反应详情

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, 133 mg, 197 μmol), HATU (75.0 mg, 197 μmol) and Hunig's base (51.0 mg, 68.9 μL, 394 μmol) were combined with dry tetrahydrofuran (1 mL) to give an off-white suspension at room temperature. The mixture was stirred for 30 min and a solution of (S)-dibenzyl 2-aminopentanedioate hydrochloride (108 mg, 296 μmol) and Hunig's base (2 eq.) in dry tetrahydrofuran (1 mL) was added. After 1 h, the reaction mix was directly purified with reverse phase high-performance liquid chromatography to isolate the desired fraction, which was neutralized with saturated aqueous sodium carbonate solution, extracted with methylene chloride. The methylene chloride layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-2-[2-(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-benzoyloxy)-acetylamino]-pentanedioic acid dibenzyl ester (63 mg, 33% yield). LCMS (ES+) m/z calcd. for C52H51Cl2F2N4O9 [(M+H)+]: 983. found: 983.

1. customto give an off-white suspension at room temperature
2. waitAfter 1 h
3. additionthe reaction mix
4. customwas directly purified with reverse phase high-performance liquid chromatography
5. customto isolate the desired fraction, which
6. extractionextracted with methylene chloride
7. washThe methylene chloride layer was washed with water and brine
8. dry with materialdried over anhydrous sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated