Preparation of 2-cyano-3,5-dichloropyridine (IV) has been reported by two alternative procedures: 3,5-Dichloropyridine (I) was converted to the corresponding N-oxide (II) by treatment with peracetic acid. Addition of cyanotrimethylsilane in the presence of dimethylcarbamoyl chloride gave rise to the cyanopyridine (IV). In a different method, displacement of the 2-chloro group of 2,3,5-trichloropyridine (III) with cuprous cyanide in refluxing diglyme led to the target nitrile (IV). Displacement of both chloro groups of pyridine (IV) by KF in hot DMSO furnished the difluoropyridine (V). The cyano group of (V) was then converted to the key amidine (VII) by two related routes. Addition of hydroxylamine to nitrile (V) provided the hydroxyamidine (VI), which was further reduced to amidine (VII) by catalytic hydrogenation. Alternatively, nitrile (V) was directly converted to (VII) by treatment with ammonium chloride and trimethylaluminium.
Knoevenagel condensation of 2-chloro-4-fluorobenzaldehyde (VIII) with methyl acetoacetate (IX) in the presence of piperidine acetate afforded the benzylidene compound (X). Cyclocondensation of (X) with amidine (VII) provided the racemic dihydropyrimidine (XI). Resolution of (XI) was accomplished either by chiral HPLC or via conversion to the diastereoisomeric salts with (-)-camphanic acid.