2,4-dichloro-1-isocyanatobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 2,4-dichlorophenyl isocyanate (0.021 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 3 (0.036 g, 0.076 mmol, 69%) as a white solid. LCMS m/z (%)=469 (M+H79Br35Cl35Cl, 60), 471 (M+H79Br35Cl37Cl&81Br35Cl35Cl, 100), 473 (M+H81Br35Cl37Cl79Br37Cl37Cl, 54), 475 (M+H81Br37Cl37Cl, 4), 1H NMR (400 MHz, acetone-d6) δ: 8.81 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 7.91 (s, 1H), 7.69 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.34 (dd, J=2.4, 9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 2,4-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (3×20 mL) and dried in vacuo to give 1-(2,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.44 g, 96% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 8.99 min (96.51%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.89-2.06 (m, 1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.78-3.06 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.38-4.53 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CH), 7.33 (dd, J=2.5, 9.1 Hz, 1H, Ar), 7.46 (d, J=7.7 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.57 (d, J=2.5 Hz, 1H, Ar), 7.62 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.20 (d, J=8.9 Hz, 1H, Ar), 8.26 (s, 1H, NH), 10.99 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.82, 47.13, 51.58, 121.63, 121.92, 122.02, 123.04, 125.33, 126.99, 127.50, 128.39, 130.45, 135.81, 142.48, 144.12, 154.67, 167.90, 170.99, 172.86; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.37; H, 3.84; N, 12.15; Cl, 15.50. the solids were isolated by filtration washed with water (3×20 mL) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The urea was prepared from 2-hydroxy 4-nitro aniiine (308 mg, 2 mmol) and 2,4-dichloro phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.26 g, 38%). EI-MS m/z 342 (M+H)+ It was purified by dilution with methylene chloride and precipitation with hexane Filtering