DE1119867B - Process for the production of new barbituric acid derivatives - Google Patents

Description

Process for the preparation of new barbituric acid derivatives It has been found that new and valuable derivatives of barbituric acid of the general formula can be obtained in which R1, R2 and R3 denote hydrogen atoms, aliphatic, cycloaliphatic, araliphatic or aromatic radicals or members of a cycloaliphatic ring that are common in pairs, are obtained when a malonic acid derivative of the general formula is obtained in which Y and Z denote an esterified carboxyl group and Y can furthermore also stand for a nitrile group and in which R1, R2 and R3 have the meaning given, in the presence of a compound of a metal of 11. Subgroup of the periodic table, especially a salt of such a metal with an organic acid, at a temperature between 120 and 300 ° C in the liquid or vapor state, optionally in the presence of a solvent or diluent, reacts in a known manner with acetylene, two vinyl groups, one of which is optionally substituted, containing malonic acid derivative is reacted in a manner known per se with urea or guanidine and any imino groups present in the barbituric acid derivative obtainable in this way are removed by hydrolysis in the presence of acids.

The first step of the process, the reaction of the malonic acid derivatives of the general Formei II with acetylene to the mentioned malonic acid derivatives, the two vinyl groups, one of which may be substituted include, is known from German Auslegeschrift 1,046,031. Protection is therefore not sought for this process step alone within the scope of the invention. Compounds of the general formula 11 are obtained by condensing malonic acid esters, in particular those derived from low molecular weight aliphatic alcohols, or from cyanoacetic esters, those of the low molecular weight aliphatic alcohols also being preferred, with aliphatic, cycloaliphatic or araliphatic aldehydes or ketones that contain at least Contain 2 carbon atoms and carry at least 1 hydrogen atom on the carbon atom adjacent to the carbonyl group. Suitable starting materials are, for example: ethylidene malonic acid diethyl ester, isopropylidene malonic acid diethyl ester, isobutylidene malonic acid dimethyl ester, cyclohexylidene malonic acid diethyl ester, isopropylidene malonic acid ethyl tert-butyl ester, isoamylidenemalonic acid ethyl ester. For example, the reaction of isopropylidene malonic acid diethyl ester with acetylene can be formulated as follows: Suitable catalysts are compounds of metals of the 11th subgroup of the periodic table, in particular those which are soluble in the reaction mixture when working in the liquid state. The preferred catalysts are salts of these metals with organic acids such as zinc acetate, zinc butyrate, zinc stearate, cadmium naphthenate and mercury-silver acetate. The reaction temperature is 120 to 30 ° C., preferably 150 to 200 ° C. The process is advantageously carried out generally in the liquid phase, expediently outside of the range of a solvent, for which all ;. Connections elg = x`-n, n, which are bastäiidig under the implementation b - #; UaI-Urgen, z. B. Carbon Hydrogen oci - r A-ti.er. The # '# cetylene is advantageously diluted under elevated pressure a: igev.-as, dt and expediently in an inert gas or gas, such as nitrogen. According to another embodiment of the first stage of the process, the compound of the general formula is passed over a solid catalyst together with acetylene and, expediently, with an inert gas. Both when working in the liquid state and when converting in the gas phase over solid catalysts, the reaction products are generally obtained from the reaction mixtures by fractional distillation.

Those obtainable in this way, on the middle carbon atom by two unsaturated Residues of substituted malonic acid derivatives are then used in a manner known per se Urea or guanidine implemented. The condensation is expediently taken in one low molecular weight aliphatic alcohol as a solvent using the appropriate Alkali alcoholate as a condensing agent at temperatures between 50 and 150 ° C before. The components are expediently used in approximately stoichiometric amounts. The condensing agent is generally used in amounts of from 10 to 150% on the malonic acid derivative added. The reaction mixture is worked up expediently by diluting with water, neutralizing the alkali metal alcoholate and shaking out of the reaction product, for example with ether. If you think of a cyanoacetate goes out and / or if guanidine was used as ring-closing component, so obtained from the barbituric acid derivatives containing imino groups which occur immediately the corresponding oxygen compounds by heating with aqueous acids, preferably with mineral acids such as 20% hydrochloric acid or 40% sulfuric acid. The end products are in turn advantageously obtained by extraction. The substituted ones are obtained Barbituric acids usually as solid after evaporation of the extractant Compounds by recrystallization, for example from benzene, toluene or Cyclohexane, can be purified.

