836-21-5

To a solution of 1-benzyl-3-methyl-piperidin-4-one (4.06 g, 20 mmol) in anhydrous THF (20 mL) at -78 °C was slowly added lithium hexamethyldisilaminate (21 mL, 21 mmol, 1.0 M THF solution). After stirring at -78 °C for 30 min, a solution of THF (5 mL) in iodomethane (1.31 mL, 21 mmol) was added dropwise to the reaction mixture. The reaction solution was gradually warmed to 25 °C and stirring was continued for 2 hours. Upon completion of the reaction, the reaction was quenched with water. The aqueous layer was extracted with dichloromethane (CH2Cl2) and the organic phases were combined, washed with saturated brine and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by fast column chromatography (eluent: hexane/ethyl acetate) to afford 1.37 g (31.5% yield) of 1-benzyl-3,5-dimethylpiperidin-4-one. The crude product 1-benzyl-3,5-dimethylpiperidin-4-ylamine (5) was prepared as a mixture of diastereoisomers with reference to the method of Scheme 1-1. LCMS assay showed the target molecular weight: 219 (M + H)+. The product could be used in the next reaction without further purification.

[1] Patent: WO2004/58736, 2004, A1. Location in patent: Page 26; 29
[2] Patent: WO2004/58709, 2004, A1. Location in patent: Page 31; 34
[3] Patent: US2002/169155, 2002, A1
[4] Patent: US2005/70549, 2005, A1
[5] Patent: US2016/31908, 2016, A1. Location in patent: Paragraph 1165; 1166; 1167