5-Bromo-2-methoxypyridine → (2,4-Dichloro-3-phenylquinolin-6-yl)(6-methoxypyridin-3-yl)(3-methylisoxazol-5-yl)methanol

HRID 526852Notes

Reaction equation

HRID 526852 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([Cl:27])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:28]([C:30]3[O:34][N:33]=[C:32]([CH3:35])[CH:31]=3)=[O:29])[CH:17]=2)[N:12]=1.[Li]CCCC>C1COCC1>[Cl:10][C:11]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([Cl:27])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:28]([C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)([C:30]3[O:34][N:33]=[C:32]([CH3:35])[CH:31]=3)[OH:29])[CH:17]=2)[N:12]=1

Participants

5

Reactant 3

HCID 27348955-Bromo-2-methoxypyridineHCID 86716078(2,4-Dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanone2×HCID 178418339Butyllithium

Product 1

HCID 117869477(2,4-Dichloro-3-phenylquinolin-6-yl)(6-methoxypyridin-3-yl)(3-methylisoxazol-5-yl)methanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

5-Bromo-2-methoxypyridine (0.019 mL, 0.15 mmol) was added to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanone (44.1 mg, 0.115 mmol, Intermediate 3: step b) in THF (1 mL) under a nitrogen atmosphere. The mixture was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.094 mL, 0.150 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 minutes, then moved to an ice bath and stirred for 30 minutes. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA) to afford the title compound along with the intended product (2,4-dichloro-3-phenylquinolin-6-yl)(6-methoxypyridin-3-yl)(3-methylisoxazol-5-yl)methanol. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.06 (d, J=8.80 Hz, 1H), 7.93 (d, J=8.80 Hz, 1H), 7.47-7.60 (m, 3H), 7.38-7.47 (m, 2H), 6.55 (br. s., 1H), 6.33 (s, 1H), 2.22-2.36 (m, 2H), 2.20 (s, 3H), 1.17-1.36 (m, 3H), 0.92-1.10 (m, 1H), 0.81 (t, J=6.97 Hz, 3H); MS m/e 441.1 (M+H)+.

Workup

  1. custommoved to an ice bath
  2. stirringstirred for 30 minutes
  3. customThe reaction was quenched by addition of saturated aqueous NH4Cl
  4. additionwas diluted with water
  5. extractionThe mixture was extracted three times with EtOAc
  6. dry with materialThe organic phase was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe crude product was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA)

Sources & evidence

ORD record
ord-02c482ec443c404fb2913ad428a788f3
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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