tert-Butyl ((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate → tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

To a solution of 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 807 μmol) in NMP (3.2 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) and the mixture heated to 140° C. Over the next 36 h three additional portions of tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) were added at 12 h intervals. At 48 h the mixture was cooled, diluted with EtOAc, and washed with water and brine (2×). The organic layer was concentrated onto silica and purified by chromatography (70% to 100% EtOAc in hexanes) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.49 (s, 1H), 8.22 (s, 1H), 8.06 (br. s, 1H), 7.29 (t, J=9.4 Hz, 1H), 6.70 (dd, J=8.9, 3.0 Hz, 1H), 6.07 (br. s, 1H), 5.50 (br. s, 1H), 5.35 (br. s, 1H), 4.26 (br. s, 1H), 4.03 (m, 2H), 3.92 (d, J=11.4 Hz, 1H), 3.68 (d, J=11.5 Hz, 1H), 3.61 (t, J=11.8 Hz, 1H), 3.41 (m, 1H), 2.24 (d, J=11.2 Hz, 1H), 1.81 (m, 1H), 1.49 (s, 9H), 1.35 (d, J=6.9 Hz, 6H).

Provenance & Evidence