Two step continuous-flow synthesis of benzocaine
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Two step continuous-flow synthesis of benzocaine Alexandre de S. França 1 & Raquel A. C. Leão 1,2 & Rodrigo O. M. A. de Souza 1 Received: 2 April 2020 / Accepted: 21 April 2020 # Akadémiai Kiadó 2020
Abstract Benzocaine (ethyl p-aminobenzoate), ethyl ester of p-aminobenzoic acid, is an anesthetic acting as a blocker of the nerve impulses and reducing the permeability of neuronal membrane to sodium iodide, it has become widespread in the pharmaceutical industry having applications as an anesthetic prior to exams such as endoscopy or as a “retarding” agent when inserted in condom. Due to the wide insertion in the pharmaceutical market, the methodologies for obtaining this molecule have already been elucidated and published in the literature, however the application of traditional reactions in refined systems, such as continuous flow are a technological bottleneck that allow approaches aimed at the optimization of productivity. Thus, the present work aimed to apply the reduction and esterification of p-nitrobenzoic acid in one step continuous flow systems, optimizing the reaction time and sequences, in order to add relevance and technology to the process as a whole. The model applied in a continuous flow system generated extremely positive values compared to the present literature, which include results with high conversion (> 99%) and selectivity (> 99%), in residence times that reach up to a minimum of 12 s. Keywords Benzocaine . Continuous flow . Esterification . Reduction
Introduction Benzocaine, an ethyl ester of p-amino benzoic acid (1), is a local anesthetic generally used as a topic pain reliever, which can also be found in many other anesthetic preparations. It was first synthesized in 1888 by the German chemist/pharmacist Eduard Ritsert. As early as 1888, Ritsert had been working on the production of an antipyretic to replace the toxic and harmless phenacetin when he synthesized p-aminobenzoic acid ethyl ester which did not presented any antipyretic activity, but it did have a local anesthetic effect. Ritsert left the new substance to the Hoechst company, where it was marketed under the name “anesthetic”, which became of outstanding importance in medicine as local anesthetics, with special menElectronic supplementary material The online version of this article (https://doi.org/10.1007/s41981-020-00098-2) contains supplementary material, which is available to authorized users. * Rodrigo O. M. A. de Souza [email protected] 1
Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941909, Brazil
2
Pharmacy Faculty, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, 373, Rio de Janeiro, RJ 21941-170, Brazil
tion being made of “Novocaine” (diethylaminoethyl paminobenzoate) invented by Alfred Einhorn in 1905 (Fig. 1) [1, 2]. Chemical synthesis of the ethyl ester of p-amino benzoic acid is quite simple and straightforward being accomplished by several groups during the past years. Two different approaches can be used st
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