反应详情

A mixture of 3-fluoro-4-morpholinylaniline (Example 1, 12.01 g, 61.21 mmol) in methylene chloride (100 ml) was added to a mixture of phosgene (1.93 M in toluene, 63.4 ml, 122.4 mmol, 2.00 eq) in p-chlorotoluene (60 ml) over 15 min, while maintaining a temperature of about −12 to 3° C. The material was rinsed in with methylene chloride (30 ml). The mixture then was warmed to 130° C. under atmospheric pressure with concomitant distillation of methylene chloride, phosgene, toluene, and hydrogen chloride gas into a caustic scrubber. The mixture was cooled to 25° C. and filtered. The precipitate was washed with methylene chloride (3×15 ml). The filtrate was concentrated under reduced pressure. Heptane (200 ml) was added to the concentrated filtrate, and the resultant slurry cooled to −32° C. The product was collected by filtration with reduced pressure, washed with heptane, cooled to −30° C., and dried in a nitrogen stream to give Compound VI, wherein R1=3-fluoro-4-morpholinylphenyl, HPLC (stationary phase is 4.6×250 mm Zorbax RX C-8 column; mobile phase is acetonitrile (650 ml), triethylamine (1.85 ml) and acetic acid (1.30 ml) and water of sufficient amount to make 1,000 ml; flow rate=3.0 ml/min; UV detection at 254 nm) RT=1.08 min. Upon derivatizing as N-carbomethoxy-3-fluoro-4-morpholinylaniline by dissolving in methanol; 1H-NMR (CDCl3) δ: 3.05, 3.86 and 6.78–6.89; CMR (CDCl3) 50.90, 66.89, 113.11, 119.15, 120.83, 124.67, 127.65, 138.06 and 155.40; MS (EI), m/z (relative intensity) 222 (37) and 164 (100).