Reaction Steps
A mixture of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (253 mg, 0.476 mmol), trimethylboroxine (0.07 mL, 0.502 mmol), PdCl2(dppf)-CH2Cl2 adduct (19 mg, 0.023 mmol), and K2CO3 (197 mg, 1.425 mmol) in 1,4-Dioxane (2.5 mL) and Water (0.5 mL) was degassed with Nitrogen for 10 minutes. The vial was then capped and the mixture was stirred at 100° C. for 15 hr. LCMS showed a mixture of starting material (20%), desired product (36%), and the deiodo byproduct (40%). The mixture was filtered, rinsing with EtOAc (about 35 mL). The filtrate was washed with water (1×25 mL) and brine (1×25 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The recovery was fairly low (<200 mg), so the aqueous phases were combined and extracted with methylene chloride (3×25 mL), and the extracts were dried (Na2SO4), filtered, combined with the EtOAc layer from the previous work-up, and concentrated in vacuo (total mass>200 mg). The residue was purified by reverse phase HPLC (Gilson, C18, 25% to 45% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were concentrated, taken up in MeOH, and passed through a PL-HCO3 cartridge. The filtrate was concentrated in vacuo, triturated with ether, and dried in the vacuum oven overnight. NMR indicated that the compound was still a TFA salt, and it showed an impurity The solid was taken up in DCM (5 mL) and poured into saturated aqueous NaHCO3 (5 mL). The organic layer was collected and the aqueous layer was extracted with methylene chloride (2×5 mL). The organic phases were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was repurified by flash chromatography (Analogix, 12 g SiO2, 50%-100% EtOAc in hexanes gradient over 7.5 minutes, EtOAc for 2.5 minutes, then 0-5% MeOH in EtOAc gradient over 10 minutes) to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methylfuro[3,2-c]pyridin-4-amine (29 mg, 0.066 mmol, 13.79% yield) as a white solid. LC/MS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.28 (t, J=8.21 Hz, 2H), 3.96 (s, 2H), 4.30 (t, J=8.46 Hz, 2H), 5.31 (s, 2H), 7.14-7.34 (m, 4H), 7.41 (s, 1H), 7.69 (s, 1H), 7.95 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).
