A general procedure for the synthesis of -methylamino acids employing the crystalline sodium derivative of dimethyl acetylmethylaminomalonate has been developed. The intermediate dimethyl methylaminomalonate has been prepared by two methods: (1) by esterification of methylaminomalonic acid with methanol and thionyl chloride and (2) by reaction of dimethyl bromomalonate with methylbenzylamine followed by hydrogenolysis in acetic acid solution in the presence of platinum. Condensation of the sodium derivative VII with gramine methiodide, with benzyl chloride and with 4(5)chloromethylimidazole, followed by hydrolysis of the intermediate alkylation products, has led to the production, respectively, of a-methylamino-/3-(3-indole)-propionic acid, N-methyl-DL-phenylalanine, and a-N-methyl-DL-histidine.
On the basis of degradation studies, lysergic acid was shown to be an unsaturated 6-methyl-8-ergolinecarboxylic acid (1). This structure appeared to be confirmed by the transformation of lysergic acid to 6,8-dimethylergoline, a substance which could be obtained by synthesis (2). More rigid confirmation of the structure has now been obtained by the synthesis of a closer derivative of lysergic acid itself, dihydro-dZ-lysergic acid. In the course of this work, a new synthesis of the difficultly accessible 3-substituted quinolines has been developed. By this procedure, it is possible to synthesize directly quinolines substituted in the hetero-ring in only the 3-position. 3-Nitroquinolines and 3-quinolinecarboxylic acids are obtained directly, while other substituents are introduced into the 3-position through these groups. Dihydro-dZ-lysergic acid was synthesized by the series of reactions shown in Formulas I-VIII.Cyanoacetal (I) was prepared from bromoacetal with potassium cyanide. The bromine atom in bromoacetal was found to be quite inert in metathetical reactions with metallic cyanides. No appreciable reaction was apparent when bromoacetal was refluxed with cuprous cyanide. With potassium cyanide in aqueous ethanol solution, 67% of the bromo compound was recovered unchanged, and the higher-boiling cyanoacetal was obtained in only 14% yield. By refluxing for a longer period, the yield was decreased. The cyanoacetal was allowed to react with ethyl formate and sodium in ether solution. The resulting sodium derivative of cyanomalonic dialdehyde (II), when dissolved in water, reacted at once with aniline hydrochloride in acid solution to give 2-cyano-2-
The main structural features of the digitalis-strophanthus group of cardiac aglycones rest on a reasonably firm foundation as a result of the investigations principally of Jacobs, Windaus, and Tschesche and their collaborators. The evidence on which these structures have been assigned has been adequately reviewed on several occasions (1). The main struc-
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