反应详情

13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (63 mg, 0.14 mMol) was dissolved in 1.7 mL of THF and carbonyldiimidazole (31 mg, 0.19 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr then heated to reflux for 1 hr. The reaction was cooled under nitrogen atmosphere and dimethylsulfamide (91 mg, 0.73 mMol) added followed by DBU (23 uL, 0.15 mMol). The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, cooled under nitrogen and stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 103 mg of a crude product as an amorphous yellow film. The crude product was dissolved in methanol and purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software; % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Column=Waters Sunfire 19 mm×100 mm; Peak collection=12.16 min to 12.96 min. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23 (1 H, br. s.), 1.36-1.45 (2 H, m), 1.56 (1 H, br. s.), 1.78 (2 H, d, J=10.07 Hz), 2.00 (2 H, br. s.), 2.07 (2 H, br. s.), 2.78-2.91 (1 H, m), 3.09 (6 H, s), 3.94 (3 H, s), 4.43 (1 H, br. s.), 5.91 (1 H, br. s.), 7.03 (1 H, d, J=2.44 Hz), 7.10 (1 H, dd, J=8.55, 2.75 Hz), 7.50 (1 H, d, J=1.53 Hz), 7.55 (1H, d, J=8.55 Hz), 7.65 (1 H, s), 7.69 (1 H, s), 7.89 (1 H, d, J=8.55 Hz), 8.24 (1 H, s), 8.81 (1 H, br. s.). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.65 min, purity 93%; Flow injection Mass Spectrometry: MS m/z 561(MH+), m/z 559(M-H)−.

1. temperaturethen heated
2. temperatureto reflux for 1 hr
3. temperatureThe reaction was cooled under nitrogen atmosphere
4. temperatureThe reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs
5. temperaturecooled under nitrogen
6. stirringstirred at room temperature overnight
7. customThe reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid
8. washThe organic phase washed with brine
9. dry with materialdried over magnesium sulfate and volatiles
10. customremoved in vacuuo