1-Methylimidazole → N-(2-(dimethylamino)ethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide

HRID 1755361Notes

Reaction equation

HRID 1755361 reaction equation
[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH2:36].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1

Participants

6

Reactant 4

HCID 13901-MethylimidazoleHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 66053N,N-DimethylethylenediamineHCID 715255203-(8-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

Product 1

HCID 71526077N-(2-(dimethylamino)ethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamideYield 42.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (83 mg, 0.2 mmol), N1,N1-dimethylethane-1,2-diamine (19 mg, 0.22 mmol), 1-methyl-1H-imidazole (66 mg, 0.8 mmol) and EDCI (153 mg, 0.8 mmol) in dichloromethane (10 mL) was stirred at room temperature for 16 h then concentrated. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:20) and further purified by Prep-TLC (silica gel, methanol:dichloromethane=1:10) to afford N-(2-(dimethylamino)ethyl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridine-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (41 mg, 42%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.89 (s, 1H), 8.48 (s, 1H), 8.13 (dd, 1H, J1=6.9 Hz, J2=1.8 Hz), 8.02-7.97 (m, 2H), 7.65-7.60 (m, 2H), 7.45 (t, 1H, J=8.1 Hz), 6.31 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.29-4.25 (m, 1H), 3.76-3.72 (m, 2H), 3.66-3.60 (m, 1H), 3.54-3.40 (m, 1H), 3.19-3.15 (m, 2H), 2.81 (s, 6H), 2.25-2.00 (m, 3H), 1.75-1.73 (m, 1H), 1.17 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 485, tR=1.062 min, HPLC: 99.08% at 214 nm, 99.16% at 254 nm, tR=4.868 min.

Workup

  1. concentrationthen concentrated
  2. customThe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:20)
  3. customfurther purified by Prep-TLC (silica gel, methanol:dichloromethane=1:10)

Sources & evidence

ORD record
ord-9c784f1698bc47a8b1d5dd4b7fe5caec
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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