title: In-line reaction monitoring of entacapone synthesis by Raman spectroscopy and multivariate analysis.
abstract: In-line Raman spectroscopy and multivariate analysis were used to monitor Knoevenagel condensation reaction, the final step in preparation of drug entacapone. By applying a fiber optical Raman probe immersed into a reaction vessel Raman spectra of the reaction mixture were recorded in situ during the entacapone synthesis in toluene, heptane and isobutyl acetate. Due to the complexity of the measured spectra, the obtained data were analyzed and interpreted by means of principal component analysis. It has been shown that progress of this reaction can be monitored in real-time and reaction end points can be determined in different solvents. The reaction was found to be the fastest in heptane due to the lower loss of the catalyst. For a comparison the reaction was independently monitored by off-line Raman spectroscopy and liquid chromatography which confirmed the results obtained in-line. The results presented here have shown that this in-line approach can be used as a fast, non destructive and reliable method to monitor the Knoevenagel reaction in real time. The knowledge gained in this study can further be exploited for the industrial process control.
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, University of Zagreb, Horvatovac 102a, Zagreb, Croatia. pnovak@chem.pmf.hr
authors.forename: Predrag
authors.initials: P
authors.lastname: Novak
authors.forename: Andrea
authors.initials: A
authors.lastname: Kišić
authors.forename: Tomica
authors.initials: T
authors.lastname: Hrenar
authors.forename: Tomislav
authors.initials: T
authors.lastname: Jednačak
authors.forename: Snežana
authors.initials: S
authors.lastname: Miljanić
authors.forename: Gordana
authors.initials: G
authors.lastname: Verbanec
mesh_terms: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D005336:Fiber Optic Technology; D005583:Fourier Analysis; D007536:Isomerism; D015999:Multivariate Analysis; D009570:Nitriles / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry; D025341:Principal Component Analysis; D011786:Quality Control; D012997:Solvents / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D012997:Solvents; C071192:entacapone