Ethanol → 4-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-4'-cyano-5-fluoro-biphenyl-3-carboxylic acid methylamide

HRID 1687789Notes

Reaction equation

HRID 1687789 reaction equation
Br[C:2]1[CH:3]=[C:4]([F:33])[C:5]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]4[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=4[CH:32]=3)[N:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:50]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)#[N:51]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][NH:9][C:7]([C:6]1[CH:11]=[C:2]([C:55]2[CH:56]=[CH:57][C:52]([C:50]#[N:51])=[CH:53][CH:54]=2)[CH:3]=[C:4]([F:33])[C:5]=1[NH:12][C:13]1[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[NH:26][C:25]=3[CH:32]=2)[N:14]=1)=[O:8]

Participants

8

Reactant 5

HCID 702EthanolHCID 1140TolueneHCID 10340Sodium CarbonateHCID 27343264-Cyanophenylboronic acidHCID 668301975-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide

Product 1

HCID 668303094-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-4'-cyano-5-fluoro-biphenyl-3-carboxylic acid methylamideYield 44%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

5-Bromo-2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (55.0 mg, 0.103 mmol) was dissolved in toluene (4.00 mL, 37.6 mmol) and ethanol (4.00 mL, 68.5 mmol). Tetrakis(triphenylphosphine)palladium(0) (11.9 mg, 0.0103 mol) was added followed by 1.00 M sodium carbonate in water (412 uL) and 4-cyanophenylboronic acid (21.2 mg, 0.144 mmol). The reaction was heated at 90° C. overnight and then concentrated under reduced pressure. The residue was taken up in DCM (10 mL) and washed with 1 M Na2CO3 (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by prep-HPLC using a gradient of 20-45% AcN/water containing 0.1% TFA as the eluting solvent to obtain 4-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-4′-cyano-5-fluoro-biphenyl-3-carboxylic acid methylamide as a white foam (25 mg, 44%). LCMS (m/e) 556 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.54 (s, 1H), 9.40-9.30 (m, 2H), 8.80-8.71 (m, 1H), 8.21 (s, 1H), 8.08-7.98 (m, 4H), 7.95 (d, 1H, J=12.1 Hz), 7.89 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.16-7.10 (m, 1H), 6.93 (d, 1H, J=8.1 Hz), 2.77 (d, 3H, J=4.2 Hz), 2.60-2.43 (m, 2H), 2.02-1.94 (m, 4H); 19F-NMR (d6-DMSO, 400 MHz) δ −75.

Workup

  1. concentrationconcentrated under reduced pressure
  2. washwashed with 1 M Na2CO3 (10 mL)
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification

Sources & evidence

ORD record
ord-6f04e616c9ef44fc9df0f7ae913a47b9
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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