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

Abstract

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.

Scalable Synthesis of 6-Chloro-1H-pyrazolo[3,4-b]pyrazine via a Continuous Flow Formylation/Hydrazine Cyclization Cascade

“…Increasing the number of CSTRs in series would counteract these effects, but cascades instead suffer from increased complexity and longer startup/shutdown sequences, and they also require an excessive amount of time and materials to develop, due to the relatively large solution volumes needed to obtain accurate scale-down results. To minimize the experimental cost for continuous flow process development, we leveraged process modeling using batch mode kinetics data to investigate the process space (reaction time, temperature, and number of vessels in series), aiming to minimize complexity, while still reliably delivering the target product profile. , …”

The role of PAT in the development of telescoped continuous flow processes

“…Recently, an example of the use of in-line UV-vis spectrometry as PAT from Kappe and co-workers was published, in collaboration with Roche (Scheme 25). 67,68 A new route towards the cannabinoid receptor type 2 agonist, RG7774 68 , was developed using a combination of batch and continuous flow processing, containing a total of seven reaction steps. Of relevance to this review was the use of in-line UV-vis spectrometry as a PAT tool for the monitoring of the outflow, containing 69 , from an intermediate amine scavenging treatment, which was telescoped with the final nucleophilic aromatic substitution step in flow.…”

Continuous Flow-Facilitated CB2 Agonist Synthesis, Part 2: Cyclization, Chlorination, and Amination

“…This final step completed the proof of principle for this new synthetic route to 6, consisting of 7 linear steps from a simple amide starting material (Figure 6). 4 The yields for each step were in the range of 80−90% with three isolated intermediates (which are necessary for intermediate product quality assessments). The overall yield of 53% is almost double that of the original route (27% overall yield).…”

“…3 The following part of the route, reaching triazole carboxamide 1, is described in an accompanying article (part 1: azidation and [3 + 2] cycloaddition). 4 To complete the synthesis carboxamide 1, which is pre-functionalized with the tetrazole side chain, is pivaloylated followed by base-mediated cyclization to pyrimidinone 3. This is then chlorinated to enable S N Ar of 4 with chiral pyrrolidinol 5, furnishing the final API 6.…”

“…The suggested new route toward CB2 agonist 6 is shown in Figure b, beginning with a chlorotetrazole whose synthesis in continuous flow has recently been disseminated . The following part of the route, reaching triazole carboxamide 1 , is described in an accompanying article (part 1: azidation and [3 + 2] cycloaddition) . To complete the synthesis carboxamide 1 , which is pre-functionalized with the tetrazole side chain, is pivaloylated followed by base-mediated cyclization to pyrimidinone 3 .…”