Reaction between phenetyl alcohol (I) and 3-chloropropionaldehyde diethyl acetal (II) under catalysis of methanesulfonic acid gives the mixed acetal (III), which is then cyclized to the isochromane (IV) by treatment with AlCl3 in nitromethane. Alkylation of 1-(4-fluorophenyl)piperazine (V) with chloride (IV) in the presence of diisopropylethylamine in ethylene glycol yields the title compound, which is converted to the dihydrocloride on treatment with a methanolic solution of hydrogen chloride.
A synthesis of the R-(+) isomer has also been reported: Reaction of phenethyl alcohol (I) and ethyl 3,3-diethoxypropionate (VI) in the presence of titanium tetrachloride affords the isochromane (VII), which is hydrolyzed to acid (VIII) with NaOH in aqueous ethanol. Resolution of the racemic acid (VIII) is effected by conversion into the diastereomeric salt with R-(+)-a-methylbenzylamine (IX) which, after recrystallization from dichloromethane and ethyl acetate, is liberated by treatment with hydrochloric acid, to yield the R-(-) acid (X). This acid is reduced to alcohol (XI) with borane-dimethyl sulfide in tetrahydrofuran. Treatment of XI with methanesulfonyl chloride, diisopropylethylamine, and a trace of dimethylaminopyridine (DMAP) in tetrahydrofuran affords mesylate (XII), which is subsequently treated with piperazine (V) in ethylene glycol to afford the R-(+) compound, isolated as the methanesulfonate salt.