Synthesis of a spiro[cyclohex-1,1 '-isobenzofuranyl] dopamine receptor antagonist

Two syntheses of the novel CNS agent, 2-fluoro-4-(trans)-(4-(3'H-spiro[cycl ohex-1,1'-isobenzofuran]-4-yl)-piperazin-1-yl)- benzonitrile, 1, are presen ted. The first relied on a reductive alkylation with low regionselectivity (I:1) hut was sufficient for the preparation of kilogram quantities, The se cond used a selective ketone reduction of 3'H-spiro[cyclohexane-1,1'-isoben zofuran]-4-one 8, with sodium borohydride to provide the cis-alcohol, 3'H-s piro[cyclohexane-1,1'-isobenzofuran]-(cis)-4-ol,11. A simple process for th e conversion of 11 to 1 is described, Regioselective reactions with 2,4-dif luorobenzonitrile under mild conditions are described.