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Combined Synthetic and NMR-based approach in Etodolac preparation


Car, Željka; Biljan, Ivana; Ribić, Rosana; Habinovec, Iva; Galić, Nives; Meštrović, Ernest; Tomić, Srđanka; Novak, Predrag
Combined Synthetic and NMR-based approach in Etodolac preparation // Programme & Book of Abstract, Pharma NMR Conference, Application of NMR Spectroscopy in Pharmaceutical Industry / Novak, Predrag ; Tomišić, Vladislav ; Bregović, Nikola (ur.).
Zagreb: IAPC, 2015. str. 22-22 (poster, domaća recenzija, sažetak, znanstveni)


Naslov
Combined Synthetic and NMR-based approach in Etodolac preparation

Autori
Car, Željka ; Biljan, Ivana ; Ribić, Rosana ; Habinovec, Iva ; Galić, Nives ; Meštrović, Ernest ; Tomić, Srđanka ; Novak, Predrag

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Programme & Book of Abstract, Pharma NMR Conference, Application of NMR Spectroscopy in Pharmaceutical Industry / Novak, Predrag ; Tomišić, Vladislav ; Bregović, Nikola - Zagreb : IAPC, 2015, 22-22

Skup
Pharma NMR Conference, Application of NMR Spectroscopy in Pharmaceutical Industry

Mjesto i datum
Crveni otok, Rovinj, Hrvatska, 23.-25.09.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Oxa Pictet Spengler reaction; Etodolac; One-step synthesis; LC NMR

Sažetak
Etodolac, 1, 8-diethyl-1, 3, 4, 9- tetrahydropyrano- [3, 4-b]indole-1-acetic acid is a racemic non- steroidal anti-inflammatory antirheumatic drug. The key intermediate in Etodolac synthesis is its methyl ester which is usually obtained by oxa-Pictet-Spengler reaction, starting from commercially available chemicals 7- ethyltryptophol and methyl 3-oxo- pentanoate, using different Brönsted and Lewis acids as promoters.1 Etodolac is than obtained by subsequent saponification step usually in a polar solvent.1, 2 We have performed extensive kinetic study of oxa-Pictet-Spengler reaction with different molar equivalents of hydrochloride and sulfuric acid as promoters. The study showed that two molar equivalents of sulfuric acid are optimal for reaction progress. Based on these results, we developed the methodology in which Etodolac can be obtained in a single step. For that purpose the novel synthetic procedure for methyl ester intermediate was firstly created using in start optimal solvent (isopropyl alcohol) for subsequent hydrolysis step. The intermediate and the final product were characterized by NMR spectroscopy. The combination of LC and NMR in an on-line and off-line mode was applied for structural elucidation of reaction impurities which may originate from starting material or are formed in methyl ester intermediate synthesis. The approach described in this study contributed to the development of more efficient synthetic procedure for the preparation of Etodolac. References 1. E. L. Larghi, T. S. Kaufman, Synthesis (2006) 187– 220. 2. E. Vigano, P.Colombo, U.S. patent (2000) US 6066741 A 20000523. Acknowledgements: This work was funded by European Regional Development Fund and Croatian state budget (project Met4Pharm).

Izvorni jezik
Engleski

Znanstvena područja
Kemija