4-(2-ETHOXYCARBONYL-ACETYL)-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER

(0032) (2) Compound 4 (14.56 g, 63.5 mmol), N, N′-carbonyldiimidazole (24.00 g, 86 mmol) were dissolved in tetrahydrofuran (100 mL), stirred at room temperature for 4 hours. Compounds potassium monoethyl malonate (28.10 g, 165 mmol), anhydrous magnesium chloride (18.15 g, 191 mmol) and 4-dimethylaminopyridine (800 mg, 6.35 mmol) were dissolved in acetonitrile (100 mL) and tetrahydrofuran (200 mL), stirred at room temperature for 6 hours. The two reaction mixtures were cooled to 0° C. after they sufficiently reacted separately. Then the above-mentioned first solution and triethylamine (52 mL, 254 mmol) were simultaneously added to the second solution, and then stirred overnight at room temperature. After completion of the reaction, the solvent is removed by evaporation. The residue is diluted with water (200 mL), extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give a yellow oily liquid 5 (18.06 g, 95percent).To a solution of boc-isonipecotic acid (150 g, 654 mmol) in tetrahydrofuran (2100 mL) was added di-1H-imidazol-1-ylmethanone (159 g, 981 mmol) and N, N-dimethylpyridin-4-amine (40.0 g, 327 mmol) at RT. The intermediate 12h was obtained as describe below: piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester (150 g, 0.655 mol) in anhydrous acetonitrile (800 ml), 1, 1'-carbonyldiimidazole was added in small portions (132 g, 0.851 mol) under vigorous stirring. The resulting mixture was stirred for 30 min at ambient temperature. Then powder of mixture of anhydrous MgClTo 2, was added abs. ethanol (200 mE) and the solution was refluxed for 48 h. The solution was concentrated in vacuo and purified by flash chromatography (DCM) to give 3 as a reddish oil (14.36 g, 85percent). ‘H NMR (500 MHz, CDC13) ö 12.09 (s, 0.14H, enol OH), 4.89 (s, 0.14H enol C——H), 4.13 (q, J=7 Hz, 2H), 4.10-3.96 (m, 2H), 3.42 (s, 2H), 2.81-2.67 (m, 2H), 2.62-2.52 (m, 1H), 1.85-1.71 (m, 2H), 1.55-1.43 (m, 2H), 1.39 (s, 9H), 1.21 (t, J=7 Hz, 3H); ‘3C NMR (125 MHz, CDC13) ö 204.0, 180.2 (enol), 172.7 (enol), 167.0, 154.4, 87.52, 79.51, 61.3, 48.5, 47.1, 28.2, 27.1, 13.9; Rf=0.2 (DCM). HRMS calculated for C, 5H26N05 (M+H) 300.1805, found 300.1808.[0535] A solution of tert-butyl 4-(2, 2-dimethyl-4, 6-dioxo-1 , 3-dioxane-5-carbonyl) piperidine-1-carboxylate (2 g, 5.63 mmol) in ethanol (50 ml) was refluxed for 20 h, then the solvent wasremoved under vacuum, and the residue was purified by silica gel chromatography eluted withDCM to afford 0.5 g (30percent) of tert-butyl 4-(3-ethoxy-3- oxopropanoyl)piperidine-1-carboxylateas a reddish oil. MS (ESI) m/e [M+23t 322.2.4-(2, 2-Dimethyl-4, 6-dioxo-1, 3-dioxan-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (2 g, 5.63 mmol) in ethanol (50 ml) solution, heated at reflux for 20 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on a silica gel column eluting with DCM to give a slightly red liquid of tert-butyl 4-(3-ethoxy-3-oxopropenyl)piperidine-1-carboxylate (0.5 g). , 30percent).tert-butyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3) To 2, was added abs. ethanol (200 mL) and the solution was refluxed for 48h. The solutionwas concentrated in vacuo and purified by flash chromatography (DCM) to give 3 as a reddish oil (14.36 g, 85percent). ‘H NMR (500 MHz, CDC13) ö 12.09 (s, 0. 14H, enol OH), 4.89(s, 0.14H enol C-H), 4.13 (q, J = 7 Hz, 2H), 4.10-3.96 (m, 2H), 3.42 (s, 2H), 2.81-2.67 (m, 2H), 2.62-2.52 (m, 1H), 1.85-1.71 (m, 2H), 1.55-1.43 (m, 2H), 1.39 (s, 9H), 1.21 (t, J = 7 Hz, 3H); ‘3C NMR (125 MHz, CDC13) ö 204.0, 180.2 (enol), 172.7 (enol), 167.0, 154.4, 87.52, 79.51, 61.3, 48.5, 47.1, 28.2, 27.1, 13.9; Rf=0.2 (DCM). HRMS calc’d for C, 5H26N05 (M+H) 300.1805, found 300.1808.To a mixture of ethyl N-Boc-piperidine-4-carboxylate (0.5 mol) and ethyl acetate (3 mol) t-BuOK(1.5 mol) was added in some portions at 0 C. The mixture was stirred at room temperature for 3h (monitored by TLC), concentrated up to a half of volume, diluted with water (200 mL) and extacted with ether. Organic layer was dried over sodium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane) afforded 4-(2-ethoxycarbonyl-acetyl)-piperidine-l-carboxylic acid tert- butyl ester (78 g, 52percent).In a 250 mL round-bottomed flask filled with dry ethanol (70 mL) was added 5 (13.0 g 36.7 mmol). The reaction mixture was heated under reflux for 8 h, then the solvent was evaporated, affording 10.9 g (99.5 percent yield) light yellow liquid.

Molecular Weight:299.36
XLogP3:1.7
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:7
Exact Mass:299.17327290
Monoisotopic Mass:299.17327290
Topological Polar Surface Area:72.9
Heavy Atom Count:21
Complexity:391
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes