Reacción #167993

Ecuación de reacción

NaHSO4

(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

diisopropylethylamine

KOH

ammonium hydroxide

2-bromoacetamide

→

(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

Disolventes

dichloromethane

water

MeCN

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturacooled to room temperature
2. 2
   Otroquenched with saturated aqueous NH4Cl
3. 3
   workup.ADDITIONThe mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate
4. 4
   Otrothe layers were separated
5. 5
   ExtracciónThe aqueous layer was extracted two additional times with dichoromethane
6. 6
   Secadodried over Na2SO4
7. 7
   Filtraciónfiltered
8. 8
   Concentraciónconcentrated
9. 9
   workup.DISSOLUTIONThe resulting residue was then dissolved in ethanol (2.1 mL)
10. 10
    Otrosealed
11. 11
    Temperaturaheated via microwave irradiation at 100° C. for 70 minutes
12. 12
    TemperaturaThe mixture was then cooled to room temperature
13. 13
    OtroThe resulting layers were separated
14. 14
    Otrothe organic layer was dried
15. 15
    ConcentraciónThe eluent was concentrated
16. 16
    Otropurified by reverse phase HPLC [10-55% MeCN/(0.1% NH4OH)water]

Procedimiento

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)+.

Fuente