DE1036857B - Process for the preparation of 5- (isobutyl) -5-ethyl-1-methylthiobarbituric acid and salts thereof - Google Patents

Description

Process for the preparation of 5- (isobutyl) -5-ethyl-l-methylthiobarbituric acid and their salts. The invention relates to a method. for production of 5- (Isohutyl) -5-ethyl-l-methylthiobarbituric acid and its therapeutically useful Salts, especially the sodium salt.

This thiobarbituric acid derivative is produced by the process according to the invention produced in that a dialkyl isobutylethylmalonate with N-methylthiourea in a solution of an alkali metal alcoholate, preferably sodium alcoholate, in one implemented low molecular weight aliphatic alcohol or a low molecular weight alkyl ester from isobutylethylcya, n-acetic acid with N-methylthiourea to the corresponding iminothiobarbituric acid condensed and this is hydrolyzed.

The thiobarb, i, tursäu, r-e can by reaction with a metal alcoholate in solution in the appropriate alcohol or with an aqueous alkali in their therapeutic valuable salts are implemented.

The compounds of the present invention are anesthetics for surgical use, which have a much shorter duration of action than the well-known compounds, which makes them particularly useful for very brief anesthesia are well usable as they are desired for minor surgical interventions.

The efficacy of these compounds has been determined by intravenous administration to mice placed on a rotating drum 3 minutes after injection. The potency (ED 50) is expressed as the dose which caused 50 % of the animals to fall.

It is already known that certain 1-methylthiobarbituric acids disubstituted in the 5-position can be prepared from the corresponding disubstituted malonic acid esters or cyanoacetic acid esters and N-methylthiourea (cf. British patent 720 826). The ethyl and allyl radicals or the 1-ethylpropyl and 1-methylbutyl radicals are mentioned as substituents in the 5-position. These acids and their salts are recommended as anesthetics and hypnotics. Compared to this prior art, the new compounds prepared according to the invention have the particularly valuable property that the narcotic effect they produce lasts only for a very short period of time (see table below), which makes them very suitable for minor surgical interventions. A study carried out with mice series of experiments confirmed this advantageous effect manner, using as comparison substance loading knew sodium salt of 5- (1'-methylbutyl) -5-ethyl-1-methyl-2-thiobarbituric acid. Tabel ED 50 LD 50 LD 50 anesthetic time Na salt from in seconds mg / kg mg / kg ED 50 (dose = 8 - ED 50) 5- (1'-methylbutyl) -5-ethyl-l-methyl- 2-thiobarbituric acid ........ 6 60 10 2529 5- (Isobtityl) -5-ethyl-1-methylthioba, rbituric acid 7.3 76 10.4 800 The compounds of the present invention have also been administered to cats to determine whether their anesthetic properties are accompanied by any adverse side effects. In these tests no irregularities in cardiac activity were found, and there was no significant difference between these compounds and known analogous substances (sodium salt of 5-ethyl-5- (1'-methylbutyl) -2-thiobarbituric acid) with regard to blood pressure or blood pressure Transmission in an autonomic ganglia. There was no significant difference in effects on respiration or blood pressure in rabbits.

The following examples illustrate the invention. Example 1 a) 5.3 g of sodium were dissolved in 100 cm3 of absolute ethyl alcohol. 62 g of diethyl isobutylethylmalonate and then 25 g of N-methylthieurea were added to this solution. The mixture was heated to reflux for 24 hours, after which it was allowed to cool and poured onto 100 g of solid carbonic acid. After 20 minutes, 400 cc of water was added to the mixture and the separated oil was taken up in ether. The ether solution was first washed with water, three times with 100 cms of a 2% aqueous Natriumbiearbonatlösung and finally with water. The solution was then dried over anhydrous magnesium sulfate and filtered. The ether was evaporated and the residue was distilled under reduced pressure and the fraction boiling at b.p. 0.7 136 to 138 ° C. was collected. This fraction consisted of 5- (isobutyl) -5-ethyl-1-methylthiobarbituric acid, which was a very pale green viscous liquid with the refractive index n " - 1-5592 .

D analysis: Calculated C 54.52, H 7.48, N 11.57, S 13.23 %; found C54.65, 117.51, N11.7, s13.050 / 0. b) 10 cm3 of a sodium ethylate solution (2.3 g of sodium in 100 cm3 of absolute ethyl alcohol) were added to 2.43 g of 5- (isobutyl) -5-ethyl-1-methylthiobarbittic acid. The solvent was removed by evaporation and the remaining solid triturated; the sodium salt of 5- (isobutyl) -5-ethyl-l-methylthiobarbituric acid formed a light yellow colored powder of melting point 264-266 'C. EXAMPLE 2 345 g Isobutyläthyleyanessigsäureäthylester and 157.6 g of N-methylthiourea were added to a solution prepared by dissolving of 40.27 g of sodium in 600 cm3 of absolute ethyl alcohol. The mixture was heated to reflux for 16 hours to boiling and then allowed to cool and poured into 31 of ice water. A mixture of 100 cm3 of concentrated hydrochloric acid and 200 cm3 of water was slowly added with stirring and the acidification was then completed by introducing carbon dioxide into the reaction table. An oil separated out and solidified. The solid reaction product was separated by filtration and dissolved in 400ems 95% ethanol. 100 cms of water was added to the solution. On cooling, 5- (isobutyl) -5-ethyl-l-methyl-4-iminobarbituric acid separated out in crystalline form, which had a melting point of 104.5 to 105.50 ° C. after recrystallization from 80% ethanol. A solution of 54 cubic meters of concentrated hydrochloric acid in 1000 cubic meters of water was added to 142 g of this compound, and the mixture was refluxed for 1 hour with constant stirring. The mixture was then allowed to cool. The organic layer which separated was extracted with ether. The ether solution was washed with water and dried over anhydrous magnesium sulfate. After filtering, the ether was removed from the filtrate by evaporation. The residue was distilled under reduced pressure, and the over at Kp. 1, 141 'C fraction was collected. 5- (isobutyl) -5-ethyl-l-methylthiobarbituous acid was obtained as a pale green viscous liquid; n ' = 1.5592.

D 86.48 cm3 of a 2.673 normal solution of sodium ethylate in absolute alcohol was added to a solution of 56 g of 5- (isobutyl) -5-ethyl-1-methylthiobarbituric acid in 200 cubic meters of anhydrous benzene. The resulting solution was filtered and the mixed solvent was removed by distillation under reduced pressure until the reaction gel became cloudy. A further 100 ml of anhydrous benzene were added and the crystals formed were filtered off and dried in vacuo. The product was a light yellow colored crystalline solid with a melting point of 258 ° C.

In the present description, the term “low molecular weight aliphatic alcohol” is understood to mean an aliphatic alcohol with not more than 3 carbon atoms.

Claims (1)

Claim: Process for the preparation of 5- (isobutyl) -5-ethyl-1-methylthiobarbituric acid and salts thereof, characterized in that dialkyl isol) utvläthylmalonsäuredester with -N-methylthiourestcff in a solution of an alkali metal alcoholate, preferably a sodium alcoholate, in a low molecular weight reacted aliphatic alcohol or that a low molecular weight alkyl ester of iso-1) utyläthvlcyanessigsäure with N-methylthiourea condenses to # the corresponding iminothiobarbituric acid and this is hydrolyzed and optionally the # - (isol) utyl) -5-ethyl-1-methylthiobarl) is converted into their salts, in particular the sodium salt, by reaction with a metal alcoholate in a solution in the corresponding alcohol or with an aqueous alkali. References considered: British Patent No. 720826.