1,3-Piperidinedicarboxylic acid, 3-(2-propen-1-yl)-, 1-(1,1-dimethylethyl) 3-ethyl ester synthesis

Yield:-

Reaction Conditions:

Stage #1: ethyl N-(t-butyloxycarbonyl)nipecotatewith lithium diisopropyl amide in tetrahydrofuran;n-heptane;ethylbenzene at -78; for 1.5 h;
Stage #2: allyl bromide in tetrahydrofuran;n-heptane;ethylbenzene at -78; for 1 h;

Steps:

2 1-tert-butyl 3-ethyl 3-allylpiperidine-1,3-dicarboxylate:

Example 2 1-tert-butyl 3-ethyl 3-allylpiperidine-1,3-dicarboxylate: A lithium diisopropylamide (2.0 mol/L in mixture of tetrahydrofuran-heptane-ethylbenzene, 22.5 mL, 45.0 mmol) was added to tetrahydrofuran (50 mL) and the mixture was cooled to -78°C. To the cooled mixture was added dropwise the solution of the compound prepared in Example 1 (7.72 g, 30.0 mmol) in tetrahydrofuran (50 mL) during 30 minutes, and the resulting mixture was stirred for 1 hour. The reaction mixture was added dropwise allyl bromide (3.9 mL, 45.1 mmol) and the mixture was stirred for 1 hour at -78°C. The reaction mixture then was allowed to warm gradually to ambient temperature. The mixture was added 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, dried over an anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 9: 1) to give the title compound (8.25 g) having the following physical data. TLC: Rf 0.29 (hexane: ethyl acetate = 9: 1); NMR: δ 1.25 (t, J=7.14 Hz, 3H), 1.53 (m, 12H), 1.99 (m, 1H), 2.21 (dd, J=13.82, 7.60 Hz, 1H), 2.36 (m, 1H), 3.34 (m, 3H), 3.82 (m, 1H), 4.13 (m, 2H), 5.05 (m, 2H), 5.70 (m, 1H).

References:

EP1683797,2006,A1 Location in patent:Page/Page column 33