A new synthesis of Entacapone and report on related studies

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-(3hydroxy-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 13 C spectra. Preliminary studies reveal in vitro activity for some compounds against tuberculosis (TB) and dengue.

Parkinson’s Disease: Advances in Treatment and the Syntheses of Various Classes of Pharmaceutical Drug Substances

“…Ring opening of aziridine (101) with PhMgCl using CuBr•SMe 2 at low temperature afforded the pymisyl-protected amphetamine (R)-102. The final three steps were performed as follows: alkylation with propargyl bromide (92), followed by deprotection with 2-mercaptoacetic acid to give secondary amine (103). The methyl group on the nitrogen was introduced by reductive alkylation to give selegiline (93) as free base in 86% yield over three steps.…”

“…In addition, it is also formulated as Stalevo drug product (Orian Pharma, Finland), containing levodopa ( 3 ), carbidopa ( 14 ), and entacapone ( 63 ). Several approaches have been reported for the preparation of entacapone ( 63 ). − The first synthesis, as shown in Scheme , was based on the condensation of 3,4-dihydroxy-5-nitrobenzaldehyde ( 61a ) with an active methylene substrate, such as 2-cyano- N , N -diethyl­acetamide ( 62 ), under acidic conditions to afford entacapone ( 63 ). , However, approximately 30% of the corresponding Z -Isomer ( 64 ) was also produced in this reaction. The pure E -isomer, entacapone ( 63 ), was later isolated (Scheme ) by treatment of the E / Z mixture ( 63 and 64 ) under acidic conditions (HCO 2 H or CH 3 CO 2 H and HCl) .…”

“…The intermediate 66 was converted to entacapone ( 63 ) by nitration and demethylation . Recently, another approach was reported based on milder amine-mediated demethylation …”

Synthesis, crystal structure and spectroscopic and Hirshfeld surface analysis of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde

“…Entacapone (II), prevents metabolism and inactivation of levodopa and carbidopa, which allows better bio-availability of these compounds. Several synthetic routes for the synthesis of entacapone have been reported (Bartra Sanmarti et al, 2008;Harisha et al, 2015;Jasti et al, 2005;Cziá ky, 2006); however, only a few intermediates/starting materials have been characterized crystallographically (Keng et al, 2011;Babu et al, 2009;Vladimirova et al, 2016). Knowledge of the crystal structure is beneficial for understanding the properties of the starting materials as well as being the gold standard for the identification of starting materials.…”

Recent Progress in the Synthesis of Drugs and Bioactive Molecules Incorporating Nitro(het)arene Core

“…To date, several approaches to entacapone have been described. Harisha et al described its synthesis from 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide using amine-mediated demethylation [23,24]. An industrial method for the synthesis of entacapone via a Knoevenagel reaction of 2-cyano-3-(3-methoxy 4-hydroxy-5-nitrophenyl)acrylic acid was reported by Guo [25].…”