An integrated flow and microwave approach to a broad spectrum protein kinase inhibitor

• Cecilia Russell^a
• Andrew J. S. Lin^a
• Peter Hains^b
• Michela I. Simone^a
• Phillip J. Robinson^b
• Adam McCluskey^{* a}

• ^A Centre for Chemical Biology, Chemistry, School of Environmental and Life Science, The University of Newcastle, University Drive, Callaghan, Australia
• ^B Children's Medical Research Institute, 214 Hawkesbury Road, Westmead, Australia

The protein kinase inhibitor CTx-0152960 (6, 2-((5-chloro-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), and the piperazinyl analogue, CTx-0294885 (7, 2-((5-chloro-2-((4-piperazin-1-ylphenyl)amino)pyrimidin-4-yl)amino)-N-methylbenzamide), were prepared using a hybrid flow and microwave approach. The use of flow chemistry approaches avoided the need for Boc-protection of piperidine in the key S_NAr coupling with 1-fluoro-4-nitrobenzene. Microwave coupling of 4-morphilinoaniline 8 and 4-(piperazine-1-yl)aniline 9 with 2-(2,5-dichloropyrimidine-4-ylamino)-N-methylbenzamide 10, proved to be the most efficacious route to the target analogues 6 and 7. This hybrid methodology reduced the number of synthetic steps, gave enhanced overall yields and increased atom economy through step reduction and minimal requirement for chromatographic purification, relative to the original batch synthesis approach.

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