Optimization and\nScale-Up Synthesis of a Lappaconitine\nAlkaloid Derivative, <b>QG3030</b>, as a Novel Osteoanabolic\nAgent

Our previous work revealed that the novel lappaconitine\nalkaloid\nderivative, <b>QG3030</b> (<b>6</b>), has an enhanced\nosteogenesis effect in the ovariectomized rat model without acute\noral toxicity. <b>QG3030</b> (<b>6</b>) recently received\napproval for the Investigational New Drug application for its osteoporosis\ntreatment from the Korean Ministry of Food and Drug Safety. Therefore,\nthe need for an economical, large-scale production of <b>QG3030</b> (<b>6</b>) motivated the development of a novel synthetic\nprocedure for its clinical studies. We herein report an efficient,\nsafe, and cost-effective synthesis of <b>QG3030</b> (<b>6</b>) as a clinical candidate for osteoporosis treatment. As an optimized\nsynthetic procedure, the reaction of lappaconitine·HBr (<b>1</b>·HBr, 1.0 kg scale) with co-oxidizing agents PhI(OAc)<sub>2</sub>-TEMPO (1.5 and 2 equiv) as a key step in a mixed EtOAc-acetone\nsolution (v/v = 2/1) furnished α,β-unsaturated ketone\n(<b>4</b>), which was then treated with aq. NaOH to provide\npure <b>QG3030</b> (<b>6</b>, 352 g) in 58% overall yield\nwith a purity of 99.8% after crystallization from EtOH–CH<sub>2</sub>Cl<sub>2</sub>. This pilot synthetic procedure was performed\nthree times, and the reproducible results were obtained with both\nnearly identical yields and purities.