Reaktion #72371

Reaktionsgleichung

Sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate

Cs2CO3

4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid

5-bromo-2-(4-fluorophenyl)-N-methylfuro[3,2-b]pyridine-3-carboxamide

→

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[3,2-b]pyridin-5-yl)-4-methylbenzoic acid

Lösungsmittel

DMF

Water

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeIt was degassed
2. 2
   workup.ADDITIONThe mixture was diluted with ethyl acetate
3. 3
   Waschenwashed with 1M HCl
4. 4
   TrocknenThe organic phase was dried over Na2SO4
5. 5
   Filtrationfiltered
6. 6
   Einengenconcentrated

Vorschrift

Sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (18 mg, 0.034 mmol), PdOAc2 (3.9 mg, 0.017 mmol), Cs2CO3 (168 mg, 0.516 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (68 mg, 0.26 mmol) was added to a stirring solution of 5-bromo-2-(4-fluorophenyl)-N-methylfuro[3,2-b]pyridine-3-carboxamide (60 mg, 0.17 mmol) in DMF (3.1 mL) and Water (310 μL). It was degassed and heated to 60° C. and allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[3,2-b]pyridin-5-yl)-4-methylbenzoic acid crude. The residue was diluted with DMF (3.1 mL) and treated with HATU (98 mg, 0.26 mmol), 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (54 mg, 0.260 mmol), followed by DIEA (150 μL, 0.859 mmol) at room temperature. The reaction was allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M NaOH, and sat NaCl. The organic phase was dried over Na2SO4, filtered, concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give 2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)furo[3,2-b]pyridine-3-carboxamide (27 mg, 0.049 mmol, 29% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, s), 8.98-9.07 (1H, m), 8.45 (1H, d, J=4.02 Hz), 8.25-8.34 (3H, m), 8.10 (1H, d, J=1.76 Hz), 7.94 (1H, dd, J=8.03, 1.76 Hz), 7.73 (1H, d, J=8.53 Hz), 7.67 (1H, td, J=7.65, 1.76 Hz), 7.50 (1H, d, J=7.78 Hz), 7.39-7.46 (2H, m), 7.35 (1H, d, J=8.03 Hz), 7.14 (1H, dd, J=6.53, 4.77 Hz), 2.91 (3H, d, J=4.77 Hz), 2.45 (3H, s), 1.52-1.59 (2H, m), 1.23-1.31 (2H, m). LC-MS retention time: 1.46 min; m/z (MH+): 521. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 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 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 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=13.35 min, purity=98%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=12.68 min, purity=98%.

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