1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → [4-(2-Fluoro-4-iodo-phenylamino)-1H-indazol-5-yl]-(3-hydroxy-azetidin-1-yl)-methanone

HRID 79071Notes

Reaction equation

HRID 79071 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.Cl.[OH:23][CH:24]1[CH2:27][NH:26][CH2:25]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>[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]([N:26]2[CH2:27][CH:24]([OH:23])[CH2:25]2)=[O:21])=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27592903-Hydroxyazetidine hydrochlorideHCID 575215054-(2-Fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid

Product 1

HCID 44603207[4-(2-Fluoro-4-iodo-phenylamino)-1H-indazol-5-yl]-(3-hydroxy-azetidin-1-yl)-methanoneYield 49%

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 3-hydroxyazetidine hydrochloride (23 mg, 0.21 mmol) in DMF (1 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 residue was triturated in cyclohexane to give the title compound as a pale tan solid (39 mg, 49%). LCMS (Method A): RT=8.23 min, [M+H]+=453. 1H NMR (DMSO-d6, 400 MHz) 13.17 (1 H, s), 9.55 (1 H, s), 7.63 (1 H, dd, J=10.47, 1.94 Hz), 7.41-7.37 (1 H, m), 7.37 (1 H, s), 7.32 (1 H, d, J=8.69 Hz), 7.05-7.00 (1 H, m), 6.92-6.82 (1 H, m), 5.67 (1 H, d, J=6.13 Hz), 4.44-4.37 (1 H, m), 4.24 (2 H, br, s), 3.83 (2 H, br, s).

Workup

  1. washwashed with saturated aqueous sodium hydrogen carbonate
  2. dry with materialwater, dried (Na2SO4)
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customThe resultant residue was triturated in cyclohexane

Sources & evidence

ORD record
ord-8829777010a645f693dc1106e69a7e1e
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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