反应详情

To a solution of (5-chloro-thiophen-2-yl)-acetic acid (0.18 g, 1.04 mmol), prepared as described in EXAMPLE 27 in 6 mL of dry CH2Cl2 is added Et3N (0.15 mL g, 1.04 mmol) and diphenylphosphoryl azide (0.24 mL, 1.04 mmol). The mixture is stirred at room temperature for 2.5 h, then heated at 50° C. for 2 hours. To the solution is added 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one (0.10 g, 0.41 mmol), EXAMPLE 72, and Et3N (0.15 mL g, 1.04 mmol) and the mixture is heated at 50° C. for 2 h, then stirred at room temperature for 16 hours. The resulting mixture is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to provide the title compound (10 mg, 0.02 mmol) as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.69 (bs, 2H), 8.80 (s, 1H), 8.48 (d, 1H), 7.61 (d, 1H), 7.60 (s, 1H), 7.41 (t, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 4.77 (d, 2H), 4.30 (d, 2H), 4.10 (s, 2H), 3.61 (m, 2H), 3.38 (m, 2H). ESI MS, [M+H]+=431,433 (Cl pattern).

1. temperatureheated at 50° C. for 2 hours
2. temperaturethe mixture is heated at 50° C. for 2 h
3. stirringstirred at room temperature for 16 hours
4. concentrationThe resulting mixture is concentrated
5. customThe crude product is purified by RP-HPLC
6. washeluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA)