Three synthetic methods for the preparation of 1,5-disubstituted
1,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-ones as heterocyclic
histamine analogues were developed. The first method starts from
easily available methyl 5-(2-aminoethyl)-1H-pyrazole-4-carboxylates,
which were N-alkylated and the resulting secondary amines were cyclised
in the presence of a base to give the title compounds in 17-92% yields
(method A). Alternatively, the amines were first cyclised to the
5-unsubstituted pyrazolo[4,3-c]pyridin-4-ones.
Subsequent N-benzylation afforded three of the title compounds in
36-49% yields (method B). The third method comprises a
six-step transformation of methyl acrylate into 1-benzylpiperidine-2,4-dione.
Treatment of the latter with N,N-dimethylformamide dimethylacetal (DMFDMA)
followed by acid-catalysed cyclisation of the formed enaminone with
methyl-, phenyl- and tert-butylhydrazine
afforded the same three title compounds in 79-87% yields
(method C).
enaminones - cyclisation - alkylation - pyrazolo[4,3-c]pyridine - histamine
