Example 22 Synthesis of ethyl 1-methylpiperidine-4-carboxylate (21): ethyl 4-piperidinecarboxylate (20) (5.00 g, 31.8 mmol) was dissolved in an ice-cold mixture of glacial acetic acid (3.80 g, 63.6 mmol) and water (11 mL). Subsequently, 37% formaldehyde aqueous solution (2.85 mL, 38.2 mmol) was added to the solution and hydrogenation reaction was carried out in the presence of Pd/C (10%, 338 mg) catalyst for 3.5 hours at room temperature and 58 psi H2 pressure. Upon completion of the reaction, the solid catalyst was removed by diatomaceous earth filtration and the filter cake was washed thoroughly with deionized water (50 mL). The filtrate was adjusted to pH 11 with 1 M NaOH solution under cooling in an ice bath. after adjusting the pH, multiple extractions were carried out with ether (5 x 100 mL) and the organic phases were combined and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give the product 21 (5.44 g, quantitative yield) in the form of a colorless liquid, which could be used in the next reaction without further purification. The product characterization data were as follows: 1H NMR (300 MHz, CDCl3): δ=1.25 (t, J=7.1 Hz, 3H, OCH2CH3), 1.69-2.06 (m, 6H, 2-Hax, 3-H2, 5-H2, 6-Hax), 2.18-2.32 (m, 1H, 4-H), 2.27 (s, 3H, NMe) , 2.75-2.87 (m, 2H, 2-Heq, 6-Heq), 4.13 (q, J=7.1Hz, 2H, OCH2CH3) ppm. 13C NMR (75.5MHz, CDCl3): δ=14.1 (OCH2CH3), 28.2 (C-3, C-5), 40.5 (C-4), 46.3 (NMe) , 54.9 (C-2, C-6), 60.2 (OCH2CH3), 175.0 (C=O) ppm. MS (70eV, EI): m/z (%) = 171 (31) [M]+, 142 (59) [M-CH2CH3]+, 126 (40) [M-OCH2CH3]+, 98 (56) [M-CO2Et]+. Molecular formula: C9H17NO2 (molecular weight: 171.24).
