A Practical and Efficient Synthesis of (3R,4S)-1-Benzyl-4-phenylpyrrolidine-3-carboxylic acid via an Aziridinium Ion Intermediate
2010
A practical and efficient synthesis of (3R,4S)-1-benzyl-4-phenylpyrrolidine-3-carboxylic acid (1), a key chiral building block for synthesis of biologically active compounds was established by utilizing a stereospecific and regioselective chlorination of in situ generated aziridinium ion, followed by a nitrile anion cyclization. Starting from commercially available (R)-styrene oxide and 3-(benzylamino)propionitrile, the four-step synthesis features a through process without purification of intermediates until isolation of crystalline 1. The robust, chromatography-free and reproducible synthesis of 1 achieved an 84% overall yield from (R)-styrene oxide. This highly efficient process was successfully demonstrated at pilot scale with 17 kg output of 1.
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