A new synthesis of Entacapone and report on related studies

Journal of Chemical Sciences

Koteppa Pari³  Suresh Parameshwar Nayak²  Pavan M S⁴  Sundarraja Rao K¹  Kuppuswamy Nagarajan1¹  Sivaramkrishnan H³  Rajendra K³  Guru Row T N3⁴  Attimogae Shivamurthy Harisha1¹  Shridhara K¹ 

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

关键词: Mild demethylation;    crystal structure;    entacapone;    Z-isomer;    carbon;    proton NMR;    E;    Z geometry.;   

DOI  :  

来源: Indian Academy of Sciences

【 摘 要 】

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 13C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue.

【 授权许可】

Unknown