Methylamine → 2-(4-Fluorophenyl)-n-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide

HRID 44073Notes

Reaction equation

HRID 44073 reaction equation
CN.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:36][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:35])[NH:25][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH3:28])[CH3:27])[CH:19]=4)[CH:17]=[C:12]3[C:11]=2[C:37](O)=[O:38])=[CH:6][CH:5]=1.C[CH2:41][N:42](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:36][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:35])[NH:25][C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)([CH3:28])[CH3:27])[CH:19]=4)[CH:17]=[C:12]3[C:11]=2[C:37]([NH:42][CH3:41])=[O:38])=[CH:8][CH:9]=1

Participants

7

Reactant 4

HCID 6329MethylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59233668HCID 59233668, compound

Product 1

HCID 592337652-(4-Fluorophenyl)-n-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamideYield 13%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

Methanamine (253 μL, 0.506 mmol, 2M in THF) was added to a stirring solution of 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (50 mg, 0.10 mmol), DIEA (53 μL, 0.30 mmol), DMAP (1.2 mg, 10 μmol), HATU (58 mg, 0.15 mmol) in DMF (1 mL) at room temperature. It was allowed to stir for 1 hour and then was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the expected product 2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxamide (7 mg, 0.013 mmol, 13% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, MeOD) δ ppm 8.65 (1H, d, J=2.14 Hz), 8.41 (1H, d, J=2.14 Hz), 8.12-8.17 (1H, m), 8.00-8.06 (2H, m), 7.84-7.92 (2H, m), 7.62 (1H, t, J=7.63 Hz), 7.43-7.50 (2H, m), 7.26-7.35 (4H, m), 7.19 (1H, t, J=7.32 Hz), 2.98 (3H, s), 1.78 (6H, s). LC-MS retention time: 1.77 min; m/z (MH+): 508. 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=12.82 min, purity=95%; Column. Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=11.20 min, purity=94%. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column. Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 mm, Rt=14.10 min, purity=95%; Column. Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=13.85 min, purity=95%.

Workup

  1. customwas purified by preparative reverse phase HPLC on a C18 column
  2. concentrationconcentrated

Sources & evidence

ORD record
ord-ca791a85cae24ca3b065580127a8b9f2
Source dataset
uspto-grants-2013_09
Patent number
US08536338B2

Reaction notes

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