Ganaplacide

Synthesis of Advanced Intermediate to Ganaplacide API

Medicines for All Institute (M4ALL) demonstrated a 7-step synthetic route to an advanced intermediate of ganaplacide that offers an overall API raw material cost (RMC) reduction of 15-25% relative to the first-generation process (J. Med. Chem. 2012, 55, 4244-4273).

Key Assumptions

• Projected material cost reductions are significantly impacted by market dynamics for starting materials and reagents, and economies of scale related thereto. Please reach out to M4ALL for more information.
• The baseline route corresponds to Novartis’s process, as outlined in the process development report (PDR) provided below.

Scientific Highlights

• Key transformations include a Bredereck imidazole synthesis, regioselective N-alkylation, and imidazolopiperazine construction via Pictet-Spengler-type annulation

Opportunities & Future Directions

• Overall yield (3%) and crude product purity (25 wt%) of the advanced intermediate are principally a consequence of process challenges in the Pictet-Spengler reaction, as discussed in the PDR. 
• Additional work is underway to improve the Pictet-Spengler annulation, including further examination of heterogeneous catalysts, continuous-flow reaction paradigms, and isolation conditions. Such optimization has potential to deliver additional, substantial RMC reduction, as outlined in the PDR (Executive Summary, Figure 1). Updated process documentation will be posted in due course.