1-Methylimidazole → 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1-oxoisoindolin-5-yl)benzamide

HRID 1755372Notes

Reaction equation

HRID 1755372 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:40])[NH:35][CH2:34]4)=[O:23])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]

Participants

8

Reactant 4

HCID 13901-MethylimidazoleHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 219562395-Amino-2,3-dihydro-isoindol-1-oneHCID 715343363-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

Product 1

HCID 715261713-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1-oxoisoindolin-5-yl)benzamideYield 20%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), 5-aminoisoindolin-1-one (38 mg, 0.26 mmol), 1-methyl-1H-imidazole (84 mg, 1.02 mmol) and EDCI (196 mg, 1.02 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with brine (10 mL) then dried over Na2SO4. The residue was concentrated and triturated with MeOH (2 mL) to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1-oxoisoindolin-5-yl)benzamide (26 mg, 20%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.68 (s, 1H), 9.97 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.24-8.08 (m, 4 h), 7.82-7.64 (m, 4 h), 7.41 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=8.4 Hz), 4.39 (s, 2H), 4.02 (s, 3H), 3.76 (s, 3H). LC-MS: [M+H]+, 521.9, tR=1.434 min, HPLC: 96.12% at 214 nm, 96.79% at 254 nm, tR=3.673 min.

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous phase was extracted with ethyl acetate (20 mL)
  3. washwashed with brine (10 mL)
  4. dry with materialthen dried over Na2SO4
  5. concentrationThe residue was concentrated
  6. customtriturated with MeOH (2 mL)

Sources & evidence

ORD record
ord-8d76f9fe116a4aa4b059f45a42734bb2
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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