Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine

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Abstract
The synthesis and resolution of 3-iodocyproheptadine [(.+-.)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(.+-.)-5b] are described. The resulting atropisomers react with trifluoromethylthiocopper to give optically active products without extensive racemization. Optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] were prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The 4 compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity resided solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b, while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b nor (+)-6b have significant peripheral anticholinergic activity.

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