Continuous Flow Conditions for High Temperature Formation of a Benzodioxan Pharmaceutical Intermediate: Rapid Scaleup for Early Phase Material Delivery

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular S_NAr cyclization. Interestingly, traditional S_NAr conditions resulted in impurity formation. When the starting material 2 was treated with alkali base in polar aprotic solvents, an undesired product regioisomer was observed. The formation of this regioisomer impurity could be suppressed by using a less polar solvent, an organic base, and high temperature. By employing continuous flow technology, these high temperature conditions could be scaled up to produce 540 g of the desired intermediate. The continuous flow reactor allowed for rapid thermal equilibration, which minimized problematic product decomposition by reducing the time that the product was exposed to high temperature.