Triethylamine → N-(5-(6-(4-(N'-hydroxycarbamimidoyl)-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide

HRID 539800Notes

Reaction equation

HRID 539800 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:35])([F:34])[F:33])[CH:4]=1)#[N:2].Cl.[NH2:37][OH:38].CCN(CC)CC>C(O)C>[OH:38][N:37]=[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([CH3:31])=[C:22]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=4)[N:17]=3)[N:14]=2)=[C:5]([C:32]([F:33])([F:35])[F:34])[CH:4]=1)[NH2:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 443297Hydroxyamine hydrochlorideHCID 57406897N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide

Product 1

HCID 136332422N-(5-(6-(4-(N'-hydroxycarbamimidoyl)-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamideYield 81.8%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

A 500-mL flask is charged with N-(5-(6-(4-cyano-2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (7.496 g, 0.0157 mol), hydroxylamine hydrochloride (6.55 g, 0.0942 mol), Et3N (15.32 mL, 0.1099 mol), ethanol (82.5 mL) and the resulting mixture is stirred for 2 hours at 80° C. The mixture is concentrated onto celite and purified by silica gel chromatography (eluted by 0 to 100% of 10:1 EtOAc:MeOH in CH2Cl2). The isolated solid material (over 20 g) contains triethylamine and hydroxylamine salts, and the salts stay even after attempted recrystallization with isopropanol. This solid product is then added to a stirred mixture of saturated aqueous NaHCO3 and EtOAc. Solid suspension is collected by filtration. The liquid portion is back extracted with EtOAc and the organic layers are combined, dried with Na2SO4, concentrated to afford additional solid product. The combined solid product is dried on a lyophilizer overnight, recrystallized from hot Isopropanol to afford the desired title product (6.56 g). LCMS (m/z)=511.6 [M+H]+, tR=2.49 min.

Workup

  1. concentrationThe mixture is concentrated onto celite
  2. custompurified by silica gel chromatography (eluted by 0 to 100% of 10:1 EtOAc:MeOH in CH2Cl2)
  3. customrecrystallization with isopropanol
  4. additionThis solid product is then added to a stirred mixture of saturated aqueous NaHCO3 and EtOAc
  5. filtrationSolid suspension is collected by filtration
  6. extractionThe liquid portion is back extracted with EtOAc
  7. dry with materialdried with Na2SO4
  8. concentrationconcentrated
  9. customto afford additional solid product
  10. customThe combined solid product is dried on a lyophilizer overnight
  11. customrecrystallized from hot Isopropanol

Sources & evidence

ORD record
ord-e3b1332fe8ca4e5e9b9461ad42e2132d
Source dataset
uspto-grants-2014_10
Patent number
US08871767B2

Reaction notes

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