Patent GB-800969-A (GB)
Title: Novel 2-hydroxy-benzo [ª‡] quinolizines, acid addition salts thereof and a process for the manufacture of same
IPC: C07D455/06
Filed: 1957-02-04
Abstract: This invention comprises compounds of the general formula: <FORM:0800969/IV (b)/1> and acid addition salts thereof, wherein R1 and R2 each represent a hydrogen atom or a hydroxy or alkoxy group or together represent an alkylenedioxy group, and R3 represents an alkyl group, an alkyl group which contains an oxygen atom in the form of a normal or cyclic ether function, or an alkenyl or aralkyl group, and wherein the broken lines denote that the isocyclic ring may contain one or two further double bonds; and a process for the manufacture thereof by reducing a compound of the general formula: <FORM:0800969/IV (b)/2> and, if desired, converting the product into an acid addition salt.  Reduction may be effected by hydrogen in the presence of a hydrogenation catalyst, in which case alkenyl groups are also reduced to alkyl groups, by alkali metal in the presence of an alcohol, or by the use of lithium-aluminium hydride or sodium boron hydride.  In an example, 2-oxo-3 - ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine is hydrogenated in glacial acetic acid, in the presence of prehydrogenated platinum oxide catalyst at ca. 20 DEG  C. to form 2-hydroxy-3-ethyl-9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo -[a] - quinolizine.  The same compound is also prepared in further examples from the same starting material by hydrogenation in methanol, in the presence of Raney-nickel, with hydrogen under pressure at 50 DEG  C.; by reaction with metallic sodium in butanol; and by reaction with lithium-aluminium hydride in the presence of a mixture of dioxane and ether (1 : 4), followed by hydrolysis with water.  In each case, the hydrobromide, the hydrochloride and the acid sulphate are formed.  2-Hydroxy-3-n-butyl-9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydrobenzo-[a]-quinolizine is prepared from the corresponding 2-oxo-compound by hydrogenation in methanol and in glacial acetic acid, by reduction with metallic sodium and butanol and by reduction with lithium-aluminium hydride, the base being converted into the hydrobromide; and 2,9,10 - trihydroxy - 3 - ethyl - 1,2,3,4,6,7-hexahydrohydro - benzo - [a] - quinolizine hydrobromide is prepared from its corresponding 2-oxo-compound, in the form of its hydrobromide, by hydrogenation in 50 per cent acetic acid in the presence of a platinum oxide catalyst.  (The product is identical with that obtained by hydrolysis of the 2-hydroxy-3-ethyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine, formed above, with 48 per cent hydrobromic acid.)  The following may also be prepared by the methods given: 2-hydroxy-3-methyl-, 2-hydroxy-3-isobutyl-, 2-hydroxy-3-amyl-, 2-hydroxy-3-hexyl-, and 2 - hydroxy - 3 - (o  - methoxy - butyl) - 9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizines and their hydrochlorides; 2-hydroxy - 3 - allyl -, and 2 - hydroxy - 3 - (tetrahydro - furfuryl) - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizines and their hydrobromides; 2-hydroxy-3-ethyl - 9,10 - diethoxy and 2 - hydroxy - 3 - ethyl - 9,10 - methylenedioxy - 1,2,3,4,6,7 - hexahydro-benzo-[a]-quinolizines and their hydrochlorides, 2,9,10 - trihydroxy - 3 - butyl - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine and its hydrobromide; 2-hydroxy-3-benzyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine and its picrate; and 2-hydroxy-3-ethyl- and 2-hydroxy-3-butyl-1,2,3,4,6,7,8,9,10,11 - decahydrobenzo - [a] - quinolizines.  Starting materials: 2-Oxo-3-ethyl-9,10-dimethoxy - 1,2,3,4,6,7 - hexahydro - benzo - [a]-quinolizine is prepared by reacting 1-ethoxycarbonylmethyl - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline, paraformaldehyde and dimethyl monoethyl-malonate to form 1-ethoxycarbonylmethyl - 2 - [21,21 - di - (methoxycarbonyl) - butyl] - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro-isoquinoline which is then reacted with sodium ethoxide to effect ring closure, and then with 3-n-hydrochloric acid to effect hydrolysis and decarboxylation.  The product is isolated as the base which is converted into the hydrochloride and hydrobromide. 2-Oxo-3-ethyl - 9,10 - dihydroxy - 1,2,3,4,6,7 - hexahydrobenzo-[a]-quinolizine hydrobromide is prepared from the corresponding 9,10-dimethoxy compound or its hydrobromide by hydrolysis with 48 per cent hydrobromic acid.  Specification 789,789 is referred to.