tert-butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate

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: To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]+. stirring for 1 hour The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL) The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organics were washed with brine (50 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-3,3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]+. stirring for 1 hour The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL) The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organics were washed with brine (50 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-3, 3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]+. stirring for 1 hour The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL) The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organics were washed with brine (50 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of 1-tert-butyloxycarbonyl-3, 3-difluoro-4-oxopiperidine (Synthonix, 0.100 g, 0.426 mmol, 1.0 eq) in dichloromethane (1.5 mL) was added benzylamine (0.070 mL, 0.638 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (0.180 g, 0.851 mmol, 2.0 eq). The reaction was stirred at room temperature for 16 hours before adding Rochelle's salt (2 mL) and stirring for 1 hour. The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL). The aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (30→70% EtOAc-hexane) yielded the title compound (0.045 g, 32%) as a colourless oil; 1H nmr (CDCl3) δ 7.33 (4H, m, 4H of C6H5), 7.27 (1H, m, 1H of C6H5), 4.02 (1H, m), 3.92 (2H, s, CH2C6H5), 3.76 (1H, m), 3.32 (1H, ddd, J 21.5, 14.0, 4.5 Hz), 3.11 (1H, m), 2.97 (1H, m), 1.90 (1H, m), 1.67-1.59 (1H, m), 1.46 (9H, s, C(CH3)3); 19F nmr (CDCl3) δ −109.0 (dd, J 243.0, 115.5 Hz), −119.5 (d, J 251.0 Hz); m/z: 327 [M+H]+. stirring for 1 hour The reaction mixture was partitioned between NaHCO3 (50 mL) and CH2Cl2 (50 mL) The aqueous phase was extracted with CH2Cl2 (2×50 mL) The combined organics were washed with brine (50 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: A suspension of 4-benzylamino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (830 mg, 2.54 mmol), Pd/C (81.2 mg, 76.3 μmol) in MeOH (30 mL) was hydrogenated at room temperature for 14 hours. The catalyst was filtered off, washed thoroughly with MeOH and the solvents were evaporated. The title compound was obtained as colorless oil (601 mg, 100%). The catalyst was filtered off washed thoroughly with MeOH the solvents were evaporated

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

Procedure: A suspension of 4-benzylamino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (830 mg, 2.54 mmol), Pd/C (81.2 mg, 76.3 μmol) in MeOH (30 mL) was hydrogenated at room temperature for 14 hours. The catalyst was filtered off, washed thoroughly with MeOH and the solvents were evaporated. The title compound was obtained as colorless oil (601 mg, 100%). The catalyst was filtered off washed thoroughly with MeOH the solvents were evaporated

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%). was heated to reflux with dean stark apparatus for 12 hours heated to reflux with dean stark apparatus for another 12 hours About 50 mL of toluene were distilled off stirred for another hour After 2 hours the reaction mixture was concentrated 2 N Na2CO3 solution was added the aqueous phase was extracted with ethyl acetate The combined organic layers were dried over Na2SO4 the solvents were evaporated The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes)

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: In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), tert-butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate (0.186 g, 0.57 mmol) was dissolved in MeOH (5 mL) and wet Pd/C 10% (50 mg) was added. The flask was purged with H2 gas and the reaction mixture stirred under an H2 atmosphere for 2 h at rt. The reaction mixture was filtered over celite and the cake was washed with MeOH and EA. The filtrate was concentrated under reduced pressure to give tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate as a colorless oil. LC-MS-conditions 08: tR=0.49 min; [M-CH3+H]+=222.32. The flask was purged with H2 gas The reaction mixture was filtered over celite the cake was washed with MeOH and EA The filtrate was concentrated under reduced pressure