Efficient Synthesis of a 5-HT_2C Receptor Agonist Precursor

Abstract

A short, scaleable, synthetic approach toward the tricyclic indole derivative 2, an intermediate in the synthesis of the 5-HT 2C agonist 1, is described. The synthesis started with Williamson etherification of inexpensive 4-nitro-3-methylphenol ( 11 ) followed by reduction to the corresponding aniline 13 and subsequent Boc protection. Acylation of the methyl group in 14 via lithiation furnished γ-chloroketone 16, which was subjected to acid promoted indole formation to afford 17 . In the final step, NaOH induced hydrolytic cleavage of the Boc protecting group followed by direct intramolecular nucleophilic substitution gave rise to target molecule 2 in an overall yield of 65% over six steps.