A number of 4-oxo-1,4-dihydro-l,8-naphthyridine derivatives that differ with respect to the sizes of the azaand carbocycles were synthesized by the reaction of 3-amino-4-ethoxycarbonyl-5,6-dihydro-7H-pyrindine and 3-amino-4-ethoxycarbonyl-5,6,7 :S-tetrahydroisoquinoline with N,N-dimethylacetamide diethylacetal and Nmethylbutyrolactam, N-methylvalerolactam, and N-methylcaprolactam diethylacetals and subsequent cyclization of the intermediate amidines. It was established by UV and IH and 13C NMR spectroscopy that the protonation of these compounds takes place at the exocyclic oxygen atom. The dependence of the ionization constants of the compounds obtained in 70% DMFA on the size of the saturated cyclic fragments of the molecules was established.
It is known [2] that aromatic and heterocyclic compounds that have amino and ethoxycarbonyl groups in adjacent positions react readily with N,N-dimethylacetamide diethylacetal (I) and N-methylbutyrolactam diethylacetal (IIa), Nmethylvalerolactam diethylacetal (nb), and N-methyleaprolactam diethylacetal (IIc) to give the corresponding amidines which, upon heating under acid-or base-catalysis conditions, undergo cyclization to condensed compounds that contain a 2-(substituted amino)-4-oxo-pyridine ring as a fragment. In the present research as starting compounds for the synthesis of heterotricyclic and heterotetracyclic systems of this type we used the previously synthesized 3-amino-4-cyano-5,6-dihydro-7Hpyrindine 0IIa) and 3-amino-4-eyano-5,6,7,8-tetrahydroisoquinoline 0/Ib). Concentrated HBr has been previously used [3] for saponification of the cyano group in HI,a, b. However, this method is preparatively inconvenient, since it requires prolonged heating and does not ensure sufficiently high yields of the con'esponding amino acids (IVa was obtained in 56% yield, and IVb was obtained in 30% yield). It is more convenient to use the method that we developed [4] for the hydrolysis of the cyano group in sulfuric acid. As in the case of 2-oxo-3-cyano derivatives [4], the yields of the hydrolysis products depended on the sulfuric acid concentration; the optimal sulfuric acid concentration proved to be 60% H2SO 4 -in this case the yield of 3amino-4-carboxy-5,6-dihydro-7H-pyrindine (IVa) was 93%, while the yield of 3-amino-4-carboxy-5,6,7,8tetrahydroisoquinoline (IVb) was 59% (amide V was also isolated in 7% yield). Refluxing in ethanol in the presence of a large excess of concentrated H2SO4 (10-13 moles per mole of the amino acid) is optimal for the esterification of acids IVa, b. The reaction of the resulting esters Via, b with aeetal I was carried out by refluxing in toluene, and the course of the process was followed from the disappearance of the signals of the NH 2 group in the IR spectra. Under these conditions we could not expose differences in the reactivities of Via, b -condensation with the formation of the corresponding amidines proceeds smoothly and in a short time (15-20 rain). The ease of cyclization of amidines VIIa, b (without isolation of them in pure form) in butanol in the presence of sodium butoxide, as a result of which tricyclic naphthyridines VIIIa, b are formed, depends on the size of the condensed carbocycle -the increase in the intensity of the longwave absorption maximum (at 334 nm), which corresponds to the naphthyridine system, in the UV spectra for isoquinoline derivative ViIb during its conversion to tricycle VIIIb takes place -1.5 times faster than for the process VIIa --, VIIIa.
*See [1] for Communication 56.