Novel and Efficient Access to Phenylamino-pyrimidine Type Protein Kinase C Inhibitors Utilizing a Negishi Cross-Coupling Strategy

• Published in: Journal of organic chemistry Vol. 70; no. 13; pp. 5215 - 5220
• Main Authors: Stanetty, Peter, Hattinger, Gregor, Schnürch, Michael, Mihovilovic, Marko D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.06.2005; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Combinatorial Chemistry Techniques; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Molecular Structure; Organic chemistry; Physical Sciences; Preparations and properties; Protein Kinase C - antagonists & inhibitors; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; MECHANISM; METALATION; Protein kinase C; Enzyme; Nitrogen heterocycle; Transferases; Cross reaction; Enzyme inhibitor; Pyrimidine derivatives; Pyridine derivatives
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0505223

A novel, short, and efficient synthetic pathway to 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-ylamino}-propanol (CGP 60474) and a series of analogues was developed. The synthetic sequence consisted of a Negishi-type cross-coupling reaction in the key step followed by two subsequent nucleophilic substitution reactions. This strategy represents a versatile and robust protocol to access diverse analogues of the title compound for subsequent SAR studies as potential phenylamino-pyrimidine type protein kinase C inhibitors.