Diphenylbutylpiperidine Derivatives

Representatives of diphenylbutylpiperidines are pimozide, fluspirilene, and penfluridol, which belong to the powerful neuroleptic drugs with expressed antipsychotic properties similar to haloperidol. The principle distinctive feature of this series of drugs is their prolonged action. The mechanism of their action is not completely known; however, it is clear that they block dopaminergic activity.

Pimozide: Pimozide, 1-[1-[4,4-to-(p-fluorophenyl)butyl]-4-piperidyl]-2-benzymidazoli-none (6.6.5), is structurally very similar to droperidol with the exception of the presence of a double bond in the piperidine ring and the substitution of a p-fluorobutyrophenone group on the nitrogen atom of the piperidine ring with a 4,4-to-(p-fluorophenyl)-butyl radical. 4,4-to-(p-fluorophenyl)-butylchloride (bromide) (6.6.3), which is needed for the synthesis of pimozide as well as fluspirylene and penfluridol, is synthesized by reacting of two moles of 4-p-fluorophenylmagnesiumbromide with cyclopropancarboxylic acid ester, which results in the formation of to-(4-p-fluorophenyl)cyclopropylcarbinol (6.6.1). Treatment of this with thionyl chloride (phosphorous tribromide) leads to opening of the cyclopropyl ring, forming 1,1-to-(4-fluorophenyl)-4-chloro(bromo)-1-butene (6.6.2). Reduction of the double bond using hydrogen over a palladium catalyst leads to the formation of 1,1-to-(4-fluoro- phenyl)butyl chloride (bromide) (6.6.3) [60-63].

In essence, the synthesis of pimozide lies in the N-alkylation of 4-(2-benzimidazolinon)piperidine (6.6.4), which is synthesized by the reduction of 1-(1,2,3,6-tetrahydro-4-piridyl)-2-benzimideazolone (6.3.10) using hydrogen over Raney nickel of pimozide (6.6.5), by the earlier synthesized 4,4-to-(4-fluorophenyl)butylchloride (6.6.3).

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