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      https://www.ias.ac.in/article/fulltext/jcsc/127/11/1977-1991

    • Keywords

       

      Mild demethylation; crystal structure; entacapone; Z-isomer; carbon, proton NMR; E, Z geometry.

    • 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 NO2 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 $_{}^{13}$C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue.

    • Author Affiliations

       

      Attimogae Shivamurthy Harisha1 2 Suresh Parameshwar Nayak2 Pavan M S3 Shridhara K1 Sundarraja Rao K1 Rajendra K4 Koteppa Pari4 Sivaramkrishnan H4 Guru Row T N3 Kuppuswamy Nagarajan1

      1. Alkem Laboratories Ltd., R & D Centre, Industrial Estate, 4th Phase, Bangalore 560 058, India
      2. Department of Chemistry, Mangalore University, Mangalagangothri, Mangalore 574 199, India
      3. Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India
      4. Piramal Life Sciences, Piramal Health Care, Mumbai, Maharashtra 400 030, India
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    • Supplementary Material

       
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