Reaction Steps
To a solution of 3-[3-[5-[(2(S)-pyrrolidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol trifluoroacetate (C19H24N2O2.3.02CF3COOH.0.57H2O, 296 mg, 443 μmol) in ethanol (1.5 mL) in a 15 mL round bottom flask was added formalin (0.18 mL, 6.6 mmol, 15 equiv.). A small amount of bromocresol green was added to the reaction mixture to monitor the pH, which was adjusted to 4-5 by addition of NaOAc. The mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (42 mg, 0.67 mmol, 1.5 equiv.) was added, whereon the pH increased. Small amounts of CF3COOH were added over several hours to keep the pH between 4 and 5. The resulting mixture was stirred at room temperature for an additional 24 h. The solvents were evaporated, and the residue was purified by CC on silica gel (38×1.0 cm, CH2Cl2/methanol/saturated aqueous ammonia 20:1:0.1). The crude product was purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 8% to 25% CH3CN in water within 20 min, from 25% to 100% for another 20 min, then 100% CH3CN for 20 min, both solvents containing 0.1 vol % CF3COOH; tR 18.0-24.3 min) to give the methylation product as a trifluoroacetate (colorless oil, 131 mg, 44%). 1H NMR (CD3OD, 500 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.06 (d, 1H, J=1.9 Hz), 7.61 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.51-7.45 (m, 1H), 7.38 (d, 1H, J=7.8 Hz), 4.92-4.88 (m, 1H, overlapping with the CD3OH peak), 4.68 (dd, 1H, J=11.2, 3.0 Hz), 4.52 (dd, 1H, J=11.0, 6.8 Hz), 4.03-3.94 (m, 1H), 3.84-3.76 (m, 1H), 3.65-3.59 (m, 2H), 3.13 (d, 3H, J=3.7 Hz), 2.82 (t, 2H, J=7.8 Hz), 2.50-2.42 (m, 1H), 2.32-2.22 (m, 1H), 2.22-2.08 (m, 2H), 1.96-1.88 (m, 2H). Anal. Calcd. for C20H26N2O2.3.00CF3COOH (FW 668.5) C, 46.71; H, 4.37; N, 4.19; F, 25.58. Found: C, 46.93; H, 4.49; N, 4.26; F, 25.83.
