Potassium Acetate → 2-(4-Methyl-3-pivalamidophenyl)imidazo[1,2-b]pyridazin-6-ylboronic acid

HRID 539798Notes

Reaction equation

HRID 539798 reaction equation
Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[B:25]1(B2OC(C)(C)C(C)(C)O2)[O:29]C(C)(C)C(C)(C)[O:26]1.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]=[C:5]3[CH:6]=[CH:7][C:2]([B:25]([OH:29])[OH:26])=[N:3][N:4]3[CH:10]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]

Participants

6

Reactant 3

HCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 86667859N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide

Product 1

HCID 680891592-(4-Methyl-3-pivalamidophenyl)imidazo[1,2-b]pyridazin-6-ylboronic acidYield 54%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (15.43 g 0.045 mol), bis(pinacolato)diboron (17.14 g, 0.0675 mol), potassium acetate (8.833 g, 0.09 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.305 g, 3.15 mmol) in dioxane (153 mL) is heated at 90° C. for 16 hours. The reaction mixture is cooled, concentrated, added to an aqueous NaOH solution (150 mL, 3 M). The mixture is stirred for 1 hour then extracted with EtOAc (300 mL). Organic layers are washed with the NaOH solution (150 mL, 3 M). The aqueous portions are combined, washed twice with ether, and the aqueous pH is lowered to 5 with an aqueous HCl solution (6 M) to cause solid formation. This heterogeneous solution is cooled in the freezer for 2 hours, the solids are collected by filtration to give the desired product (8.56 g). The resulting aqueous solution is back extracted with EtOAc, combined with earlier organic portions and filtered through celite. The combined organic layer is dried, concentrated and taken up into an aqueous HCl solution (0.5 M). The solid product formed is collected by filtration and combined with the earlier batch, to afford a total 10.16 g of the desired title compound. LCMS (m/z)=353.5 [M+H]+, tR=2.04 min.

Workup

  1. temperatureThe reaction mixture is cooled
  2. concentrationconcentrated
  3. additionadded to an aqueous NaOH solution (150 mL, 3 M)
  4. extractionthen extracted with EtOAc (300 mL)
  5. washOrganic layers are washed with the NaOH solution (150 mL, 3 M)
  6. washwashed twice with ether
  7. temperatureThis heterogeneous solution is cooled in the freezer for 2 hours
  8. filtrationthe solids are collected by filtration

Sources & evidence

ORD record
ord-fb554412c5fa4aafbfb5f676a670656f
Source dataset
uspto-grants-2014_10
Patent number
US08871767B2

Reaction notes

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