Alkylation of 1-benzylpiperazine (VI) with 2-(4-fluorophenoxy)ethyl bromide (VII) produced the dialkylated piperazine (VIII). The benzyl protecting group of (VIII) was then removed hydrogenolysis in the presence of Pearlman's catalyst to furnish (IX). The title compound was then obtained by condensation of piperazine (IX) with mesylate (V) or, alternatively, by reductive alkylation of (IX) with aldehyde (X) in the presence of sodium triacetoxyborohydride.
The precursor mesylate (V) was synthesized as follows. Alkylation of phenylacetonitrile (I) using isopropyl bromide in the presence of KOH provided 2-phenylisovaleronitrile (II). Michael addition of ethyl acrylate to the potassium anion of nitrile (II) afforded cyano ester (III). After ester group reduction with LiAlH4, the resultant alcohol (IV) was treated with methanesulfonyl chloride and triethylamine to yield mesylate (V).
In a further procedure, 1-benzylpiperazine (VI) was alkylated with mesylate (V) to yield adduct (XI). Catalytic hydrogenolysis of the benzyl group of (XI) afforded piperazine (XII), which was finally alkylated with 2-(4-fluorophenoxy)ethyl bromide (VII) in the presence of triethylamine.