1,3-dimethyl-1H-pyrazol-4-amine → 6-[(1,3-Dimethylpyrazol-4-yl)amino]-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile

関与物質

反応条件

反応手順

6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (500 mg, 1.60 mmol), 1,3-Dimethyl-1H-pyrazol-4-ylamine (355 mg, 3.20 mmol) and Cesium carbonate (625 mg, 1.92 mmol), Palladium(II) acetate (28.7 mg, 0.13 mmol) and (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t- butylphosphine (90 mg, 0.16 mmol) were suspended in DME (10 mL) and sealed into a microwave tube. The reaction was heated to 150 °C for 30 minutes in the microwave reactor and cooled to RT. This was combined with reactions EN01370-84-87 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Mixed fractions were combined and re-columned. This prcess was repeated a further 3 times! 'Pure' fractions were combined and evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (484 mg, 15.63 %) as a yellow solid (1.08g) - 100% by LCMS and clean by TLC but the NMR is not great. Passed onto the purification group.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5µ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the required product. 200mg trial purification - resulted in 137mg pure - EN01370-88-1 Rest of the material processed to give EN01370-88-2 (347mg and 177mg)

情報源と証拠