Synthesis of 6-hydroxy-2-(2-phenylethyl)chromone Derivatives as Potential Serotonin Receptor Ligands

Abstract

Previous studies have shown that natural compound 5-hydroxy-2-(2- phenylethyl)chromone (5-HPEC, 5) acts as a non-nitrogenous antagonist for the serotonin receptor 5-HT2B. Additionally, a 7-hydroxy-2-(2-phenylethyl)chromone (7-HPEC) analog (9a) has shown moderate inhibitory activity against radioligand binding at the serotonin receptor 5-HT2C. This led us to consider that the C-5 hydroxy group may be favorable for 5-HT2B receptor selectivity and that the C-4′ hydroxy group may be favorable for 5-HT2C receptor selectivity. We synthesized 6-hydroxy-2-(2-phenylethyl)chromone (6-HPEC, 10) and its analogs (18a-n) with the goal of gaining more information about the 2-(2- phenylethyl)chromone family. The synthesis of 6-HPEC derivatives was successfully carried out by a three step reaction series. The first step was synthesis of ethyl 3- phenylpropanoate analogs (14a-k) by way of the Wittig reaction followed by a hydrogenation. The second step was the synthesis of the protected acetophenone, 1-(2- hydroxy-5-(methoxymethoxy)phenyl)ethanone (16), and the third step in the synthesis of the 6-HPEC analogs was completed via Claisen condensation resulting in 15-88% yields. We deduced that the reason for a broad spectrum of yields is due to the solvent used for purification, and the allowed time of purification.