Process for the preparation of tetramisole.

摘要

There is disclosed a process for the preparation of tetramisole which comprises the steps of: a) reacting an imidoyl halide having the formula F: X-C(R1)=NCH(Ar)CH2-X wherein Ar is phenyl, R1 is hydrogen, lower alkyl, or phenyl or lower alkyl-substituted phenyl, R2 is hydrogen or lower alkyl, and X is halo, with hydroxyethylamine or alkoxyethylamine having the formula: R2O-(CH2)2-NH2 wherein R2 is hydrogen or lower alkyl to obtain an amidine hydrohalide having the formula: R2O-CH2-CH2-NH-C(R1)=NCH(Ar)CH2X.HX; b) reacting the latter amidine hydrohalide with either an inorganic base, hydroxyethylamine or alkoxyethylamine having the formula: H2N-CH2-CH2-OR2 in the presence of an inert halogenated hydrocarbon to obtain an imidazoline having the formula: <CHEM> where Ar, R1, and R2 are as defined above; c) hydrolyzing the latter imidazoline to cleave the ring to thereby obtain an amidoamine having the formula: R1CONH-CH(Ar)-CH2-NH-CH2-CH2-OR2 wherein Ar, R1, and R2 are as defined above; d) further reacting the latter amidoamine with a suitable inorganic base or acid to obtain a diamine having the formula: NH2-CH(Ar)-CH2NH-CH2-CH2-OR2 wherein Ar, R1, and R2 are as above defined; e) reacting the latter diamine with carbon disulfide to provide a dithiocarbamate having the tautomeric formula: <(-)>SC(S)-NH-C(Ar)-CH2-<(+)>NH2(CH2)2-OR2; f) heating the latter dithiocarbamate to produce a thione having the formula: <CHEM> g) reacting the latter thione with an acid having the formula: HA to provide an imidazothiazole having the formula: <CHEM> wherein Ar, R1, and R2 are as defined above, and A is an anion of a pharmaceutically acceptable acid, and h) neutralizing the latter to obtain tetramisole having the formula: <CHEM> Certain of the intermediates obtained in this process, as well as certain of the individual steps thereof, are novel per se.