Process Development and Scale-Up of an Hsp90 Inhibitor

Abstract

A scalable process for the manufacture of a Hsp90 inhibitor was developed and optimized. Key features in the seven-step process include a selective SNAr reaction followed by an Ullmann-type coupling of indazolone to an aryl halide. This improved process afforded 65% yield over two critical steps compared to 25% following the Medicinal Chemistry route.

Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells

“…The small molecular inhibitor of Hsp90, SNX-5422, has been previously described (Fadden et al, 2010;Huang et al, 2009). The compound was synthesized in-house (Duan et al, 2012) and was characterized by proton nuclear magnetic resonance (NMR) and liquid chromatography/mass-spectrometry (LC/MS). The compound was solubilized in 100% DMSO to a 10 mM stock concentration.…”

Synthesis of Tamibarotene via Ullmann-Type Coupling

“…Initially, our study was focused on the optimization of Route B and Route C; however, the Friedel–Crafts reaction of N -phenyl-amide always yielded a complex mixture of products which had to be further purified by column chromatography to provide a small amount of target compound. Encouraged by the fact that copper has been used as an effective catalyst for the useful and practical formation of C­(aryl)–N bond, and such copper-mediated coupling reactions have numerous industrial applications, we adopted Ullmann-type coupling to prepare the key intermediate 3 . The alternative synthetic route of 1 , from commercially available 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalene 2 , involved Ullmann-type coupling, condensation of 3 and terephthalic acid monomethyl ester, and hydrolysis of ester.…”

Oral Hsp90 inhibitor, SNX-5422, attenuates SARS-CoV-2 replication and dampens inflammation in airway cells

“…The small molecular inhibitor of Hsp90, SNX-5422, has been previously described (Fadden et al, 2010, Huang et al, 2009). The compound was synthesized in-house using previously described methods (Duan et al, 2012) and was characterized by proton nuclear magnetic resonance (NMR) and liquid chromatography/mass-spectrometry (LC/MS). The compound was solubilized in 100% DMSO to a 10mM stock concentration.…”