cis-Piperidine-2,6-dicarboxylic acid dimethyl ester synthesis

Yield:59234-46-7 97%

Reaction Conditions:

with 20% Pd/C;hydrogen in methanol at 50; under 45004.5 Torr;

Steps:

cis-O1-tert-butyl O2,O6-dimethyl piperidine-1,2,6-tricarboxylate 5

A solution of dimethyl pyridine-2,6-dicarboxylate (2.00 g, 10.2 mmol) in methanol (400 mL) was passed through the H-Cube flow hydrogenator at a flow rate of 1 mL/min, over a 20% Pd on carbon catalyst bed, at 50 ^oC under 60 bar of hydrogen pressure. The reaction was complete after a single run, the solvent was then removed at reduced pressure to afford cis-dimethyl-piperidine-2,6-dicarboxylate (2.01 g, 97%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 3.64 (s, 6H), 3.35 (dd, J=2.0, 11.4 Hz, 2H), 2.33 (s, 1H), 1.89 - 1.78 (m, 3H), 1.53 - 1.38 (m, 1H), 1.29 - 1.15 (m, 2H). ¹³C NMR (100 MHz, DMSO-d6) δ 172.8, 57.5, 51.6, 28.3, 23.5. ESI-HRMS: calculated for C₉H₁₅NO₄ [(M+H)⁺]: 202.1001. Found: 202.1074. To a solution of cis-dimethyl-piperidine-2,6-dicarboxylate (4.00 g, 19.9 mmol) in toluene (150 ml) was added di-tert-butyl dicarbonate (6.51 g, 29.8 mmol). Then the mixture was heated at 95 ^oC for 16h. The solvent was then removed at reduced pressure. The residue was purified by flash column chromatography eluting with a gradient of EA:PE (10:100 to 30:100) to afford compound (±)-5 (5.80 g, 97%) as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ: 4.82 - 4.74 (m, 2H), 3.70 (s, 6H), 2.19 - 2.09 (m, 2H), 1.77 - 1.63 (m, 3H), 1.54 (m, 1H), 1.49 (s, 9H).

References:

Wu, Guolong;Wang, Di;Zhu, Wei;Shen, Hong;Liu, Haixia;Fu, Lei [Synthetic Communications,2019,vol. 49,# 1,p. 12 - 21] Location in patent:supporting information