Development of Multikilogram Continuous Flow Cyclopropanation of N-Benzylmaleimide through Kinetic Analysis

作者：Buono Frederic G^*; Eriksson Magnus C; Yang Bing Shiou; Kapadia Suresh R; Lee Heewon; Brazzillo Jason; Lorenz Jon C; Nummy Laurence; Busacca Carl A; Yee Nathan; Senanayake Chris

来源：Organic Process Research & Development, 2014, 18(11): 1527-1534.

DOI：10.1021/op500263m

A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the trans-isomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.

• 出版日期2014-11