2,2,2-三氟-N-(1,2,3,4-四氢异喹啉-4-基)乙酰胺

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-(3,5-dichlorophenylamino)acetic acid (0.332 g, 1.5 mmol) in DMF (10 mL) was added HOBt (0.30 g, 2.2 mmol) EDCI: HCl (0.434 g, 2.2 mmol), DIEA (0.39 g, 3.0 mmol) and 2,2,2-trifluoro-N-(1,2,3,4-tetrahydroisoquinolin-4-yl)acetamide (370 mg, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred overnight. After the reaction was shown to be complete as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL), and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to give (0.45 g, 74%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 7.56 (s, 1H), 7.37-7.21 (m, 4H), 6.74 (d, J=11.6 Hz, 2H), 6.61 (s, 1H), 6.4-6.2 (m, 1H), 5.20-5.06 (m, 1H), 4.85 (t, J=16.4 Hz, 1H), 4.60 (d, J=16.8 Hz, 1H), 4.58 (d, J=17.6, 1 H), 4.12-4.03 (m, 1H), 3.9-3.8 (m, 1H), 3.58-3.39 (m, 1H). LCMS: M/z: (M+1):446 at 0° C washed with water (20 mL×3) The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,2,2-trifluoro-N-(isoquinolin-4-yl)acetamide (1.0 g, 1.49 mmol) in AcOH (20 mL) was adde PtO2 (0.2 g) was added under nitrogen atmosphere. The reaction mixture placed under an atmosphere of hydrogen at rt for 10 h. The reaction mixture was filtered through a pad of celite, washed several times with MeOH. The filtrate was concentrated in vacuo to give a residue that was diluted with water, neutralized with NaHCO3, extracted with EtOAc (100 mL×3), the combined EtOAc layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc) to give (0.380 g, 33%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.24-7.07 (m, 4H), 4.98 (s, 1H), 3.89 (d, J=16.4 Hz, 1H), 3.82 (d, J=16.4 Hz, 1H), 3.10 (dd, J=4.8, 12.8 Hz, 1H), 2.88 (dd, J=6.8 Hz, 12.8 Hz, 1H), 2.50 (m, 1H). LCMS: M/z: (M+1):245 was added under nitrogen atmosphere The reaction mixture was filtered through a pad of celite washed several times with MeOH The filtrate was concentrated in vacuo to give a residue that extracted with EtOAc (100 mL×3) the combined EtOAc layer was washed with water dried over Na2SO4 concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-(3,5-dichlorophenylamino)acetic acid (0.332 g, 1.5 mmol) in DMF (10 mL) was added HOBt (0.30 g, 2.2 mmol) EDCI: HCl (0.434 g, 2.2 mmol), DIEA (0.39 g, 3.0 mmol) and 2,2,2-trifluoro-N-(1,2,3,4-tetrahydroisoquinolin-4-yl)acetamide (370 mg, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred overnight. After the reaction was shown to be complete as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL), and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to give (0.45 g, 74%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 7.56 (s, 1H), 7.37-7.21 (m, 4H), 6.74 (d, J=11.6 Hz, 2H), 6.61 (s, 1H), 6.4-6.2 (m, 1H), 5.20-5.06 (m, 1H), 4.85 (t, J=16.4 Hz, 1H), 4.60 (d, J=16.8 Hz, 1H), 4.58 (d, J=17.6, 1 H), 4.12-4.03 (m, 1H), 3.9-3.8 (m, 1H), 3.58-3.39 (m, 1H). LCMS: M/z: (M+1):446 at 0° C washed with water (20 mL×3) The EtOAc layer was concentrated in vacuo to give crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,2,2-trifluoro-N-(isoquinolin-4-yl)acetamide (1.0 g, 1.49 mmol) in AcOH (20 mL) was adde PtO2 (0.2 g) was added under nitrogen atmosphere. The reaction mixture placed under an atmosphere of hydrogen at rt for 10 h. The reaction mixture was filtered through a pad of celite, washed several times with MeOH. The filtrate was concentrated in vacuo to give a residue that was diluted with water, neutralized with NaHCO3, extracted with EtOAc (100 mL×3), the combined EtOAc layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc) to give (0.380 g, 33%) of the titled intermediate. 1H NMR (DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.24-7.07 (m, 4H), 4.98 (s, 1H), 3.89 (d, J=16.4 Hz, 1H), 3.82 (d, J=16.4 Hz, 1H), 3.10 (dd, J=4.8, 12.8 Hz, 1H), 2.88 (dd, J=6.8 Hz, 12.8 Hz, 1H), 2.50 (m, 1H). LCMS: M/z: (M+1):245 was added under nitrogen atmosphere The reaction mixture was filtered through a pad of celite washed several times with MeOH The filtrate was concentrated in vacuo to give a residue that extracted with EtOAc (100 mL×3) the combined EtOAc layer was washed with water dried over Na2SO4 concentrated in vacuo to give a crude reaction mixture which was purified by column chromatography (silica gel, gradient MeOH in EtOAc)