Sodium Bicarbonate → Isocyanate

Participants

Reaction Steps

A saturated aqueous NaHCO3 solution was added slowly to a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine dihydrochloride (37) (918 mg, 3.0 mmol) in dry toluene (30 mL) with stirring to neutralize to pH ˜7. The organic and water layer were separated and the water layer was extracted with toluene (3×10 mL). The organic layer and extracts were combined, dried over Na2SO4, and then added dropwise to a stirred solution of trichlorimethylchloroformate (593 mg, 365 μL, 3.0 mmol) in dry toluene (10 mL) containing active carbon (20 mg) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then refluxed for 30 min to form a clear solution, which was cooled, filtered through a pad of Celite. The filtrate was evaporated in vacuo to dryness to give crude bis(2-chloroethyl)-4-isocyanatophenylamine, 430 mg (39) (1.66 mmol). This intermediate was dissolved in anhydrous DMF (1 mL) and then added dropwise to a solution of 4-amino-6-methoxy-2-(3-methoxyphenyl)quinoline (280 mg, 1.0 mmol) in dry DMF (1 mL). The reaction mixture was stirred at 50° C. for 9 h and the solvent was removed by vacuum distillation. The residue was chromatographed on a silica gel column (2×24 cm) using CHCl3/MeOH/(100:1 v/v) as eluent. The fractions containing the desired product were combined, evaporated and the solid residue was recrystallized from EtOH to give 1-{4-[bis(2-chloroethyl)amino]phenyl-3-[6-methoxy-2-(4-methoxyphenyl)quinolin-4-yl]urea (22, BO-1049); 400 mg (74.2%); mp 112-113° C.; 1H NMR (DMSO-d6) δ3.72 (8H, m, 4×CH2), 3.87 (3H, s, OMe), 4.01 (3H, s, OMe), 6.72 (2H, d, J=8.8 Hz, ArH), 7.07 (1H, dd, J=2.2 and 8.1 Hz, ArH), 7.41 (2H, d, J=8.8 Hz, 2×ArH), 7.47 (2H, m, 2×ArH), 7.65 (3H, m, ArH), 7.99 (2H, d, J=10.3 Hz, 2×ArH), 8.80 (1H, d, J=8.8 Hz, ArH), 9.25 (2H, brs, exchangeable, 2×NH). Anal. Calcd. for (C28H28Cl2N4O3): C, 62.61; H, 5.23; N, 10.39. Found: C, 62.34; H, 4.99; N, 10.59.

Provenance & Evidence