Syntheses of an Antipsychotic Pyrroloisoquinoline from Areca Alkaloids

Article abstract of DOI:10.1021/jo00200a019

2,6-Dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo<2,3-q>isoquinolin-4-one, a conformationally defined antipsychotic agent of current clinical interest, can be synthesized in a two-step, single-pot process from arecoline, a commercially available member of the areca alkaloid group.The yield is diminished by the competing, base-induced rearrangement of arecoline to 1,3-dimethyl-2-pyridone.This problem can be circumvented by using arecolone as the starting material.A convenient synthesis of arecolone from 3-acetylpyridine is described.A modifiedform of the Neber rearrangement was used to prepare 2-amino-3-pentanone hydrochloride for use in the Knorr pyrrole synthesis step of the process.Two isomeric pyrroloisoquinolines produced as minor byproducts were isolated and characterized as the cis-<2,3-g> and trans-<2,3-h> isomers.Characterization of the latter included an X-ray crystal structure determination.