Hydrochloric Acid → 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid

HRID 1183772Notes

Reaction equation

HRID 1183772 reaction equation
[H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Br[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=1.Cl.O1CCOCC1>CN(C)C=O.CC#N.O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1

Participants

8

Reactant 5

HCID 313Hydrochloric Acid2×HCID 24758Sodium hydrideHCID 312751,4-Dioxane2×HCID 11414578Tert-butyl 4-(bromomethyl)benzoateHCID 120009366-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one

Product 1

HCID 462066174-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acidYield 53.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 18373917Acetonitrile--water (1/1)Solvent

Procedure

To a mixture of 95% dry sodium hydride (12 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (4 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.30 mmol) (PT-010 made as in Example 1B, above) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 4-(bromomethyl)benzoate (271 mg, 1.00 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (checked by LCMS), then it was quenched by addition of methanol (5 mL). The reaction mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added, and the solvent removed under reduced pressure. To this crude product (tert-butyl 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate) was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent removed under reduced pressure. A second portion of 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) was added with stirring at room temperature for another 13 hours, the solvent removed under reduced pressure. The crude reaction product was subjected to reverse phase HPLC with a gradient of MeCN/H2O (2% to 98%) to afford 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid (70 mg, 0.16 mmol, 53%) (PT-088). LCMS mz 488.0 (M+H), 510.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; DMSO-d6) δ 7.90 (d, J=8.2 Hz, 2H); 7.86 (d, J=8.2 Hz, 2H); 7.78 (d, J=8.2 Hz, 2H); 7.68 (d, J=2.1 Hz, 1H); 7.53 (dd, J=8.3 and 2.1 Hz, 1H); 7.38 (d, J=8.2 Hz, 2H); 7.00 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 3.08 (m, 2H), 2.79 (m, 2H).

Workup

  1. stirringThe reaction mixture was stirred at room temperature until the majority of the starting material
  2. customit was quenched by addition of methanol (5 mL)
  3. concentrationThe reaction mixture was concentrated under reduced pressure, anhydrous toluene (10 mL)
  4. additionwas added
  5. customthe solvent removed under reduced pressure
  6. stirringThe reaction mixture was stirred at room temperature for 4 hours
  7. customthe solvent removed under reduced pressure
  8. stirringwith stirring at room temperature for another 13 hours
  9. customthe solvent removed under reduced pressure
  10. customThe crude reaction product

Sources & evidence

ORD record
ord-dacdeae197e94ecf97d0f8765847c725
Source dataset
uspto-grants-2014_03
Patent number
US08664379B2

Reaction notes

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