1-Methylimidazole → 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide

HRID 1755343Notes

Reaction equation

HRID 1755343 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:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=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:26]=[CH:25][C:21]([C:22]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=4)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]

Participants

7

Reactant 4

HCID 13901-MethylimidazoleHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 683792224-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochlorideHCID 715258044-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

Product 1

HCID 715258954-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamideYield 38.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.265 mmol), 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (16 mg, 0.132 mmol), 1-methyl-1H-imidazole (118 mg, 1.45 mmol) and EDCI (276 mg, 1.45 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (5 mL×2), then brine (5 mL×2). After drying and concentration, the residue was purified by chromatography (silica gel, 5 g, 200˜300 mesh, methanol:dichloromethane=1:30) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (27 mg, 21%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.94 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 4 h), 7.66 (s, 1H), 7.58 (d, 1H, J=6.6 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.23 (s, 1H), 6.13 (d, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.77 (s, 3H), 3.53-3.47 (m, 2H), 3.36 (s, 3H), 2.69 (t, 2H, J=6.6 Hz). LC-MS: [M+H]+, 526, tR=1.367 min, HPLC: 98.9% at 214 nm, 99.36% at 254 nm, tR=4.615 min.

Workup

  1. extractionthen extracted with ethyl acetate (50 mL)
  2. washThe combined extracts were washed with water (5 mL×2)
  3. customAfter drying
  4. concentrationconcentration
  5. customthe residue was purified by chromatography (silica gel, 5 g, 200˜300 mesh, methanol:dichloromethane=1:30)

Sources & evidence

ORD record
ord-a357784c06eb437992bae6b7facfb6ef
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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