[Synthesis]
Sodium hydride (60% dispersed in mineral oil, 6.63 g, 166 mmol) was slowly added to a solution of 2-aminoethanol (10.0 mL, 166 mmol) in dioxane (150 mL) at room temperature and under nitrogen atmosphere. After stirring for 10 minutes, 2-chloropyridine (15.6 mL, 166 mmol) was added and the reaction mixture was subsequently heated to reflux. After maintaining reflux stirring for 14 hours, it was cooled to room temperature and the reaction mixture was diluted with water (100 mL) and dichloromethane (200 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 100 mL). The organic phases were combined, washed with brine (200 mL), dried over magnesium sulfate, filtered and concentrated to give an orange colored oil. Purification by rapid column chromatography on silica gel using a 50% (80:18:2 CHCl3/MeOH/concentrated NH4OH) solution of dichloromethane as eluent gave 2-(2-pyridinyloxy)ethylamine as a yellow oil (17.9 g, 78%).1H NMR (CDCl3) δ 8.09-8.15 (m, 1H), 7.53-7.56 (m , 1H), 6.80-6.85 (m, 1H), 6.70-6.75 (m, 1H), 4.27-4.31 (m, 2H), 3.06-3.10 (m, 2H); MS (ES): m/z 139 (M + H). 2-(Pyridin-2-yloxy)ethylamine (500 mg, 3.62 mmol) was added to a solution of 2-thioacetyl-isoindole-1,3-dione (743 mg, 3.62 mmol) in CHCl3 (18 mL) at 0 °C. After stirring for 15 min, the reaction solution was concentrated, redissolved in ethyl acetate (25 mL), filtered and concentrated again. Purification by silica gel fast column chromatography (SiO2, 1:1 EtOAc/hexane) afforded N-(2-(pyridin-2-yloxy)ethyl)thioacetamide (350 mg, 49%) as a beige/pink solid.1H NMR (CDCl3) δ 8.79 (br s, 1H), 8.10-8.08 (m, 1H), 7.58-7.65 (m , 1H), 6.92-7.00 (m, 1H), 6.76-6.82 (m, 1H), 4.57-4.65 (m, 2H), 3.98-4.05 (m, 2H), 2.56 (s, 3H). A solution of N-(2-(pyridin-2-yloxy)ethyl)thioacetamide (50 mg, 0.25 mmol) and methyl methyl trifluoromethanesulfonate (0.028 mL, 0.25 mmol) was mixed in a solution of dichloromethane (1.5 mL), stirred at room temperature for 10 min and concentrated to dryness. To the residue was added a solution of pyridine (3 mL) of biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (95 mg, 0.275 mmol), and after stirring for 18 hours at room temperature, the pyridine was removed in vacuo. Purification by silica gel fast column chromatography (SiO2, 1:1 EtOAc/hexane to 80:18:2 CHCl3/MeOH/concentrated NH4OH) afforded 2-(2-pyridinyloxy)ethanamine (21 mg, 17%) as a white solid.1H NMR (CDCl3) δ 7.88-7.95 (m, 2H), 7.65-7.74 (m, 2H ), 7.60-7.70 (m, 2H), 7.40-7.53 (m, 3H), 7.24-7.26 (m, 2H), 7.02-7.99 (m, 1H), 6.62-6.70 (m, 1H), 5.35-5.42 (m, 1H), 4.55-4.62 (m, 1H), 3.78-3.90 (m, 4H) 3.30-3.43 (m, 1H), 2.92-3.08 (m, 1H), 2.02 (s, 3H); MS (ES): m/z 507 (M + H). |