Issue in Honor of Prof. J. Elguero and P. Molina ARKIVOC 2005 (ix) 200-206 Synthesis of 2- and 4-hydroxymethyl Loratadine, usual impurities in Loratadine syrup formulations Verónica Cerrada, M. Paz Matía-Martín, J. Luis Novella, and Julio Alvarez-Builla* Planta Piloto de Química Fina, Universidad de Alcalá. 28871 Alcalá de Henares, Madrid, Spain E-mail: julio.alvarez@uah.es Dedicated to Prof. José Elguero (received 31 Dec 04; accepted 21 Mar 05; published on the web 25 Mar 05) Abstract The synthesis of two contaminants of Loratadine, generated when the product is formulated as a syrup, is described. The products, identified as 2- and 4-hydroxymethyl derivatives of the starting compounds, are obtained by the corresponding substitution of the pyridine moiety of Loratadine. Keywords: Fused pyridines, pharmaceuticals, Loratadine, synthesis, contaminants Introduction Loratadine, 1, is [4-(8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine -1-carboxylic acid ethyl ester]. It is a non-sedating anthistamine,1 marketed, inter alia, as a syrup. The formation of the 2- and 4-hydroxymethyl derivatives 2,3 (Figure 1) on the pyridine ring has been described, which result from a redox process of the drug with other formulation components.2,3 Accelerated degradation experiments showed the formation of 0.5% of both contaminants in the syrup, dependent on the presence of air, and eventually related to the in situ generation of formaldehyde. 3 The preparation of both contaminants has been necessary to prepare references for quality control of drug formulations, and a scheme has been developed starting from the parent Loratadine 1. N N OO CH3 Cl R2 1 Loratadine R1 = R2 = H R1 2 R1= CH2OH; R2 = H 3 R1 = H; R2 = CH2OH Figure 1 ISSN 1424-6376 Page 200 ©ARKAT USA, Inc
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