Acetonitrile dry ice → 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol

HRID 526860Notes

Reaction equation

HRID 526860 reaction equation
[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[CH3:33]C#N.C(=O)=O.[Li]C>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)([OH:13])[CH3:33])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1

Participants

5

Reactant 3

HCID 86587134Acetonitrile dry iceHCID 118006338(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone2×HCID 178418348HCID 178418348, compound

Product 1

HCID 1180065891-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (400 mg, 0.87 mmol, Intermediate 12: step b) was added THF (20 mL) and the solution was cooled to −43° C. (CH3CN—CO2). MeLi (1.6 M in Et2O, 0.63 mL, 1.01 mmol) was then introduced. After 30 minutes, the reaction mixture was quenched with saturated aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (30% CH3CN-DCM increasing to 3% MeOH-DCM) provided the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.49 (dd, J=8.6, 2.2 Hz, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.34 (s, 1H), 7.17 (d, J=0.8 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 3H), 3.25 (s, 3H), 3.0 (br. s, 1H), 1.99 (s, 3H); MS (ESI): mass calcd. for C24H21ClF3N3O2, 475.1, m/z found 475.9 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol was purified by chiral SFC: (Stationary phase: CHIRALCEL OD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 9b and the second eluting enantiomer was Example 9c.

Workup

  1. customthe reaction mixture was quenched with saturated aqueous NH4Cl solution
  2. extractionThe aqueous portion was extracted with EtOAc (4×30 mL)
  3. washthe combined organics were washed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-31f681dd89024cefa982a305a1cd76c1
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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