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A new synthesis of Entacapone and report on related studies

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Abstract

A new synthesis of the catechol-O-methyltransferase (COMT) inhibitor, entacapone (E-isomer) has been achieved under mild conditions by amine-mediated demethylation of the precursor 2-Cyano-3-(3- hydroxy-4-methoxy-5-nitrophenyl) prop-2-eneamide, wherein the methoxyl group adjacent to a nitro group gets demethylated under nucleophilic attack. Similar demethylation was achieved on ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate, 2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N,N-diethylprop-2-enamide, ethyl 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl) prop-2-enoate and ethyl 2-cyano-3-(4-methoxy-3-nitrophenyl) prop-2-enoate. The scope of demethylation has been studied. Analogues of ethyl 2-cyano-3-(3, 4-dimethoxy-5-nitrophenyl) prop-2-enoate wherein a methoxyl group is not adjacent to a NO 2 group are unaffected and phenolic derivatives yield the amine salts. Entacapone has been converted to salts with organic bases. The crystal structure of the isomer of entacapone (Z-isomer), a significant human metabolite of E-isomer has been established. NMR methods for deriving E and Z geometry and other similar molecules have been successfully established, mainly by studying the proton coupled 13C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue.

A new synthesis of entacapone 1 of a designed precursor under very mild conditions is reported. Crystal structure of its Z isomer, NMR methods for establishment of E and Z geometry of benzylidene derivatives are also reported.

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Acknowledgements

We thank Alkem laboratories of India for providing research facilities and OSDD CSIR for in vitro anti TB results.

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Authors and Affiliations

  1. Alkem Laboratories Ltd., R & D Centre, Industrial Estate, 4th Phase, Bangalore, 560 058, India

    ATTIMOGAE SHIVAMURTHY HARISHA, SHRIDHARA K, SUNDARRAJA RAO K & KUPPUSWAMY NAGARAJAN

  2. Department of Chemistry, Mangalore University, Mangalagangothri, Mangalore, 574 199, India

    ATTIMOGAE SHIVAMURTHY HARISHA & SURESH PARAMESHWAR NAYAK

  3. Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, 560 012, India

    PAVAN M S & GURU ROW T N

  4. Piramal Life Sciences, Piramal Health Care, Mumbai, Maharashtra, 400 030, India

    RAJENDRA K, KOTEPPA PARI & SIVARAMKRISHNAN H

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  1. ATTIMOGAE SHIVAMURTHY HARISHA
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  2. SURESH PARAMESHWAR NAYAK
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Correspondence to GURU ROW T N or KUPPUSWAMY NAGARAJAN.

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Supplementary Information

1H, 13C NMR, HSQC and 2D 1H-1H NOESY spectra for all new compounds are available. available at www.ias.ac.in/chemsci. Crystallographic data 2 (CCDC1027892), 23 (CCDC1027891), 25 (CCDC10 27893), 30 (CCDC1027894) and 32 (1027895) have been deposited at the Cambridge Crystallographic Database Centre and are available on request (http:www.ccdc.cam.ac.uk).

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HARISHA, A.S., NAYAK, S.P., S, P.M. et al. A new synthesis of Entacapone and report on related studies. J Chem Sci 127, 1977–1991 (2015). https://doi.org/10.1007/s12039-015-0961-4

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