lable at ScienceDirect

Tetrahedron xxx (xxxx) xxx

Contents lists avai

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. Le~ao, 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

a r t i c l e i n f o

Article history:Received 13 April 2020Received in revised form16 September 2020Accepted 18 September 2020Available online xxx

Keywords:AnestheticsMedicinal chemistryOrganic synthesisMepivacaíne

* Corresponding author.E-mail addresses: souzarod21@gmail.com,

(R.O.M.A. de Souza).

https://doi.org/10.1016/j.tet.2020.1316280040-4020/© 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: M.M. Bezerra, R.Ahttps://doi.org/10.1016/j.tet.2020.131628

a b s t r a c t

The chemistry behind the discovery of local anesthetics is a beautiful way of understanding the devel-opment and improvement of medicinal/organic chemistry protocols towards the synthesis of biologicallyactive molecules. Here in we present a brief history based on the chemistry development of the mostused local anesthetics trying to draw a line between the first achievements obtained by the use ofcocaine until the synthesis of the mepivacaine analogs nowadays.

© 2020 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.1. Pain and anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.2. Ancient techniques to achieve anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 001.3. The objective of this work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2. Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.1. Scientific explorations in South America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. The interest in coca leaves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. Albert Niemann isolates cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.4. Cocaine’s popularity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.5. The discovery of local anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.6. Cocaine’s rise and decline on local anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.7. Essential characteristics of a local anesthetic candidate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Eucaines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Cocaine as a model for novel local anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Importance, effects, and disadvantages of the eucaines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4. Benzocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1. The discovery of benzocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.2. Nitro reducing methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3. Catalytic hydrogenation methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.4. Amination of aryl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.5. Alternative methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.6. Benzocaine limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Procaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.1. The invention of procaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.2. The original synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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.C. Le~ao, L.S.M. Miranda et al.,

A brief history behind the most used local anesthetics, Tetrahedron,

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5.3. A modern catalytic hydrogenation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.4. Copper-mediated C-N coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.5. Sustainable oxidation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.6. Dealkylating amination of secondary alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005.7. Limitations of procaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

6. Tetracaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.1. Invention of tetracaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.2. The original synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.3. Catalytic hydrogenation of amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.4. Continuous flow photoredox amination of aryl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006.5. Limitations of tetracaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

7. Lidocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.1. The invention of lidocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.2. The original synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.3. Ugi tricomponent reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.4. Transamidation methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.5. Batch and continuous flow processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.6. Across-the-world automated synthesis of lidocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007.7. Challenges involving the discovery of new local anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

8. Mepivacaine family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.1. Invention of the mepivacaine family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.2. The original syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.3. The a-C-H carbamoylation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.4. Stereospecific synthesis of levobupivacaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.5. The asymmetric synthesis of mepivacaine family via a “cation-pool” strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.6. Continuous flow telescoped hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008.7. Perspectives on the synthesis of mepivacaine family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction

1.1. Pain and anesthesia

Pain is a subjective experience that has both physical and psy-chological origins. This sensation is part of the human condition,however, since the dawn of civilization, humanity has tried todevelop tools to deal with pain. Anesthesia is a state of numbness ofthe senses that can be achieved in two ways: through the loss ofconsciousness, induced by general anesthetics, or by blocking painconduction in part of the body, what is called local anesthesia.

1.2. Ancient techniques to achieve anesthesia

The first strategies to achieve local anesthesia involved physicalmethods, such as electric shocks, cooling, and pressure [1]. Addi-tionally, today we know that some abundant natural products, suchas menthol, thymol, and eugenol have mild anesthetic properties[2,3]. However, none of these molecules or techniques enabledpainless dental treatments, obstetric procedures, and major sur-geries. These advances in medicine were made possible thanks tothe discovery of local anesthetics.

1.3. The objective of this work

This article aims to present the most relevant local anestheticsthrough time starting with cocaine until ropivacaine. This work isdivided into two parts: the first one is a historical review of cocaineand its first synthetic analogs, the eucaines; the second part is areview of the synthetic methodologies developed throughout theyears to prepare benzocaine, procaine, tetracaine, lidocaine,

2

mepivacaine, bupivacaine, and ropivacaine.

