ethyl 2,2-difluoro-3-(propan-2-ylamino)propanoate

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6H) 1.34 (t, J=7.20 Hz, 3H) 3.63-3.75 (m, 1H) 4.24 (t, J=13.14 Hz, 2H) 4.34 (q, J=7.07 Hz, 2H) 8.74 (s, 1H). The solution was purged with nitrogen gas to slowly warm to room temperature filtered The filtrate was concentrated in vacuo the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (5.00 g, 15.0 mmol) was dissolved in EtOH (25 mL) and trifluoroacetic acid was added (1.15 mL, 15.5 mmol). To this mixture, Pd(OH)2/C (20%, 250 mg) was added, and the reaction mixture was hydrogenated at 60 psi overnight. The mixture was filtered through a pad of Celite, the Celite pad was washed with ethanol and the filtrate was concentrated in vacuo. The residue was dissolved in THF (65 mL) and to the solution was added acetone (0.872 g, 15.0 mmol) and sodium acetate (1.23 g, 15.0 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (4.77 g, 22.5 mmol) was added in portions over 5 min. The mixture was stirred vigorously at room temperature overnight and then was poured into a cold (0° C.) brine solution (100 mL). The pH was adjusted to 12.5 with NaOH (50%) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract were dried (MgSO4) and concentrated in vacuo to afford the title compound as a clear light yellow oil (1.54 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.32 Hz, 6H) 1.36 (t, J=7.20 Hz, 3H) 2.73-2.94 (m, 1H) 3.20 (t, J=13.52 Hz, 2H) 4.34 (q, J=7.24 Hz, 2H) was hydrogenated at 60 psi overnight The mixture was filtered through a pad of Celite the Celite pad was washed with ethanol the filtrate was concentrated in vacuo The residue was dissolved in THF (65 mL) and to the solution the mixture was extracted with ethyl acetate (3×50 mL) The combined organic extract were dried (MgSO4) concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6 H) 1.34 (t, J=7.20 Hz, 3 H) 3.63-3.75 (m, 1 H) 4.24 (t, J=13.14 Hz, 2 H) 4.34 (q, J=7.07 Hz, 2 H) 8.74 (s, 1 H). The solution was purged with nitrogen gas to slowly warm to room temperature filtered The filtrate was concentrated in vacuo the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (5.00 g, 15.0 mmol) was dissolved in EtOH (25 mL) and trifluoroacetic acid was added (1.15 mL, 15.5 mmol). To this mixture, Pd(OH)2/C (20%, 250 mg) was added, and the reaction mixture was hydrogenated at 60 psi overnight. The mixture was filtered through a pad of Celite, the Celite pad was washed with ethanol and the filtrate was concentrated in vacuo. The residue was dissolved in THF (65 mL) and to the solution was added acetone (0.872 g, 15.0 mmol) and sodium acetate (1.23 g, 15.0 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (4.77 g, 22.5 mmol) was added in portions over 5 min. The mixture was stirred vigorously at room temperature overnight and then was poured into a cold (0° C.) brine solution (100 mL). The pH was adjusted to 12.5 with NaOH (50%) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract were dried (MgSO4) and concentrated in vacuo to afford the title compound as a clear light yellow oil (1.54 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.32 Hz, 6 H) 1.36 (t, J=7.20 Hz, 3 H) 2.73-2.94 (m, 1 H) 3.20 (t, J=13.52 Hz, 2 H) 4.34 (q, J=7.24 Hz, 2 H) was hydrogenated at 60 psi overnight The mixture was filtered through a pad of Celite the Celite pad was washed with ethanol the filtrate was concentrated in vacuo The residue was dissolved in THF (65 mL) and to the solution the mixture was extracted with ethyl acetate (3×50 mL) The combined organic extract were dried (MgSO4) concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2,2-difluoro-3-(isopropylamino)propanoate (1.50 g, 7.68 mmol) was dissolved in acetone and K2CO3 (2.12 g, 15.3 mmol) was added. The solution was purged with nitrogen gas and cooled to 0° C. A solution of 2,4-dichloro-5-nitropyrimidine (1.64 g, 8.45 mmol) in acetone (10 mL) was added dropwise at 0° C. over 1 h. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. It was diluted with dichloromethane (50 mL) and filtered thru a celite plug. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1) to afford the title compound as a yellow oil (1.96 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.82 Hz, 6H) 1.34 (t, J=7.20 Hz, 3H) 3.63-3.75 (m, 1H) 4.24 (t, J=13.14 Hz, 2H) 4.34 (q, J=7.07 Hz, 2H) 8.74 (s, 1H). The solution was purged with nitrogen gas to slowly warm to room temperature filtered The filtrate was concentrated in vacuo the residue purified by flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 10:1-3:1)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (5.00 g, 15.0 mmol) was dissolved in EtOH (25 mL) and trifluoroacetic acid was added (1.15 mL, 15.5 mmol). To this mixture, Pd(OH)2/C (20%, 250 mg) was added, and the reaction mixture was hydrogenated at 60 psi overnight. The mixture was filtered through a pad of Celite, the Celite pad was washed with ethanol and the filtrate was concentrated in vacuo. The residue was dissolved in THF (65 mL) and to the solution was added acetone (0.872 g, 15.0 mmol) and sodium acetate (1.23 g, 15.0 mmol). The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (4.77 g, 22.5 mmol) was added in portions over 5 min. The mixture was stirred vigorously at room temperature overnight and then was poured into a cold (0° C.) brine solution (100 mL). The pH was adjusted to 12.5 with NaOH (50%) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extract were dried (MgSO4) and concentrated in vacuo to afford the title compound as a clear light yellow oil (1.54 g, 54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.32 Hz, 6H) 1.36 (t, J=7.20 Hz, 3H) 2.73-2.94 (m, 1H) 3.20 (t, J=13.52 Hz, 2H) 4.34 (q, J=7.24 Hz, 2H) was hydrogenated at 60 psi overnight The mixture was filtered through a pad of Celite the Celite pad was washed with ethanol the filtrate was concentrated in vacuo The residue was dissolved in THF (65 mL) and to the solution the mixture was extracted with ethyl acetate (3×50 mL) The combined organic extract were dried (MgSO4) concentrated in vacuo