Continuous-flow synthesis of 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]triazolo[4,5-<i>c</i>]pyridines towards key intermediates of clinical candidates JNJ-54175446 and zanvipixant (JNJ-55308942) with antidepressant activity

1,4,6,7-Tetrahydro-5<i>H</i>-[1,2,3]triazolo[4,5-<i>c</i>]pyridines are potent antagonists of the P2X7 receptor, a key regulator of neuroinflammation associated with depression. Two clinical candidates, JNJ-54175446 and JNJ-55308942 were developed based on this scaffold, together with a stereoselective synthesis involving a one-pot [3 + 2] cycloaddition/Cope-elimination cascade. Besides challenging regioselectivity, this route raises safety concerns, as both steps involve hazardous reagents. Herein, we report a two-step continuous-flow strategy for the synthesis of this valuable scaffold, which enables access to intermediates of JNJ-54175446 and JNJ-55308942 <i>via</i> temperature-controlled regioselectivity. Applying the optimized conditions, yields of 48% (58% regioselectivity) and 45% (91% regioselectivity) were achieved, respectively. The method ensures safe utilization of azide in the cycloaddition, and uses a safer oxidant for the elimination, offering a scalable and affordable alternative synthetic route.