2. Cocaine

2.1. Scientific explorations in South America

The emperor Francis I of Austria (1768e1835) aspired to restorehis power after the Napoleonic wars, so he arranged themarriage ofhis daughter with the heir to the Portuguese throne, which waslocated in Rio de Janeiro at the time. A team of Austrian scientistsaccompanied the newly married into South America, ventured thesub-continent for years, and gathered precious research on itsnatural resources [4,5].

2.2. The interest in coca leaves

Years later, the stimulant properties of Peruvian coca leavesprovoked the curiosity of renowned chemists as Friedrich W€ohler(1800e1882). The plant abounded in South America, so W€ohlerrequested a large sample of coca leaves to a friend, who was aboutto sail around the globe on board of SS Novara serving an Austrianscientific expedition [6,7]. W€ohler delegated his student, AlbertNiemann (1834e1861), to investigate the substances present incoca leaves [8].

2.3. Albert Niemann isolates cocaine

Niemann isolated an alkaloid, baptized it cocaine, and illustratedthe numbness it caused in 1860: “The solutions have an alkalinereaction, a bitterish taste, promote the flow of the saliva, and leaveupon the tongue a peculiar numbness, followed by a sensation of

M.M. Bezerra, R.A.C. Le~ao, L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

cold” [9,10].

2.4. Cocaine’s popularity

Cocaine-based drinks spread throughout the world afterNiemman’s discovery; Even Pope Leo XIII (1810e1903) com-mended Vin Mariani, a popular tonic wine at the time, in recog-nition of its benefits [11].

2.5. The discovery of local anesthesia

The Peruvian PhysicianMoreno yMaíz tested cocaine in animalsand detected its peripheral effect at the first study on the alkaloid,conducted in 1868 [12,13]. Twelve years later, Basil von Anrepinjected cocaine under his skin and declared its efficacy as ananesthetic [14,15]. Despite these observations, local anesthesiaarose years later; Carl Koller - influenced by Sigmund Freud, hiscolleague and cocaine enthusiast [16e18] - anesthetized a patient’seye with cocaine, operated his glaucoma, and placed a milestone inmedical surgery [19e21].

2.6. Cocaine’s rise and decline on local anesthesia

Cocaine anesthesia popularized among surgeons [22], whoinvented numerous techniques to anesthetize increasingly broaderparts of the human body [23e25]; Some doctors believed it washarmless [26]. However, important reports exposed dozens ofdeaths associatedwith cocaine use and it changed the perception ofdoctors and society [27]. Cocaine proved to be unsafe, but localanesthesia was too valuable to be forsaken. Since then, chemistshave pursued new local anesthetics that fit the demand forincreasingly complex medical procedures.

2.7. Essential characteristics of a local anesthetic candidate

The new substances should present five essential characteristicsto be considered a successful local anesthetic, accordingly to Dr.Braun, a German physician that studied novel local anesthetics inthe early XX century [28,29].

1) A lower degree of toxicity than cocaine in proportion to its localanesthetic power;

2) Sufficient solubility inwater. The solutions should be stable, thatis, they should keep without deterioration and capable of ster-ilization by boiling;

3) Absence of any sign of irritation. There should be no injury to thetissues. The local anesthetics should be easily absorbed withoutcausing any after-effects, such as hyperemia, inflammation, in-filtrations, or necroses;

4) Compatibility with epinephrine (a vasoconstrictor that in-creases the duration of anesthesia);

5) Rapid penetration of the mucous membrane, and sustainabilityfor medullary anesthesia.A molecule capable of accomplishing these five points would beconsidered a great candidate to be the next blockbuster localanesthetic.

3. Eucaines

3.1. Cocaine as a model for novel local anesthetics

Chemists inspired themselves in cocaine structure (1) to searchfor new synthetic local anesthetics. Cocaine is composed of twomoieties: the ecgonine ring (2) and the benzoic acid (3) (Scheme 1).

The ecgonine ring synthesis would be challenging due to its

3

bicyclic structure. Therefore, chemists invented simplified analogsof ecgonine, such as 4-hydroxy-1,2,2,6,6-pentamethylpiperidine-4-carboxylic acid (4) and 2,2,6-trimethylpiperidin-4-ol (5) (Scheme2). These molecules were used by George Merling to synthesizethe first synthetic local anesthetics, a-eucaine (6), and b-eucaine(7), in 1896 (Fig. 1) [30e32].

