| 78% |
With iodine at 20℃; for 2.33333h; |
|
| 73% |
With triethylamine In dichloromethane at 35℃; for 3h; |
1.a
Preparation 1; (4-Methyl-1-nitroso-2-oxo-1,2,5,6-tetrahydropyridin-3-yl)acetic acid ethyl ester; (a) 4-Methvlpiperidine-l-carboxylic acid tert-butyl ester; 4-Methylpiperidine (5.0 g, 50 mmol) and di-tert-butyl dicarbonate (13 g, 60 mmol) were dissolved in DCM (50 mL). TEA (7.65 mL, 1. 1 mol equiv.) was added and the reaction mixture was stirred at 35°C for 3 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (Si02, hexane) to give the sub-title compound (7.29 g, 73%). 1H NMR (400 MHz, CDC13) 6 0. 81 (d, 3H), 0.86-1. 00 (m, 2H), 1.33 (s, 9H), 1.13-1. 49 (m, 3H), 2.55 (m, 2H), 3.93 (m, 2H) |
| 73% |
With triethylamine In dichloromethane at 35℃; |
|
| 73% |
With triethylamine In dichloromethane at 35℃; for 3h; |
1.a
Preparation 1 (1-Amino-4-methyl-2-oxo-l,2,5,6-tetrahvdropyridin-3-yl)acetic acid ethyl ester (a) 4-Methyrpiperidine-l-carboxylic acid fert-butyl ester 4-Methylpiperidine (5.0 g, 50 mmol) and dhtert -butyl dicarbonate (13 g, 60 mmol) were dissolved in DCM (50 mL). TEA (7.65 mL, 1.1 mol equiv.) was EPO added and the reaction mixture was stirred at 35°C for 3 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO2, hexane) to give the sub-title compound (7.29 g, 73%).1H NMR (400 MHz5 CDQ) δ 0.81 (d, 3H), 0.86 - 1.00 (m, 2H), 1.33 (s, 9H), 1.13 - 1.49 (m, 3H), 2.55 (m, 2H), 3.93 (m, 2H) |
|
With sodium hydroxide In tetrahydrofuran; water at 20℃; Cooling with ice; |
|
| 926.5 mg |
With triethylamine at 0 - 20℃; |
6 Preparation of compound 54
To a solution of 4-methylpiperidine (53) (600 µL, 5.0 mmol) in MeOH (20 mL) was added Et3N (770 µL, 5.5 mmol) followed by Boc2O (1.2 g, 5.5 mmol) at 0°C. After 15 minutes, the reaction mixture was warmed to room temperature and allowed to stir overnight. The reaction solution was then diluted with H2O and extracted several times with ether. The ether extracts were combined, dried over Mg2SO4, filtered, and concentrated to provide compound 54 (926.5 mg) quantitatively as a colorless oil. |
|
With dmap In toluene at 0 - 20℃; for 0.5h; Inert atmosphere; |
N-Boc-trans-4-methyl-2-phenylthiopiperidine (1b).
To a solution of 4-methylpiperidine (1.98 g, 20.0mmol) and DMAP (0.0999 g, 0.818 mmol) in toluene (30 mL) was added slowly (Boc)2O (4.59 mL, 4.80 g,22.0 mmol) at 0 °C. After being stirred at room temperature for 30 min, the reaction was quenched withwater. The solvent was removed under reduced pressure. The residue was quickly filtered through a shortcolumn of alumina. The combined solution was concentrated to give crude tert-butyl4-methylpiperidinecarboxylate (3.35 g, 12.9 mmol, 65%) which was used directly for the next step. To asolution of tert-butyl 4-methylpiperidinecarboxylate (3.35 g, 12.9 mmol) in dry Et2O (17 mL) was slowlyadded TMEDA (2.51 mL, 1.95 g, 16.8 mmol) at -78 °C, followed by dropwise addition of sec-BuLi (1.02 Min hexane, 16.5 mL, 16.8 mmol) at the same temperature. Then the mixture was slowly warmed to -40 °C,stirred for 30 min, and then cooled again to -78 °C. To this mixture was added dropwise diphenyl disulfide(PhSSPh, 11.3 g, 51.6 mmol) in Et2O (22 mL). Then the mixture was slowly allowed to warm to roomtemperature and stirred for 24 h. The reaction mixture was quenched with water (30 mL), extracted withEt2O (3×30 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL), driedover MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography(hexane/EtOAc 30:1 to 10:1) to obtain the title compound (9.90 g, 3.22 mmol, 25%) |
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