Practical Synthesis of Methyl N2-(tert-butoxycarbonyl)-N4-(1-(tert-butyl)-1H-pyrazol-4-yl)-L-asparaginyl-L-phenylalaninate Utilizing Continuous-Flow Technology

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.

Equipment used in this paper: Large Diameter Tubular Reactor for Rapid Mixing

• Zhang X
• Gajula PK
• Vasilev M
• Hibbert G
• Chen A
• Sirasani S
• Gangu A
• Qu B
• Senanayake C

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