3.2. Importance, effects, and disadvantages of the eucaines

The eucaines were received with enthusiasm among physicians[33e36]. The eucaine’s effects were similar to those observed incocaine, both had similar duration and produced smarting wheninjected [36]. The b-eucaine was considered superior to a-eucainebecause the first was not eyeing irritating and remained stablewhen sterilized by boiling [33]; these advantages made b-eucaineimportant during world war I [37].

4. Benzocaine

4.1. The discovery of benzocaine

Benzocaine (9) is an ethyl ester of 4-aminobenzoic aciddiscovered as a local anesthetic by the pharmacist Eduard Ritsert in1903 [38]. It was firstly synthesized in 1898 when Limprichtreduced the nitro group of ethyl 4-nitrobenzoate (10) usingammonium sulfide (Scheme 3) [39].

Since then, benzocaine became a good target molecule forstudies on nitro reduction, amination of aryl halides, and alterna-tive methods to obtain anilines. Some other works were committedspecifically in the improvement of benzocaine synthesis, findingmore efficient methods, or investing in enabling technologies.

4.2. Nitro reducing methods

Treating nitro-compounds with metals in acidic media is asimple technique to obtain amines and anilines. Basa and co-workers developed an efficient one-pot nitro reduction/esterifica-tion using tin and hydrogen chloride; this synthesis started from 4-nitrobenzoic acid (11) and afforded benzocaine (9) in a 93% yield(Scheme 4) [40].

Following works explored a broad scope of nitroarenes,including benzocaine, to find milder reaction conditions anddifferent metals, - as indium [41,42], tellurium [43], and iron [44] -obtaining yields between 90 and 95% for the local anesthetic.

The Wang’s method is a successful example of nitro reduction;the author reduced ethyl p-nitrobenzoate using a simple autoclavecontaining nanosized activated iron powder and tap water;Benzocaine was obtained in 94% after 2 h at 120 �C (Scheme 5) [44].

Alternatively, the reductions with metal chlorides in proticsolvents can be carried out in milder temperatures and pHs. Someworks studied the synthesis of benzocaine and other anilines,evaluating the chemoselectivity of the proposed methods. Theauthors used titanium tetrachloride [45], tin (II) chloride [46], andferric chloride [47] under diverse reaction conditions, obtainingbenzocaine in 85e98% yields.

Kumar and co-workers revisited an old but atom economicmethod for the highly chemoselective nitro reduction of nitro-arenes: mixing the substrate with a 57% HI aqueous solution andheating it at 90 �C for 2 e 4 h. This method affords benzocaine in a60% yield (Scheme 6) [48] - which is far from being excellent, but itsspeed and simplicity make it noteworthy.

A few works investigated the synthesis of benzocaine and abroad scope of anilines using NaBH4 in combination with catalysts;Yanada and co-workers used the reducing agent in presence ofMoO3 and Na2SeO3 [49]; Yoon and co-workers used a borohydride

Scheme 1. Retrosynthesis of cocaine (1) leading to ecgonine (2) and benzoic acid (3).

Scheme 2. Molecular simplification of ecgonine ring (2) leading to the analogs 4-hydroxy-1,2,2,6,6-pentamethylpiperidine-4-carboxylic acid (4) and 2,2,6-trimethylpiperidin-4-ol(5).

Fig. 1. Chemical structures of a-eucaine (7) and b-eucaine (8).

Scheme 3. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) describedby Limpritch.

Scheme 4. One-pot esterification/nitro reduction of 4-nitrobenzoic (11) acid produc-ing benzocaine (9).

Scheme 5. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) using anautoclave reactor.

Scheme 6. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) promotedby a 57% HI aqueous solution.

M.M. Bezerra, R.A.C. Le~ao, L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

4

exchange resin in combination with Ni(OAc)2 [50]; Gohain and co-workers used NaBH4 in combination with ammonium sulfate [51];Prathap and co-workers used NaBH4 with NiCl2 in an aqueous so-lution of TEMPO-oxidized cellulose [52]. The goal of these workswas to study the chemoselectivity of the methods by preparing alarge variety of anilines. These methods require a large excess ofNaBH4, which is not optimal under the perspective of benzocainesynthesis, despite the yields between 82 and 97% and the mildreaction conditions.

Füldner and co-workers developed an efficient photocatalyzednitro reduction. The authors used a blue light LED as (Scheme 7) alight source, PbBiO2X (X ¼ Cl, Br) as a heterogeneous photocatalystand triethanolamine as an electron donor; this method affordedbenzocaine from ethyl 4-nitrobenzoate in 95% yield [53].

