Highly Enantioselective Catalytic Asymmetric Synthesis of a (R)-Sibutramin Precursor

Authors

  • Ulrich Berens BASF SE, GCI/P-M 311, D-67056 Ludwigshafen am Rhein, Germany;, Email: ulrich.berens@basf.com
  • Andreas Hafner Ciba Inc. (now part of BASF), Performance Chemicals Research, Klybeckstrasse 141, CH-4002 Basel;, Email: andreas.hafner@ciba.com
  • Oliver Dosenbach Ciba Inc. (now part of BASF), Performance Chemicals Research, Klybeckstrasse 141, CH-4002 Basel
  • Tanja Tritschler Ciba Inc. (now part of BASF), Performance Chemicals Research, Klybeckstrasse 141, CH-4002 Basel
  • Franz Schwarzenbach Ciba Inc. (now part of BASF), Performance Chemicals Research, Klybeckstrasse 141, CH-4002 Basel
  • Hans-Jörg Kirner Ciba Inc. (now part of BASF), Performance Chemicals Research, Klybeckstrasse 141, CH-4002 Basel
  • Christophe Malan Solvias AG, Klybeckstrasse 191, CH-4002 Basel
  • Oanh Mai-Huynh Solvias AG, Klybeckstrasse 191, CH-4002 Basel

DOI:

https://doi.org/10.2533/chimia.2010.59

Keywords:

Catalytic asymmetric hydrogenation, Enantioselective synthesis, Sibutramine

Abstract

The first highly enantioselective, catalytic asymmetric synthesis of di-des-methylsibutramine 3 is described. Dienamide 10, prepared by acetic acid anhydride quenching of the condensation product of nitrile 4 with a methallyl magnesium chloride, proved to be an excellent substrate for ruthenium-catalyzed asymmetric hydrogenation with atropisomeric diphosphine ligands. Hydrogenation with a ruthenium/(R)- MeOBiPheP catalyst at S/C = 500, gave the chiral amide (R)-9 in 98.5% ee in almost quantitative yield. After acidic amide hydrolysis the desired amine (R)-3 was obtained without erosion of enantioselectivity. It is anticipated that the overall process will be amenable to large-scale production.

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Published

2010-02-26

How to Cite

[1]
U. Berens, A. Hafner, O. Dosenbach, T. Tritschler, F. Schwarzenbach, H.-J. Kirner, C. Malan, O. Mai-Huynh, Chimia 2010, 64, 59, DOI: 10.2533/chimia.2010.59.