Tetrahydrofuran → 7-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine

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A suspension of phenylmethyl[2-(4-amino-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-7-yl)ethyl]carbamate (91 mg, 0.156 mmol) and Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (27 mg, 0.013 mmol) in Ethanol (1 mL) and Tetrahydrofuran (THF) (5 mL) was stirred under an atmosphere of hydrogen for 3 hours. LCMS showed no conversion, and it appeared that the starting material was not very soluble in the reaction mixture. Some N,N-Dimethylformamide (DMF) (2 mL) was added along with another portion of Pd/C (10 wt. % dry basis), wet (ca. 50% water), Degussa type E101 NE/W (65 mg, 0.031 mmol), and the mixture was stirred under an atmosphere of hydrogen for another 19 hours. LCMS showed a mixture of product and a byproduct. The mixture was filtered and the filtrate was concentrated in vacuo. An attempt was made to convert the byproduct to the desired product by taking the mixture up in MeOH (ca. 10 mL), adding 2 M HCl (ca. 1 mL), and stirring at room temperature for 5 hours. No reaction was observed, so it was heated to 50° C. for another 16 hours. HPLC still showed no conversion, so the mixture was concentrated in vacuo. The residue was taken up in MeOH (1.5 mL) and purified by reverse phase HPLC (Gilson, C18, 20% to 27% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were concentrated in vacuo and azeotroped with acetonitrile three times. The residue was then taken up in DCM and passed through a Varian PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was then concentrated in vacuo and dried in the vacuum oven overnight to give the free base of 7-(2-aminoethyl)-3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (18 mg, 24.41% yield) as a white solid. LC/MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d 1.53 (br. s., 2H), 2.72-2.79 (m, 2H), 2.79-2.86 (m, 2H), 3.28 (t, J=8.34 Hz, 2H), 3.96 (s, 2H), 4.30 (t, J=8.59 Hz, 2H), 5.33 (s, 2H), 7.14-7.33 (m, 4H), 7.41 (s, 1H), 7.69 (s, 1H), 7.93 (s, 1H), 8.12 (d, J=8.34 Hz, 1H).

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