Patent GB-789789-A (GB)
Title: 2-keto-benzo[ª]quinolizines and the manufacture thereof
Filed: 1956-06-04
Abstract: The invention comprises 2-ketobenzo-[a]-quinolizines of the formula <FORM:0789789/IV (b)/1> in which the benzo moiety may be hydrogenated at positions 8-11 and the optional substituents R1 and R2 represent alkoxy groups containing up to three carbon atoms or together represent an alkylenedioxy group; R3 is an alkyl (excepting ethyl, when the benzo ring is unsaturated), alkenyl, or aralkyl group containing up to eight carbon atoms or the tetrahydrofurfuryl group; and a process for their preparation (and of their salts) by condensing a 1-alkoxycarbonylmethyl-1,2,3,4 - tetrahydro - isoquinoline (or the 1 ... 8-octahydro analogue) which may contain alkoxy or an alkylene-dioxy substituent(s) at the 6- and 7-positions with formaldehyde or paraformaldehyde and a malonic acid or its dimethyl ester substituted by the group R3, cyclizing the 1-alkoxycarbonylmethyl-2-[21,21-(dicarboxy or dimethoxycarbonyl)-21-R3-substituted-ethyl] - 1,2,3,4 - tetrahydro - (or - 1 ... 8-octahydro-) isoquinoline or its 6,7-di(alkoxy) or alkylenedioxy derivative so obtained (after conversion of any carboxy groups to methoxycarbonyl by methylation) by heating with an alkaline condensing agent, hydrolysing and decarboxylating the resulting 1-alkoxycarbonyl-2-oxo - 3 - methoxycarbonyl - 3 - R3 - substituted-1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine or derivative thereof and converting the resulting salt of a 2-oxo-3-R3-substituted-1,2,3,4,6, 7-hexahydro-benzo-[a]-quinolizine into the free base or further salts, e.g. with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, citric or ethane sulphonic acid.  In examples: (1) 1 - ethoxycarbonylmethyl - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline, paraformaldehyde and dimethyl methylmalonate are refluxed in methanol and the resulting 1-ethoxycarbonylmethyl - 2 - (21,21 - dimethoxy - carbonyl - propyl) - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline treated with sodium methoxide in toluene and then hydrolysed and decarboxylated with 3N HCl, whereupon addition of ammonia precipitates 3 - methyl - 9,10 - dimethoxy - 2 - oxo - 1,2,3,4,6,7 - hexahydro - benzo - [a] - quinolizine, characterized as its hydrochloride; similarly (2), (5), (7), and (9) to (13) and (15) to (17) are prepared the following 2-oxo-1,2,3,4,6,7-hexahydrobenzo - [a] - quinolizines:-3 - ethyl - 9,10 - dimethoxy -, 3 - allyl - 9,10 - dimethoxy -, 3 - butyl - 9,10 - dimethoxy -, 3 - benzyl - 9,10 - dimethoxy -, 3 - isobutyl - 9,10 - dimethoxy -, 3 - amyl - 9,10 - dimethoxy -, 3 - hexyl - 9,10 - dimethoxy -, 3 - ethyl - 9,10 - methylenedioxy -, and 3 - tetrahydrofurfuryl - 9,10 - dimethoxy -; (3) and (4) 1-ethoxy-carbonylmethyl-6,7-dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline and ethylmalonic acid are treated with aqueous formaldehyde, the resulting 1-ethoxycarbonylmethyl - 2 - (21,21 - dicarboxybutyl) - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinoline methylated with diazomethane or dimethylsulphate and then cyclised, hydrolysed and decarboxylated to the product of (2); similarly, (6) and (8), are prepared 2-oxo-3-isopropyl- and 2 - oxo - 3 - butyl - 9,10 - dimethoxy - 1,2,3,4,6,7-hexahydrobenzo - [a] - quinolizine; and (14) 1 - methoxycarbonylmethyl - 1,2,3,4,5,6,7,8 - octahydro-isoquinoline, dimethyl ethylmalonate and paraformaldehyde yield 1-methoxycarbonylmethyl - 2 - (21,21 - dimethoxycarbonyl - butyl) - 1,2,3,4,5,6,7,8 - octahydro - isoquinoline which is cyclized, hydrolysed and decarboxylated to 2 - oxo - 3 - ethyl - 1,2,3,4,6,7,8,9,10,11 - decahydro-benzo-[a]-quinolizine.  The preparation of 2-hydroxy-3-ethyl- and 2 - hydroxy - 3 - butyl - 9,10 - dimethoxy - 1,2,3,4,6,7 - hexahydrobenzo - [a] - quinolizine by reduction of the corresponding 2-oxo compounds with hydrogen and platinum dioxide and with lithium aluminium hydride respectively is also described.  The compounds are characterized as acid addition salts.