A Practical and Scaleable Synthesis of A-224817.0, a Novel Nonsteroidal Ligand for the Glucocorticoid Receptor

• Published in: Journal of organic chemistry 2003-04, Vol.68 (8), p.3238-3240
• Main Authors: Ku, Yi-Yin, Grieme, Tim, Raje, Prasad, Sharma, Padam, Morton, Howard E, Rozema, Mike, King, Steve A
• Format: Article
• Language: English
• Subjects: Catalysis; Chemistry; Combinatorial Chemistry Techniques; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Heterocyclic Compounds, 2-Ring - analysis; Heterocyclic Compounds, 2-Ring - chemical synthesis; Indicators and Reagents; Ligands; Molecular Structure; Organic chemistry; Preparations and properties; Quinolines - analysis; Quinolines - chemical synthesis; Receptors, Glucocorticoid - metabolism; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0268613

A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized high-yielding and high-throughput Negishi protocol. The quinoline core 8 was constructed by using a modified Skraup reaction. The final product was obtained by a direct allylation reaction of lactol 10 with allyltrimethylsilane. The process was accomplished efficiently to produce 1A in 25% overall yield and >99% purity with simple and practical isolation and purification procedures.