1,2-Dichloroethane → HCID 68776336, compound

Participants

Reaction Steps

To a solution of Example 254 (300 mg, 0.44 mmol) in DCM (20 mL) was added triethylamine (0.6 mL, 4.35 mmol), EDC (334 mg, 1.74 mmol) and 1-hydroxybenzo-triazole (10 mg, 0.09 mmol) and the reaction mixture was stirred at room temperature for 2 h. (3R)-(+)-3-(tert-Butoxycarbonylamino)pyrrolidine (323 mg, 1.74 mmol) was then added and stirring was continued at room temperature for 18 h. Water (30 mL) was added and the mixture was extracted into DCM (100 mL). The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DMF (5.0 mL) and sodium hydride (60% dispersion in oil, 14 mg, 0.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, then iodomethane (20 μL, 0.36 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the reaction mixture was extracted with EtOAc (80 mL). The organic phase was washed with water (6×20 mL) and brine (20 mL), then dried (magnesium sulfate). The solvent was removed in vacuo and the residue was purified by column chromatography (SiO2, 75-100% EtOAc/heptane). The obtained solid was taken up in DCM (5.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes and the solvent was removed in vacuo. The residue was purified by preparative HPLC (pH 5.8) and the obtained product was partitioned between sodium hydrogencarbonate solution (20 mL) and DCM (2×75 mL). The combined organic phases were dried (magnesium sulfate) and the solvent was removed in vacuo to give the title compound (25 mg, 8%) as an off-white solid. δH (CD3OD) 8.75 (1H, d, J 5.1 Hz), 8.28-8.13 (2H, m), 8.01 (1H, s), 7.69-7.60 (2H, m), 7.51-7.45 (1H, m), 3.88-3.50 (7H, m), 3.41-3.22 (2H, m), 3.14-3.02 (4H, m), 2.64 (2H, s), 2.46 (3H, 2×s), 2.33 (2H, s), 2.30-2.06 (1H, m), 1.98-1.80 (1H, m), 1.05 (6H, s). LCMS (ES+) 545.3 (M+H)+.

Provenance & Evidence