(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone → HCID 74221008, compound

HRID 928845Notes

Reaction equation

HRID 928845 reaction equation
[Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3C(C)=NC(C)=CC=3)O)[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1.[CH3:40][N:41]1[C:45]([C:46]([C:48]2[CH:49]=[N:50][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:53]=2)=[O:47])=[CH:44][N:43]=[CH:42]1>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:46]([C:45]3[N:41]([CH3:40])[CH:42]=[N:43][CH:44]=3)([C:48]3[CH:49]=[N:50][C:51]([C:54]([F:57])([F:55])[F:56])=[CH:52][CH:53]=3)[OH:47])[CH:15]=2)[N:10]=[C:9]([O:27][CH3:28])[C:8]=1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=1

Participants

5

Reactant 3

HCID 86715442(1-Methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone2×HCID 86715629(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol2×HCID 178418339Butyllithium

Product 1

HCID 74221008HCID 74221008, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 1.85 mL, 4.62 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.00 g, 4.65 mmol, Intermediate 47: step d) in dry THF (30 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (1.26 g, 4.92 mmol, Intermediate 36: step c) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred for 2 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and DCM. The separated aqueous phase was further extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated to provide the title compound as crude white solid. MS m/e 607.2 [M+H]+ Example 62A was purified by chiral HPLC (ChiralPak AD, 50:50 methanol/ethanol) to provide two enantiomers, Example 62B and Example 62C. The first eluting enantiomer was Example 62B: 1H NMR (500 MHz, CDCl3) δ ppm 8.80 (d, J=1.8 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.94 (s, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.8, 2.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.05 (s, 1H), 6.15 (s, 1H), 4.30 (s, 2H), 4.07 (s, 3H), 3.29 (s, 3H); MS m/e 607.2 [M+H]+ and the second eluting enantiomer was Example 62C: 1H NMR (500 MHz, CDCl3) δ ppm 8.80 (d, J=1.7 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J=8.2, 1.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.8, 2.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 7.06 (s, 1H), 6.16 (s, 1H), 4.30 (s, 2H), 4.07 (s, 3H), 3.30 (s, 3H); MS m/e 607.2 [M+H]+.

Workup

  1. customthe reaction flask was placed into an ice-water bath
  2. waitAfter 10 minutes
  3. customthe reaction was quenched with saturated ammonium chloride
  4. customThe mixture was partitioned between water and DCM
  5. extractionThe separated aqueous phase was further extracted with DCM
  6. dry with materialThe organic phase was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-baaa1e2cb4b44ac79534019e9022f138
Source dataset
uspto-grants-2016_03
Patent number
US09290476B2

Reaction notes

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