Tetrahydrofuran → (1-Methyl-1H-imidazol-5-yl)(3-phenyl-2,4-bis(trifluoromethyl)quinolin-6-yl)(pyridin-2-yl)methanol

HRID 627572Notes

Reaction equation

HRID 627572 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]2[C:27]([F:30])([F:29])[F:28].CC(S(N=[C:38]([C:45]1[N:49]([CH3:50])[CH:48]=[N:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=O)(C)C.C1C[O:54]CC1>>[CH3:50][N:49]1[C:45]([C:38]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]3[C:27]([F:30])([F:29])[F:28])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[OH:54])=[CH:46][N:47]=[CH:48]1

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 867160666-Bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline2×HCID 867161542-methyl-N-((1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methylene)propane-2-sulfinamide2×HCID 178418339Butyllithium

Product 1

HCID 86716153(1-Methyl-1H-imidazol-5-yl)(3-phenyl-2,4-bis(trifluoromethyl)quinolin-6-yl)(pyridin-2-yl)methanol

Procedure

A solution of n-BuLi (2.5 M in hexanes, 0.10 mL, 0.25 mmol) was added dropwise by syringe to a solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (122 mg, 0.261 mmol, Intermediate 8, step d) in dry THF (4.5 mL) in a dry ice-acetone bath. After 2 min, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.0540 g, 0.288 mmol, Intermediate 11, step b) in dry THF (0.25 mL) was added dropwise. The reaction mixture was stirred for 5 min in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 5 min, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by reverse-phase chromatography (acetonitrile w/0.05% TFA in water). Saturated sodium bicarbonate was used to form the free-base product, which was extracted with DCM and concentrated to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.4 Hz, 1H), 8.32 (d, J=8.9 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.9, 1.8 Hz, 1H), 7.75 (td, J=7.7, 1.7 Hz, 1H), 7.51 (s, 1H), 7.49-7.40 (m, 3H), 7.35 (dd, J=7.0, 5.3 Hz, 1H), 7.28 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 6.72 (s, 1H), 6.39 (s, 1H), 3.44 (s, 3H). MS m/e 529.2 [M+H]+.

Workup

  1. customthe reaction flask was placed into an ice-water bath
  2. waitAfter 5 min
  3. customthe reaction was quenched with methanol and water
  4. customThe mixture was partitioned between water and ethyl acetate
  5. extractionThe separated aqueous phase was further extracted with ethyl acetate
  6. dry with materialThe organic phase was dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by reverse-phase chromatography (acetonitrile w/0.05% TFA in water)
  10. customto form the free-base product, which
  11. extractionwas extracted with DCM
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-ac6985d688dd495e87b96a27031b7fe2
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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