2-(4-methoxypiperidin-1-yl)ethanamine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of nitrile 287 (10.25 g, 66.5 mmol) and Raney Nickel (50% w/w in water, ca. 10 mL) in EtOH (150 mL) and cNH3 (10 mL) was stirred under H2 (60 psi) for 16 h. The mixture was filtered through Celite, washed with EtOH (3×10 mL) and the solvent evaporated to give crude diamine 288 as an oil which was used directly. The mixture was filtered through Celite washed with EtOH (3×10 mL) the solvent evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 2-(4-methoxy-1-piperidinyl)ethylamine (288) (3.8 g, 23.9 mmol) was added to a stirred solution of chloride 21 (1.77 g, 8.0 mmol) and Et3N (2.2 mL, 16.0 mmol) in DME (80 mL) and the solution stirred at reflux temperature for 6 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 42 (2.16 g, 79%) as a yellow solid: mp (MeOH/EtOAc) 131-133° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.82 (br s, 1H, NH), 3.50-3.56 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.21-3.26 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.72-2.82 (m, 2H, CH2N), 2.60 (dd, J=6.0, 5.8 Hz, 2H, CH2N), 2.20-2.26 (m, 2H, CH2N), 2.15 (br p, J=7.4 Hz, 2H, H-7), 1.84-1.92 (m, 2H, CH2), 1.57-1.65 (m, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 76.2, 56.3, 55.5, 50.7 (2), 38.2, 33.1, 32.3, 30.8 (2), 25.7. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.0; H, 7.4; N, 20.4%. at reflux temperature for 6 h The solvent was evaporated the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL) The organic fraction was dried the solvent evaporated The residue was purified by chromatography eluting with a gradient (0-15%) of MeOH/DCM