Reaction Steps
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (2.00 g, 4 mmol) in anhydrous DMF (12 ml) was treated with HBTU (2.12 g, 5.6 mmol), (S)-1-N-boc-β-proline (0.95 g, 4.4 mmol) and diisopropylethyl amine (2.09 mL, 12 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (200 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to a tan solid, 2.43 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford (S)-tert-butyl 3-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (34) as a tan solid, 1.68 g (60%), that had one peak by LC/MS (+ESI) m/z 697 (M++1) and 711 (M++1) (both ions in the same LC peak), and was pure by 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 1H), 7.48 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.93 (m, 1H), 6.81 (m, 2H), 6.50 (m, 1H), 5.67 (s, 2H), 5.28 (s, 2H), 4.22 (s, 3H), 3.81 (m, 1H), 3.50 (m, 4H), 3.25 (m, 4H), 2.91 (m, 1H), 2.08 (m, 3H), 1.44 (s, 9H). 13CNMR (100 MHz, CDCl3) δ 168.2, 156.8, 156.1, 154.3, 149.6, 149.0, 138.4, 138.1, 137.0, 136.5, 135.8, 135.4, 130.1, 129.8, 122.6, 121.7, 120.8, 107.4, 103.1, 79.3, 67.1, 64.3, 60.4, 57.5, 48.6, 47.7, 41.9, 35.9, 30.7, 28.5, 21.0, 19.1, 14.2, 13.7. LN-15495-57.
