaves a mercaptan-like smell which is oily Residue, which is dissolved in methanol and mixed with 100 ml of ethyl acetate. b) 15 ml of pyridine are added to the solution and it is oxidized with a solution of bromine in ethyl acetate (9.6 g of bromine in 50 ml of ethyl acetate). Consumption: 0.11 g-atom of bromine. To Shaking with 50 ml of water, the ethyl acetate phase is lifted off, dried and evaporated. After repeated recrystallization, the viscous brown residue becomes 3.3 g (31% based on benzoylacetamide) of the desired, still yellow 3-hydroxy-5-phenylisothiazole isolated.

The substance forms colorless tablets with a melting point of 182 "C (from methylene chloride). It is not readily soluble in ether, acetone, methylene chloride, ethyl acetate and ethanol soluble in water and petroleum ether.

Iron (III) chloride turns the alcoholic solution blood red.

CH7NOS (177.2).

Calculated C 60.98, H 3.98, N 7.90, S 18.09, 0 9.03; found C 61.45, H 4.14, N 7.92, S 18.40, 0 9.15.

Molecular Weight (Cryoscopically in Dioxane) 171.

Example 3 a) In a solution of 21.4 g (0.1 mol) of benzoylacetimidomethyl ester hydrochloride in 150ml methanol, which has been treated with hydrogen chloride for 30 minutes, passes a vigorous stream of hydrogen sulfide at -6 to 0 ° C for 6 hours. To After 2 hours of exposure to hydrogen sulfide, the crystallization begins to be colorless Needles. After the reaction has ended, 17 g of the hydrochloride are filtered off. The filtrate is concentrated to a quarter of its volume in vacuo at room temperature and mixed with 100 ml of absolute ether, with a further 4 g of thiobenzoylacetimidomethyl ester hydrochloride accumulate. Overall yield: 91% of theory. The hydrochloride loses constantly hydrogen chloride, so that the analytical values are always too high.

With water it forms the poorly soluble, yellow, free base, which also can be obtained in pure form thermally (above 100 ° C).

10 milimoles of the hydrochloride obtained above are mixed with 20 ml of water, to which 0.8 g (10 milimoles) of pyridine were added, hydrolyzed with stirring and cooling. There are yellow crusts that are washed with water until none Chlorine ions are more detectable. For further cleaning be at room temperature saturated solutions in ethanol or methylene chloride with a lot of petroleum ether (b.p. 40 up to 60 "C) and cooled to 0 ° C.

Lemon yellow needles of decomposition point 109 "C are obtained. The Thiobenzoylacetimidomethyl ester is very easily soluble in methylene chloride, easily in methanol, glacial acetic acid and benzene, moderately in ether and insoluble in water and petroleum ether. In dilute caustic soda it dissolves colorless and leaves itself with it when blunted Precipitate acid again. b) 5.8 g of the thiobenzoylacetimidomethyl ester are in 50 ml of ethyl acetate are mixed with 4.8 g (60 milimoles) of pyridine and the mixture is stirred and cooled with ice 4.8 g (60 mg atom) of bromine in 50 ml of ethyl acetate are added dropwise. The bromine will quickly discolored.

The mixture is stirred for a few more minutes, 100 ml of water are added while stirring, After the sediment has dissolved, the ethyl acetate phase is separated off and the aqueous phase is shaken Layer twice more with fresh ethyl acetate. The combined extracts will be washed twice with water, dried with magnesium sulfate and evaporated.

The oily residue crystallizes in the refrigerator after several hours. The yield is 5.2 g (910 in theory). Crystallized from 5 mol of ethanol 3-methoxy-5-phenylisothiazole in colorless flakes with a melting point of 64 "C. The Compound is easily soluble in all organic solvents except water.

CloH9NOS (191.2).

Calculated .... N 7.33, S 16.77; found .... N 7.38, S16.95.

Molecular weight (cryoscopically in dioxane) 194.

Example 4 a) In an analogous manner, from 11.4 g (50 milimoles) Benzoylacetimidoethyl ester hydrochloride 10.6 g (87 0 / o) thiobenzoylacetimidoethyl ester hydrochloride, which analogously to the procedure in Example 3 gives the thiobenzoylacetimidoethyl ester, which crystallizes in lemon-yellow prisms from the decomposition point 142 to 144 "C. b) 6.2 g (30 milimoles) of this thiobenzoylacetimidoethyl ester are analogous to the example 3 cyclized with bromine to give 3-ethoxy-5-phenylisothiazole. 3-Ethoxy-5-phenylisothiazole is obtained as a slightly yellow-colored oil. This oil is over a 20 cm long Vigreux column fractionally distilled. At 0.01 Torr and 67 "C, a colorless liquid appears which has a pleasant aromatic smell. The yield is 5.2 g (85 0 / o of theory). Melting point 13 "C, d20 = 1.1698 g / ml, n2o0 = 1.5992.

Ci1H11NOS (205.3).

Calculated .... C 64.36, H 5.42, N 6.82, S15.62; found .... C 64.13, H 5.25, N 7.05, S15.54.

Molecular weight (cryoscopically in dioxane) 203.

Example 5 To a solution of 19.3 g of thiobenzoylacetamidine in 500 ml of methanol are 16 g of pyridine and then 16 g of bromine in 100 ml of methanol under vigorous Stirring at room temperature was added dropwise. It will be 12 hours at room temperature stirred, the solvent driven off in vacuo, the residue mixed with water and sucked off. After recrystallization from 500/0 in alcohol, what is obtained melts 3-Amino-5-phenylisothiozole at 192 to 194 "C. Crude yield: 16.8 g = 97% of theory.

Claims (3)

Claims: 1. Process for the preparation of isothiazoles of the general formula in which R1 is a hydroxy, alkoxy or amino group and R2 is an alkyl or aryl group, characterized in that compounds of the general formula wherein R3 is a carbamide, carbiminoalkyl ester or amidine group, treated with an approximately equimolar amount of bromine in a solvent. 2. The method according to claim 1, characterized in that the solvent Alcohols or esters can be used 3. The method according to claim 1, characterized in, that pyridine is used as the solvent. Documents considered: German Auslegeschrift No. 1,068,716; "Reports of the German Chemical Society", Vol. 61, 1928, pp. 1308ff. and 1681ff.