Synthesis of enantiopure (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid—a key intermediate for the preparation of Aliskiren |
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Authors: | Natalia Andrushko Vasyl Andrushko Gerd König |
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Affiliation: | a Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany b Ratiopharm Schweiz AG, Pelikanweg 2, 4054 Basel, Switzerland c Ratiopharm GmbH, Graf-Arco-Str. 3, 89070 Ulm, Germany d Institut für Chemie der Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany |
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Abstract: | The enantioselective hydrogenation of (E)-2-(4-methoxy-3-(3-methoxypropoxy)-benzylidene)-3-methylbutanoic acid (1) to (R)-2-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-3-methylbutanoic acid (2)—a key intermediate in the synthesis of the pharmacologically important renin inhibitor Aliskiren—is described. The stereochemistry of the catalytic transformation has been studied using a number of homogeneous chiral Rh(I) and Ru(II) complexes bearing ferrocene-based phosphine ligands. The highest enantioselectivity for the homogeneous hydrogenation of 1 (up to 95% ee) was achieved with a Rh(NBD)2]BF4 pre-catalyst (substrate/catalyst ratio 100:1, 10 bar H2, 40 °C, in MeOH). To bring the enantioselectivity to perfection an effective method for the isolation of the enantiopure carboxylic acid is suggested likewise. |
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