Hydrochloric Acid → 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-oxoindolin-5-yl)benzamide hydrochloride

HRID 1755375Notes

Reaction equation

HRID 1755375 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)[NH:36][C:35](=[O:40])[CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C.[ClH:58]>CN(C=O)C.O.C(OCC)(=O)C>[ClH:58].[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)[NH:36][C:35](=[O:40])[CH2:34]4)=[O:23])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 13901-MethylimidazoleHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 27732135-Amino-2-oxindoleHCID 715343363-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid

Product 1

HCID 866827303-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-oxoindolin-5-yl)benzamide hydrochlorideYield 2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

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-aminoindolin-2-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 at 50° C. for 48 h. 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 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: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give a residue that was treated with 0.5 mL HCl and the suspension stirred for 5 min. Concentration gave 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-oxoindolin-5-yl)benzamide hydrochloride (2.3 mg, 2%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.67 (s, 1H), 10.36 (s, 1H), 10.31 (s, 1H), 8.88 (s, 1H), 8.51-8.47 (m, 2H), 8.20-8.12 (m, 3H), 7.75-7.68 (m, 2H), 7.54-7.44 (m, 2H), 7.09 (d, 1H, J=8.1 Hz), 6.81 (d, 1H, J=7.8 Hz), 4.03 (s, 3H), 3.78 (s, 3H), 3.08 (s, 2H). LC-MS: [M+H]+, 522, tR=1.48 min, HPLC: 99.05% at 214 nm, 96.91% at 254 nm, tR=5.184 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. custompurified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  7. waitgradient conditions: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min
  8. custom) to give a residue that
  9. stirringthe suspension stirred for 5 min
  10. concentrationConcentration

Sources & evidence

ORD record
ord-2c27a759a903414ab6d4e0063342fcf6
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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