Catalysis of Organic..

Gőbölös et al. 456. Highly Selective Preparation oftrans-4-Aminocyclohexane Carboxylic Acid fromcis-Isomer over Raney® Nickel CatalystAbstractSándor Gőbölös, Zoltán Banka, Zoltán Tóth, János Szammer andJózsef L. MargitfalviChemical Research Center, Institute of Surface Chemistry and Catalysis,H-1025 Budapest, Pusztaszeri út 59-67, Hungarygobolos@chemres.hu4-Amino-benzoicacid was hydrogenated to 4-aminocyclohexane carboxylic acidover different alumina supported 5 wt.% Ru and Rh catalysts Complete ringsaturation was achieved in 2 wt. % NaOH-H 2 O at 80-100 °C, 10 MPa H 2 , and 5 hhowever, the ratio of trans/cis stereo-isomers of the product was only between 1/3-1/1. Raw reaction mixture was further processed in the presence of a commercialRaney® nickel catalyst at 130°C, 100 bar H 2 for 5 h. In this alkali mediatedisomerization the trans/cis isomer ratio was 7/3. The cis isomer was isolated byfractional crystallization, and then reacted on Raney® nickel catalysts in 2%NaOH-H 2 O at 120-140°C, 1 MPa H 2 for 5 h to obtain the trans isomer with a yield of ca. 70%. The two-step synthesis resulted in trans-4-aminocyclohexane carboxylic acidwith a yield above 90%. Catalytic tests were performed in a high-throughput reactorsystem equipped with 16 mini autoclaves (SPR16 AMTEC GmbH, Germany).IntroductionRecent years, stereochemically pure drugs have increasingly dominated the globalpharmaceutical industry. The need for single isomers has fueled the development ofstereochemical reactions with the aim to synthesize compounds of desiredconfiguration, rather than mixtures of stereoisomers that must be separated later.Stereochemically pure amino acid derivatives containing N-terminal trans-4-alkylcyclohexanoyl fragment are reported as precursors of physiologically activeagents in the treatment of various diseases (cancer, osteoporosis). The hydrogenationof disubstituted aromatics, particularly amino benzoic acids to the correspondingcyclohexane carboxylic acids, has therefore attracted the interest of the industry (1).These compounds are used as key intermediates for the manufacture ofpharmaceuticals. It is noteworthy that trans-isomer of 4-aminocyclohexanecarboxylic acid esters are reported as the physiologically active agents. Trans-4-substituted cyclohexane carboxylic acids can be obtained by the hydrogenation of thecorresponding benzoic acid compounds followed by the isomerization of theresulting mixture of trans- and cis-isomers.Due to the absence of electron withdrawing groups the aromatic amines arehydrogenated with difficulty. Supported noble metal catalysts (Pd, Pt, Ru, Rh, Ir) areusually active at elevated temperature and pressure. The perhydrogenation ofaromatic amines is mainly accompanied by two side reactions, i.e. the