Sodium borohydride → HCID 56655516, compound

Participants

Reaction Steps

A solution of 2-[8-fluoro-2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile (224 mg, 0.35 mmol) in methanol (2.8 ml) and dichloromethane (4.3 ml) was cooled in an ice bath. To this was added a solution of sodium borohydride (65 mg, 1.7 mmol) in water (0.75 ml), via slow drop-wise addition. The mixture was stirred for 10 minutes and additional sodium borohydride (as describe above was added twice more over 20 minutes. The aqueous upper phase was carefully removed from the biphasic reaction solution. Methanol (1 ml) was added and with rapid stirring 3 more additions of aqueous sodium borohydride were made (as described above) over about 25 minutes. Water (60 ml) and dichloromethane (60 ml) were added and the material was transferred to a separatory funnel and the organic phase was collected. This was washed with an equal volume of 50% diluted brine solution and the dichloromethane phase collected. The aqueous phases were back extracted with dichloromethane (2×40 ml). The combined organic phase was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC on silica gel, eluting with 1% to 8% methanol/dichloromethane to provide the desired product which was further purified by crystallization from hot dichloromethane/hexane to provide desired product as a white solid (120 mg). (M+H)+=650 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81 (s, 6H) 3.53-3.81 (m, 8H) 3.83-3.91 (m, 1H) 3.92 (s, 3H) 4.26-4.45 (m, 2H) 6.62 (dd, J=7.55, 1.89 Hz, 1H) 7.00 (d, J=8.31 Hz, 1H) 7.22 (dd, J=12.46, 1.89 Hz, 1H) 7.33 (d, J=7.18 Hz, 1H) 7.42 (dd, J=7.93, 1.51 Hz, 1H) 7.53 (d, J=1.89 Hz, 1H) 7.57 (t, J=7.93 Hz, 1H) 7.65-7.70 (m, 1H) 7.78 (dd, J=8.69, 2.27 Hz, 1H) 8.41-8.47 (m, 2H) 8.70 (s, 1H).

Provenance & Evidence