How our novel, scalable route efficiently led to a crucial GMP intermediate

Our Groningen site worked with a virtual company, Dezima Pharma, on a project involving a cholesteryl ester transfer protein (CETP) inhibitor. CETP inhibitors are of interest for the management of dyslipidemia. The starting point was a synthetic route, used for early clinical manufacturing, that was not amenable to scale-up.

Our objective was to find a robust route and process that would permit the production of material for phase II and III clinical trials. The original route was long with low-yielding steps. It started from an optically pure starting material, which was produced by a single, undisclosed source.

MercachemSyncom developed a new route to prepare a crucial GMP starting material. By replacing the less stable benzyl vinylcarbamate by the cheaper, stable, and readily available N-vinylformamide in the three-component Povarov reaction, we came to a short and efficient assembly of the central core. We were able to identify conditions that allowed the direct crystallization of the desired diastereomerically pure core from the reaction mixture. Also, a very efficient and readily scalable chiral resolution method was developed using considerable expertise in this field at MercachemSyncom. Exploiting the process we developed, significant amounts of material were subsequently produced under cGMP conditions.

“It was a pleasure working with Dezima Pharma,” commented Dr. Bas Dros, Director of Chemistry. “Communication was transparent and intensive, aimed both at solving problems and generating new ideas, which made for an inspiring and fruitful collaboration.” The work resulted in a patent, covering the route developed by MercachemSyncom.

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