Reacción #1605832

Ecuación de reacción

isopropylchloroformate

Aripiprazole

diisopropylamine

n-BuLi

→

Isopropyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate

Disolventes

2-methyltetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.WAITAfter a further 10 minutes
2. 2
   workup.WAITThe reaction was held at −78° C. for 2 hours
3. 3
   Temperaturato warm to room temperature overnight
4. 4
   OtroThe reaction was quenched with saturated aqueous ammonium chloride solution (30 mL)
5. 5
   Extracciónextracted with ethyl acetate (2×30 mL)
6. 6
   Lavadowashed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL)
7. 7
   Secadodried over MgSO4
8. 8
   Concentraciónconcentrated
9. 9
   OtroThe crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 2% methanol in 1:1 ethyl acetate to dichloromethane
10. 10
    Otroto give the product
11. 11
    OtroThe product was recrystallized from isopropanol
12. 12
    Otroto remove aliphatic impurities
13. 13
    Otrowas purified by column chromatography
14. 14
    Lavadoeluting with 0 to 10% tetrahydrofuran in ethyl acetate
15. 15
    OtroThe product was triturated in heptane
16. 16
    Filtraciónfiltered
17. 17
    Otroto afford Compound-75 (0.593 g) as a colorless solid

Procedimiento

To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, isopropylchloroformate (9.37 mL, 1.0 mol in toluene, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 1:1 ethyl acetate to dichloromethane to 2% methanol in 1:1 ethyl acetate to dichloromethane to give the product. The product was recrystallized from isopropanol to remove aliphatic impurities. The product was not sufficiently pure so was purified by column chromatography eluting with 0 to 10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane and filtered to afford Compound-75 (0.593 g) as a colorless solid.

Fuente