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 SNAr cyclization. Interestingly, traditional SNAr 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.

• Shanghai SynTheAll Pharmaceutical Co., Ltd. (“STA”)
• Eli Lilly and Company

• Intermediate

1. benzodioxan
2. Continuous flow reactor
3. Intermediate
4. Research Article
5. Scale-up
6. SNAr cyclization