Potassium Hydroxide → HCID 71244695, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of (R)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (78 mg, 0.122 mmol) in MeCN (2 mL) was added diisopropylethylamine (0.064 mL, 0.37 mmol) followed by 2-bromoacetamide (20 mg, 0.146 mmol). The mixture was heated to 55° C. and stirred for 105 minutes, then cooled to room temperature quenched with saturated aqueous NH4Cl. The mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two additional times with dichoromethane and the organic layers were then combined, dried over Na2SO4, filtered and concentrated. The resulting residue was then dissolved in ethanol (2.1 mL) and placed in a microwave vial. The vial was charged with KOH (69 mg, 1.24 mmol) and 28% aqueous ammonium hydroxide (0.7 mL, 5.1 mmol), sealed and heated via microwave irradiation at 100° C. for 70 minutes. The mixture was then cooled to room temperature, diluted with dichloromethane and water and then neutralized with 1M aqueous NaHSO4. The resulting layers were separated and the organic layer was dried by passing through a phase separator. The eluent was concentrated and purified by reverse phase HPLC [10-55% MeCN/(0.1% NH4OH)water] to furnish (R)-2-(4-(6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.3 Hz, 3 H) 1.16 (d, J=6.8 Hz, 6 H) 2.02 (s, 3 H) 2.59-2.66 (m, 1 H) 2.72-2.85 (m, 3 H) 2.89-3.00 (m, 3 H) 3.13 (d, J=16.2 Hz, 1 H) 3.20-3.26 (m, 1 H) 3.27-3.30 (m, 3 H) 3.56-3.64 (m, 5 H) 4.01 (s, 2 H) 5.73 (s, 1 H) 7.08-7.13 (m, 2 H) 7.13-7.16 (m, 1 H) 7.18-7.22 (m, 1 H) 7.26 (d, J=2.8 Hz, 1 H) 7.41 (dd, J=8.1, 1.0 Hz, 1 H) 10.90 (s, 1H); MS (ESI+) m/z 542.4 (M+H)+.

Provenance & Evidence