Patent GB-960182-A (GB)
Title: New isoquinoline derivatives and their preparation
Inventor: WALKER THOMAS
IPC: C07D455/08
Filed: 1960-05-27
Abstract: The invention comprises compounds of the skeletal formula:-<FORM:0960182/C1/1> in which R3 represents an aliphatic or araliphatic hydrocarbon group, particularly a benzyl group, and which may be further substituted in one or both of the isoquinoline rings by one or more alkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, or di-substituted amino groups, particularly methyl, ethyl, propyl, isobutyl, butyl, amyl, benzyl, phenyl, methoxy, ethoxy, propoxy, butoxy, benzyloxy, phenoxy, methylenedioxy or dialkylamino groups, and especially methoxy groups in positions 6,7,61 and 71, together with a process for their preparation by reacting a compound of the skeletal formula:- <FORM:0960182/C1/2> (wherein R is H or COOH, and which is prepared by condensation of an appropriately substituted 3,4-dihydroisoquinoline with acetone or acetone dicarboxylic acid) with an isoquinoline pseudobase of the skeletal formula <FORM:0960182/C1/3> (itself prepared by quaternising an appropriately substituted 3,4-dihydroisoquinoline with R3X(X is an anion-forming atom or group) followed by reaction with alkali).  When R represents H, the reaction is preferably effected in the presence of an acid or basic catalyst, particularly anhydrous sodium carbonate in ethanol. The invention further provides a process for the preparation of benzoquinolizines of the skeletal structure:- <FORM:0960182/C1/4> (R1 is an aliphatic, aromatic or araliphatic hydrocarbon group) by reaction of a vinyl ketone CH2:CHCOR1 with a compound of the first general formula given above and cyclisation of the product in the presence of a condensation catalyst, particularly an alkali metal hydroxide, hydride, amide or alkoxide. Subsequent treatment of the benzoquinolizine with a dehydrating agent, e.g. a mineral acid preferably at about 100 DEG C. yields a 2,3-unsaturated benzoquinolizine of the skeletal formula:- <FORM:0960182/C1/5> (or an isomer in which the unsaturation is elsewhere in Ring C) which upon reduction with a reducing agent serving to reduce carbon-carbon double bonds, e.g. a metal/ammonia or metal/amine system, yields to corresponding Ring C saturated compound, which upon further reduction with a carbonyl rducing agent, preceded if desired by acid isomerisation at C3, yields a compound of the skeletal formula:- <FORM:0960182/C1/6> The process of carbonyl group reduction may be achieved via an intermediate thioketal derivative. Finally, the group R3, e.g. benzyl, may be removed by hydrogenolysis to give emetine or an analogue thereof.  The invention is illustrated by 10 examples. An alternative synthesis of emetine analogues from the compounds of the invention is described, involving condensation with an anhydride or acid halide of R2CH2COOH, and then cyclisation, preferably in the presence of a basic catalyst to give a compound of the formula:- <FORM:0960182/C1/7> (R2 is an aliphatic, araliphatic or aromatic hydrocarbon group) or the g :d  unsaturated isomer thereof, followed by reduction of the C ring unsaturation and of the amide grouping. Specification 960,181 is referred to.