Azasteroidal Hormone Analogues Related to Doisynolic Acid

Abstract

Condensation of P-712-methoxyphenethyla~nine with methyl coumalate followed by saponification of the ester gave ~-(m-111cthoxyphenethyl)-5-carboxy-2-pyrido1e (I). Cyclization of the pyridone using phosphorus oxychloride gave 3-carboxy-6,7-dihydro-9-methoxybe1~zo[a]-quinolizinium chloride ( I l e ) , which, on catalytic reduction, afforded the two possible racemic 3 -c a r b o x y -1 , 3 , 4 , 6 , 7 , l l b -h e x a h y d r o -~o i i n e s ( I I I b and IVb). The corresponding ethyl esters were prepared in an analogous manner and their stereochemistry was assigned on the basis of equilibration experin~ents. Mercuric acetate oxidation of the racernic esters gave 3-carbethoxy-1,2,3,4,6,7-hexahydro-9-methoxybenzo[a]quinolizinium perchlorate ( V ) .In continuing our worli on the preparation of amino acid analogues of artificial estrogens (I), we became interested in incorporating a nitrogen atom into the skeleton of coinpounds related to doisyilolic acid. Several isomers of the latter compound are linown to be potent estrogens (2). This paper describes the preparation of soine polyhydrobenzo[a]quinolizines (111-V) which represent 8-aza analogues of doisynolic acid.By the method of Wiley, Smith, and Knabeschuh (3), treatment of inethyl coumalate (4) with an excess of m-methoxyphenethylamine and saponification of the crude product gave N-(m-nlethoxyphenethy1)-5-carboxy-2-pyridone (I) in 82y0 yield. Cyclization of this pyridone using phosphorus oxychloride in xylene (3) followed by treatment of the intermediate acid chloride with absolute ethanol gave 3-carbethoxy-6,7-dihydro-9-n~ethoxybenzo[a]quinolizii~ium chloride (IIa) in 72% yield. Treatment of the crude reaction mixture with potassi~im iodide gave the corresponding iodide (IIb). I-Iydrolysis of the intermediate acid chloride gave the quinolizinium acid salts IId and IIe.A iluinber of attempted cyclizations of pyridones to produce substituted quinolizinium con~pounds have yielded simply the corresponding pyridiniuin salts (ref. 5 and references therein). That N-(m-inethoxypl~enetl~yl)-5-carboxy-2-pyridone did undergo cyclization to the quinolizinium ring system is evidenced by the fact that the products IIa-IIe have ultraviolet absorption s p x t r a characteristic of this ring system (3), but different from what would be expected froin a composite of the isolated m-methoxyphenyl and carboxychloropyridinium chroinophores had cyclization not occurred. I t is generally found that Bischler-Napieralski reactions of N-m-methoxyphenethylamides and lactams occur preferentially with cyclization para to the methoxyl group (6-8). That a para ring closure occurred in the present work is indicated by spectral means, and will be discussed later under the preparation of IIIa.Catalytic hydrogenation of the quinolizinium ester salts IIa-IIc using Adams catalyst resulted in the isolation of the two possible racemic forms of the free amino ester. The best results were obtained when the chloride salt IIa was used because of its greater 1Frowz part of tlze thesis presented by ...

A + C → Ac → Abc → Abcd

“…Several nitrogen-containing ABC tricyclic intermediates have been prepared [40][41][42] (including 42 which was obtained in over 40% yield from m-methoxyphenethylamine and methyl coumalate [43]), but the synthesis discussed here has been brought to fruition [44,45]. Reaction of m-anisidine (34) with ethyl orthoformate gave 35, which, when heated with cyclohexane-l,3-dione yielded 36.…”