Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 1: Azidation and [3 + 2] Cycloaddition

We report the use of continuous flow processing to enable the first two steps of a new route toward a cannabinoid receptor type 2 agonist, RG7774. First, an alkyl azide is formed using sodium azide at an elevated temperature. Flow processing allows this to be done in a safe and rapid manner, providing a quantitative yield in 1 min residence time. The subsequent [3 + 2] cycloaddition with 2-cyanoacetamide requires basicity within a fairly narrow range to facilitate the reaction while preventing the decomposition of starting materials. A kinetic model was proposed for the cycloaddition step, with validation in both batch and flow. Three different flow reactor setups were then examined to emulate combinations of plug flow reactors (PFRs) and continuous stirred tank reactors (CSTRs). The use of CSTRs enables operation above the solubility limit of the product, improving the mass intensity and productivity. The desired triazole product can consistently be isolated in ∼80% yield with >99% purity and ∼9.5 g/h productivity. This serves to lay the foundation for the remaining route development to RG7774. Furthermore, the developed kinetic models are used as a basis for the proposed scale-up setup of a combined PFR (1 L) + CSTR cascade (3 × 5 L) for a pilot scale, which would produce up to 8.9 kg/h of the triazole product.