Hydrochloric Acid → 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

HRID 1773687Notes

Reaction equation

HRID 1773687 reaction equation
Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)([OH:49])[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 753981-Bromo-2,4,6-trifluorobenzeneHCID 117601919tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 862967766-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
70 °C

Procedure

To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.

Workup

  1. customto the reaction
  2. waitAfter 60 minutes
  3. temperaturethe reaction was warmed
  4. customquenched with saturated NH4Cl(aq) (10 mL)
  5. extractionextracted with ethyl acetate (3×10 mL)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customPurification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ)

Sources & evidence

ORD record
ord-8217d4ce270e43bb81862f4f0c77e469
Source dataset
uspto-grants-2016_02
Patent number
US09255089B2

Reaction notes

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