4-tert-butylpiperidine;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Charge a five liter round-bottom flask with DCM (1.5 L) and 4-tert-butylpiperidine hydrochloride (89 g, 0.5 mol). Add triethylamine (101.4 g, 1.0 mol) to the mixture at 21° C. followed by N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)ethyl]methanesulfonamide (155 g, 0.55 mol), and acetic acid (36 g, 0.6 mol). Add sodium triacetoxyborohydride (318.6 g, 1.5 mol) portion-wise and stir the suspension at 22° C. for 15 hours. Add saturated aqueous solution of sodium bicarbonate (1800 mL) slowly with stirring until pH of the mixture is 8. Separate the organic layer and extract the aqueous layer with DCM (3×2000 mL). Dry the combined organic layers over MgSO4; filter; collect the filtrate; and concentrate the filtrate under vacuum. Purify the residue on silica gel column chromatography eluting with DCM:MeOH (100 to 95%) to provide the title compound as an off-white solid (126 g, 61.9%). MS (m/z): 407 (M+1). at 21° C. Separate the organic layer extract the aqueous layer with DCM (3×2000 mL) Dry the combined organic layers over MgSO4 filter collect the filtrate and concentrate the filtrate under vacuum Purify the residue on silica gel column chromatography eluting with DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 4-tert-butylpiperidine hydrochloride (5.0 g, 28.1 mmol) in 150 mL of sodium bicarbonate (saturated aqueous solution), then extract three times with DCM. Combine the organic fractions; dry over sodium sulfate; filter; collect the filtrate; and concentrate under reduced pressure to give 4-tert-butylpiperidine free base. Add N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (7.0 g, 24.9 mmol) to the free base and dissolve the mixture in DCM (150 mL). Stir the mixture at ambient temperature for two hours, and then add sodium triacetoxyborohydride (26.37 g, 124.44 mmol) and acetic acid (1.71 mL, 29.87 mmol). Stir for 72 hours at ambient temperature. Quench the reaction with the addition of 50% saturated sodium bicarbonate solution. Separate the layers, and extract the aqueous layer twice with EtOAc. Combine the organic layers; dry over sodium sulphate; filter; collect the filtrate; and concentrate under reduced pressure. Purify the crude material with silica gel flash column chromatography eluting with MeOH in DCM (0-7%). Collect and concentrate the appropriate fractions under reduced pressure to give the desired compound as a free base (ee>98%). Dissolve the free base in a mixture of MeOH and DCM (1:1, 30 mL). Add HCl (1.0 M in diethyl ether, 40 mL) and swirl the mixture for one minute. Concentrate under reduced pressure to afford the title compound (8.2 g, 74.4%). MS (m/z): 407 (M-HCl+1). extract three times with DCM dry over sodium sulfate filter collect the filtrate and concentrate under reduced pressure

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Place 4-tert-butylpyridine hydrochloride (50 g, 277 mmol) in a PARR reactor and add EtOH (350 mL) followed by platinum (IV) oxide (5.0 g, 22.02 mmol). Stir the mixture at 22° C. under a hydrogen atmosphere (500 psi) for 18 hours. Evacuate the excess hydrogen and filter the suspension the a Celite® pad. Concentrate the filtrate and dry the residue under vacuum (40° C., 5 mbar) to give the title compound as an off-white solid (45.1 g, 92%). 1H-NMR (d6-DMSO) δ 0.83 (s, 9H), δ 1.2-1.5 (m, 3H), δ 1.7 (d, 2H), δ 2.7-2.8 (m, 2H), δ 3.2 (d, 2H), δ 8.7-9.3 (2 bs, 2H). Evacuate the excess hydrogen filter the suspension the a Celite® pad Concentrate the filtrate dry the residue under vacuum (40° C., 5 mbar)