反应详情

To a flask containing tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8) (48 mg, 0.066 mmol) in DCM (3 ml) was added TFA (0.5 ml, 6.49 mmol). The reaction mixture was then stirred at room temperature. Followed by LC/MS . . . after ˜20 minutes the reaction mixture was diluted/quenched with DMSO, then MeOH, then filtered (syringe filter) then concentrated (to remove DCM), then diluted with MeOH/DMSO & purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added saturated HCl in EtOAc (˜4N) & concentrated to yield 5-fluoro-3-((4-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (24-9). HRMS [M+H]: calculated; 480.0606, observed; 480.0587. 1H NMR (400 MHz, CD3 OD): δ 8.22 (s, 1H); 7.80 (d, J=5.5 Hz, 1H); 7.63-7.57 (m, 1H); 7.57-7.48 (m, 2H); 7.11 (d, J=9.3 Hz, 1H); 5.81 (d, J=48.5 Hz, 1H); 5.16-5.10 (m, 2H); 4.74-4.66 (m, 1H); 4.47-4.39 (m, 1H); 4.02-3.92 (m, 1H); 3.71-3.55 (m, 1H);

1. customafter ˜20 minutes the reaction mixture was diluted/quenched with DMSO
2. filtrationMeOH, then filtered
3. filtration(syringe filter)
4. concentrationthen concentrated
5. custom(to remove DCM)
6. additiondiluted with MeOH/DMSO
7. custompurified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column)
8. concentrationdesired fractions concentrated (GENEVAC)
9. dissolutiondissolved in MeOH/DCM
10. additionadded saturated HCl in EtOAc (˜4N)
11. concentrationconcentrated