Development of a New Synthesis for the Large-Scale Preparation of Triple Reuptake Inhibitor (−)-GSK1360707

Abstract

The triple reuptake inhibitor, GSK1360707, was synthesized via an efficient, scalable route, which features a vinyl triflate Suzuki coupling followed by a single-step, double alkylative cyclopropanation with a dihalomethane. Also, a mechanistic understanding of the Suzuki reaction (as it relates to the control of a polychlorinated biphenyl impurity) is discussed.

Synthesis of Polycyclic δ-Lactams with Bridged Benzomorphan Skeleton: Selectivity and Diversity Driven by Substituents

“…As azabicyclo[4.1.0]­heptane ring systems, present in both obtained bridged benzomorphans 7 and 9 , consist of the central cores of some biologically active compounds, e.g., of piperidine: (−)-GSK1360707 (developed by GlaxoSmithKline as potent dopamine reuptake inhibitor for the treatment of the major depressive disorder (MDD) and amidine: ONO-1714 (acting as a potent inhibitor of inducible nitric oxide synthase and as a potential neuroprotective agent in stroke patients (Figure ), finally, we converted two representatives of bridged benzomorphans 7a and 9o into amidine and piperidine derivatives, respectively, according to Scheme . The results of not optimized transformations indicate high stability of obtained ring systems present in compounds 16 – 18 and designate starting lactams as prospect derivatives for further functionalizations toward bridged benzomorphans.…”

Design, preparation and application of conjugated microporous polymers

“…The Suzuki reaction is an arguably efficient method for aryl–aryl bond formation since initial reports in 1979 . The development of the Suzuki reaction has proceeded, including boronic acid and aryl chloride coupling, boronic acid and aryl bromide coupling, boronic acid and aryl iodide coupling, boronic acid and alkenyl triflate coupling, borane and aryl halide coupling, borane and alkyl halide coupling, boronic ester and aryl halide coupling, boronic ester and alkyl halide coupling, borate complexes, etc.…”

An Enyne Cycloisomerization Approach to the Triple Reuptake Inhibitor GSK1360707F

“…GSK1360707F is a potent serotonin, noradrenaline, dopamine reuptake (triple reuptake) inhibitor under development at GlaxoSmithKline for the treatment of major depressive disorder (MDD) . We recently disclosed our first generation route for the multikilogram scale synthesis of (−)-GSK1360707F, which took advantage of a novel double alkylation with a dihalomethane to construct the cyclopropane ring. While this route was utilized for the supply of 15 kg of drug substance, it had some potential long-term drawbacks, namely, the formation of polychlorinated biphenyl (PCB) byproducts in the Suzuki coupling, high cost of goods (COGs), and low atom efficiency.…”