A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to kilogram-scale production was achieved using a short residence time (0.25 s) and noncryogenic temperature (0 °C), without the need to increase the number of reactors. A comparison of the flow process with a Miyaura borylation process suggested some potential benefit in the overall process operating efficiency from avoiding the use of Pd and genotoxic boron reagents.

• Takeda Pharmaceutical Company Ltd.
• Takeda Pharmaceutical International Co.

• Intermediate

1. Boronic Acid
2. Intermediate
3. Lithiation
4. Miyaura borylation
5. organolithium
6. Research Article
7. Scale-up