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

HRID 926459Notes

Reaction equation

HRID 926459 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 12: step d) was added THF (55 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. (the solution remained homogeneous) and then n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added dropwise. 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. additionwas added dropwise
  3. waitAfter 15 minutes
  4. temperatureto warm to −20° C. over 40 minutes at which time the reaction
  5. customwas quenched with aqueous NH4Cl solution
  6. additionThe reaction was diluted further with water
  7. extractionextracted with EtOAc (3×50 mL)
  8. washThe combined organics were washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto provide an orange foam
  13. customThe crude product was chromatographed on silica gel (10% acetone-hexane increasing to 30% acetone)

Sources & evidence

ORD record
ord-8772ad89b26f4b66ad00c09e6ed9a662
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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