Desenvolvimento de processos contínuos para a síntese de canabinoides

Abstract

This work presents the development and optimization of continuous flow processes for the synthesis of cannabinoids, with cannabidiol (CBD) as the central intermediate. The work is structured around three main stages: (i) a Friedel–Crafts alkylation reaction between methyl olivetolate and p-menthadienol to obtain the ester intermediate (EM CBDA), (ii) a base-catalyzed hydrolysis and decarboxylation to produce CBD, and (iii) catalytic hydrogenation of CBD and THC to yield semi-synthetic cannabinoids such as H2CBD, H4CBD, and HHC. The optimized Friedel–Crafts reaction using BF₃·OEt₂ achieved 74% conversion and 90% selectivity with a residence time of only 1 minute. The hydrolysis/decarboxylation step using 3.0 M NaOH in methanol reached over 99% conversion and 94% selectivity. Cyclization reactions under acidic conditions were investigated to understand the formation pathways of Δ⁹-THC, Δ⁸-THC, and iso-Δ⁸-THC, providing mechanistic insights into isomer distribution. In the final stage, catalytic hydrogenation in flow reactors using Pt/Al₂O₃-packed static mixers demonstrated excellent performance and catalyst stability. The developed processes proved to be scalable, efficient, and compatible with industrial applications, enabling the safe and selective production of high-purity cannabinoids through continuous flow chemistry.