By reaction of 2-aminocyclopent-1-ene-1-carbonitrile (I) with cyclohexanone (II) in presence of polyphosphoric acid in benzene followed by treatment with hydrochloric acid in ethanol.
The monohydroxylated metabolite of NIK-247, (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-ol (VI) has been synthesized as follows: The condensation of cyclohexane-1,3-dione (I) with 2-amino-1-cyclopentene-1-carbonitrile (II) by means of PPE gives 2-(3-oxo-1-cyclohexen-1-yl)-1-cyclopentene-1-carbonitrile (III), which is cyclized by means of BF3.Et2O to yield 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-8-one (IV). The reduction of (IV) with NaBH4 affords the corresponding racemic alcohol (V), which is submitted to optical resolution with (+)-di-p-toluyltartaric acid to give the desired compound (VI).
The monohydroxylated metabolite of NIK-247, (+)-9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-ol (XII) has been synthesized as follows: The condensation of cyclopentane-1,3-dione (VIII) with 2-amino-1-cyclohexene-1-carbonitrile (VII) by means of PPE gives 2-(3-oxo-1-cyclopenten-1-yl)-1-cyclohexene-1-carbonitrile (IX), which is cyclized by means of BF3.Et2O to yield 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-1-one (X). The reduction of (X) with NaBH4 affords the corresponding racemic alcohol (XI), which is submitted to optical resolution with (+)-di-p-toluyltartaric acid to give the desired compound (XII).
The synthesis of two dihydroxylated metabolites of NIK-247 has been reported: Two diastereomeric isomers 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-diol (VI) and (VII) have been synthesized as follows. The oxidation of 2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-amine (I) with CrO3.H2SO4 gives 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline-1,8-dione (II), which is selectively reduced with 1 equivalent of NaBH4 yielding a mixture of the two hydroxyketones (III) and (IV), separated by crystallization. The optical resolution of (III) with (-)-di-p-toluyltartaric acid affords the pre (+)-isomer (V), which is further reduced with NaBH4 to afford a diastereomeric mixture of the 1,8-diols (VI) and (VII), which is separated by HPLC over Chiracel OG in n-hexane ethanol (9:1).