Diisopropylethylamine → Methyl 5-(2-chloro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate

DIEA (142 μL, 0.810 mmol) was added to a stirring solution of 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (84 mg, 0.405 mmol), 4-chloro-3-(2-(4-fluorophenyl)-3-(methoxycarbonyl)furo[2,3-b]pyridin-5-yl)benzoic acid (115 mg, 0.270 mmol) and HATU (154 mg, 0.405 mmol) in DMF (2.7 mL) at room temperature. It was allowed to stir for 1 hour. The mixture was diluted with ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give crude methyl 5-(2-chloro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylate. The crude residue was diluted with MeOH (4 mL) and treated with NaOH (810 μL, 0.810 mmol) in H2O; the reaction was heated to 60° C. and allowed to stir for 1 hr. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give crude 5-(2-chloro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid. The crude residue was diluted with DMF (2 mL) and treated with HATU (154 mg, 0.405 mmol), methanamine (675 μL, 1.35 mmol, 2 M in THF) in THF, followed by DIEA (142 μL, 0.810 mmol). The reaction was allowed to stir at room temperature for 1 hour. The mixture was concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (1H, s), 8.52 (1H, d, J=4.77 Hz), 8.50 (1H, d, J=2.01 Hz), 8.44 (1H, d, J=4.77 Hz), 8.23 (1H, d, J=2.01 Hz), 8.12 (1H, d, J=2.01 Hz), 7.97-8.09 (3H, m), 7.78 (1H, d, J=8.28 Hz), 7.67 (1H, td, J=7.72, 1.88 Hz), 7.39-7.47 (2H, m), 7.36 (1H, d, J=8.03 Hz), 7.15 (1H, dd, J=7.40, 4.89 Hz), 2.83 (3H, d, J=4.52 Hz), 1.50-1.60 (2H, m), 1.22-1.32 (2H, m). LC-MS retention time: 1.31 min; m/z (MH+): 541. 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=9.66 mM, purity=98%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=9.69 min, purity=98%.

1. washwashed
2. dry with materialThe organic phase was dried over Na2SO4
3. filtrationfiltered
4. concentrationconcentrated

ORD record

ord-42890a3585bf4b3b9bc255a22135b798

Source dataset

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08198449B2