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Synthesis 2012(2): 241-246  
DOI: 10.1055/s-0031-1289646
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

First Enantioselective Synthesis of Aptazepine

Piotr Roszkowskia, Jan K. Maurinb,c, Zbigniew Czarnocki*a
a Faculty of Chemistry, Warsaw University, Pasteura 1, 02-093, Warsaw, Poland
Fax: +48(22)8225996; e-Mail: czarnoz@chem.uw.edu.pl;
b National Medicines Institute, Chemska 30/34, 00-725 Warsaw, Poland
c National Centre for Nuclear Research, 05-400 Otwock-Œwierk, Poland
Further Information

Publication History

Received 6 September 2011
Publication Date:
14 December 2011 (online)

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Abstract

Aptazepine (2-methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine), a potent tetracyclic antidepressant, was synthesized in both its enantiopure forms by using an asymmetric transfer hydrogenation in a key step. Reduction of the prochiral imine 7 gave the products (R)- and (S)-8 in 63% and 61% ee, respectively, but a single crystallization improved the enantiomeric purity to 98% ee. The final (R)- and (S)-aptazepines were prepared in four subsequent steps. The absolute configuration of intermediate (S)-8 was determined by X-ray crystallography.

Key words

asymmetric synthesis - asymmetric catalysis - total synthesis - reductions - heterocycles

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