72% |
In tetrahydrofuran; diethyl ether at 0 - 20℃; for 18h; |
5.1
To a solution of methyl magnesium bromide (6.00 mmol) in ethyl ether (27 mL) was added l-benzyl-piperidin-4-one (0.53 g, 0.28 mmol) at 0 °C followed by tetrahydrofuran (10 mL). The reaction mixture was warmed to room temperature and stirred for 18 h. Saturated ammonium chloride was added and the aqueous layer was extracted with ethyl acetate (3 x). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (2-10% methanol in dichloromethane) afforded l-benzyl-4-methylpiperidin-4-ol (0.42 g, 72% yield). |
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In tetrahydrofuran; diethyl ether at 0℃; |
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In tetrahydrofuran; diethyl ether at 0℃; for 1h; |
10.1
Example 10-1 1-Benzyl-4-methyl-4-piperidinol Under nitrogen atmosphere, methylmagnesium bromide (3. 0M solution in diethyl ether, 10. 8mL) was diluted with tetrahydrofuran (llOmL) with cooling on an ice bath. To the solution, was added dropwise a solution of l-benzyl-4-piperidinone (5.6g) in tetrahydrofuran (40mL), and the mixture was stirred for lhr. The reaction mixture was quenched by adding 1N hydrochloric acid. The aqueous layer was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over MgS04, and concentrated. The residue was purified by silica gel chromatography (eluent : ethyl acetate/methanol = 50/1) to give the title compound as a pale yellow oil (3.34g). H-NMR (300MHz, CDCl3) : No. 1.21 (1H, br-s), 1.24 (3H, s), 1.54-1. 73 (4H, m), 2.33-2. 41 (2H, m), 2.53-2. 60 (2H, m), 3.52 (2H, s), 7.22-7. 33 (5H, m). Mass (ES+) m/z : 206 (M+1). |
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Stage #1: 1-phenylmethyl-4-piperidone; methylmagnesium bromide In tetrahydrofuran; diethyl ether at -15 - 20℃;
Stage #2: With water; ammonium chloride In tetrahydrofuran; diethyl ether |
37
A solution of 1-benzyl-4-piperidone (26.5 mmol, 5 g) in THF (50 mL) was cooled to -15°C and a solution of methyl magnesium bromide in ether (3 M, 22 mL) was added. The mixture was stirred for 0.5 hours then allowed to warm to room temperature. Saturated aqueous ammonium chloride (50 mL) was added and the products were extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a pale yellow solid (5.0 g) that was used directly without further purification. |
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In tetrahydrofuran at 0 - 20℃; |
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In tetrahydrofuran at 0 - 20℃; for 3h; |
I.1.2.1
To RMgBr (0.5 M, 20 mmol) in THF was added a solution of Compound 1 (2.0 g, 10.56 mmol) in THF (20 mL) at 0-4 °C. The formed mixture was stirred at rt for 3 h. The reaction was quenched by NH4CI solution, and the mixture was extracted with EtOAc (20 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product |