Reaction Steps
To a solution of {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester (0.0745 g, 0.1220 mmol) in dimethylformamide (2.0 mL) was added sodium hydride (61% suspension in mineral oil, 0.0216 g, 0.5499 mmol). Deprotonation was allowed to occur over 3 minutes while stirring under inert atmosphere. 4-Bromo-2-fluorobenzyl bromide (0.1559 g, 0.5819 mmol) was added to the anion solution. The mixture was stirred an additional 10 minutes, then quenched with water (5.0 mL). The reaction solution was extracted with ethyl acetate (15 mL), and the organic phase was washed with brine (2×10 mL), dried over magnesium sulfate, filtered, and evaporated to dryness. Purification of the residue on silica gel eluting first with ethyl acetate/methylene chloride/hexane (1:1:2, v/v/v) and then with ethyl acetate and methylene chloride (1:1, v/v) afforded (4-bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester as a colorless oil (0.0917 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.59. 1H NMR (300 MHz, CDCl3) δ 8.47-8.51 (m, 2H), 7.61 (br s, 1H), 7.07-7.32 (m, 7H), 4.89 (s, 2H), 4.78 (s, 2H), 4.77-4.92 (m partially obscured, 1H), 3.68-3.83 (br m, 1H), 3.09-3.24 (br, m, 1H), 2.70-2.97 (m, 2H), 1.45 (s, 18H), 1.44 (s, 9H), 1.30-2.04 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.0, 160.4 (d, 250.8), 154.0, 152.7, 148.5, 144.9, 139.0, 138.7, 132.2, 131.9, 130.7, 129.7, 127.9 (d, 3.4), 125.8, 125.7, 125.3, 123.8 (d, 14.5), 121.8 (d, 9.7), 119.3 (d, 24.8), 82.5, 82.2, 49.5, 46.9, 42.6, 32.8 (br), 28.4, 28.2, 28.0; 19F NMR (282 MHz, CDCl3) δ-114.9; MS (CI) m/z 797 (M+H).
