Dimethyl Sulfoxide → N-(6-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide

HRID 1162454Notes

Reaction equation

HRID 1162454 reaction equation
[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].CS(C)=O.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=4)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 10340Sodium CarbonateHCID 27339863-Fluorophenylboronic acidHCID 44125500N-(6-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide

Product 1

HCID 44125499N-(6-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-3-(3-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamideYield 76.7%

Reagents, catalysts & solvents 1

HCID 178418476HCID 178418476, compoundCatalyst

Conditions

Temperature
90 °C

Procedure

To a 10 mL round-bottomed flask was added N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 21) (0.0820 g, 0.162 mmol), DMSO (2.50 mL, 35.2 mmol), 3-fluorophenylboronic acid (0.0272 g, 0.194 mmol, Aldrich, St. Louis, Mo.), and sodium carbonate (0.405 mL, 0.809 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. To the mixture was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.011 g, 0.0162 mmol, Strem Chemical, Inc., Newburyport, Mass.). Again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 90° C. for 40 min, allowed to cool to rt. and then directly purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 75% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product concentrated to afford the title compound as a yellow solid (0.059 g, 62%). MS (ESI, positive ion) m/z: 475 (M−TFA+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H), 3.20 (s, 3H), 7.25-7.28 (m, 1H), 7.53-7.60 (m, 1H), 7.70-7.75 (m, 1H), 7.77-7.81 (m, 1H), 8.02 (d, J=9.6 Hz, 1H), 8.32 (d, J=9.6 Hz, 1H), 8.52 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.2 Hz, 1H), 9.92 (s, 1H), 10.24 (s, 1H).

Workup

  1. customThe mixture was carefully evacuated
  2. customAgain, the mixture was carefully evacuated
  3. temperatureto cool to rt
  4. customand then directly purified by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.)
  5. waitC18, 100×30 mm, 5 to 75% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min
  6. addition100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) with the fractions containing suspected product
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-4631850522884cc49dedd1776dae741b
Source dataset
uspto-grants-2010_10
Patent number
US07820665B2

Reaction notes

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