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To a solution of 1-tert-butyl 2-methyl (25,5>S)-5-hydroxypiperidine-l,2-dicarboxylate (3.36 g) in dichloromethane (40 mL) were added triethylamine (2.8 mL) and methanesulfonyl chloride (1.2 mL). After 1 1A hours, the reaction mixture was diluted with dichloromethane, washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 4.54 g of the title compound.
NaBH4 (191 mg, 5.0 mmol) was added at 0C to solution of 3 (651 mg, 2.5 mmol) in methanol (10 ml_) and the solution was stirred for 2 h at 0 C. The reaction mixture was warm to room temperature and quenched with water. EtOAc was added and the organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by flash chromatography using cyclohexane/EtOAc (6/4) as eluent to give 4 (596 mg, 91 %) as a colorless oil. HRMS: calculated for C12H22NO5 [M+H]+: 260.1498; found: 260.1488.
91%
With sodium tetrahydroborate; water; In methanol; for 2.0h;
NaBH4 (191 mg, 5.0 mmol) was added at 0C to solution of 3 (651 mg, 2.5 mmol) in methanol (10 ml_) and the solution was stirred for 2 h at 0C. The reaction mixture was warm to room temperature and quenched with water. EtOAc was added and the organic layer was washed with brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by flash chromatography using cyclohexane/EtOAc (6/4) as eluent to give 4 (596 mg, 91 %) as a colorless oil. HRMS: calculated for C12H22NO5 [M+H]+: 260.1498; found: 260.1488.
To a solution of l-tert-butyl 2-methyl (2S)-5-oxopiperidine-l,2-dicarboxylate (3.69 g) in methanol (100 mL) at 0 C was added sodium borohydride (NaBH4) (0.51 g). After 3 hours at 0 C, the reaction was concentrated slightly, diluted with ethyl acetate, washed with 1 M HCl, 1 M NaOH, and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3.36 g of the title compound.ES (M+Na)+= 282.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20.0℃; for 24.0h;
Triphenylphosphine (3 g, 1 1 .6 mmol) and N-nitrosulfonyl-O-benzyl hydroxylamine (2 g, 6.3 mmol) were added to a solution of 4 (1.5 g, 5.8 mmol) in THF (50 ml_). DEAD (2.1 ml_, 1 1.6 mmol) was added dropwise and the reaction mixture stirred 24 h at room temperature and concentred in vacuo. The crude product was purified by flash chromatography using cyclohexane/EtOAc (8/2) as eluent to give 5 (2.67 g, 83 %) as a colorless oil. (0225) HRMS: calculated for C25H32N3O9S [M+H]+: 550.1859; found: 550.1850.
83%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20.0℃; for 24.0h;
Triphenylphosphine (3 g, 1 1 .6 mmol) and N-nitrosulfonyl-O-benzyl hydroxylamine (2 g, 6.3 mmol) were added to a solution of 4 (1 .5 g, 5.8 mmol) in THF (50 ml_). DEAD(2.1 ml_, 1 1 .6 mmol) was added dropwise and the reaction mixture stirred 24 h at room temperature and concentred in vacuo. The crude product was purified by flash chromatography using cyclohexane/EtOAc (8/2) as eluent to give 5 (2.67 g, 83%) as a colorless oil. HRMS: calculated for C25H32N3O9S [M+H]+: 550.1859; found: 550.1850.
With potassium carbonate; In tetrahydrofuran; water; at 20.0℃; for 24.0h;Inert atmosphere; Cooling with ice;
Methyl (2S, 5S) -5-hydroxypiperidin-2-carboxyate (21.10 g, 131.93 mmol) was dissolved in THF (240 mL) in a flask. Then K 2CO 3 (46.60 g, 337 mmol) was dissolved in H 2O (120 mL) , and the solution was added into the flask under ice-bath condition. The reaction mixture was mixed uniformly, then Boc 2O (45 mL, 200 mmol) was added dropwise slowly under ice-bath condition. The mixture was stirred at room temperature for 24 h. The mixture was extracted with EtOAc (200 mL×3) , and the combined organic layers were dried over anhydous Na 2SO 4, concentrated in vacuo to give yellow oil (33 g, 96%) . [2350] MS (ESI, pos. ion) m/z: 282.3 [M+23] +.
(2S)-N-ethyl-1-(4-(((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)carbamoyl)phenyl)-N-methyl-5-(4-(trifluoromethyl)phenyl)piperidine-2-carboxamide[ No CAS ]
N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-((2S)-2-((((R)-tetrahydrofuran-3-yl)oxy)methyl)-5-(4-(trifluoromethyl)phenyl)piperidin-1-yl)benzamide[ No CAS ]
4-((2S)-2-((cyclopropylmethoxy)methyl)-5-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide[ No CAS ]