Scalable Synthesis of Cinnamylamines Via the Heck Reaction: Application in the Synthesis of Abamine, Naftifine and Reboxetine

Abstract

Following an extensive screening of reaction parameters such as the nature and amount of bases, Pd pre‐catalysts, ligands, additives, solvents and temperature range, we succeeded in developing a Heck reaction using N‐Boc‐allylamine and commercially available aryl bromides, capable of delivering a wide range of Boc‐protected trans‐cinnamylamines with 75–85 % regio‐ and stereoselectivity over other isomers. Optimisation of the Boc‐deprotection step and its work‐up procedure allowed for all minor isomers and impurities to be purged thus isolating pure trans‐cinnamylamines typically in 55–65 % yield without need for chromatography. We have successfully performed this chemistry in up to 5 g scale and demonstrated its usefulness by applying it to the synthesis of abamine, naftifine hydrochloride and a formal synthesis reboxetine mesylate.

A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates

“…The Mizoroki-Heck reaction (often referred to simply as Heck reaction) is one of the most popular Pd-catalysed cross-coupling reactions, allowing easy access to substituted alkenes ( Oestreich, 2009 ; Jagtap, 2017 ). This reaction is now an indispensable implement in the organic chemist’s toolbox, and it has been used in synthesizing a variety of active pharmaceutical ingredients (APIs), clinical candidates, natural products and fine chemicals ( Prashad, 2004 ; Bollikonda et al, 2015 ; Neumann et al, 2020 ; Zhang, 2021 ; Deng et al, 2022 ; Tabassum et al, 2022 ; Cai et al, 2023 ; Stanway-Gordon et al, 2023 ; Moschona et al, 2024 ). Some notable examples are reported in Figure 1 .…”