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To tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (2.57 g, 8.8 mmol) in acetone (60 mL) was added sodium iodide (2.63 g, 17.5 mmol). The yellow solution formed was heated at reflux overnight. The resulting orange suspension formed was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue partitionedbetween DCM (100 ml) and water (20 ml). The organic portion was dried (MgSO4) and treated with silica (10 g). This was filtered and the filtrate concentrated to give the title compound as an orange oil (2.19 g);1H NMR (400MHz, ODd3) o 1.14 (2H, dq), 1.48 (9H, 5), 1.57-1.70 (1H, m), 1.82-1.90 (2H, m), 2.73 (2H, t), 3.12 (2H, d), 4.10-4.20 (2H, m).
Amixture of 2 (1eq, 11.72 g, 40 mmol) and lithium bromide (5eq,17.20 g, 200 mmol) in acetone (80 mL) was heated to reflux overnight.The mixture was evaporated, then the residue was partitionedbetween EtOAc and water. The organic layer was washedwith s brine, dried over Na2SO4, filtered, and evaporated to offer the title product 3 as pale yellow oil (9.46 g, 85.40percent yield).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 96 - 112
3
[ 773837-37-9 ]
[ 161975-39-9 ]
[ 256411-39-9 ]
Yield
Reaction Conditions
Operation in experiment
6.87 g
at 80℃; for 24 h;
4-(cyanomethyl)piperidine-1-carboxylate tert-Butyl 4-[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (15.3 g) was dissolved in ethanol (80 mL), water (20 mL) and sodium cyanide (4.0 g, 80 mmol) were added, and stirring was conducted at 80° C. for 24 hours. Ethanol was distilled off, water and ethyl acetate were added, and then the resultant mixture was subject to Celite filtration, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by using silica gel column chromatography (hexane:ethyl acetate=3:1→2:1) to give tert-butyl 4-(cyanomethyl)piperidine-1-carboxylate (6.87 g, 77percent, 3 steps) as a white solid. 1H-NMR (CDCl3) δ: 1.21-1.31 (2H, m), 1.46 (9H, s), 1.78-1.86 (3H, m), 2.31 (2H, d, J=6.4 Hz), 2.64-2.78 (2H, m), 4.07-4.21 (2H, m).
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