Potassium Phosphate, Tribasic → 2-[4-(1-Methyl-1H-indol-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

HRID 474149Notes

Reaction equation

HRID 474149 reaction equation
[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1B(O)O.I[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[CH:29][N:28]=2)[CH3:26])=[O:23])=[CH:17][CH:16]=1.ON1C2N=CC=CC=2N=N1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[CH:29][N:28]=2)[CH3:26])=[O:23])=[CH:19][CH:20]=1

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 181649HOAtHCID 22733820(1-Methyl-1H-indol-2-yl)boronic acidHCID 668924152-(4-iodophenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide

Product 1

HCID 426100132-[4-(1-Methyl-1H-indol-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamideYield 79.2%

Reagents, catalysts & solvents 5

HCID 75806TricyclohexylphosphineCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

To a mixture of (1-methyl-1H-indol-2-yl)boronic acid (37.7 mg mg, 0.215 mmol), 2-(4-iodophenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50.0 mg, 0.108 mmol), tricyclohexylphosphine (0.7 mg, 0.003 mmol), 1-hydroxy-7-azabenzotriazole (101 mg, 0.744 mmol) and Pd2(dba)3 (1 mg, 0.001 mmol) were added dioxane (0.4 mL) and a solution of K3PO4 in H2O (0.2 mL, 1.27 M). The resulting solution was heated in microwave at 150° C. for 0.5 hr. The reaction was completed and diluted with EtOAc. The water later was removed. The remaining organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by reverse-phase HPLC to give the product as a TFA salt (40 mg, 79%). 1H NMR (CDCl3, 400 MHz) δ 8.22 (dd, J=0.8, 2.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.49 (dd, J=2.0, 6.4 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.37 (d, J=6.4, 1H), 7.27-7.19 (m, 2H), 7.14 (t, J=8.0 Hz, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.56 (s, 1H), 5.14 (quintet, J=7.2 Hz, 1H), 4.38 (q, J=8.0 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); HRMS (ES) [M+1]+ calcd for C26H25F3N3O2: 468.1893, Found: 468.1889. FLIPR alpha1I IP=36 nM.

Workup

  1. customThe water later was removed
  2. dry with materialThe remaining organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-21504919dc03448da312f4dfeab10bd0
Source dataset
uspto-grants-2014_01
Patent number
US08637513B2

Reaction notes

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