tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylate

Step 1. tert-butyl 2-methyl-4-oxopiperidine-l-carboxylate [0757] Di-tert-butyl dicarbonate (1.09 g, 5.01 mmol) was added to a 0 °C solution of 2- methylpiperidin-4-one hydrochloride (1 : 1 mixture of isomers, 0.500 g, 3.34 mmol) and DMAP (0.817 g, 6.68 mmol) in dry THF (10 mL), and the resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (70 mL) was added. The aqueous phase was separated and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 25-35percent ethyl acetate in hexanes) to afford tert-butyl 2-methyl-4-oxopiperidine- 1 -carboxylate (0.660 g, 93percent) as a white solid. 1H NMR (300 MHz, DMSO-i δ ppm 1.06 (d, J=6.74 Hz, 3 H), 1.40 (s, 9 H), 2.1 1 - 2.25 (m, 2 H), 2.36 - 2.45 (m, 1 H), 2.68 (dd, J=14.51, 6.6 Hz, 1 H), 3.25 - 3.36 (m, 1 H), 3.93 - 4.06 (m, 1 H), 4.42 - 4.48 (m, 1 H).To a solution of 1-t-butoxycarbonyl-2-methyl-4-piperidone ethylene ketal (6.00 g) obtained in reference example 82 in acetone (150 ml) was added p-toluenensulfonic acid monohydrate (4.40 g) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature overnight. After stirring, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford the title compound (2.40 g, yield: 48 percent) as a yellow oil. 1H NMR (500MHz, CDCl3) δ ppm : 1.18 (3H, d, J=7.0), 1.49 (9H, s), 2.20-2.30 (1H, m), 2.30-2.40 (1H, m), 2.45-2.55 (1H, m), 2.65-2.70 (1H, m), 3.25-3.35 (1H, m), 3.90-4.05 (1H, m), 4.20-4.30 (1H, m).110 g (0.44 mol) of the compound prepared in the step (2) was dissolved in 800 ml of methanol, 186 g (0.66 mol) of di-tert-butyl dicarbonate was added, and 5percent by weight of palladium on carbon percent), Hydrogenation, the reaction for 8 hours, after the completion of the reaction filtration, palladium-carbon filter, with a small amount of methanol washing filter cake 2 times, the combined filtrate, vacuum distillation of methanol, 500 ml of ethyl acetate dissolved, L hydrochloric acid, potassium carbonate solution, saturated brine, dried over anhydrous sodium sulfate and evaporated to give 170 g of a pale yellow oil. Crystallization was carried out at about 0C using a 5: 1 mixture of petroleum ether and ethyl acetate , Filtered to obtain 85 grams of white solid, that is, broad-1-tert-butoxy-2-methyl-4-piperidine pay. Yield 95percent.A solution of 5 mL (49 mMol) 4-methoxypyridine in 200 mL tetrahydrofuran was cooled to -40°C, and then 6.9 mL (55 mMol) phenyl chloroformate were added dropwise. After stirring for 15 minutes, 20 mL (60 mMol) methyl magnesium chloride (3M in tetrahydrofuran) were added dropwise and the reaction mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was cooled to -40°C and treated with 340 mMol potassium tert-butoxide. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour, the reaction mixture was cooled to -40°C and was treated with. 200 mL saturated aqueous oxalic acid. The reaction was warmed to 20°C and allowed to stir for 1 hour. The mixture was extracted 2 x 200 mL diethyl ether. The combined organic phases were washed sequentially with 4 x 100 mL 0.5 N sodium hydroxide, 2 x 100 mL saturated aqueous sodium bicarbonate, 3 x 100 mL deionized water, and 100 mL saturated aqueous sodium chloride. The remaining organics were dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing 40percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 4.9 gm (47percent) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine. EA: Calculated for: C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.78; H, 8.08; N, 6.76. A solution of 1.65 gm (7.81 mmol) 1-(tert-butoxycarbonyl)-2-methyl-4-oxopiperidine in 20 mL tetrahydrofuran was cooled to -40°C and was then treated with 8.59 mL (8.59 mMol) lithium tri(sec-butyl)borohydride (1M in tetrahydrofuran). After stirring for 2 hours, the solution was treated with 3.37 gm (8.59 mMol) 2-[N, N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine and the solution was allowed to warm to room temperature. After stirring for 1 hour, the reaction was diluted with 250 ml diethyl ether and filtered through celite. The celite pad was rinsed with 250 mL diethyl ether and the combined filtrates concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes containing from 0-9percent ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.02 gm (75percent) of the title compound. ISMS: m/e = 346 (M+H)Description 156; 1.1-Dimethvlethvl 2-methvl-4-oxo-1-piperidinecarboxvlate (D156); To a solution of 2-methyl-4-piperidinone acetate (D154) (14g, 0.081 mol) in NaOH1M (30 ml) was added di-ferf butyl carbonate (18g, 0.081 mol) and the reactionmixture was stirred overnight at 20°C. The reaction mixture was diluted with ethylacetate (50ml) and extracted several time (50ml). The combined organic layers weredried (Na

Molecular Weight:213.27
XLogP3:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:213.13649347
Monoisotopic Mass:213.13649347
Topological Polar Surface Area:46.6
Heavy Atom Count:15
Complexity:268
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes