(4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol

Temperature

-78 °C

A solution of n-BuLi (2.5 M in hexanes, 2.67 mL, 6.66 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (3.00 g, 7.00 mmol, Intermediate 16) in dry THF (80 mL) at −78° C. After 3 minutes, a solution of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (1.65 g, 7.48 mmol, Intermediate 1: step b) in dry THF (80 mL) was added dropwise over the course of 3 minutes. The reaction mixture was stirred for 10 minutes at −78° C., then the reaction flask was removed from the cooling bath. After 10 minutes, the reaction flask was placed into an ice-water bath. After 30 minutes, saturated aqueous ammonium chloride solution (10 mL) was added. The biphasic mixture was warmed to room temperature then partitioned between half-saturated aqueous ammonium chloride solution (300 mL) and ethyl acetate (300 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were combined. The combined solution was dried with sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 20% acetone-dichloromethane initially, grading to 100% acetone) to provide the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.58-7.54 (m, 2H), 7.54-7.51 (m, 1H), 7.40-7.34 (m, 3H), 7.33-7.27 (m, 4H), 6.43 (t, J=2.1 Hz, 1H), 6.41-6.38 (m, 1H), 4.31 (s, 2H), 4.08 (s, 3H), 3.72 (s, 1H), 3.38 (s, 3H). MS (ESI): mass calcd. C31H25Cl2N5O2, 569.1; m/z found, 570.1 [M+H]+.

1. customthe reaction flask was removed from the cooling bath
2. waitAfter 10 minutes
3. customthe reaction flask was placed into an ice-water bath
4. waitAfter 30 minutes
5. additionsaturated aqueous ammonium chloride solution (10 mL) was added
6. temperatureThe biphasic mixture was warmed to room temperature
7. customthen partitioned between half-saturated aqueous ammonium chloride solution (300 mL) and ethyl acetate (300 mL)
8. customThe layers were separated
9. extractionThe aqueous layer was extracted with ethyl acetate (150 mL)
10. dry with materialThe combined solution was dried with sodium sulfate
11. filtrationThe dried solution was filtered
12. concentrationthe filtrate was concentrated
13. customThe residue was purified by flash column chromatography (silica gel, 20% acetone-dichloromethane initially

ORD record

ord-6630d810ecf2483aa1a905f36ab6a6e8

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290476B2