In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 150 mg, 152 μL, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethanol (43.0 mg, 222 μmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with 0-10% methanol in ethyl acetate over 20 min gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-methyl ester as an off-white solid (20 mg, 10% yield). LCMS (ES+) m/z calcd. for C41H48Cl2F2N4O9 [(M+H)+]: 849. found: 849.
