Reaction Steps
To a solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-chloropyrimidin-4-yl)oxy]cyclopentyl}methanol (15) (11.2 g, 0.0312 mol) and N,5-dichloro-2-methoxy-2,3-dihydro-1H-inden-1-amine (9.00 g, 0.0384 mol) in 1-butanol (99.2 mL, 1.09 mol), in a 350 mL sealable reaction vessel, was added triethylamine (21.7 mL, 0.156 mol). The vessel was sealed and then heated with stirring to 148° C. in an oil bath for 72 hours. The vessel was cooled to room temperature and the volatiles were removed in vacuo and Et2O (200 mL) was added to the resulting residue. The solids were homogenized by sonication, filtered, and rinsed with Et2O (50 mL). To the filtrate was added Celite® (100 mL) and the volatiles were removed in vacuo. The product adsorbed onto Celite® was added to a dry load cartridge and purified via column chromatography (400 g column, eluent 0-80% EtOAc:hexanes over 80 min) to afford {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]cyclopentyl}methanol (11.5 g, 71%). LCMS: (FA) ES+ 520; 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.24-7.13 (m, 3H), 5.75 (s, 1H), 5.56 (s, 1H), 5.45 (dt, J=2.9, 5.8, 2H), 4.57 (dd, J=5.9, 11.2, 1H), 4.19 (td, J=1.3, 4.7, 1H), 3.84-3.77 (m, 1H), 3.75-3.65 (m, 1H), 3.37 (s, 3H), 3.10 (d, J=16.6, 1H), 2.97 (dd, J=4.5, 16.7, 1H), 2.58 (dd, J=4.8, 7.4, 1H), 2.43-2.32 (m, 1H), 2.23-2.06 (m, 3H), 1.90 (dd, J=8.0, 14.2, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H).
