Hydrochloric Acid → 1-(4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)propan-1-ol

HRID 526856Notes

Reaction equation

HRID 526856 reaction equation
[CH2:1]([Mg]Br)[CH3:2].BrC1C=CC(C(F)(F)F)=NC=1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)=[O:28])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1.Cl>C1COCC1.C(Cl)Cl.O>[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([OH:28])[CH2:1][CH3:2])[CH:25]=2)[N:20]=[C:19]([O:35][CH3:36])[C:18]=1[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([CH3:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 27611975-Bromo-2-(trifluoromethyl)pyridineHCID 86715613(4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone2×HCID 178418443HCID 178418443, compound

Product 1

HCID 1180069991-(4-Chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)propan-1-ol

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

Ethyl magnesium bromide solution (3 M in Et2O, 0.1 mL, 0.334 mmol) was added slowly to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.075 g, 0.334 mmol) in dry THF (3 mL). The resulting cloudy solution was stirred at room temperature for 20 minutes, cooled to 0° C. and then (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.056 g, 0.119 mmol, Intermediate 7: step e) in dry DCM (1 mL) was added. The resulting suspension was stirred at room temperature for 10 minutes then heated in a 60° C. oil bath, for 6 hours, then at 80° C. for an additional 12 hours. The mixture was cooled to room temperature, then H2O was added followed by 6 N aqueous HCl to bring the contents to a neutral pH. The solvents were removed under reduced pressure and the product extracted out with CH2Cl2 (2×). The combined organic extract was dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (0-10% MeOH in DCM) to provide a yellow solid by-product. Further purification by RP-HPLC (water/acetonitrile/0.1% TFA) of this by-product provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.84 (d, J=7.6 Hz, 4H), 7.51 (d, J=8.6 Hz, 3H), 4.44 (s, 2H), 4.07 (s, 3H), 3.53 (s, 3H), 3.07 (s, 3H), 2.26-2.48 (m, 2H), 0.83 (t, J=7.0 Hz, 3H); MS (ESI) 500 [M+H]+.

Workup

  1. temperaturecooled to 0° C.
  2. stirringThe resulting suspension was stirred at room temperature for 10 minutes
  3. temperaturethen heated in a 60° C. oil bath
  4. waitfor 6 hours
  5. waitat 80° C. for an additional 12 hours
  6. temperatureThe mixture was cooled to room temperature
  7. customThe solvents were removed under reduced pressure
  8. extractionthe product extracted out with CH2Cl2 (2×)
  9. extractionThe combined organic extract
  10. dry with materialwas dried (Na2SO4)
  11. filtrationfiltered
  12. customevaporated in vacuo
  13. customchromatographed (0-10% MeOH in DCM)
  14. customto provide a yellow solid by-product
  15. customFurther purification by RP-HPLC (water/acetonitrile/0.1% TFA) of this by-product

Sources & evidence

ORD record
ord-31ebf2a736e440cfac6e63741cf8a136
Source dataset
uspto-grants-2016_05
Patent number
US09346782B2

Reaction notes

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