Janssen PA. J,
Van de Westeringh C,
Jageneau AH. M,
Demoen PJ. A,
Hermans BK. F,
Van Daele GH. P,
Schellekens KH. L,
Van der Eycken CA. M,
Niemegeers CJ. E.
Pharmacological, Analytical and Chemical Departments of Research Laboratories Dr.
C. Janssen Pharmaceutica, Beerse (Turnhout), Belgium
Chemistry and Pharmacology of CNS Depressants Related to 4-(4-Hydroxy-4-phenylpiperidino)butyrophenone.
Part I — Synthesis and Screening Data in Mice.
J. Med. Pharm. Chem. 1959;
1: 281-297
DOI:
10.1021/jm50004a007
Key words
Prins reaction - Friedel–Crafts acylation - piperidine - schizophrenia
Significance
Schizophrenia is a condition marked by positive and negative symptoms such as hallucinations
and cognitive disruption. The global prevalence has been estimated to reach up to
one percent of all people across their lifetime; as such, pharmacological and non-pharmacological
interventions have been investigated for decades. The discovery of Haloperidol by
Janssen and co-workers in 1959 invigorated efforts to discover molecules with antipsychotic
effects, efforts that continue to this day.
Comment
Haloperidol was discovered in the course of screening hundreds of Brønsted basic ketones.
Its synthesis follows a convergent approach that unites the piperidine (Brønsted base)
and butyrophenone (ketone) fragments via a substitution reaction. The substituted
piperidines are formed in an aza-Prins-type reaction of α-methylstyrenes (J. Am. Chem. Soc.
1955, 77, 5698), forming 4-phenyl-tetrahydropiperidine intermediates that undergo hydrobromination
and hydrolysis. Friedel–Crafts acylation affords the requisite 4-chlorobutyrophenones.
The desired combination of potency and duration were observed when L = F and R = Cl
(Haloperidol).
