Ethyl(3-hydroxy-n-butyl)barbituric acid as a metabolite of neonal.

Earlier studies (1, 2) from this laboratory indicated that in the dog the alkyl side chains of pentobarbital and Amytal do not undergo w oxidation but are subject to oxidation at the y-carbon atom of the amyl chains. Dogs excrete pentobarbital as two optically active diastereoisomers of ethyl(3hydroxy-1-methylbutyl)barbituric acid and Amytal as ethyl(3-hydroxyisoamyl)barbituric acid. In order to learn whether this unusual oxidative pattern is general for a straight chain of 4 carbon atoms attached to a barbituric acid ring the metabolic fate of Neonal, 5-n-butyl-5-ethylbarbituric acid, was investigated. The procedure used for the isolation of other barbiturate metabolites yielded only one end-product of Neonal. Elementary analyses, ultraviolet and infra-red absorption spectra, and a positive iodoform test characterized the substance as 5-ethyl-5-(3-hydroxybutyl)barbituric acid (IV). Inasmuch as the compound was optically inactive, it was decided to confirm the structure by synthesis. 4-Bromobutene-1 (I) was prepared by the method of Linstead and Rydon (3) which involves the addition of ally1 magnesium bromide to trioxymethylene and subsequent treatment of the unsaturated alcohol with phosphorus tribromide in pyridine. The bromide was caused to react with ethyl ethylmalonate to yield 3-butenylethylmalonic ester (II). The disubstituted ester was condensed with urea to form 5-(3-butenyl)-5-ethylbarbituric acid (III). Treatment of the latter substance with sulfuric acid and then water led to the desired 5-ethyl-5-(3-hydroxybutyl)barbituric acid (IV). This compound proved to be identical with the metabolite of Neonal. It is now evident that, in the metabolism of substances containing alkyl chains, non-terminal as well as w oxidation must be considered. Previous work on the metabolic fate of compounds containing alkyl groups has been largely confined to carboxylic acids, in which ,6 oxidation occurs with facility. Few substances containing alkyl chains attached to carbocyclic