SYNTHESIS OF H-3-LABELED AND C-14-LABELED CP-88,059 - A POTENT ATYPICAL ANTIPSYCHOTIC AGENT

The syntheses of H-3- and C-14-labelled CP-88,059 [i.e., 5-(2-(4-(1,2-benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-1, 3-dihydro-2H-indol-2-one] are described. CP-88,059 (5 b) is a combined D-2/5-HT2 antagonist currently undergoing clinical evaluation as an antipsychotic agent with reduced potential for induction of EPS in schizophrenic patients. Displacement of bromine from the 7-position of the benzisothiazole moiety, by reductive dehydrogenation with tritium gas and Pd/BaSO4 catalysis, provided H-3-CP-88,059 (5c). Incorporation of C-14 into the ethylene portion of the molecule was achieved via the Friedel-Crafts acylation of 6-chlorooxindole with [2-C-14]-chloroacetyl chloride, followed by triethylsilane reduction of the aryl carbonyl and coupling with N-(1,2-benzisothiazol-3-yl)piperazine in refluxing aqueous Na2CO3.