Continuous Flow-Facilitated CB2 Agonist Synthesis (1)

Org. Process Res. Dev. 2023, 27, 592−600. DOI: 10.1021/acs.oprd.3c00035

◆A cannabinoid receptor type 2 (CB2) agonist, RG7774 (5), is currently in a phase II trial for the treatment of diabetic retinopathy. The original route furnished the desired regioisomer of the API 5 with poor selectivity (1:1 for the desired isomer).

◆An alternative route was envisaged in which the tetrazole fragment would be incorporated from the beginning of the synthetic route.

◆The formation of the azido-tetrazole intermediate 2 was examined in batch using NaN3 as the azide source, with analysis using benchtop NMR as a process analytical technology (PAT).

◆The precipitation of NaCl was observed over time, which may serve as a driving force for this reaction but will provide an obstacle to operation in a microreactor.

◆A clear solution was obtained with a water content of >40% in DMSO; however, as anticipated, the reaction rate was considerably slower with increasing water content.

◆The reaction progress was investigated in flow at 80, 100, and 120 °C, whereby the increased temperature dramatically accelerated the reaction. Full conversion was observed in ∼1 min at 120 °C.

◆Differential scanning calorimetry (DSC) analysis of this reaction mixture showed an exothermic event with an onset temperature of 115 °C as well as a highly exothermic event with an onset at 215 °C.

◆Therefore, for safety reasons, it was decided to operate at a lower temperature where possible. To achieve this while still operating with a short residence time, the final process conditions were selected as a 4 min residence time at 100 °C.

◆Gratifyingly, the reaction appeared to proceed cleanly, with no side products detected by NMR analysis.