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

HRID 1755355Notes

Reaction equation

HRID 1755355 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]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:23](=[O:25])[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)[CH3:36]

Participants

7

Reactant 4

HCID 13901-MethylimidazoleHCID 51262-AminopropanolHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 715255203-(8-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

Product 1

HCID 71525987N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamideYield 15.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (10 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 20 h then extracted with ethyl acetate (50 mL) and washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (8.7 mg, 14%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.91 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.17-8.00 (m, 4 h), 7.65 (t, 1H, J=7.8 Hz), 7.58-7.55 (m, 1H), 6.40 (d, 1H, J=7.5 Hz), 6.28 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 2H), 3.71-3.58 (m, 3H), 3.54-3.48 (m, 1H), 2.19-2.07 (m, 3H), 1.81 (brs, 1H), 1.29 (d, 3H, J=6.3 Hz), 1.19 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 472, tR=1.654 min, HPLC: 99.36% at 214 nm, 98.85% at 254 nm, tR=5.697 min.

Workup

  1. extractionthen extracted with ethyl acetate (50 mL)
  2. washwashed with water (2×2 mL)
  3. customAfter drying
  4. concentrationconcentration
  5. customthe residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50)
  6. customfurther purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm
  7. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min

Sources & evidence

ORD record
ord-f9c0c40751d647069ac685dad0b9fcda
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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