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

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.

Mapping the Catechol Binding Site in Dopamine D1Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

“…Deoxygenation of such lactol systems with boron trifluoride diethyl etherate (BF 3 ·OEt 2 ) results in formation of oxonium ions, which in turn may be reduced with a hydride source [22] or trapped with an appropriate nucleophile. [23, 24] A deep red color was formed, indicative of the oxonium ion, but attempts to trap it with a variety of electrophilic reagents such as cyclohexylMgCl, phenylMgBr, adamantylMgCl, or adamantylZnCl at either 0 °C or −78 °C yielded numerous products. Triethylsilane did prove to be an effective hydride source to yield the unsubstituted 10 (Scheme 2).…”

“…We were then successful in attaching an allyl group ( 11 ) in good yield by this methodology. [24, 25] Catalytic hydrogenation then afforded the reduced propyl compound 2e . Optimal yields were obtained when a large excess (4.5 molar eq.)…”

Recent Advances on Synthesis of Fused Chromeno‐Quinoline Heterocycles under Transition Metal‐Free Condition

“…[18] The chromene-fused quinoline moieties act as progesterone receptor modulator [19] and glucocorticoid modulator. [20] Some of the other activities of such moieties include anti-inflammatory property, [21] bacteriostatic property [22] and such moieties also prevent cell-proliferation against MCF-7 breast cancer and MDA-MB-231 cancer cell lines (Figure 1). [23] Apart from biological activities, some of the derivatives have also been reported to have fluorescence sensing property.…”

Novel and Efficient One-Step Parallel Synthesis of Dibenzopyranones via Suzuki−Miyaura Cross Coupling

“…More recently the Diels-Alder cycloaddition of 4-cyanocoumarins,8 tert -butyllithium-mediated cyclization of bromobenzylfluorophenyl ethers,9 and ruthenium-catalysed cyclotrimerization of aryl diynes10 have been reported. In 2002, Abbott Laboratories reported a practicable and scalable synthesis of glucocorticoid receptor A-224817.0 through a Negishi cross coupling 11. However, none of these methods are suitable for the parallel synthesis approach to generating large numbers of analogues for drug discovery research.…”