Cyclohexanecarboxaldehyde → (+/-)-6-[4-(1-Cyclohexylmethyl-piperidin-3-yl)-phenoxy]-nicotinamide

Reaction equation

Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH4-].[Na+]>>[CH:24]1([CH2:30][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)=[CH:22][CH:23]=3)[CH2:3]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1

Participants

Reactant 3

HCID 16275Cyclohexanecarboxaldehyde

HCID 4311764Sodium borohydride

HCID 68747046(+/-)-6-(4-Piperidin-3-yl-phenoxy)-nicotinamide hydrochloride2×

Product 1

HCID 59730407(+/-)-6-[4-(1-Cyclohexylmethyl-piperidin-3-yl)-phenoxy]-nicotinamideYield 19%

Procedure

Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.96 mL of 0.12 M stock solution in methanol, 0.0344 g, 0.116 mmol) and cyclohexanecarboxaldehyde (0.021 mL, 0.173 mmol), and stir overnight. Add sodium borohydride (0.0108 g, 0.285 mmol), stir for 4.5 h, then concentrate and purify by silica gel chromatography (20:1→10:1 ethyl acetate:methanol) to provide 0.0085 g (19%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H32N3O2 394.2495, found 394.2488; 1H NMR (CDCl3): 8.58 (s, 1H), 8.14 (d, 1H, J=7.8 Hz), 7.27 (d, 2H, J=8.3 Hz), 7.05 (d, 2H, J=7.8 Hz), 6.93 (d, 1H, J=8.8 Hz), 5.89 (s br, 2H), 2.99-2.77 (m, 3H), 2.16-2.06 (m, 2H), 1.97-1.83 (m, 3H), 1.80-1.59 (m, 7H), 1.54-1.34 (m, 2H), 1.29-1.03 (m, 5H), 0.93-0.77 (m, 3H).