Sodium hydride → 2-(4-Fluorophenyl)-N-methyl-5-(3-(2-methyl-1-(5-methylisoxazol-3-ylamino)-1-oxopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

HRID 1025104Notes

Reaction equation

HRID 1025104 reaction equation
CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[O:50][N:49]=[C:48]([NH2:51])[CH:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:40])([CH3:41])[C:37]([NH:51][C:48]5[CH:47]=[C:46]([CH3:45])[O:50][N:49]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:15][CH:16]=1

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 661723-Amino-5-methylisoxazoleHCID 81531DiisopropylethylamineHCID 592755572-(3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid

Product 1

HCID 592755122-(4-Fluorophenyl)-N-methyl-5-(3-(2-methyl-1-(5-methylisoxazol-3-ylamino)-1-oxopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamideYield 9.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 5-methylisoxazol-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (2.8 mg, 9%). 1H NMR (500 MHz, CD3OD) δ ppm 8.17-8.25 (1 H, m), 7.92-8.00 (3 H, m), 7.83-7.91 (2 H, m), 7.66-7.76 (2 H, m), 7.58 (1 H, t, J=7.78 Hz), 7.27 (2 H, t, J=8.85 Hz), 6.63 (1 H, s), 2.98 (3 H, s), 2.39 (3 H, s), 1.65 (6 H, s). LC-MS retention time: 1.69 min; m/z (MH+): 555. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.20 min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=11.30 min, purity=90%.

Workup

  1. stirringto stir overnight
  2. customwas purified by preparative reverse phase HPLC on a C18 column
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-3fcc594f59d84c52baa5d101716f81c8
Source dataset
uspto-grants-2014_05
Patent number
US08722688B2

Reaction notes

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