反应详情

温度

-78 °C

To a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (579 mg, 1.22 mmol, Intermediate 4: step e) in THF (5 mL) at −78° C. under argon was added n-butyllithium (1.6 M in hexane, 0.725 mL, 1.16 mmol) over 1 minute. The resulting dark brown solution was stirred for 1 minute before addition of a solution of (1-methyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (237 mg, 1.22 mmol, Intermediate 1: step b) in THF (4 mL). The resulting orange solution was stirred at −78° C. for 5 minutes, then was transferred to an ice bath and stirred 30 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash column chromatography (0-6% MeOH-DCM) to afford the title compound. MS m/e 544.2 [M+H]+. Example 1a was purified by chiral HPLC (Chiralcel OD-H, 20% EtOH-heptane) to give 2 enantiomers. The second enantiomer to elute was then further purified on a silica gel column (0-5% MeOH-DCM). Example 1b: (first enantiomer to elute off chiral column) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 8.09 (d, J=2.53 Hz, 1H), 7.75 (d, J=8.59 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.56 (d, J=8.59 Hz, 2H), 7.43-7.52 (m, 2H), 7.34 (d, J=8.59 Hz, 2H), 7.24 (s, 1H), 6.38-6.54 (m, 1H), 4.28 (s, 2H), 4.05 (s, 3H), 4.00 (dd, J=3.28, 11.37 Hz, 1H), 3.79 (dd, J=3.54, 11.12 Hz, 1H), 3.54 (t, J=11.12 Hz, 1H), 3.32-3.37 (m, 1H), 3.30 (s, 3H), 2.46-2.61 (m, 1H), 2.07 (d, J=13.64 Hz, 1H), 1.57-1.75 (m, 1H), 1.39 (qd, J=4.55, 12.63 Hz, 1H), 0.95 (d, J=13.14 Hz, 1H); MS m/e 544.1 [M+H]+ and Example 1c: (second enantiomer to elute off chiral column) 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.86 (d, J=2.02 Hz, 1H), 7.76 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.59 Hz, 2H), 7.36-7.46 (m, 3H), 7.32 (s, 1H), 7.21 (s, 1H), 6.43 (s, 1H), 4.32 (s, 2H), 4.03-4.14 (m, 4H), 3.90 (dd, J=3.28, 11.37 Hz, 1H), 3.52 (t, J=11.12 Hz, 1H), 3.33 (t, J=11.37 Hz, 1H), 3.25 (s, 3H), 2.42-2.54 (m, 1H), 2.36 (s, 1H), 2.12 (d, J=13.64 Hz, 1H), 1.42 (qd, J=4.29, 12.72 Hz, 1H), 1.21-1.35 (m, 1H), 1.03 (d, J=13.14 Hz, 1H); MS m/e 544.2 [M+H]+.

1. customwas transferred to an ice bath
2. stirringstirred 30 minutes
3. customThe reaction was quenched by the addition of saturated aqueous NH4Cl
4. additiondiluted with water
5. extractionextracted with EtOAc (3×)
6. dry with materialThe organic phase was dried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated to dryness
9. customThe residue was purified by flash column chromatography (0-6% MeOH-DCM)