Cbz-L-tert-Leucine

Pale Yellow Thick Oil

2S-Benzyloxycarbonylamino-3, 3-dimethyl-butyric acid; To a suspension of L-tert-leucine (11.88 g, 90.7 mmol) in methanol (200 ml) were added triethylamine (26.56 ml, 190 mmol) and N-(benzyloxycarbonyl- oxy)-succinimide (24.88 g, 99.8 mmol). The reaction mixture was stirred at room temperature for 14 h. Methanol was removed in vacuo to afford a viscous pale yellow oil, which was dissolved in ethyl acetate (100 ml). The organic layer was washed with 1M hydrochloric acid (15 ml) and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to fumish the title compound as an oil (24 g, quant.). 1H-NMR; δ(CDCl3), 7.43-7.36 (5H, m), 5.36 (1H, d, J = 9.4 Hz), 5.12 (2H, br s), 4.20 (1H, d, J = 9.6 Hz) and 1.02 (9H, s). LRMS: +ve ion 266 [M+H], -ve ion 264 [M-H], 529 [2M-H].2-Benzyloxycarbonylamino-3, 3-dimethyl-butyric acid (2) ;To a solution of L-tert-leucine (1) (50.0 g, 38.0 mmol) and NaHCOTo a solution of 50% aqueous dimethylamine solution(0.816 g) and N- [ (benzyloxy) carbonyl] -3-methyl-L-valine (2.00 g) and N-ethyl-N- (1-methylethyl) propan-2-amine (1.95 g) in DMF (20 mL) was added 0- (7-azabenzotriazol-l-yl) -N, N, N' , N' - tetramethyluronium hexafluorophosphate (3.15 g) at room temperature. The reaction mixture was stirred at roomtemperature overnight. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by short silica gel column chromatography (NH, ethyl acetate) to give a crude product containing the title compound. XH NMR (300 MHz, DMSO-d6) delta 0.92 (9H, s) , 2.83 (3H, s) , 3.08 (3H, s), 4.45 (1H, d, J = 9.2 Hz), 4.94-5.11 (2H, m) , 7.17 (1H, d, J = 9.3 Hz), 7.25-7.43 (5H, m) .Step B: 2S-[1-(4-Benzyl-piperidine-1-carbonyl)-2, 2-dimethyl-propyl-carbamic acid benzyl ester; To a solution of 2S-Benzyloxycarbonylamino-3, 3-dimethyl-butyric acid (923 mg, 3.48 mmol) and 4-benzyl piperidine (735mul, 4.18 mmol) in DMF (16 ml) were added EDC (734 mg, 3.83 mmol) and HOAt (10 mg, 0.07 mmol). The reaction mixture was stirred for 14 h at room temperature. DMF was removed in vacuo and the crude residue was dissolved in ethyl acetate. The organic layer was washed with 1M hydrochloric acid (2x10 ml), water (10 ml), brine (10 ml), dried over anhydrous magnesium sulfate and filtered. Removal of the solvent in vacuo and purification by column chromatography (hexanes:ethyl acetate, 5:1) provided the desired amide (784 mg, 54%). 1H-NMR; delta(CDCl3), 7.36-7.14 (10H, m), 5.65 (1H, m), 5.17-5.05 (2H, m), 4.70-4.49 (2H, m), 2.96 (1H, m), 2.57-2.47 (2H, m), 1.90-1.59 (2H, m) and 1.38-0.87 (14H, m). LRMS: +ve ion 423 [M+H].

Leucine derivative used in the preparation of various pharmaceutical agents such as TRPV4 antagonists, HIV-1 protease inhibitors and serine protease inhibitors.