Hydrazine → 4-(ethyloxy)-6-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1H-indazol-3-amine

Participants

Reaction Steps

A stock solution of sodium ethoxide in ethanol was generated by the addition of ethanol (10 mL) to NaH (204 mg, 8.48 mmol), followed by stirring at room temperature for 30 mins. To a 20-mL vial was added 2,6-difluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (293 mg, 0.848 mmol), N,N-dimethylformamide (DMF) (1 mL) and ethanol (1.5 mL). The reaction was cooled to 0° C., and a solution of sodium ethoxide in ethanol (from 0.848 M stock solution) (1.101 mL, 0.933 mmol) was added dropwise. The reaction was stirred at room temperature for 90 min. Ammonium chloride (aq., sat., 2 mL) and water (2 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organics were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (0-50% EtOAc in hexanes, 10-g column) to afford a white solid which was added to a 5-mL microwave vial with hydrazine (0.259 mL, 4.48 mmol), DIEA (0.391 mL, 2.239 mmol) and ethanol (3 mL). The resulting suspension was heated for 90 min at 150° C. in a microwave reactor. The reaction mixture was concentrated and dry-loaded onto silica and purified by flash chromatography (0-10% MeOH in DCM, 25-g column) to afford the title compound (175.4 mg, 0.457 mmol, 54% yield) as an off-white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (d, 3H), 1.45 (t, J=6.95 Hz, 3H), 2.83 (d, J=4.04 Hz, 3H), 3.05-3.18 (m, 1H), 3.45 (td, J=11.75, 2.53 Hz, 1H), 3.56-3.66 (m, 1H), 3.67-3.78 (m, 1H), 3.93 (dd, J=11.12, 3.03 Hz, 1H), 4.11 (d, J=12.88 Hz, 1H), 4.22 (q, J=6.99 Hz, 2H), 4.52 (d, J=4.80 Hz, 1H), 5.00 (s, 2H), 6.35-6.64 (m, 2H), 6.95 (s, 1H), 7.52 (br. s., 1H), 11.52 (s, 1H).

Provenance & Evidence