New Scalable Synthetic Routes to ELQ-300, ELQ-316, and Other Antiparasitic Quinolones

Abstract

The endochin-like quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad–Limpach reaction to produce 3-substituted 4­(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial-scale production, is relatively short (five reaction steps), does not require palladium, chromatographic separation, or protecting group chemistry, and may be performed without high vacuum distillation.

Synthesis and characterization of highly efficient and recoverable Cu@MCM-41-(2-hydroxy-3-propoxypropyl) metformin mesoporous catalyst and its uses in Ullmann type reactions

“…This reaction was also carried out in 2014 using thioamides as a source of sulfur 21 , 22 . In 2021, the Ullmann reaction was used to produce endochin-like quinolone compounds, which are safe treatments for a range of important human and animal afflictions in Sovitj Pou research group 23 . Also, cellulose-supported poly(hydroxamic acid) − Cu(II) complex was successfully applied to the Ullmann etherification 24 .…”

Iridium-Catalyzed Borylation of 6-Fluoroquinolines: Access to 6-Fluoroquinolones

“…In our choice of groups at C4, we were conscious that a quinoline to quinolone transformation would be very valuable as this methodology could provide an excellent route to substituted fluoroquinolones. We anticipated that compounds 2a , 2b , 2d , and 2e could undergo acid-hydrolysis to provide the corresponding 4-quinolone, while orthogonally, 2c could be deprotected using palladium-catalyzed hydrogenation ( vide infra ) …”

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

“…Although Ullmann coupling of 1,4-dibromobenzene ( 384 ) and phenol 385 in the presence of CuCl, DMG ( L2 ), and K 2 CO 3 in DMF in the original route afforded the diaryl ether 386 in good yields of 60–80%, this route involved two expensive Pd-catalyzed reactions to derivatize compound 386 as its boronic ester 387 and subsequent Suzuki–Miyaura cross-coupling with 388 to construct the final product ELQ-300 (Original Route, Scheme ). In addition, two regioisomers were formed during the cyclization reaction for the preparation of quinolone 388 , which resulted in low yields of 40–50% after selective crystallization. Although this route was scaled up to deliver hundreds of grams of a variety of ELQ analogs, these concerns promoted Pou et al at the VA Portland Healthcare System to search for alternative routes that could be practiced on a larger scale.…”