4.3. Catalytic hydrogenation methods

Catalytic hydrogenation is themost efficient and atom economicstrategy to reduce the nitro group and obtain benzocaine. Adamsand Cohen firstly investigated the catalytic hydrogenation of ethyl4-nitrobenzoate (10), using a PtO2 catalyst in ethanol under 3 atmH2 pressure. The authors obtained benzocaine (9) in 91e100%yields in gram scale (Scheme 8) [54].

Other studies used benzocaine as a target to investigate thechemoselectivity of the reduction of nitroarenes, exploringdifferent catalysts, ligands, and supports [55e60]. Regardingbenzocaine synthesis, these methods did not provide great ad-vances in reaction time, H2 pressure, or yields.

Glycerol and hydrazine can also be used as a hydrogen source tonitro reduction. Gawande and co-workers used Fe-Ni magneticnanoparticle catalyst and glycerol to produce benzocaine (9) in 94%yield (Scheme 9) [61]. This method has two major advantages: thecatalyst can be easily recovered by filtration and glycerol is a saferreagent than hydrogen gas.

Scheme 7. Photocatalyzed nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine(9).

Scheme 8. Hydrogenation of ethyl 4-nitrobenzoate (10) to benzocaine (9) catalyzed byPtO2.

Scheme 9. Nitro reduction of ethyl 4-nitrobenzoate (10) to benzocaine (9) usingglycerol as a hydrogen donor.

Scheme 11. Amination of ethyl 4-iodobenzoate (12) promoted by a CuI catalyst.

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Hydrazine offers broader catalyst alternatives: Shi synthesizedbenzocaine using hydrazine and a nickel-iron mixed oxide catalyst[62]. Zhao used a cobalt-promoted molybdenum carbide catalyst[63]. Lin used a metal-free carbon nanotubes catalyst [64]. Patilused immobilized iron metal containing ionic liquid as a catalyst[65]. These methods afforded benzocaine in yields between 94 and100%.

Jensen developed a continuous flow mobile reactor unit fortransfer hydrogenations. The system afforded benzocaine in 99%yield, in laboratory scale, using Pd/C as the catalyst (Scheme 10).The entire reactor and its components fitted inside a suitcase,resulting in a setup weighing less than 10 kg. Aside from theexceptional mobility, this continuous flow system provides betterthermal and pressure control, and it is safer when compared to aconventional batch hydrogenator [66].

4.4. Amination of aryl halides

The amination of aryl halides via transmetalation is a modern

Scheme 10. Continuous flow catalytic hydrogenation of ethyl 4-nitrob

5

and efficient alternative to the classic nitro reductions. The majoradvantages are high yields and mild reaction conditions; Thesereactions require a metallic catalyst - palladium or copper - and anitrogen source. Hori investigated the effect of Pd(dba)2 catalyst incombination with a titanium-nitrogen complex prepared frommolecular nitrogen, to synthesize benzocaine and a broad scope ofanilines; This method afforded benzocaine in 32% yield [67]. Pos-terior works investigated other nitrogen sources as Zn(N(SiMe3))[68] and ammonia gas [69], obtaining benzocaine in 93e94% yields.Tao studied the action of a CuI catalyst in the synthesis of benzo-caine and a broad scope of anilines; the author used 2,2,2-trifluoroacetamide as a nitrogen source and obtained the localanesthetic from ethyl 4-iodobenzoate (12) in 99% yield (Scheme 11)[70].

Subsequent works investigated different nitrogen sources andCu (I) salts [71e73], obtaining benzocaine in 89e97% yields.

4.5. Alternative methods

Alternative transformations can also afford benzocaine andother anilines using unconventional reagents and different rawmaterials. In recent work, Wang and co-workers developed an Ag-catalyzed amination of fluoroarenes using the simple salts Ag2CO3and K2S2O8, and NaN3 as a nitrogen source, obtaining benzocainefrom ethyl 4-fluorobenzoate (13) in 89% yield (Scheme 12) [74]. Thisstrategy requires longer reaction times and higher temperatures -20 h reaction at 120 �C - when compared to the previouslydemonstrated transmetalation method but enables the preparationof anilines from aryl fluorides.

