Dimethylformamide → Methy 6-amino-4'-fluoro-5-[(2-hydroxy-2-methylpropyl)amino]biphenyl-3-carboxylate

HRID 592329Notes

Reaction equation

HRID 592329 reaction equation
[NH2:1][C:2]1[C:11]([NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1Br.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.CN(C=O)C.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.P(C1C=CC(S(O)(=O)=O)=CC=1)(C1C=CC(S(O)(=O)=O)=CC=1)C1C=CC(S(O)(=O)=O)=CC=1.[Na].O>[NH2:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[NH:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15]

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 7912DiisopropylamineHCID 2856454-Fluorophenylboronic acidHCID 66693821Methy 4-amino-3-bromo-5-[(2-hydroxy-2-methylpropyl)amino]benzoate

Product 1

HCID 66693327Methy 6-amino-4'-fluoro-5-[(2-hydroxy-2-methylpropyl)amino]biphenyl-3-carboxylateYield 70.1%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1317345524,4',4''-Phosphinetriyltribenzenesulfonic acid sodiumCatalystHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of methy 4-amino-3-bromo-5-[(2-hydroxy-2-methylpropyl)amino]benzoate (513 mg, 1.617 mmol), palladium(II) acetate (7.26 mg, 0.032 mmol), (4-fluorophenyl)boronic acid (453 mg, 3.23 mmol) and 4,4′,4″-phosphinetriyltribenzenesulfonic acid-sodium salt (48.8 mg, 0.097 mmol) were added DMF (2.43 mL) and water (0.809 mL) followed by diisopropylamine (0.461 mL, 3.23 mmol). The reaction was capped and heated at 80° C. for 2 h. The reaction was cooled, quenched with saturated sodium bicarbonate and diluted with EtOAc. The aqueous layers were washed with EtOAc (2×) and the combined organics were washed with water (3×) and brine (1×). Organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (377 mg): LC-MS [M+1]=333.3.

Workup

  1. customThe reaction was capped
  2. temperatureThe reaction was cooled
  3. customquenched with saturated sodium bicarbonate
  4. additiondiluted with EtOAc
  5. washThe aqueous layers were washed with EtOAc (2×)
  6. washthe combined organics were washed with water (3×) and brine (1×)
  7. dry with materialOrganics were dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA)

Sources & evidence

ORD record
ord-e8f7bc8eed9a44e7a52b71be25df9a72
Source dataset
uspto-grants-2016_01
Patent number
US09238647B2

Reaction notes

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