Acetic Acid → Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-methylene-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate

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Reaction Conditions

Reaction Steps

To a solution of di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-(dimethylaminomethylene)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (620.4 g, 1.33 mol) in dry tetrahydrofuran (12 L), triethylamine (277.3 ml, 1.99 mol) is added at room temperature under nitrogen. The mixture is cooled to −47° C. and diisobutylaluminum hydride (1M in hexane, 2.06 L, 2.06 mol) is added dropwise over 2 hours. The resulting mixture is stirred at −47° C. After 1 hour 15 minutes, acetic acid (118 ml, 2.06 mol) is dropwise added at −47° C., warmed to room temperature, and then stirred overnight. Add 20% H3PO4 in water until pH=2. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×1.7 L). The combined organic phases are washed successively with 10% aqueous HCl (1.5 L), water (1.5 L), and brine (1.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a solid. The resulting solid is triturated with water (3.2 L), collected by filtration, and then dried to yield the title compound (558.2 g, yield 99%). HPLC-MS: 97.4%.

Provenance & Evidence