合成路线1

Treatment of a commercial mixture of 4-chloro-tetrafluropyridine (I) and 3-chlorotetrafluoropyridine (II) with sodium tert-butoxide, followed by chromatographic separation, afforded 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (III). Subsequent hydrogenolysis of the chlorine atom of (III) provided (IV), which was methylated with iodomethane in the presence of LDA yielding methylpyridine (V). Selective removal of the 6-fluorine of (V) to give (VI) was achieved by treatment with hydrazine hydrate in boiling n-propanol, followed by air oxidation of the intermediate pyridyl hydrazine. Alkylation of cyclopropaneacetonitrile (VII) with (VI) furnished the pyridinyl cyclopropaneacetonitrile (VIII). After acid cleavage of the tert-butyl group of (VIII), treatment with phosphoryl chloride in DMF gave rise to 4-chloropyridine derivative (IX). Then, alcoholysis of the cyano group of (IX) produced ethyl ester (X). Ester reduction by means of LiAlH4 and subsequent Swern oxidation of the resulting alcohol (XI) provided aldehyde (XII). The required quinolizinone system (XIII) was prepared by Knoevenagel condensation of pyridine aldehyde (XII) with diethyl malonate (1). The chiral piperidine (XV) was obtained by chiral HPLC resolution of racemic cis-N-carbobenzoxy-3-(tert-butoxycarbonylamino)-4-methylpiperidine (XIV), followed by hydrogenolytic cleavage of the carbobenzoxy group. Aromatic substitution of chloroquinolizinone (XIII) with piperidine (XV) yielded adduct (XVI). Hydrolysis of the ethyl ester of (XVI) with LiOH and further acid deprotection of the Boc group furnished the title compound.