In previous work, Chatterjee demonstrated that is also possibleto prepare benzocaine and other anilines via amination of boronicacids; this metal-free amination requires [Bis(trifluoroacetoxy)iodo]benzene (PIFA), N-Bromosuccinimide (NBS) and cyanamide,affording benzocaine in 83% yield [75].

The previous transformations were concerned about the aminogroup preparation. Verma and co-workers demonstrated a simpleand efficient method to prepare a broad scope of esters, startingfrom alcohols, via photochemical C-H activation catalyzed by anoxo-vanadium-graphitic carbon nitride (VO@g-C3N4). The authorsprepared benzocaine (9) starting from (4-aminophenyl)methanol

enzoate (10) producing benzocaine (9) in a suitcase-sized reactor.

Scheme 12. Amination of ethyl 4-fluorobenzoate (13) promoted by Ag2CO3/K2S2O8.

Scheme 13. Photochemical oxidation of (4-aminophenyl)methanol (14) promoted byan oxo-vanadium-graphitic carbon nitride catalyst.

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(14) by mixing the starting material with H2O2 under a 40 Wattdomestic bulb, affording the local anesthetic in 85% yield (Scheme13) [76].

A recent methodology developed by Qiu and co-workerstransformed naturally occurring phenols and its derivatives intoanilines. The authors used cheap reducing agents to obtainbenzocaine (9) and other anilines. The reaction requires hightemperature, a large excess of hydrazine, and substoichiometricamounts of NaBH4 and Pd/C; the authors started from ethyl 4-hydroxybenzoate (15) obtained benzocaine (9) in 32% yield(Scheme 14) [77].

4.6. Benzocaine limitations

A great number of authors visited benzocaine synthesisthroughout the decades, studying new catalysts, inventing newtransformations, and exploring new technologies. The small size,simplicity, and practical value of this local anesthetic are essentialto its importance in organic synthesis. However, unlike the previ-ously mentioned eucaines, benzocaine does not have an aliphaticfree amine portion and because of that it is poorly water-soluble;so, benzocaine was limited to topic anesthesia and could not be asubstitute to the eucaines.

5. Procaine

5.1. The invention of procaine

Procaine is another ester of 4-aminobenzoic acid, invented byAlfred Einhorn in 1905 [78]. Procaine’s preeminent characteristicwas a great safety; therefore, despite being less potent than cocaineor the eucaines, it was considered a superior local anesthetic [28].Sanofi launched procaine in the same year it was invented, underthe trade name of Novocaine; this product dominated themarket oflocal anesthesia for approximately four decades.

Scheme 14. Synthesis of benzocaine (9) starting from ethyl 4-hydroxybenzoate (15).

6

5.2. The original synthesis

Originally, procaine (17) was obtained in two steps. The first stepwas the esterification of the 4-nitrobenzoyl chloride (18) with 2-(diethylamino)ethan-1-ol (19), resulting in the intermediatenitrocaine (20); the last step was the nitro reduction promoted bytin and concentrated hydrochloric acid, furnishing procaine (17)(Scheme 15) [78].

5.3. A modern catalytic hydrogenation method

Similar to benzocaine, some authors also used procaine as atarget to study the chemoselectivity of reducing agents. Gholinejadand co-workers used a naturally occurring clay, clinochlore, as acatalyst for a nitro reduction via NaBH4; the authors reducednitrocaine at room temperature, in a 6 h reaction, affording pro-caine in 93% yield [79]. Zhang and co-workers studied a catalytichydrogenation method for nitroarenes using a catalyst containingCoNx and CoyZnS supported on N-doped porous carbon; thereduction of nitrocaine was carried at 90 �C and 5 bar H2 pressure,furnishing procaine in 99.9% yield after 3 h [60].

5.4. Copper-mediated C-N coupling

Maejima and co-workers developed a copper-mediated C-Ncoupling reaction; the authors reacted 2-(diethylamino)ethyl 4-bromobenzoate (21) with metallic copper, 2-aminoethanol, andTMSN3 at 95 �C for 24 h, obtaining procaine in 63% yield (Scheme16) [80]. The conventional nitro reductions give higher yields andoffer better atom economy, but the metal-catalyzed C-N couplingstrategies must always be considered as an option because it opensthe possibility of using aryl halides as starting materials.

