Pilot-Scale Synthesis and Purification of α-Asaronol for Antiepileptic Drug Development

Abstract

A simple and efficient pilot-scale process was developed for the synthesis and purification of α-asaronol ((E)-3′-hydroxyasarone). 4.29 kg of α-asaronol 4 (purity 99.92%) was produced in one batch, starting with 2,4,5-trimethoxybenzaldehyde 1 and ethyl hydrogen malonate 2 as raw materials to form intermediate ethyl (E)-3-(2,4,5-trimethoxyphenyl)acrylate 3 (yield 93.3%) by the Knoevenagel condensation reaction, which was then reduced by diisobutylaluminum hydride to produce α-asaronol 4 with a yield of 89.2%. Liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy analysis revealed four major impurities in the synthesis process, namely, (2,4,5-trimethoxyphenyl)methanol, 3-(2,4,5-trimethoxyphenyl)propan-1-ol, 5,5′-((1E,1′E)-oxybis(prop-1-ene-3,1-diyl)) bis(1,2,4-trimethoxybenzene), and diethyl 2-(2,4,5-trimethoxybenzyl)malonate. By adapting a commonly used recrystallization process through optimization, a large-scale purification method was developed for the purification of α-asaronol, achieving a purity of 99.92% by recrystallization. The pilot study lays the groundwork for the large-scale, high-yield, and high-purity preparation of the candidate drug.