The alkylation of the alpha-N-piperidinylethyl derivative of the 2-chlorophenylacetonitrile (I) with N-benzyl-N-isopropylaminoethyl chloride (II) (4) and sodium amide in refluxing toluene gives (rac)-alpha-(2-chlorophenyl)-alpha-[2-[(1-methylethyl)(phenylmethyl) amino]ethyl]-1-piperidinebutanenitrile (III). Hydration of the nitrile (III) with sulfuric acid provided (rac)-alpha-[1-[(1-methylethyl)(phenylmethyl)amino]ethyl]-1-piperidinebutanamide (IV), and subsequent catalytic hydrogenolysis of the N-benzyl group yielded (rac)-alpha-(2-chlorophenyl)-alpha-[(1-methylethyl)amino]ethyl] piperidinebutanamide (V). Final acylation of the secondary amine (V) with acetyl chloride in chloroform in the presence of triethylamine was carried out at 0 C to provide bidisomide (SC-40230).
The reaction of N-isopropylethanolamine (I) with allyl bromide (II) in THF gives the secondary amine (III), which is treated with SOCl2 in dichloromethane to yield the chloroethylamine (IV). The condensation of (IV) with 2-(2-chlorophenyl)-4-(1-piperidinyl)butyronitrile (V) by means of KOH in DMSO affords the adduct (VI), whose nitrile group is hydrolyzed with H2SO4 to provide the corresponding amide (VII). The elimination of the allyl group of (VII) by means of a Rh catalyst and 1,4-diazabicyclo[2,2,2]octane (DABCO) in refluxing aqueous ethanol gives the secondary amine (VIII), which is finally acetylated with Ac2O in ethyl acetate to yield the target diamide.