The Synthesis Of Related Impurities In Felodipine And Oseltamivir Phosphate

Drug is a special commodity, of which every country has its strict standards forits quality. Substances effecting drug’s purity are referred to as impurities, and theexistence of these impurities is inevitable. Impurity control is a key element of thedrug safety guarantee. This paper is on the synthesis of impurities of felodipine andoseltamivir phosphate with good results.Felodipine(3-ethyl5-methy4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) is a new type of dihydropyridine calcium channel blocker withhigh vascular selectivity and significantly reducing blood pressure and total peripheralresistance, widely used in clinical treatment of hypertension. It is included thatfelodipine quality standards in China Pharmacopoeia (2010), but only the impurity A(3,5-Pyridinedicarboxylic acid,4-(2,3-dichlorophenyl)-2,6-dimethyl3-ethyl5-methyl ester) is controlled. The impurity B (3,5-Pyridinedicarboxylicacid,4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl3,5-dimethyl ester) and impurity C (3,5-Pyridinedicarboxylicacid,4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-diethyl ester) are not controlled. However, In the European Pharmacopoeia (7.8edition),the three impurities are all controlled. Therefore, the synthesis and structureidentification of the three impurities in felodipine are of practical significance to itsproduction, inspection, storage, etc.In the synthesis of the impurity A, through the screening of catalyst system, wehave chosen mild oxidation conditions and the product was purified by ordinaryrecrystallization.In the synthesis of the impurity B and the impurity C, we first simulated theconditions for the synthesis of modified amino crotonic acid ethyl ester. As a result,the impurity B and the impurity C were obtained, which were confirmed by HPLC,MS, H-NMR. The result proved the proposed mechanism suggesting that the productobtained from the first step should be purified before the cyclization and the storageconditions of amino crotonic acid ethyl ester should be strictly controlled to avoidhydrolysis. Then the process was optimized: the levo-lactic acid ethyl ester solutionas solvent, under the initiation of visible light, reaction at room temperature, simpleoperation. This process is so advantageous that higher yields were obtainedcomparing to the previously reported methods. This paper also studied the synthesis of impurities in Oseltamivir phosphate,Oseltamivir phosphate, is a potent and selective influenza virus neuraminidaseinhibitors. USA Pharmacopoeia (38edition) presents2related substances A((3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylicacid) and B (4-Acetylamino-3-hydroxybenzoic acid ethyl ester) in Oseltamivirphosphate with the limits of control. Currently, no large-scale preparation processconditions can be adopted to the synthesis of impurity A and there is no synthesisreport on impurity B. This paper describes the generation mechanisms of impurity Aand B. Synthesis route of impurity B was designed and the impurity B wassuccessfully synthesized. Each step of the synthesis process was optimized. Thus,the entire synthetic route has the advantages of simple operation, mild reactioncondition and no environmental pollution. Structures were confirmed by1H-NMR.It is of practical significance for the production, inspection and storage of Oseltamivirphosphate.