Phosgene → HCID 10008863, compound

Participants

Reaction Steps

To a solution of cis-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (5.48 g, 12.03 mmol, example 2) in methylene chloride (100 mL) cooled to 0° C. were sequentially added triethylamine (11.8 mL, 84.21 mmol) and phosgene (30.53 mL, 60.15 mmol, 21% solution in toluene). The reaction mixture was stirred at 0° C. under argon for 0.5 h or until thin layer chromatography (silica gel, 100% ethyl acetate) showed no starting material left. The solvent and excess reagents were removed under reduced pressure, and the residue was dried under vacuum for 1 h. The residue was dissolved in methylene chloride (100 mL) then a solution of 1-acetylpiperazine (1.619 g, 12.63 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred for 1 h at room temperature (or until no starting material was seen by thin layer chromatography). Saturated sodium bicarbonate solution (10 mL) was added. The product was extracted with methylene chloride (2×50 mL). The organic layers were washed with brine (1×20 mL), dried (anhydrous sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then with 5% methanol in ethyl acetate gave rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone as an orange foam (˜7.2 g). It was recrystallized with methylene chloride and ethyl ether (6.721 g, white solids). Additional amount of rac-1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone (201 mg, tan color) was recovered from the mother liquor after purification by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 100% ethyl acetate then 5% methanol in ethyl acetate. Total yield: 6.922 g (94%). HR-MS (ES, m/z) calculated for C32H35N4O4Cl2 [(M+H)+] 609.2030, observed 609.2045.

Provenance & Evidence