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A Brief History Behind the Most Used Local Anesthetics

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A Brief History Behind the Most Used Local Anesthetics Tetrahedron xxx (xxxx) xxx Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron report XXX A brief history behind the most used local anesthetics * Marco M. Bezerra, Raquel A.C. Leao,~ Leandro S.M. Miranda, Rodrigo O.M.A. de Souza Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, 21941-909, Brazil article info abstract Article history: The chemistry behind the discovery of local anesthetics is a beautiful way of understanding the devel- Received 13 April 2020 opment and improvement of medicinal/organic chemistry protocols towards the synthesis of biologically Received in revised form active molecules. Here in we present a brief history based on the chemistry development of the most 16 September 2020 used local anesthetics trying to draw a line between the first achievements obtained by the use of Accepted 18 September 2020 cocaine until the synthesis of the mepivacaine analogs nowadays. Available online xxx © 2020 Elsevier Ltd. All rights reserved. Keywords: Anesthetics Medicinal chemistry Organic synthesis Mepivacaíne Contents 1. Introduction . ............................. 00 1.1. Pain and anesthesia . ............................................... 00 1.2. Ancient techniques to achieve anesthesia . ............................... 00 1.3. The objective of this work . .......................................... 00 2. Cocaine .............................................................................................. ............................. 00 2.1. Scientific explorations in South America . ............................... 00 2.2. The interest in coca leaves . .......................................... 00 2.3. Albert Niemann isolates cocaine . .. .......................................... 00 2.4. Cocaine’s popularity . ............................................... 00 2.5. The discovery of local anesthesia . .......................................... 00 2.6. Cocaine’s rise and decline on local anesthesia . ............................... 00 2.7. Essential characteristics of a local anesthetic candidate . ............................... 00 3. Eucaines ................................................................. ........................... ............................. 00 3.1. Cocaine as a model for novel local anesthetics . ............................... 00 3.2. Importance, effects, and disadvantages of the eucaines . ............................... 00 4. Benzocaine . ............................. 00 4.1. The discovery of benzocaine . .......................................... 00 4.2. Nitro reducing methods . ............................................... 00 4.3. Catalytic hydrogenation methods . .......................................... 00 4.4. Amination of aryl halides . .......................................... 00 4.5. Alternative methods . ............................................... 00 4.6. Benzocaine limitations . ............................................... 00 5. Procaine ............................................................................................. ............................. 00 5.1. The invention of procaine . .......................................... 00 5.2. The original synthesis . ............................................... 00 * Corresponding author. E-mail addresses: [email protected], [email protected] (R.O.M.A. de Souza). https://doi.org/10.1016/j.tet.2020.131628 0040-4020/© 2020 Elsevier Ltd. All rights reserved. Please cite this article as: M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al., A brief history behind the most used local anesthetics, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131628 M.M. Bezerra, R.A.C. Leao,~ L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx 5.3. A modern catalytic hydrogenation method . ............................... 00 5.4. Copper-mediated C-N coupling . .......................................... 00 5.5. Sustainable oxidation method . .......................................... 00 5.6. Dealkylating amination of secondary alcohols . ............................... 00 5.7. Limitations of procaine . ............................................... 00 6. Tetracaine................................................................. ........................... ............................. 00 6.1. Invention of tetracaine . ............................................... 00 6.2. The original synthesis . ............................................... 00 6.3. Catalytic hydrogenation of amides . .......................................... 00 6.4. Continuous flow photoredox amination of aryl halides . ............................... 00 6.5. Limitations of tetracaine . ............................................... 00 7. Lidocaine.................................................................. ........................... ............................. 00 7.1. The invention of lidocaine . .......................................... 00 7.2. The original synthesis . ............................................... 00 7.3. Ugi tricomponent reactions . .......................................... 00 7.4. Transamidation methods . ............................................... 00 7.5. Batch and continuous flow processes . .......................................... 00 7.6. Across-the-world automated synthesis of lidocaine . ............................... 00 7.7. Challenges involving the discovery of new local anesthetics . ............................... 00 8. Mepivacaine family . ............................. 00 8.1. Invention of the mepivacaine family . .......................................... 00 8.2. The original syntheses . ............................................... 00 8.3. The a-C-H carbamoylation method . .......................................... 00 8.4. Stereospecific synthesis of levobupivacaine . ............................... 00 8.5. The asymmetric synthesis of mepivacaine family via a “cation-pool” strategy . .................... 00 8.6. Continuous flow telescoped hydrogenation . ............................... 00 8.7. Perspectives on the synthesis of mepivacaine family . ............................... 00 9. Conclusion . ............................. 00 Declaration of competing interest . .......................................... 00 Acknowledgement . .................................................... 00 References . ..................................................... 00 1. Introduction mepivacaine, bupivacaine, and ropivacaine. 1.1. Pain and anesthesia 2. Cocaine Pain is a subjective experience that has both physical and psy- 2.1. Scientific explorations in South America chological origins. This sensation is part of the human condition, however, since the dawn of civilization, humanity has tried to The emperor Francis I of Austria (1768e1835) aspired to restore develop tools to deal with pain. Anesthesia is a state of numbness of his power after the Napoleonic wars, so he arranged the marriage of the senses that can be achieved in two ways: through the loss of his daughter with the heir to the Portuguese throne, which was consciousness, induced by general anesthetics, or by blocking pain located in Rio de Janeiro at.
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