title: Identification and structural elucidation of process impurities generated in the end-game synthesis of taranabant (MK-0364) via cyanuric chloride.
abstract: Taranabant (MK-0364) is a highly potent and selective cannabinoid-1 receptor (CB-1R) inverse agonist. It is being developed at Merck & Company to treat obesity. The chemical synthesis of MK-0364 drug substance involved the direct coupling of chiral amine and pyridine acid side chains mediated by cyanuric chloride. Four major process impurities were observed and characterized using high performance liquid chromatography (HPLC) coupled with ultraviolet (UV) and electrospray ionization (ESI) mass spectrometry (MS) detectors. The exact mass data was used for structural elucidation which suggests that the impurities are derivatives of cyanuric chloride formed in the coupling step. Owing to the reactive nature of these impurities, an interesting degradation phenomenon was observed during stability testing of MK-0364 drug substance when stored at 40 degrees C/75% RH and 25 degrees C/60% RH conditions. Degradation pathways were proposed to explain the changes observed in the HPLC impurity profile. Forced degradation experiments were also conducted to confirm the degradation pathways and assess the stability of the impurities. Finally, the complete stability data of the bulk drug are reported to support the hypothesis.
authors.affiliation: Analytical Development and Commercialization-API, Rahway, NJ 07065, USA. Yadan_chen@merck.com
authors.forename: Yadan W
authors.initials: YW
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Novak
authors.forename: Lisa
authors.initials: L
authors.lastname: Frey
authors.forename: Kevin
authors.initials: K
authors.lastname: Campos
authors.forename: Artis
authors.initials: A
authors.lastname: Klapars
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Brain
authors.initials: B
authors.lastname: Phenix
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents; D004340:Drug Contamination; D004355:Drug Stability; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet; D014227:Triazines / Q000737:chemistry*
chemical_list: D000577:Amides; D019440:Anti-Obesity Agents; D003432:Cross-Linking Reagents; D007202:Indicators and Reagents; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D014227:Triazines; C019309:cyanuric chloride; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide