Iodine → 3-((6-Chloro-3-cyanoimidazo[1,2-b]pyridazin-8-yl)(4-methoxybenzyl)amino)benzoic acid

HRID 2206366Notes

Reaction equation

HRID 2206366 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([O:19]C(C)(C)C)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.II.O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:14]2[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=2)[C:17]([OH:19])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1

Participants

6

Reactant 3

HCID 807IodineHCID 962WaterHCID 59314053tert-Butyl 3-((6-chloro-3-cyanoimidazo[1,2-b]pyridazin-8-yl)(4-methoxybenzyl)amino)benzoate

Product 1

HCID 593140063-((6-Chloro-3-cyanoimidazo[1,2-b]pyridazin-8-yl)(4-methoxybenzyl)amino)benzoic acidYield 66.3%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 253B (100 mg, 0.20 mmol) in acetonitrile (5 mL) was treated with iodine (15.54 mg, 0.061 mmol) and water (50 μL, 2.78 mmol). The reaction mixture was stirred at 80° C. for 8 hours. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate (4×20 mL). The pooled organic phase was dried over Na2SO4 and concentrated. The residue was triturated with DCM and filtered. The filtrate was concentrated, dissolved in DCM, and purified by flash chromatography, silica column (12 g, gradient elution from hexanes-ethyl acetate in 15 min.). The appropriate fraction was concentrated under reduced pressure and dried in vacuo to yield 253C (57.5 mg, 64.9% yield) as a yellow solid. HPLC: Rt=4.23 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=434.0 [M+H]+.

Workup

  1. washwashed with water
  2. extractionThe aqueous layer was extracted with ethyl acetate (4×20 mL)
  3. dry with materialThe pooled organic phase was dried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue was triturated with DCM
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated
  8. dissolutiondissolved in DCM
  9. custompurified by flash chromatography, silica column (12 g, gradient elution from hexanes-ethyl acetate in 15 min.)
  10. concentrationThe appropriate fraction was concentrated under reduced pressure
  11. customdried in vacuo

Sources & evidence

ORD record
ord-18d7c9de9dfb48aeb32f7f665027f1aa
Source dataset
uspto-grants-2016_06
Patent number
US09371328B2

Reaction notes

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