Potassium Carbonate → 5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

HRID 2272385Notes

Reaction equation

HRID 2272385 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[CH2:36][CH2:37][OH:38].C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)O[B:48](B2OC(C)(C)C(C)(C)O2)[O:47]1>O1CCOCC1.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]>[CH:33]1([C:32]2[C:13]([N:8]([C:5]3[CH:6]=[CH:7][C:2]4[B:48]([OH:47])[O:38][CH2:37][CH2:36][C:3]=4[CH:4]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27]([NH:29][CH3:30])=[O:28])[C:16]=3[CH:31]=2)[CH2:34][CH2:35]1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 2733548Bis(pinacolato)diboraneHCID 1317323346-(N-(4-Bromo-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Product 1

HCID 712635925-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamideYield 65%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
70 °C

Procedure

To a deoxygenated solution of 6-(N-(4-bromo-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.166 mmol) in 1,4-dioxane (4 mL) and water (1.0 mL) was added K2CO3 (92 mg, 0.665 mmol) followed by 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (84 mg, 0.33 mmol) and PdCl2(dppf) (12.16 mg, 0.017 mmol) under nitrogen purging. Then the reaction mixture was heated to 70° C. for 2 h. The mixture was cooled to RT and filtered to remove solids. The filtrate was diluted with water and extracted with EtOAc. The EtOAc solution was washed with water (1×), dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by RP-HPLC (C18, MeCN/water/0.1% formic acid) to afford the title compound in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=8.60, 5.28 Hz, 2H) 7.67-7.71 (m, 1H) 7.57-7.62 (m, 1H) 7.45-7.49 (m, 1H) 7.13-7.25 (m, 4H) 5.79 (d, J=3.91 Hz, 1H) 4.31 (s, 1H) 4.19 (t, J=5.96 Hz, 2H) 3.29 (s, 3H) 3.01 (d, J=4.89 Hz, 3H) 2.89 (t, J=5.86 Hz, 2H) 2.02-2.13 (m, 1H) 1.02 (br. s., 1H) 0.83 (br. s., 2H) 0.61 (br. s., 1H). LCMS (m/z, ES+)=549 (M+H+).

Workup

  1. temperatureThe mixture was cooled to RT
  2. filtrationfiltered
  3. customto remove solids
  4. additionThe filtrate was diluted with water
  5. extractionextracted with EtOAc
  6. washThe EtOAc solution was washed with water (1×)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated to dryness at reduced pressure
  9. customThe crude product was purified by RP-HPLC (C18, MeCN/water/0.1% formic acid)

Sources & evidence

ORD record
ord-bb1d80eb751c4b5ea50fb2c5925e5028
Source dataset
uspto-grants-2015_09
Patent number
US09119868B2

Reaction notes

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