Trifluoromethanesulfonic acid → 1-(4-bromo-5-fluoro-2-(pyrrolidin-3-yloxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide

Participants

Reaction Steps

To a solution of tert-butyl 3-(5-bromo-4-fluoro-2-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)phenoxy)pyrrolidine-1-carboxy late (74.7 mg, 0.097 mmol) in DCM (970 μl) at RT was added trifluoromethanesulfonic acid (25.8 μl, 0.291 mmol). The resulting solution was stirred overnight. LCMS indicated that the reaction was not complete. 0.012 mL of triflic acid was added and the solution stirred 16 hr. LCMS indicated that product was generated but there was a significant amount of PMB protected material. Another equivalent of triflic acid was added and the resulting solution was stirred for 48 hr. The reaction mixture was concentrated by sending a stream of N2 gas into the uncapped reaction vial. The residue was then dissolved in 1 ml of DMSO and 0.050 mL of saturated NaHCO3 was added and the mixture stirred for 5 minutes. The solution was then passed through a 0.20 micron filter. An additional 0.5 ml was used to sinse the reaction vial and the solution was passed through the same filter. The DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 5 to 30% MeCN in water (containing 0.1% ammonium hydroxide as an additive), flow rate 40 mL/min to yield 1-(4-bromo-5-fluoro-2-(pyrrolidin-3-yloxy)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5.5 mgs, 10% yield for two steps). 1H NMR (500 MHz, DMSO-d6) δ=ppm 1.22-1.36 (m, 1 H) 1.82-2.01 (m, 2 H) 2.61-2.81 (m, 1 H) 2.84-3.06 (m, 2 H) 3.30 (br. s., 7 H) 5.13 (br. s., 1 H) 6.09 (d, J=11.67 Hz, 1 H) 6.61-6.71 (m, 2 H) 7.60 (t, J=8.19 Hz, 1 H) 7.71 (t, J=8.01 Hz, 1 H) 7.78 (t, J=7.13 Hz, 1 H) 8.07-8.18 (m, 3H). m/z (ESI) 548.8.

Provenance & Evidence