The Synthesis of a 5HT_2C Receptor Agonist

Abstract

This report describes the large-scale synthesis of 1 that features a Fischer indole strategy to form an advanced intermediate followed by reduction to the indoline to construct the tetracyclic core of the molecule. Resolution using dibenzoyl-D-tartaric acid affords access to a single enantiomer, from which a Suzuki coupling builds in the biaryl functionality. Deprotection followed by salt formation furnishes the desired target molecule.

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

“…20 Thus, the incidence of use of these "cohort of concern" reactive intermediates was 1 out of 1782 synthetic stages assessed, i.e., 0.06%. This N-nitroso was formed as a nonisolated intermediate in the preparation of a hydrazine intermediate.…”

Indole synthesis – something old, something new

“…This reduction can be effected with zinc dust in acetic acid 12 or lithium aluminium hydride; 13 sodium dithionite provides a milder alternative, 14 and has been used on pilot plant scale in the synthesis of the 5HT 2C receptor agonist 7 (Scheme 8). 15 Hydroamination of alkynes represents another approach to the required enehydrazine intermediates. 16 In the rst reported example, heating hydrazidozirconocene 8 with alkynes gave the aminozirconocene 9, presumably by hydroamination and [3,3]sigmatropic rearrangement.…”

γ-Carbolines and their hydrogenated derivatives 3.* Hydrogenated derivatives of γ-carbolines: chemical and biological poperties (Review)

“…A series of 1,2,3,4,4a,9b-hexahydro-γ-carbolines are ligands of 5-HT-receptors [194], including an agonist of serotonin receptors of the 5-HT 2C subtype responsible for the sense of satiety, which can be used effectively for the treatment of obesity [195].…”