Step 1. Synthesis of (3-fluoropyridin-4-yl)methanol
3-Fluoropyridine (600 g, 6.18 mol) was dissolved in anhydrous THF (6 L) under nitrogen protection, mechanically stirred and cooled to -65 °C. A THF solution of lithium diisopropylamine (3.4 L, 6.5 mol) was slowly added over a period of 2 h. The reaction temperature was kept below -60 °C and stirring was continued for 1 h at this temperature. Subsequently, pure DMF (804 mL, 10.4 mol) was added dropwise over 1 h, the temperature was maintained below -60 °C and the reaction was monitored by TLC until the 3-fluoropyridine was completely consumed.
Upon completion of the reaction, the mixture was slowly warmed to -10 °C and water (1.1 Kg, 62 mol) was added. Sodium borohydride (234 g, 6.18 mol) was added in batches at 0 °C and stirred for a few minutes. Next, 6 M HCl (5.6 L) was added slowly over 1 h. The quenching temperature was controlled to be between 0-25°C. The reaction mixture was heated to 40°C and stirred overnight.
After cooling to 0-15 °C, the pH was adjusted to 12 by slow addition of 6 M NaOH. the aqueous layer was extracted with isopropyl acetate (500 mL x 1,1L x 3). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Heptane-isopropyl acetate (1.2L, v/v=5/1) was added to the crude product and the product was stirred at 0°C for 30 min to crystallize. Filtered, the filter cake was washed with cooled heptane (250 mL x 1) and dried under vacuum to give the light yellow solid title compound (688 g, 88% yield).
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=4.8 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.49 (t, J=4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).
