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Potassium Acetate → (4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic acid

HRID 1424818
Notes
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Reaction equation

HRID 1424818 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH:36]([F:38])[F:37].C([O-])(=O)C.[K+].[B:44]1(B2OC(C)(C)C(C)(C)O2)[O:48]C(C)(C)C(C)(C)[O:45]1>O1CCOCC1.CCOC(C)=O.O.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].C(Cl)Cl>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([B:44]([OH:48])[OH:45])=[C:3]([CH:36]([F:37])[F:38])[CH:4]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27](=[O:28])[NH:29][CH3:30])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 1317322796-(N-(4-bromo-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Product 1

HCID 71263590(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic acidYield 45%

Reagents, catalysts & solvents

4
HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 6-(N-(4-bromo-3-(difluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.20 g, 0.33 mmol), potassium acetate (0.13 g, 1.32 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.027 g, 0.033 mmol), and bis(pinacolato)diboron (0.25 g, 0.99 mmol) in 1,4-dioxane (4.12 ml) was degassed, purged with nitrogen and heated at 80° C. for 3 h 45 mins. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in 10 mL THF, and 5 mL 1M HCl. NaIO4 (0.56 g, 2.63 mmol) was added and the suspension was stirred for 1 h and diluted with EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4), filtered, evaporated and purified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid)) to afford the title compound (0.085 g, 45%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.90-7.97 (m, 2H), 7.87 (s, 1H), 7.43-7.61 (m, 3H), 7.30 (s, 1H), 7.21-7.29 (m, 2H), 6.65-7.01 (m, 1H), 3.33 (s, 3H), 2.94 (s, 3H), 2.08-2.21 (m, 1H), 0.35-1.10 (m, 4H). LCMS (m/z, ES+)=573.3 (M+H+).

Workup

  1. custompurged with nitrogen
  2. additionThe reaction mixture was diluted with EtOAc and water
  3. filtrationfiltered through celite
  4. customevaporated
  5. dissolutionThe brown residue was dissolved in 10 mL THF
  6. washThe organic layer was washed with water, brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated
  10. custompurified by reverse phase chromatography (5-100% CH3CN/H2O (0.1% formic acid))

Sources & evidence

ORD record
ord-c7cac32e02fc4f4b97e2dfa43ada5c37
Source dataset
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08927593B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes