1,3,4-Thiadiazol-2-amine → 2-(4-Fluorophenyl)-N-Methyl-5-[3-({2-Methyl-1-Oxo-1-[(1,3,4-Thiadiazol-2-Yl)amino]propan-2-Yl}carbamoyl)phenyl]-1-Benzofuran-3-Carboxamide

HRID 555064Notes

Reaction equation

HRID 555064 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](O)=[O:38])=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH2:50].[H-].[Na+]>CN(C=O)C>[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH:50][C:37](=[O:38])[C:36]([NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=1)=[O:34])([CH3:40])[CH3:41]

Participants

6

Reactant 4

HCID 199091,3,4-Thiadiazol-2-amineHCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 592755572-(3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid

Product 1

HCID 592754272-(4-Fluorophenyl)-N-Methyl-5-[3-({2-Methyl-1-Oxo-1-[(1,3,4-Thiadiazol-2-Yl)amino]propan-2-Yl}carbamoyl)phenyl]-1-Benzofuran-3-CarboxamideYield 47%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

DIEA (44 μL, 0.253 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169 mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and the slurry became a clear solution after 10 min. It was allowed to stir overnight. The reaction 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 (22 mg, 45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1H, br. s.), 8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3H, m), 7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d, J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u 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=11.23 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 mm, Rt=10.56 min, purity=96%.

Workup

  1. customafter 10 min
  2. customThe reaction was purified by preparative reverse phase HPLC on a C18 column
  3. concentrationconcentrated

Sources & evidence

ORD record
ord-b8c64b9e732d4552b2a22fd5d9f168e7
Source dataset
uspto-grants-2011_11
Patent number
US08048887B2

Reaction notes

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