1-(cyclopropylmethyl)piperidin-4-one

41979-39-9

7051-34-5

49682-96-4

Preparative Example 18: Synthesis of 1-(cyclopropylmethyl)piperidin-4-one; To a round-bottomed flask was added piperidin-4-one hydrochloride monohydrate (10 g, 65.1 mmol), acetonitrile (70 mL), bromomethylcyclopropane (8.79 g, 65.1 mmol), and sodium carbonate (20.7 g, 195.3 mmol). The mixture was heated and reacted at 85 °C overnight, subsequently cooled to room temperature, filtered and concentrated the filtrate. The crude product was purified by fast column chromatography (160 g silica gel column, eluent: 0-7% 2N NH3 in MeOH/DCM solution) to afford 1-(cyclopropylmethyl)piperidin-4-one as a yellow liquid (5.6 g, 56% yield).1H NMR (400 MHz, CDCl3) δ ppm 0.09-0.17 (m, 2H), 0.52- 0.59 (m, 2H), 0.85-0.97 (m, 1H), 2.38 (d, J = 6.57 Hz, 2H), 2.49 (t, J = 6.19 Hz, 4H), 2.84 (t, J = 6.19 Hz, 4H).MS (ES) [M + H]+ Calculated value C9H15NO: 154; measured value: 154. To a solution of 1-(cyclopropylmethyl)piperidin-4-one (750 mg, 4.9 mmol) and N-(BOC amino)piperidine (982 mg, 4.9 mmol) in THF (30 mL) was added acetic acid (20 drops) and sodium triacetoxyborohydride (3.1 g, 14.7 mmol). The reaction mixture was stirred overnight. Subsequently, the reaction was quenched by the addition of water (40 mL) and the organic layer was separated and discarded. The aqueous layer was alkalized with saturated sodium carbonate solution (10 mL) and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl-(1-(cyclopropylmethyl)piperidin-4-yl)(piperidin-4-yl)carbamate (513 mg, 31% yield).MS (ES) [M + H]+ Calculated value C19H35N3O2: 338; measured value: 338. Tert-butyl-(1-(cyclopropylmethyl)piperidin-4-yl)(piperidin-4-yl)carbamate (513 mg, 1.52 mmol) was dissolved in methanol (15 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was heated to 70 °C for 3 hours. Upon completion of the reaction, the mixture was cooled, the product was collected by filtration, washed with ether, and dried to give the title compound (530 mg, quantitative yield) as a white solid.MS (ES) [M + H]+ Measured value: 238.