Optimization and Scale-Up Synthesis of a Lappaconitine Alkaloid Derivative, QG3030, as a Novel Osteoanabolic Agent

Our previous work revealed that the novel lappaconitine alkaloid derivative, QG3030 (6), has an enhanced osteogenesis effect in the ovariectomized rat model without acute oral toxicity. QG3030 (6) recently received approval for the Investigational New Drug application for its osteoporosis treatment from the Korean Ministry of Food and Drug Safety. Therefore, the need for an economical, large-scale production of QG3030 (6) motivated the development of a novel synthetic procedure for its clinical studies. We herein report an efficient, safe, and cost-effective synthesis of QG3030 (6) as a clinical candidate for osteoporosis treatment. As an optimized synthetic procedure, the reaction of lappaconitine·HBr (1·HBr, 1.0 kg scale) with co-oxidizing agents PhI(OAc)₂-TEMPO (1.5 and 2 equiv) as a key step in a mixed EtOAc-acetone solution (v/v = 2/1) furnished α,β-unsaturated ketone (4), which was then treated with aq. NaOH to provide pure QG3030 (6, 352 g) in 58% overall yield with a purity of 99.8% after crystallization from EtOH-CH₂Cl₂. This pilot synthetic procedure was performed three times, and the reproducible results were obtained with both nearly identical yields and purities.