Pharmacologically Relevant Bifunctional Compounds Containing Chloroquinoline and Dihydropyrimidone Moieties: Syntheses and Crystal Structures of a Target Molecule and Selected Intermediates

Abstract  We report the regioselective synthesis and X-ray structure of the pharmacologically relevant 3-[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-4-(4-methoxy-phenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (3) (triclinic, space group , a = 11.1775 (3), b = 13.6470 (4), c = 16.3680 (6) ?, α = 82.645 (1), β = 86.423 (1), γ = 88.415 (2)°, V = 2470.9 (1) ?³, Z = 4). Further support for the regioselectivity is provided by the X-ray structures of two intermediates, namely 4-(4-methoxy-phenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester, 8 (monoclinic, space group P2₁/c, a = 11.7710 (2), b = 5.5290 (1), c = 22.9500 (5) ?, β = 104.342 (1)°, V = 1447.08 (5) ?³, Z = 4), and 4-(4-methoxy-phenyl)-1,3,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester, 9 (monoclinic, space group P2₁/c, a = 16.6529 (7), b = 10.9426 (4), c = 8.2819 (3) ?, β = 91.395 (2)°, V = 1508.7 (1) ?³, Z = 4), which are also reported. The three compounds display significant differences in the conformations of their DHPM rings as well as a variety of hydrogen bonding arrangements in their crystals. Graphical Abstract  The synthetic strategy for deriving pharmacologically-relevant bifunctional compounds based on linked dihydropyrimidone and chloroquinoline moieties is reported, together with supporting X-ray structures of two synthetic intermediates and a representative target compound.