Preparation of semisynthetic (+)-tubocurarine chloride.

Semisynthetic (+)-tubocurarine chloride (II) was prepared by monoquaternization of (+)-tubocurine. The method involved treating (+)-tubocurine with a 0.5 M equivalent of hydrochloric acid prior to quaternization with methyl iodide, followed by neutralization and iodide-chloride ion-exchange. Column chromatography and crystallization procedures were utilized for pure semisynthetic II preparation. The neuromuscular junction blocking activities of the semisynthetic and commercial II were determined by the in vivo cat hypoglossal nerve-tongue muscle preparation. No delectable differences among physical constants, spectral data, and neuromuscular junction blocking activities were noted between the commercial product and the semisynthetic II. This result substantiates the chemical and biological data for the well-accepted new formula for II. The unexplained M + n14 mass spectral peaks shown by the curare-type bases are characteristic of the molecular species rather than a result of contaminants.

Dequaternization of curare bases with sodium thiophenoxide and ethanolamine.

To prepare (+)-tubocurine and O,O-dimethyl-(+)-tubocurine, the commonly used dequaternization procedures with sodium theophenoxide and ethanolamine were investigated. The quaternary compounds were (+)-tubocurarine chloride and the chloride and iodide salts of O,O-dimethyl-(+)-chondocurarine. The results obtained with ethanolamine indicate that Hofmann elimination is a major pathway and that N-demethylation is minor. The elimination products of O,O-dimethyl-(+)-chondocurarine iodide with ethanolamine were identified as O,O-dimethyltubocurinemethine, O,O-dimethyltubocurineisomethine, and O,O-dimethyltubocurinedimethine. N-Demethylation was the primary reaction with sodium thiophenoxide. Thus, dequaternization of (+)-tubocurarine chloride with sodium thiophenoxide provided (+)-tubocurine which, on diazomethylation, yielded O,O-dimethyl-(+)-tubocurine, identical to the compound obtained by N-demethylation of O,O-dimethyl-(+)-chondocurarine chloride with the same reagent.

Hofmann elimination with diazomethane on curare bases and selected quaternary tetrahydroisoquinoline alkaloids.

Use of a large excess of alkali-free diazomethane resulted in a Hofmann elimination with selected curare bases and some other quaternary tetrahydroisoquinoline alkaloids. (+)-Tubocurarine chloride provided a monostilbene methine, O,O-dimethyltubocurinemethine, and a monostilbene--monostyrene compound, O,O-dimethyltubocurinedimethine. The major elimination products of (+)-isotubocurarine chloride and (+)-carnegine methiodide were monostyrene methines, O,O-dimethyltubocurineisomethine and carneginemethine, respectively. Treatment of (+)-laudanosine methiodide with potassium hydroxide, under the conditions of Hofmann degradation, or alkali-free diazomethane solution provided the same stilbene compound, laudanosinemethine. The structures of the elimination compounds were further confirmed by catalytic reduction and quaternization with methyl iodide.