4-(4-(p-Chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone → Hexane

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This example describes the synthesis of both 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone (UCSF51) and 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone (UCSF52). The ortho and meta biphenyl analogs of halopeddol were prepared from the opening of the cyclopropyl ring of the corresponding biphenyl cyclopropyl ketone (875 mg of the ortho isomer and 500 mg of the meta isomer) by 4-(4 chlorophenyl)4-hydroxy pipeddine by refluxing the two reagents in xylene for 5 days. The reaction was worked up as described for the synthesis of para-biphenyl haloperidol. The products were separated by flash chromatography using a slow gradient from 100% CH2Cl2 to 100% ethyl acetate to 10% methanol in ethyl acetate as eluent. Pooling of the fractions containing product followed by evaporation of the solvent resulted in an orange liquid for the ortho isomer, and a tan solid for the meta. In ethyl acetate, the Rf 's are 0.17 for o-biphenyl haldol, UCSF51, and 0.26 for the meta derivative, UCSF52. Both products were recrystallized from hexane yielding approximately 200 mg (12% yield), and 350 mg (35% yield), of the ortho and meta isomers respectively. A melting point of 96°-97° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-2'-phenylbutyrophenone, and a melting point of 99°-100° C. was determined for 4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)-3'-phenylbutyrophenone. Spectral data supported the assigned structures for both products.

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