title: Kinetic and mechanistic insight into the thermodynamic degradation of saxagliptin.
abstract: The dipeptidyl peptidase-IV inhibitor saxagliptin (Onglyza) can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. The kinetics and mechanism of this conversion were examined to develop a commercial synthesis that afforded saxagliptin with only trace levels of this key byproduct. Important findings of this work are the identification of a profound solvent effect and the determination of an autocatalytic pathway. Both of these phenomena result from transition structures involving proton transfer.
authors: Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, USA. scott.jones@bms.com
authors: G Scott
authors: GS
authors: Jones
authors: Scott A
authors: SA
authors: Savage
authors: Sabrina
authors: S
authors: Ivy
authors: Patrick L
authors: PL
authors: Benitez
authors: Antonio
authors: A
authors: Ramirez
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry; D000578:Amidines / Q000737:chemistry*; D003500:Cyclization; D054659:Diketopiperazines / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011522:Protons; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D000578:Amidines; D054659:Diketopiperazines; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011522:Protons; D012997:Solvents; C502994:saxagliptin; D018819:Dipeptidyl Peptidase 4; D000218:Adamantane