Ethanamine, 2,2,2-trifluoro- → 2-Fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid

Participants

Reaction Conditions

Reaction Steps

Sodium 2-methylbutan-2-olate (311 mg, 2.82 mmol), 5-(6-chloro-2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-2-fluorobenzoic acid (250 mg, 0.565 mmol), 2,2,2-trifluoroethanamine (280 mg, 2.82 mmol), Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (45 mg, 0.056 mmol) were combined, degassed, and taken up in dioxane (12 ml) at rt and then was heated to 90° C. for 1 h. The mixture was then diluted with EtOAc and washed with 1M HCl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with DCM to give 250 mg crude material which 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-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-((2,2,2-trifluoroethyl)amino)furo[2,3-b]pyridin-5-yl)benzoic acid (100 mg, 0.198 mmol, 35% yield) consistent by LCMS and NMR. LC-MS retention time: 1.74 min; m/z (MH+): 506. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 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 1 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% 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. 1H NMR (400 MHz, DMSO-d6) δ 13.34 (br. s, 1H), 8.38-8.29 (m, 1H), 7.98 (dd, J=8.8, 5.5 Hz, 2H), 7.89 (dd, J=7.0, 2.3 Hz, 1H), 7.70-7.62 (m, 2H), 7.51-7.43 (m, 1H), 7.34 (t, J=8.9 Hz, 2H), 6.72 (s, 1H), 4.23-4.10 (m, 2H), 2.80 (d, J=4.8 Hz, 3H).

Provenance & Evidence