Wednesday, June 25, 2008 - 2:20 PM
New York (Capital Hilton)
129

A Practical and Green Chemical Approach for the Manufacture of NK1 Antagonist LY686017

Dr. Michael E. Kopach, Dr. Tony Zhang, Dr. Scott Coffey, Dr. Alfio Borghese, Michael Kobierski, and William Trankle. Eli Lilly and Company, Indianapolis, IN

An innovative and environmental friendly route for the commercial production of an investigational new drug candidate LY686017, an antagonist of the Neurokinin 1 (NK1) subtype of tachykinin receptor, is described. LY686017 has undergone phase 2 clinical trials for the treatment of treatment of anxiety and irritable bowel syndrome (IBS). The improved route of manufacture delivers LY686017 in exceptionally high purity (>99.9%), a significant accomplishment considering the potential for positional isomers for all 5 aromatic rings. Eli Lilly and Company uses a metric called “e-factor” internally that is similar, but not identical to Sheldon's E factor. Lilly's e-factor is the total mass of all raw materials, including water that are used to produce each kg of active pharmaceutical ingredient “API” beginning from routinely available commercial starting materials. Despite the structural complexity of the API, the new route has a net e-factor of 146 kg/kg API, an 84% reduction relative to the original route executed for Phase I clinical trials. The selected commercial route for LY686017 was demonstrated on a pilot plant scale during 2006 in Indianapolis, Indiana. Two prior synthetic routes have been executed at pilot plant scale at Eli Lilly's Indianapolis, Indiana and Mount Saint Guibert, Belgium facilities, respectively. Improvement of key green chemistry parameters across the evolution of these route demonstrates the power of technical innovations and is testimonial to the importance of incorporating the 12 green chemistry principles to the design and definition of synthetic processes.