Cesium carbonate → (R)-3-(1-(Dimethylamino)propan-2-yloxy)-5-(8-methoxyisoquinolin-3-ylamino)pyrazine-2-carbonitrile

Participants

Reaction Conditions

Reaction Steps

A mixture of tris(dibenzylideneacetone)dipalladium (0) (7.9 mg, 0.009 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.017 mmol) in toluene (1 mL) and DMF (1 mL) was degassed under a stream of nitrogen gas with stirring for 15 minutes. 8-Methoxyisoquinolin-3-yl trifluoromethanesulfonate (26.6 mg, 0.087 mmol), cesium carbonate (28 mg, 0.087 mmol) and (R)-5-amino-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (19 mg, 0.087 mmol) were added and the mixture degassed for a further 5 minutes. The mixture was heated at 130° C. for 30 minutes in a microwave reactor and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) and brine, then dried (Na2SO4) and passed sequentially through 2 PS-Thiol cartridges and concentrated to dryness. Preparative HPLC afforded the title compound (0.62 mg, 0.00016 mmol, 2%). 1H NMR (d6-DMSO, 400 MHz) δ 9.34 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.69-7.65 (m, 1H), 7.37 (d, 1H, J=8.3 Hz), 6.99 (d, 1H, J=7.6 Hz), 5.53-5.47 (m, 1H), 4.02 (s, 3H), 2.68-2.63 (m, 1H), 2.57-2.53 (m, 1H), 2.21 (s, 6H), 1.46 (d, 3H, J=6.3 Hz). LC-MS (2) Rt=3.18 min; m/z (ESI+) 379 (M+H).

Provenance & Evidence