tert-butyl 2-amino-2-methylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Into a 100-mL 3-necked round-bottom flask was placed a solution of tert-butyl 2-amino-2-methylpropanoate (1.2 g, 7.54 mmol, 1.00 equiv) in dichloromethane (20 mL). This was followed by the addition of ditrichloromethyl carbonate (750 mg, 2.53 mmol, 0.34 equiv), in portions at 0° C. After 30 min, triethylamine (2.3 g, 22.73 mmol, 3.02 equiv) was added dropwise with stirring. The resulting solution was stirred for 5 h at room temperature and then concentrated under vacuum. The residue was diluted with 20 mL of ethyl ether. The solids were filtered out. The filtrate was concentrated under vacuum. Purification afforded 1.4 g (crude) of tert-butyl 2-isocyanato-2-methylpropanoate (110.2) as a yellow oil. Into a 100-mL 3-necked round-bottom flask was placed The resulting solution was stirred for 5 h at room temperature concentrated under vacuum The residue was diluted with 20 mL of ethyl ether The solids were filtered out The filtrate was concentrated under vacuum Purification

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 2-amino-2-methylpropanoate (Bachem, 7.9 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro benzyl bromide (10.6 g, 0.05 mol) and NaHCO3 (8.3 g, 0.099 mol) as a solid. The reaction mixture was stirred for 16 h at 70° C. Water (70 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent, affording the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.69 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H). extracted with ethyl acetate (100 mL) The organic layer was washed with water (3×100 mL) the solvent was dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of tert-butyl 2-amino-2-methylpropanoate (Bachem, 7.9 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro benzyl bromide (10.6 g, 0.05 mol) and NaHCO3 (8.3 g, 0.099 mol) as a solid. The reaction mixture was stirred for 16 h at 70° C. Water (70 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent, affording the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.69 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H). extracted with ethyl acetate (100 mL) The organic layer was washed with water (3×100 mL) the solvent was dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography

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

Procedure: The title compound was prepared following general procedure 10 starting from tert-butyl 2-amino-2-methylpropanoate and 4-cyano-2-fluoro benzyl bromide. The title compound was isolated as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78-7.75 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.70-3.68 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H). The title compound was prepared

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

Procedure: To the solution of tert-butyl 2-(benzylamino)-2-methylpropanoate (20 g, 0.08 mol) in ethyl acetate (1 L), was added the catalyst Palladium-carbon (10%, 2.2 g). The resulting mixture was put under the hydrogen pressure of 5 Kg/cm2, at RT for 18 h. The reaction mixture was filtered. The filtrate was concentrated affording the title compound as pale green liquid. 1H NMR (DMSO-d6, 400 MHz) δ 1.38 (brs, 2H), 1.14 (s, 9H), 1.14-1.11 (d, J=10.7 Hz, 6H). The reaction mixture was filtered The filtrate was concentrated

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

Procedure: To the solution of tert-butyl 2-(benzylamino)-2-methylpropanoate (20 g, 0.08 mol) in ethyl acetate (1 L), was added the catalyst Palladium-carbon (10%, 2.2 g). The resulting mixture was put under the hydrogen pressure of 5 Kg/cm2, at RT for 18 h. The reaction mixture was filtered. The filtrate was concentrated affording the title compound as pale green liquid. 1H NMR (DMSO-d6, 400 MHz) δ 1.38 (brs, 2H), 1.14 (s, 9H), 1.14-1.11 (d, J=10.7 Hz, 6H). The reaction mixture was filtered The filtrate was concentrated

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

Procedure: To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.35 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 494 [M+H]+. the solvent was evaporated the residue purified over RP-HPLC

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

Procedure: To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.35 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 494 [M+H]+. the solvent was evaporated the residue purified over RP-HPLC