First Multigram Scale-Up and Synthesis of Novel Valerolactam- Benzimidazole Hybrid Anthelmintic

Background: Infections caused by helminth parasites are the main cause of economic losses in the livestock industry worldwide. The rapid resistance acquired by different parasites against commercially available drugs motivates the search, design, and development of new compounds capable of overcoming this situation. Previously, our group reported the novel hybrid valerolactam-fenbendazole (VALFBZ) compound with in vitro anthelmintic activity and good ex vivo parasite permeation. Objective: This study aimed at optimizing the novel hybrid VAL-FBZ compound synthesis and scaling up to the multigram order necessary for in vivo assays. Methods: For the hybrid VAL-FBZ synthesis, a convergent strategy was utilized. To obtain the benzimidazole core, widely available fenbendazole and L-Ornithine hydrochloride synthesis were used. The key step was the coupling reaction, for which an inexpensive coupling agent of the uronium salt family was used. Optimization was carried out by minimizing the risks and costs of upscaling at the multigram level. Results: In the first stage, the precursors of Valerolactam and Benzimidazole cores were synthesized on a decagram scale to obtain better results than previous reports. Also, the coupling reaction was carried out using HBTU to obtain VAL-FBZ with above 99% HPLC purity, and an overall yield of 48%. The successful synthesis was carried out without performing chromatographic purification in any step to minimize a few risks for the operator. Conclusion: Successfully, an efficient multigram and economic process is developed.