Ethyl 1-methyl-4-piperidinecarboxylate

Chemical Properties

Colorless liquid

Uses

Reactant for synthesis of:

• Piperidine derivatives as inhibitors of S. aureus and E. coli enoyl-ACP reductase
• GABAA receptor agonists
• Water-soluble DNA-binding subunits for analogues of cytotoxic antibiotic CC-1065 and their prodrugs
• Tricyclic pharmaceuticals
• 5-HT3 antagonists

Synthesis

1126-09-6

50-00-0

24252-37-7

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).

References

[1] European Journal of Organic Chemistry, 2006, # 10, p. 2314 - 2321
[2] Patent: US2009/318668, 2009, A1. Location in patent: Page/Page column 52
[3] Patent: WO2007/89149, 2007, A2. Location in patent: Page/Page column 96
[4] Patent: US2011/9390, 2011, A1. Location in patent: Page/Page column 13-14
[5] European Journal of Medicinal Chemistry, 1994, vol. 29, # 1, p. 115 - 120