The new substituted barbituric acid derivatives obtainable by the process are valuable sleeping pills which, compared to the known compounds which carry an ethyl radical in place of the vinyl group, are characterized by lower toxicity with comparable effectiveness and thus by a more favorable therapeutic index, as can be seen from the following table : Thera- SD " LDSO more peutic mg / kg mg / kg index LD eo / SDs or similar 5-ethyl-5-cyclo- hexen- (I) -yl- barbituric acid .... 40 540 13.5 5-vinyl-5-cyclo- hexen- (1) -yl- barbituric acid .... 40 840 21 The sedative effectiveness was determined according to F. Gross, J. Tripod and R. Meier, "Schweizerische Medizin Wochenschrift";, Vol. 85, 1953, pp. 305 to 309, the calculation of the LD50 value according to the method of Härber ( see "Naunyn-Selimiedebergs Archive", vol. 162, 1931, p. 490). In both cases the active ingredients were administered orally.

Another comparison with the well-known 5-cycloliepten- (1) -yl-5-allylbarbituric acid could not be carried out because this connection was established after the References were not successful. However, it can be assumed that the advantageous Properties of the products of the process of the vinyl group; can be attributed to since after our own experiments, the not described 5-cyclohexen- (1) -yl-5-ailylbarbituric acid is less effective (SD "= 75 mg / kg, LD50 = 620 mg / kg, therapeutic index = 8.3) as the compound obtainable according to the method used for comparison above.

The parts mentioned in the following examples are parts by weight. Example 1 520 parts of diethyl isopropylidene malonate and 16 parts of zinc stearate are heated to 1.80 ° C. in a pressure vessel with an acetylene-nitrogen mixture in a ratio of 2: 1 and under a pressure of 25 atmospheres. You replace the consumed acetylene by running out of time. at time presses fresh. If the pressure remains constant, the reaction mixture is cooled and let down. Distillation of the liquid mixture gives 430 parts, corresponding to 76 % of theory, of vinyl isopropenyl malonic acid diethyl ester with a boiling point of 120 ° C./18 torr.

First 23 parts of sodium are carried in 550 parts of absolute alcohol and then 103 parts of guanidine carbonate and heated the mixture for 30 minutes Reflux. Then 142 parts of vinyl isopropenyl malonic acid diethyl ester are added, and the mixture is refluxed for an additional 5 hours. One distills the Alcohol is removed under reduced pressure, the residue is treated with 2100 parts of 19% Hydrochloric acid and heated to boiling for 3 hours, with a total of about 100 parts of distillate subtracted from. The cooled residue is extracted several times with ether, the ethereal solution is dried and the ether is distilled off. 90 parts are obtained 5-vinyl-5-isopropenyl-barbituric acid, which, recrystallized from benzene, at 149.5'C melts. Example 2 260 parts of cyclohexylidenemalonic acid diethyl ester are present in the presence of 8 parts of zinc stearate under the conditions described in Example 1 with acetylene implemented. 200 parts are obtained, corresponding to 70% of theory, of diethyl vinylcyclohexen (1) -yl malonate from the boiling point 116 to 118 ° C / 0.4 Torr.

First 23 parts of sodium are added to 550 parts of absolute alcohol and then 103 parts of guanidine carbonate. The mixture is refluxed for 30 minutes, adds 165 parts of vinylcyclohexen- (1) -yl-malonic acid diethyl ester and keeps the mixture another 5 hours simmering. The alcohol is removed under reduced pressure, 2100 parts of 19% hydrochloric acid are added to the residue, and more 3 Heated under reflux for hours, a total of 100 parts of distillate being removed. The mixture is cooled to room temperature, the organic phase is separated off and extracted the aqueous three times with ether. The organic phase is combined with the ethereal solution, the mixture dried over sodium sulfate and the solvent under reduced Distilled pressure. 140 parts of 5-vinyl-5-cyclohexen- (1) -yl-barbituric acid remain as residue, which, after recrystallization from benzene, melts at 166 to 168 ° C.

Claims (1)

PATENT CLAIM: Process for the production of new barbituric acid derivatives of the general formula in which R1, R2 and R3 denote hydrogen atoms, aliphatic, cycloaliphatic, araliphatic or aromatic radicals or members of a cycloaliphatic ring which are common in pairs, characterized in that a malonic acid derivative of the general formula in which Y and Z denote an esterified carboxyl group, Y can also stand for a nitrile group and in which Ri, R2 and R3 have the meaning given, in the presence of a compound of a metal of subgroup II of the periodic table, especially a salt of such Metal with an organic acid, at a temperature between 120 and 300 ° C in the liquid or vapor state, optionally in the presence of a solvent or diluent, reacts in a known manner with acetylene, the resulting two vinyl groups, one of which is optionally substituted , containing malonic acid derivative is reacted in a manner known per se with urea or guanidine and any imino groups present in the barbituric acid derivative obtainable in this way are removed by hydrolysis in the presence of acids. Documents considered: German Patent No. 756 489; German interpretative document No. 1 046 031; "Journal of the American Chemical Society" c, Vol. 61 (1939), pp. 353/354 and 776-779.