合成路线1

The reaction of 3-chlorotetrafluoropyridine (I) with potassium tert-butoxide in THF gives the 4-tert-butoxypyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and LDA in THF affords the 5-methyl derivative (IV), which is partially defluorinated with hydrazine in refluxing propanol to provide 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF gives the alpha substituted acetonitrile (VII), which is treated with trifluoroacetic acid yielding the phenol (VIII). The reaction of (VIII) with POCl3 in dichloromethane/DMF affords the corresponding chloro derivative (IX), which is treated with dry HCl in ethanol giving the carboxylic ester (X). The reduction of (X) with LiAlH4 in THF affords the expected aldehyde (XI), which is cyclized with diethyl malonate, piperidine and acetic acid in refluxing ethanol giving the quinolizine carboxylate (XIII). The reaction of (XIII) with (1S,6S)-2-(tert-butoxycarbonyl)-2,8-diazabicyclo[4.3.0]nonane (XIV) by means of NaHCO3 in refluxing acetonitrile yields the condensation product (XV), which is saponified with LiOH in THF/wter providing the protcted target compound (XVI). Finally, this compound is deprotected with HCl in dioxane/methylene chloride.