Practical Synthesis of Methyl N 2-( tert -butoxycarbonyl)- N 4-(1-( tert -butyl)-1 H -pyrazol-4-yl)- L -asparaginyl- L -phenylalaninate Utilizing Continuous-Flow Technology

Abstract A practical synthesis of methyl N2-(tert-butoxycarbonyl)-N4-(1-(tert-butyl)-1H-pyrazol-4-yl)-L-asparaginyl-L-phenylalaninate (5) utilizing two continuous-flow processes is reported. The first is the trickle-bed continuous-flow hydrogenation of the nitro compound 1-tert-butyl-4-nitro-1H-pyrazole (1) on a multikilogram scale, followed by T3P-mediated amide coupling in flow with the dipeptide (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoic acid (4) to obtain compound 5 in an overall 80–84% yield and >99.9 A% HPLC purity. In situ ReactIR was applied for real-time reaction monitoring. A catalyst-bed packing protocol was engineered to mitigate pressure drop and maintain catalyst-bed reactivity and longevity, which enabled a low catalyst loading of 0.1 mol % Pd/C for nitro reduction on a multikilogram scale.