Dimethyl Sulfoxide → 5-Fluoro-2-(((3R,6R)-6-methylpiperidin-3-yl)methoxy)pyridine

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A 3-L, three-necked, round-bottomed flask equipped with a septum, nitrogen inlet adapter, mechanical stirrer, and thermocouple was charged with A-5 (87.0 g), 2,5-difluoropyridine (30.0 g), and 870 mL of DMSO (110 ppm water) at room temperature (23° C.). Sodium t-butoxide (50.1 g) was added portion wise over 4 min keeping the internal temperature below 29° C. The resulting reaction mixture was stirred at room temperature (ea. 25° C.) until HPLC analysis indicated less than 5% difluoropyridine compared to the desired product. (Agilent Eclipse XDB-C18 4.6×150 mm column; 35° C.; Mobile phase: (A) 0.1% H3PO4/water; (B) Acetonitrile. Linear gradient, Time 0: 95% A, 5% B; Time 6 min: 5% A, 95% B; Time 10 min: 5% A, 95% B. Flow rate, 1.5 mL/min. UV=210 tun; A-5 RT=2.8 min, A-9 RT=3.2 min, 2,5-difluoropyridine RT=4.1). The reaction mixture was then diluted with water (20 vol., 1740 mL) and EtOAc (10 vol., 870 mL). The organic layer was separated, washed with water (10 vol., 870 mL), and transferred to a 2-L round-bottomed flask. HCl (3.9 N solution in IPA) was slowly added via addition funnel over 30 min and the resulting white slurry was stirred at room temperature for 1 h. The crystals were collected, washed with EtOAc (3 vol., 2610 mL), and dried under vacuum with a nitrogen sweep to give 55.0 g of A-9 as white crystals.

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