Ammonium Chloride → Trifluoroacetic acid

HRID 926626Notes

Reaction equation

HRID 926626 reaction equation
[CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40]C(C)(C)C)=[O:39])[CH2:34][CH2:33]2)=[O:31])=[CH:28][N:27]=[CH:26]1.[Li][CH2:46]CCC.CC(C)=O.[C:54](=[O:56])=[O:55].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:8]1[C:9]([C:20]([F:23])([F:22])[F:21])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:30]([OH:31])([C:29]1[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=1)[CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:46])[CH2:34][CH2:33]1)=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([OH:56])([C:20]([F:23])([F:22])[F:21])=[O:55].[C:38]([OH:40])([C:20]([F:23])([F:22])[F:21])=[O:39]

Participants

8

Reactant 5

HCID 25517Ammonium ChlorideHCID 18522661Acetone cardiceHCID 66677755tert-Butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate2×HCID 1180063363-Benzyl-6-bromo-4-chloro-2-(trifluoromethyl)quinoline2×HCID 178418339Butyllithium

Product 2

HCID 6422Trifluoroacetic acidHCID 1317350271-(4-((3-Benzyl-4-chloro-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)piperidin-1-yl)ethanone.TFA

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A mixture of 3-benzyl-6-bromo-4-chloro-2-(trifluoromethyl)quinoline (632 mg, 1.58 mmol, Intermediate 72: step b), 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (371 mg, 1.58 mmol, Intermediate 58: step c), and 15 mL of THF was sparged with N2 and cooled to −78° C. To the mixture was added n-BuLi (1.6 M in hexanes, 2.6 mL, 4.2 mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 minutes, then the acetone-dry ice bath was replaced with a water-ice bath. Stirring was continued for 20 minutes at 4° C. Saturated NH4Cl (aq) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic phases were dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM) followed by reverse phase HPLC (water/acetonitrile/0.1% TFA) to afford the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4, ˜1:1 mixture of rotamers) δ 8.84 (s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.24 (d, J=9.09 Hz, 1H), 8.07 (s, 1H), 7.78 (d, J=9.09 Hz, 1H), 7.21-7.29 (m, 2H), 7.15-7.21 (m, 1H), 7.01 (d, J=7.07 Hz, 2H), 4.65 (d, J=13.14 Hz, 0.5H), 4.57 (s, 2H), 4.45 (d, J=13.14 Hz, 0.5H), 4.03 (d, J=13.64 Hz, 0.5H), 3.84 (d, J=14.15 Hz, 0.5H), 3.59 (s, 1.5H), 3.57 (s, 1.5H), 3.23-3.32 (m, overlapping with solvent), 3.03 (td, J=2.02, 13.14 Hz, 0.5H), 2.66-2.82 (m, 1H), 2.53 (td, J=2.53, 13.64 Hz, 0.5H), 2.09-2.24 (m, 1H), 2.07 (s, 1.5H), 2.02 (s, 1.5H), 1.41-1.60 (m, 1H), 1.26-1.39 (m, 1H), 1.11-1.26 (m, 1H), 1.05 (d, J=13.14 Hz, 0.5H); MS m/e 557.1 [M+H]+.

Workup

  1. customwas sparged with N2
  2. stirringStirring
  3. waitwas continued for 20 minutes at 4° C
  4. customthe organic layer was separated
  5. extractionThe aqueous layer was extracted with dichloromethane
  6. dry with materialThe combined organic phases were dried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customThe crude material was purified by flash column chromatography (silica gel, 0-10% MeOH in DCM)

Sources & evidence

ORD record
ord-adb848f3cb2a48e182843df4fbd945e9
Source dataset
uspto-grants-2016_03
Patent number
US09284308B2

Reaction notes

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