Cumylamine → 2-(4-Fluorophenyl)-n-methyl-6-(methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Temperature

90 °C

Step 1: DIEA (134 μL, 0.765 mmol) was added to Pd(Ph3P)4 (30 mg, 0.025 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-(methylsulfonyl)methylsulfonamido)benzofuran-5-yl trifluoromethanesulfonate (150 mg, 0.255 mmol), 3-(ethoxycarbonyl)phenylboronic acid (74 mg, 0.382 mmol). Dioxane (5 mL) and water (1 mL) was added at rt. The reaction was degassed 3× and heated to 90° C. overnight. It was allowed to cool and left to stir for 3 days at rt. Step 2: The mixture was concentrated and diluted with EtOH (5 mL) and treated with excess 1N NaOH (˜1 mL) and allowed to stir at rt overnight to give the meta-acid. The mixture was diluted with EtOAc and washed with 1M HCl, and 1M HCl. The organic phase was dried over Na2SO4, filtered and concentrated. Step 3: The crude residue was diluted with DMF (5 mL) and treated with HATU (145 mg, 0.382 mmol), 2-phenylpropan-2-amine (52 mg, 0.382 mmol) and DIEA (134 μL, 0.765 mmol) and allowed to stir at rt overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered gradient, and concentrated. The isolated titled compound was re-purified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.2 50% EtOAc/hexanes, fraction collection at λ=254 nm) to give the titled compound (7 mg, 4%). 1H NMR (500 MHz, CD3OD) δ ppm 7.94-8.01 (2H, m), 7.92 (1H, s), 7.83 (1H, d, J=7.63 Hz), 7.77 (1H, s), 7.63-7.68 (2H, m), 7.59 (1H, t, J=7.63 Hz), 7.46 (2H, d, J=7.32 Hz), 7.24-7.32 (4H, m), 7.18 (1H, t, J=7.32 Hz), 2.94 (3H, s), 2.88 (3H, s), 1.77 (6H, s). LC-MS retention time: 2.25 min; m/z (MH+): 600. 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 5% acetonitrile/95% H2O/0.1% TFA and solvent B was 5% H2O/95% acetonitrile/0.1% TFA. 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 μm, Rt=12.87 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=11.97 min, purity=98%.

1. customThe reaction was degassed 3×
2. temperatureto cool
3. waitleft
4. concentrationStep 2: The mixture was concentrated
5. additiondiluted with EtOH (5 mL)
6. additiontreated with excess 1N NaOH (˜1 mL)
7. stirringto stir at rt overnight
8. customto give the meta-acid
9. washwashed with 1M HCl, and 1M HCl
10. dry with materialThe organic phase was dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. additionStep 3: The crude residue was diluted with DMF (5 mL)
14. stirringto stir at rt overnight
15. concentrationThe mixture was concentrated
16. custompurified by preparative reverse phase HPLC on a C18 column
17. concentrationconcentrated

ORD record

ord-44e9050b96fc4166a29c835f0b5ebe7f

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07994171B2