Triethylene glycol monomethyl ether → 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-methoxy-ethoxy)-ethoxy]-ethoxycarbonylmethyl ester

Participants

Reaction Steps

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, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (1 mL) to give a light brown suspension at room temperature. It was stirred for 30 min and the solution became clear. Triethylene glycol monomethyl ether (76.9 mg, 73.4 μL, 445 μmol) was added drop wise to the mixture. 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 ethyl acetate 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-methoxy-ethoxy)-ethoxy]-ethoxycarbonylmethyl ester as an off-white solid (65 mg, 35% yield). LCMS (ES+) m/z calcd. for C40H46Cl2F2N3O9 [(M+H)+]: 820. found: 820.

Provenance & Evidence