Kinetic and Mechanistic Insight into the Thermodynamic Degradation of Saxagliptin

• Published in: Journal of organic chemistry Vol. 76; no. 24; pp. 10332 - 10337
• Main Authors: Jones, G. Scott, Savage, Scott A, Ivy, Sabrina, Benitez, Patrick L, Ramirez, Antonio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.12.2011; Amer Chemical Soc
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemistry; Amidines - chemistry; Chemistry; Chemistry, Organic; Cyclization; Diketopiperazines - chemistry; Dipeptides - chemistry; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Drug Stability; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Hydrogen Bonding; Hypoglycemic Agents - chemistry; Kinetics; Kinetics and mechanisms; Magnetic Resonance Spectroscopy; Organic chemistry; Physical Sciences; Preparations and properties; Protons; Reactivity and mechanisms; Science & Technology; Solvents - chemistry; Thermodynamics; Solvent effect; Molecular structure; Proton transfer; Autocatalysis; Thermodynamics; Amidine; Cyclization; Cyclic compound; Transition state; Reaction mechanism; Dipeptidyl-peptidase IV inhibitor; Kinetics; Chemical synthesis; By product; Saxagliptin
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo202052a

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.