Telescoped Lithiation, C-Arylation and Methoxylation in Flow-Batch Hybrid toward the Synthesis of Canagliflozin

• Dominik Polterauer^a,b
• Jason D. Williams^a,b
• Christopher A.Hone^a,b
• C. Oliver Kappe^a,b

• ^aCenter for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, A-8010 Graz, Austria
• ^bInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria

We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before undergoing completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.

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