Abstract: These lectures demonstrate that the key drivers for Process Research and Green Chemistry are frequently the same, and many Green Chemistry aspects have been major elements in traditional Process Research. The Merck manufacturing processes for Sitagliptin (A DPPIV inhibitor for the treatment of diabetes) and Aprepitant (an NK1 receptor antagonist for the treatment of chemotherapeutic induced emesis) will be used to develop these ideas.

Sitagliptin is essentially an enantiopure β-amino acid amide that is manufactured by a novel asymmetric hydrogenation of a primary enamine derived from a β-ketoacid amide. The development of this new method for the ready synthesis of β-amino acids and derivatives will be discussed in detail. A full paper describing this chemistry has been reported in a recent JACS paper (JACS, 2009, 131 8798-8804), with additional relevant references cited in that paper.

Aprepitant contains an unusual cis-2-alkoxy-3-arylmorpholine core structure featuring three stereogenic centers in close proximity that provides the opportunity, after establishment of the first chiral center, to generate the other two chiral centers via stereoselective transformations. The search for the most economical and green manufacturing process using crystallization-induced diastereomeric transformations (CIDT) will be described. The manufacturing process is described in JACS, 2003, 125, 2129-2135.

Both the Sitagliptin and Aprepitant processes have been recognized by awards from the Green Chemical Community nationally and internationally.

Biosketch: Drs. Dolling and Grabowski have had more than seventy years of experience in Process Research. Dr. Dolling received his BS from Hamburg, his PhD from Rutgers and did post doctoral studies at Chicago. Dr. Grabowski received his BS from MIT and his PhD from Rochester.

Co-hosts: Joel Freundlich, Visiting Professor, Dept. of Medicinal Chemistry, Ernest Mario School of Pharmacy; Daniel Seidel, CCB