Tetrahydrofuran → (4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol

HRID 928797Notes

Reaction equation

HRID 928797 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].C1COCC1.C([Li])CCC.[CH3:36][C:37]1[C:42]([CH:43]=[O:44])=[CH:41][CH:40]=[C:39]([CH3:45])[N:38]=1>CC(C)=O.CCCCCC>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:43]([C:42]3[C:37]([CH3:36])=[N:38][C:39]([CH3:45])=[CH:40][CH:41]=3)[OH:44])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 27847532,6-DimethylnicotinaldehydeHCID 867156276-Bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline2×HCID 178418339Butyllithium

Product 1

HCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol

Reagents, catalysts & solvents 1

HCID 21880519Acetone hexaneSolvent

Conditions

Temperature
-70 °C

Procedure

To a 100 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.5 g, 5.8 mmol, Intermediate 47: step d) was added THF (55 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added drop wise. The color of the solution became a reddish-brown color. After 1 minute, (2,6-dimethylpyridine-3-carboxaldehyde (1.01 g, 7.5 mmol in 2 mL THF) was introduced and the color of the mixture became a light greenish-yellow color. After 15 minutes, HPLC and TLC (50% acetone-hexane) indicated that the reaction was complete. The mixture was allowed to warm to −20° C. over 40 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The reaction was diluted further with water and extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide an orange foam. The crude product was chromatographed on silica gel (10% acetone-hexane increasing to 30% acetone) to afford the title compound as a light yellow foam.

Workup

  1. customresulted in a colorless homogeneous mixture
  2. waitAfter 15 minutes
  3. temperatureto warm to −20° C. over 40 minutes at which time the reaction
  4. customwas quenched with aqueous NH4Cl solution
  5. additionThe reaction was diluted further with water
  6. extractionextracted with EtOAc (3×50 mL)
  7. washThe combined organics were washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto provide an orange foam
  12. customThe crude product was chromatographed on silica gel (10% acetone-hexane increasing to 30% acetone)

Sources & evidence

ORD record
ord-f7768ccc7a8d4ac6a590460c4d211018
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

Loading…