Triisopropyl borate → (5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)boronic acid

HRID 2108962Notes

Reaction equation

HRID 2108962 reaction equation
[CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 21531Triisopropyl borateHCID 24758Sodium hydrideHCID 21914570N-Cyclopropyl-3-fluoro-5-iodo-4-methylbenzamide2×HCID 178418339Butyllithium

Product 1

HCID 21914527(5-(Cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)boronic acid

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-75 °C

Procedure

N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5 g) in THF (75 ml) was cooled to 0° C. and sodium hydride (60%, 1.23 g) added portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) added over 25 minutes maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added to the reaction over 10 minutes and the reaction stirred at −70° C. for 4 hours. The reaction was quenched with water (20 ml) and the mixture allowed to warm to 5° C. The reaction was concentrated under vacuum and the residue partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in DCM/ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate/DCM gradient (5-100% ethyl acetate) and then methanol. The product fractions were combined and the solvent evaporated under vacuum to give {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid. LCMS MH+238, retention time 2.19 min.

Workup

  1. temperaturemaintaining a temperature of <−70° C
  2. customThe reaction was quenched with water (20 ml)
  3. temperatureto warm to 5° C
  4. concentrationThe reaction was concentrated under vacuum
  5. customthe residue partitioned between saturated ammonium chloride and ethyl acetate
  6. washThe organic phase was washed with saturated ammonium chloride, brine
  7. dry with materialdried (sodium sulphate)
  8. dissolutionThe residue was dissolved in DCM/ethyl acetate
  9. custompurified by column chromatography on silica eluting with an ethyl acetate/DCM gradient (5-100% ethyl acetate)
  10. customthe solvent evaporated under vacuum

Sources & evidence

ORD record
ord-33bafc5df51642eda8a53e4dcb4a4d8b
Source dataset
uspto-grants-2009_04
Patent number
US07514456B2

Reaction notes

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