(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone → 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,6-dimethylpyridin-3-yl)ethanol

HRID 526864Notes

Reaction equation

HRID 526864 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li][CH3:36]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)([OH:13])[CH3:36])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=1

Participants

4

Reactant 2

HCID 86715630(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone2×HCID 178418348HCID 178418348, compound

Product 1

HCID 1180062611-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,6-dimethylpyridin-3-yl)ethanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (220 mg, 0.45 mmol, Intermediate 10: step b) was added THF (15 mL). The solution was cooled in a dry ice bath and then MeLi (1.6 M in Et2O, 0.33 mL, 0.53 mmol) was introduced. After 40 minutes, the reaction was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford an amber gum. Chromatography on silica gel (3% MeOH-DCM increasing to 5% MeOH) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.35 (m, 3H), 7.07 (d, J=8.0 Hz, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.24 (s, 1H), 2.17 (s, 3H), 2.01 (s, 3H); MS (ESI): mass calcd. for C27H24ClF3N2O2, 500.2, m/z found 501.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(2,6-dimethylpyridin-3-yl)ethanol was purified by chiral SFC (Stationary phase: Chiracel OD column (50×250 mm, 5 micron), Mobile phase: 12% EtOH-hexane with 0.2% Et3N), to give 2 enantiomers. The first eluting enantiomer was Example 13b and the second eluting enantiomer was Example 13c.

Workup

  1. temperatureThe solution was cooled in a dry ice bath
  2. customthe reaction was quenched with aqueous NH4Cl solution
  3. extractionthe aqueous portion was extracted with EtOAc (4×30 mL)
  4. washThe combined organics were washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customto afford an amber gum

Sources & evidence

ORD record
ord-539e001391254d48a270073905fa507c
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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