1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 4-(2-Fluoro-4-iodo-phenylamino)-1H-indazole-5-carboxylic acid cyclopropylmethoxy-amide

HRID 79068Notes

Reaction equation

HRID 79068 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.[CH:22]1([CH2:25][O:26][NH2:27])[CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:22]1([CH2:25][O:26][NH:27][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])[CH2:24][CH2:23]1

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11182605O-(cyclopropylmethyl)hydroxylamineHCID 575215054-(2-Fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid

Product 1

HCID 446032044-(2-Fluoro-4-iodo-phenylamino)-1H-indazole-5-carboxylic acid cyclopropylmethoxy-amideYield 29.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and O-cyclopropylmethyl-hydroxylamine (23 mg, 0.21 mmol) in DMF (3 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 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 solid was triturated with a solution of hot methanol/water/NaHCO3, the solid filtered off, washed with water to give the title compound as a pale pink solid (24 mg, 29%). LCMS (Method A): RT=10.42 min, [M+H]+=467. 1H NMR (DMSO-d6, 400 MHz) 13.17 (1 H, s), 7.64 (1 H, dd, J=10.37, 1.95 Hz), 7.48 (1 H, d, J=8.76 Hz), 7.42-7.37 (1 H, m), 7.26 (1 H, d, J=0.95 Hz), 7.01 (1 H, dd, J=8.76, 0.99 Hz), 6.87 (1 H, t, J=8.66 Hz), 3.62 (2 H, d, J=7.13 Hz), 1.08-1.00 (1 H, m), 0.50-0.44 (2 H, m), 0.23-0.17 (2 H, m).

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 with a solution of hot methanol/water/NaHCO3
  6. filtrationthe solid filtered off
  7. washwashed with water

Sources & evidence

ORD record
ord-01807d3c0d7949c8b41900d8ad3b9307
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

Loading…