Sodium Carbonate → 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 ((S)-1-allyloxycarbonyl-5-tert-butoxycarbonylamino-pentylcarbamoyl)-methyl ester

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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, 144 mg, 213 μmol), HATU (106 mg, 278 μmol), and Hunig's base (69.0 mg, 93.2 μL, 534 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 2 h. Then the mixture of (S)-allyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate hydrochloride (103 mg, 320 μmol) and Hunig's base (55.2 mg, 74.6 μL, 427 μmol) in dry tetrahydrofuran (2 mL) was added. After 20 min, the reaction mixture was purified with high-performance liquid chromatography (C18, eluting with a gradient of 60-80% acetonitrile in water over 10 min) to isolate the desired fractions, which were 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 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 ((S)-1-allyloxycarbonyl-5-tert-butoxycarbonylamino-pentylcarbamoyl)-methyl ester (16 mg, 8% yield). LCMS (ES+) m/z calcd. for C47H56Cl2F2N5O9 [(M+H)+]: 942. found: 942.

Provenance & Evidence