ABSTRACT
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.
Subject(s)
Combinatorial Chemistry Techniques , Heterocyclic Compounds, 2-Ring/chemical synthesis , Quinolines/chemical synthesis , Receptors, Glucocorticoid/metabolism , Catalysis , Heterocyclic Compounds, 2-Ring/analysis , Indicators and Reagents , Ligands , Molecular Structure , Quinolines/analysis , StereoisomerismABSTRACT
A-240610.0 is a novel non-steroidal glucocorticoid receptor-selective ligand. It has demonstrated an anti-inflammatory activity equivalent to that of the synthetic glucocorticoids, and has shown an improved side-effects profile in vivo. This review will present the process research and development proceeding from the initial racemic route to an efficient asymmetric process. This process relied on the development of a novel atropselective synthesis of an axially chiral biaryl to form the critical atropisomer intermediate in good yields (85%) and with high diastereoselectivity (99:1).
Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Technology, Pharmaceutical/methods , Animals , Humans , StereoisomerismABSTRACT
A new approach for atropselective preparation of axially chiral biaryl was developed. This process proceeded through a chirality transfer from a stereogenic center of a secondary alcohol to the stereogenic axis via regioselective intramolecular silyl group migration. This methodology allowed for the preparation of a single atropisomer 2 in good yield (85%) with high diastereoselectivity (99:1), which subsequently led to the successful development of an efficient asymmetric synthesis of A-240610.0, 1.
