Dr. Russell D. Cink
Dr. Russell D. Cink
Senior Principal Research Scientist
AbbVie
“Process Development of Glecaprevir”
Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and an enabling synthesis was required to support early clinical trials. The key steps in the enabling route involved a ring-closing metathesis (RCM) reaction to form the 18-membered macrocycle and a challenging fluorination step to form a key difluoromethyl-substituted cyclopropyl amino acid. To support the late-stage clinical trials and subsequent commercial launch, a large-scale synthetic route to glecaprevir was required. The large-scale route to the macrocycle employed a unique intramolecular etherification reaction as the key step. The large-scale route to the difluoromethyl-substituted cyclopropyl amino acid avoided the fluorination challenges by constructing the amino acid from a commercially available difluoromethyl-substituted hemi-acetal. The key steps in the amino acid synthesis were a Knoevenagel condensation, a Corey- Chaykovsky cyclopropanation, a Curtius rearrangement, and a chiral resolution. Subsequent coupling of the macrocycle to the amino acid containing sidechain produced glecaprevir in 16% overall yield.
Russell D. Cink
Russell D. Cink graduated from the University of Minnesota in 1991 with a B.S. in Chemical Engineering. While an undergraduate, he conducted research under the direction of Wayland E. Noland which sparked his interest in synthetic organic chemistry. After working for 2 years as a consultant, he returned to the University of Minnesota and obtained a Ph.D. in Chemistry in 1998 under the direction of Craig J. Forsyth. Since 1998 he has worked as a process chemist at Abbott / AbbVie, primarily focused on small molecule process development and antibody drug conjugates.
Sponsored by Organic Syntheses and AbbVie
