Acetic Acid → HCID 86693848, compound

Participants

Reaction Steps

To a solution of N-{3-[4-(2-amino-pyridin-4-yl)-1-(tetrahydro-pyran-4-yl)-1H-pyrazol-3-yl]-2-fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (55 mg, 0.095 mmol) (prepared as described in Example 4) in MeOH (1 mL) at r.t. absolute acetic acid (0.011 mL, 0.2 mmol), formaldehyde (37% aq., 0.008 mL, 0.1 mmol) and sodium cyanoborohydride (7 mg, 0.11 mmol) were added and the reaction was stirred at r.t. for 1 h. All the reagents were added a second time in the same quantity and the reaction mixture was left stirring for an hour more. The reaction mixture was concentrated under reduced pressure and the crude was dissolved in a mixture of TFA:water 9:1 (1.5 mL) and stirred for 2 h at 70° C. The reaction mixture was concentrated under reduced pressure, then taken up with NaOH 1N and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM/MeOH/NH3 7N in MeOH 96:3:1) affording 3 mg of 2,5-difluoro-N-(2-fluoro-3-{4-[2-(methylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}phenyl)benzenesulfonamide (6% yield) and 29 mg of N-(3-{4-[2-(dimethylamino)pyridin-4-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (54% yield). HPLC (254 nm): Rt: 4.44 min; 1H NMR (DMSO-d6) Shift: 10.71 (br. s., 1H), 8.25 (s, 1H), 7.76 (d, J=5.4 Hz, 1H), 7.60-7.51 (m, 1H), 7.51-7.40 (m, 2H), 7.32 (dt, J=2.1, 7.5 Hz, 1H), 727-7.09 (m, 2H), 6.34-6.22 (m, 1H), 6.17 (s, 1H), 6.16-6.12 (m, 1H), 4.51-4.35 (m, 1H), 4.01-3.92 (m, 2H), 3.47 (dt, J=2.6, 11.6 Hz, 2H), 2.63 (d, J=4.8 Hz, 3H), 2.10-1.88 (m, 4H); HRMS (ESI) calcd for C26H25F3N5O3S [M+H]+ 544.1625. found 544.1622.

Provenance & Evidence