[Synthesis]
General procedure for the synthesis of 1-(cyclopropylsulfonyl)piperidine-4-carboxamide as starting material for the synthesis of 1-(cyclopropylsulfonyl)-4-cyanopiperidine: 1-(cyclopropylsulfonyl)piperidine-4-carboxamide (50.0 g, 215 mmol) and acetonitrile (200 mL) were added to a 1 L jacketed reaction flask and heated to 55-60 °C. Subsequently, phosphorus oxychloride (POCl3, 50.1 g, 323 mmol) was slowly added and the reaction temperature was maintained at about 60 °C. After the reaction was stirred continuously at 60 °C for about 6 hours, toluene (250 mL) was added. The reaction mixture was cooled to 25 °C and quenched slowly with saturated aqueous potassium bicarbonate (350 mL), ensuring the temperature did not exceed 30 °C. The organic and aqueous layers were separated and the aqueous layer was further extracted with toluene (200 mL). All organic layers were combined and washed with brine (75 mL) and subsequently dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to afford 42.1 g (91.3% yield) of the target product 1-(cyclopropylsulfonyl)-4-cyanopiperidine as an off-white solid.1H NMR (CDCl3, 400 MHz): δ 3.44-3.42 (4H, m), 2.89 (1H, tt, J = 6.0, 4.8 Hz), 2.27 (1H tt, J = 8.0, 4.8 Hz), 2.05-1.97 (4H, m), 1.19 (2H, m), 1.03 (2H, m). Melting point: 91.90°C. |