反应详情

To a 25 mL RBF was added 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (20.5 mg, 0.049 mmol) in DMF (1 mL) along with N-ethyl-N-isopropylpropan-2-amine (0.042 mL, 0.243 mmol), 1-(1,8-naphthyridin-2-yl)cyclopropanamine, HCl (20.17 mg, 0.073 mmol) and finally 5 eq. of HATU, 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (74.0 mg, 0.195 mmol). The flask was sealed with a septa, placed under nitrogen and the mixture stirred overnight at room temperature. The crude product was purified using a Shimadzu preparative HPLC employing methanol/water/trifluoroacetic acid where solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with a Phenomenex Luna 10 μm C18 30×100 mm column at a gradient of 40-100% B and a flow rate of 40 mL/min. over 12 minutes with a 13 minute hold. The solvent was removed giving 33.3 mgs (96% yield) of 5-(5-(1-(1,8-naphthyridin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA as a yellow powder. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC purity was then confirmed with an orthogonal solvent system and column using a Shimadzu analytical LC with a Xbridge Phenyl C18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 1.40-1.49 (m, 2H), 1.95 (m, 2 H), 2.25 (s, 3 H), 2.88 (m, 3 H), 7.17-7.29 (m, 3 H), 7.37-7.47 (m, 2 H), 7.50 (dd, J=8.03, 4.52 Hz, 1 H), 7.74 (d, J=8.53 Hz, 2 H), 7.85-7.97 (m, 2 H), 8.03-8.09 (m, 2 H), 8.18 (d, J=8.53 Hz, 1 H), 8.33-8.39 (m, 1 H), 8.74 (s, 1 H), 9.05 (dd, J=4.27, 1.76 Hz, 1 H). LCMS rt=2.475 min, m/z 589.3 (M+H), 95.7% purity. HPLC rt=6.728 min. (Sunfire C18), 100% purity and 11.261 min. (XBridge C18), 99.0% purity.

1. customThe flask was sealed with a septa
2. customThe crude product was purified
3. waita flow rate of 40 mL/min. over 12 minutes with a 13 minute hold
4. customThe solvent was removed