Aniline → 4,4,4-trifluoro-3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-N-phenylbutanamide

HRID 2193762Notes

Reaction equation

HRID 2193762 reaction equation
[F:1][C:2]([F:33])([F:32])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[C:23]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)[S:24][C:17]=23)=[C:11]([F:31])[CH:10]=1)[CH2:4][C:5]([OH:7])=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:33][C:2]([F:32])([F:1])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[C:23]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)[S:24][C:17]=23)=[C:11]([F:31])[CH:10]=1)[CH2:4][C:5]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:7]

Participants

7

Reactant 5

HCID 6115AnilineHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 587904194,4,4-Trifluoro-3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)butanoic acid

Product 1

HCID 250545994,4,4-trifluoro-3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-N-phenylbutanamideYield 64.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 320 (150 mg, 0.31 mmol), aniline (43 μL, 0.47 mmol) and N, N-diisopropylethylamine (0.19 mL, 1.09 mmol) in dry N,N-dimethylformamide (4 mL) at room temperature was added HATU reagent (356 mg, 0.94 mmol). The mixture was stirred at room temperature for 16 h. A saturated aqueous solution of sodium bicarbonate was added and the aqueous solution was extracted twice with EtOAc, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 3:97 to 8:92) to afford the title compound 317 (111 mg, 0.20 mmol, 64% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.11 (s, 1H), 8.39 (d, J=5.6 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.66 (s, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.30 (t, J=8.0 Hz, 2H), 7.21 (t, J=8.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.86 (dd, J=13.6, 2.4 Hz, 1H), 6.67 (dd, J=8.8, 2.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 6.44 (d, J=5.6 Hz, 1H), 4.86-4.53 (m, 1H), 3.72 (s, 3H), 2.92 (dd, J=15.6, 3.2 Hz, 1H), 2.76 (dd, J=15.6, 9.6 Hz, 1H). LRMS (M+1) 556.0 (100%).

Workup

  1. extractionthe aqueous solution was extracted twice with EtOAc
  2. dry with materialdried over anhydrous sodium sulfate
  3. customthe solvent was removed under reduced pressure
  4. customThe residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 3:97 to 8:92)

Sources & evidence

ORD record
ord-2d6db4cef1a8498886e972231437c170
Source dataset
uspto-grants-2012_12
Patent number
US08329726B2

Reaction notes

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