Dimethylformamide → 4-(2-Fluoro-4-iodo-phenylamino)-1H-indazole-5-carboxylic acid (tetrahydro-pyran-4-yloxy)-amide

HRID 79067Notes

Reaction equation

HRID 79067 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.C1C=CC2[N:30]([OH:31])N=NC=2C=1.CCN=C=N[CH2:37][CH2:38][CH2:39]N(C)C.CCN([CH:49]([CH3:51])C)C(C)C.CN(C=[O:56])C>C(OCC)(=O)C>[O:56]1[CH2:37][CH2:38][CH:39]([O:31][NH:30][C:19]([C:18]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:21])[CH2:51][CH2:49]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 575215054-(2-Fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid

Product 1

HCID 446032034-(2-Fluoro-4-iodo-phenylamino)-1H-indazole-5-carboxylic acid (tetrahydro-pyran-4-yloxy)-amideYield 26%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (100 mg, 0.252 mmol) in DMF (3 mL) was added 0-(tetrahydro-pyran-4-yl)-hydroxylamine (44 mg, 0.378 mmol), HOBt (37 mg, 0.277 mmol), EDCI (53 mg, 0.277 mmol) and DIPEA (92 μl, 0.529 mmol). The reaction was stirred at room temperature for 70 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 30-100% ethyl acetate in cyclohexane). The resultant solid was triturated in methanol, the solid filtered off, washed with methanol to yield the title compound (33 mg, 26%). LCMS (Method A): RT=9.27 min, [M+H]+=497. 1H NMR (DMSO-d6, 400 MHz): 13.19 (1 H, s), 11.44 (1 H, s), 9.87 (1 H, s), 7.65 (1 H, dd, J=10.36, 1.95 Hz), 7.48 (1H, d, J=8.77 Hz), 7.44-7.38 (1H, m), 7.28 (1 H, s), 7.03 (1 H, d, J=8.75 Hz), 6.89 (1 H, t, J=8.66 Hz), 4.02-3.93 (1 H, m), 3.84-3.76 (2 H, m), 3.36-3.28 (2 H, m), 1.88-1.81 (2 H, m), 1.51 (2 H, dddd, J=12.96, 9.42, 8.75, 4.11 Hz).

Workup

  1. washwashed with saturated aqueous sodium hydrogen carbonate
  2. dry with materialwater, dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe resultant solid was triturated in methanol
  6. filtrationthe solid filtered off
  7. washwashed with methanol

Sources & evidence

ORD record
ord-0cdb74b162574982b9afc1e7ca37853c
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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