Potassium Hydroxide → HCID 71244695, compound

Temperature

55 °C

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)+.

1. temperaturecooled to room temperature
2. customquenched with saturated aqueous NH4Cl
3. additionThe mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate
4. customthe layers were separated
5. extractionThe aqueous layer was extracted two additional times with dichoromethane
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. dissolutionThe resulting residue was then dissolved in ethanol (2.1 mL)
10. customsealed
11. temperatureheated via microwave irradiation at 100° C. for 70 minutes
12. temperatureThe mixture was then cooled to room temperature
13. customThe resulting layers were separated
14. customthe organic layer was dried
15. concentrationThe eluent was concentrated
16. custompurified by reverse phase HPLC [10-55% MeCN/(0.1% NH4OH)water]

ORD record

ord-f707471d880a4a2f81df3505d7a69019

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08846656B2