tert-Butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate → 1-(4-(Hydroxy(1-methyl-1H-imidazol-5-yl)(3-phenyl-2,4-bis(trifluoromethyl)quinolin-6-yl)methyl)piperidin-1-yl)ethanone

HRID 627569Notes

Reaction equation

HRID 627569 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:5]2[C:22]([F:25])([F:24])[F:23].[CH:26]([Mg]Cl)(C)C.[CH3:31][N:32]1[C:36]([C:37]([CH:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47]C(C)(C)C)=O)[CH2:41][CH2:40]2)=[O:38])=[CH:35][N:34]=[CH:33]1>C1COCC1>[OH:38][C:37]([C:36]1[N:32]([CH3:31])[CH:33]=[N:34][CH:35]=1)([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:13])([F:15])[F:14])[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[C:5]2[C:22]([F:23])([F:24])[F:25])[CH:39]1[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:26])[CH2:41][CH2:40]1

Participants

5

Reactant 3

HCID 66677755tert-Butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate2×HCID 867160666-Bromo-3-phenyl-2,4-bis(trifluoromethyl)quinoline2×HCID 178418918HCID 178418918, compound

Product 1

HCID 867161491-(4-(Hydroxy(1-methyl-1H-imidazol-5-yl)(3-phenyl-2,4-bis(trifluoromethyl)quinolin-6-yl)methyl)piperidin-1-yl)ethanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A ˜−70° C. solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (150 mg, 0.322 mmol; Intermediate 8, step d) in THF (0.322 mL) was treated with iPrMgCl (2.06 M in THF; 0.156 mL, 0.322 mmol) dropwise via syringe under argon over the course of 30 sec to provide a light amber solution that became a yellow opaque slurry within 2 min. After 8 additional min the reaction was removed from the cold bath and stirred on a room temperature water bath for 10 min, at which point solid 1-(4-(1-methyl-1H-imidazole-5-carbonyl)piperidin-1-yl)ethanone (90.9 mg, 0.386 mmol; Intermediate 53, step c) was added in one portion and the reaction quickly evacuated and flushed with argon four times. After 5 min, additional THF (2.6 mL) was added to aid the dissolution of the ketone, and the reaction became an opaque easily stirred tan slurry within 30 min. After 110 min, the reaction was quenched with D2O (0.2 mL) and partitioned with 5 M NH4Cl (1 mL) and heptane (1 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was flash chromatographed using a DCM to 9:1 DCM/MeOH gradient to provide the title compound as a white powder.

Workup

  1. customto provide a light amber solution that
  2. customwithin 2 min
  3. customAfter 8 additional min the reaction was removed from the cold bath
  4. customthe reaction
  5. customquickly evacuated
  6. customflushed with argon four times
  7. waitAfter 5 min
  8. additionadditional THF (2.6 mL) was added
  9. dissolutionthe dissolution of the ketone
  10. customwithin 30 min
  11. waitAfter 110 min
  12. customthe reaction was quenched with D2O (0.2 mL)
  13. custompartitioned with 5 M NH4Cl (1 mL) and heptane (1 mL)
  14. dry with materialthe organic layer was dried (Na2SO4)
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customchromatographed

Sources & evidence

ORD record
ord-d2a390ad81fe4649aabcec58c8864acc
Source dataset
uspto-grants-2016_04
Patent number
US09309222B2

Reaction notes

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