合成路线1

1) The reaction of diethyl-2-benzylmalonate (I) with acrylonitrile (II) by means of sodium ethoxide in methyl-tert-butyl ether gives diethyl 2-benzyl-2-(2-cyanoethyl)malonate (III), which is reduced with H2 over Pd/C in ethanol/aq. HCl yielding diethyl 2-(3-aminopropyl-2-benzylmalonate (IV). The protection of (IV) with tert-butoxycarbonyl anhydride affords carbamate (V), which is regioselectively hydrolyzed with porcine liver estearase giving 2(S)-benzyl-5-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)pentanoic acid (VI). The deprotection of the amino group of (VI) with trifluoroacetic acid, followed by cyclization by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in methyl-tert-butyl ether gives piperidone (VII), which is protected with tert-butoxycarbonyl anhydride yielding 3(S)-benzyl-1-(tert-butoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (VIII). The reduction of (VIII) with lithium triethylborohydride gives the 2-hydroxy deerivative (IX), which is dehydroxylated with triethylsilane in dichloromethane and deprotected with boron trifluoride ethearate to yield 2(S)-benzylpiperidine-2-carboxylic acid ethyl ester (X). 2) The reduction of the piperidone (VII) to the piperidine (X) can also be performed by reaction of (VII) with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide] in refluxing toluene to give the corresponding piperidinethione (XIV), which is then desulfurized by means of Raney Nickel and NaBH4 in THF/water yielding the desired piperidine (X).