1-Cbz-4-piperidone 4.012g (17.2 mmol) with 4A powdered activated molecular sieves 9.1g and 2,4-difluoroaniline 2.582g (20 mmol) was suspended in anhydrous 1,2-dichloroethane (150mL) and acetic acid 6mL was added. The mixture was stirred under Ar overnight (11h30 min). Solid sodium triacetoxyborohydride 12.72g (60mmol) was added and the reaction was continued at RT over an extended weekend (3 days). The reaction mixture was then filtered, the solids were washed with ethyl acetate 350mL. The combined filtrates were washed with saturated NaHCO3 250mL and then with half-saturated NaHCO3 (250mL), the aqueous phases were re-extracted with ethyl acetate (250mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was dried on highvac to remove some of the difluoroaniline, then purified on a column of silica (190g) in a 3:1 mixture hexane-EtOAc.
The obtained Cbz-protected piperidine (pink syrup, 3.8g, 64%Y) was hydrogenated under baloon of H2 in ethanol 200mL in presence of Pd-C(10%), 2.5g and 4M HCl in dioxane 5mL for 19 hours (overnight). The catalyst was removed by filtration through a pad of Celite, the filtrated were evaporated and the residue dried on highvac. Y=3.075g (62.5% overall) of a white hygroscopic solid. LC/MS(+ESI): 213 (M+1)
1H(d6-DMSO, 400MHz): 9.5-7.5(very br s, 2H), 9.272(br m, 1H), 8.975(br m, 1H), 7.158(m, 1H), 6.940(m, 2H), 3.547(m, 1H), 3.268(br d, 13.0Hz, 2H), 2.930(br q, 10.4Hz, 2H), 2.008(br d, 11.5Hz, 2H), 1.703(m, 2H)