Rapid, microwave-assisted organic synthesis of selective V600EBRAF inhibitors for preclinical cancer research
We report dramatically improved total syntheses of two highly selective V600EBRAF inhibitors, PLX4720 and PLX4032, that leverages microwave-assisted organic synthesis (MAOS). Compared with previously reported approaches, our novel MAOS method significantly reduces overall reaction time without compromising yield. In addition to providing a gram-scale route to these compounds for preclinical oncology research, we anticipate this approach could accelerate the synthesis of azaindoles in high-throughput, library-based formats.
Buck, Jason R.,Saleh, Sam,Imam Uddin, Md.,Manning, H. Charles
Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes: A facile route to novel di-7-azaindolylmethanes
A novel and highly efficient synthetic method leveraging microwave-assisted organic synthesis (MAOS) to yield di-7-azaindolylmethanes (DAIMs) is reported. Under MAOS conditions, reaction of 7-azaindole with aldehydes resulted predominantly in DAIMs, as opposed to the expected 7-azaindole addition products that form at ambient temperature. Based upon studies of different indoles and azaindoles with various aromatic and aliphatic aldehydes, we herein propose a mechanism where rapid and efficient microwave heating promotes nucleophilicity of 7-azaindoles toward the corresponding alkylidene-azaindolene intermediate to form the DAIM. This sequence provides a versatile approach to efficiently synthesize novel DAIMs that may be useful pharmaceuticals.
Uddin, Md. Imam,Buck, Jason R.,Schulte, Michael L.,Tang, Dewei,Saleh, Samir A.,Cheung, Yiu-Yin,Harp, Joel,Manning, H. Charles
p. 169 - 173
(2014/01/06)
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