5.5. Sustainable oxidation method

Fang developed a metal-free method for the oxidation of nitroalkyl arenes to carboxylic acids using O2 and NaOH/EtOH mixture.The authors synthesized procaine (17) in three steps: the oxidationof 4-nitrotoluene (22), affording 4-nitrobenzoic acid (23) in 65%yield; then, the telescoped esterification and catalytic hydrogena-tion of 4-nitrobenzoic acid (23), affording procaine (17) in 91% yield(Scheme 17) [81]. This method is highly atom economic and can beconsidered a sustainable approach for the synthesis of procaine.

5.6. Dealkylating amination of secondary alcohols

Liu and co-workers developed a novel transformation to obtainanilines using procaine (17) synthesis as a practical example; thedealkylating amination is successful in transforming secondaryalcohols into anilines. The reaction requires NaN3 and trifluoro-acetic acid (TFA); procaine was obtained in 63% yield from 2-(diethylamino)ethyl 4-(1-hydroxyethyl)benzoate (23) after reac-tion at 40 �C for 4 h (Scheme 18). This new transformation enablesdifferent strategies to obtain procaine, avoiding nitro reduction.

5.7. Limitations of procaine

Procaine, benzocaine, and other 4-aminobenzoic acid de-rivatives share similar synthetic challenges, due to its structuralresemblances. So, some works may present solutions that apply tomultiple anesthetics. The major difference between procaine andbenzocaine is the diethylamine moiety present in the first one; thisbasic group enhances hydrophilicity, enabling the use of procaineas an injectable solution, and plays an important role in the potencyof the anesthetic. But high hydrophilicity is related to a short

Scheme 15. Two-step synthesis of procaine (17) described by Einhorn; firstly, the esterification of 4-nitrobenzoyl chloride (18) followed by the nitro reduction of nitrocaine (20).

Scheme 16. C-N coupling of 2-(diethylamino)ethyl 4-bromobenzoate (21) promoted by metallic copper.

Scheme 17. Metal-free oxidation of 4-nitrotoluene (22) and telescoped esterification-reduction of 4-nitrobenzoic acid (11).

Scheme 18. Dealkylating amination of 2-(diethylamino)ethyl 4-(1-hydroxyethyl)benzoate (23).

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duration of the anesthesia, which is themajor weakness of procaine[82]. So, chemists looked for a molecule that could deliver a longereffect.

6. Tetracaine

6.1. Invention of tetracaine

Tetracaine is also a 4-aminobenzoic acid derivative, invented byOtto Eisleb in 1930 [83]. Its structure was inspired in procaine, withtwo main differences: tetracaine had a dimethylamino group,instead of a diethylamino; andmost important, tetracaine had an n-butyl group attached to the aromatic nitrogen. These aspects madetetracaine be the longer-acting local anesthetic available at thetime. However, it was very toxic. Especially dangerous in surgeriesthat required larger volumes of anesthetic [84].

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6.2. The original synthesis

According to the original synthesis, Eisleb prepared tetracaine(24) in two steps, starting from sodium 4-aminobenzoate (25): thefirst stepwas the amine alkylation using 1-bromobutane furnishingthe intermediate 4-(butylamino)benzoic acid (26); the second stepwas the esterification with dimethylethanolamine (27), affordingtetracaine (24) (Scheme 19).

6.3. Catalytic hydrogenation of amides

Yuan developed a method for the catalytic hydrogenation ofamides to amines using a [Ru(H)(CO)(Triphos)] catalyst. The au-thors synthesized tetracaine (24) in two steps: firstly, the catalytichydrogenation of ethyl 4-butyramidobenzoate (28), affording theintermediate ethyl 4-(pent-1-en-2-ylamino)benzoate (29) in 89%yield; then, the transesterification with 2-(dimethylamino)ethanol

Scheme 19. Original synthesis of procaine described by Otto Eisleb.

Scheme 20. Amide reduction of 4-butyramidobenzoate (28) followed by transesterification of ethyl 4-(pent-1-en-2-ylamino)benzoate (29).

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(27), furnishing tetracaine (24) in 85% yield (Scheme 20) [85]. Thismethod is a consistent alternative to the classic N-alkylation using1-bromobutane but requires one more reaction step.

A similar approach was developed by Pan, who preparedtetracaine in an 83% overall yield applying the same trans-formations in a metal-free approach. The authors reduced theamide precursor to the amine using B(C6F5)3 in place of theRuthenium catalyst [86].

6.4. Continuous flow photoredox amination of aryl halides

In recent work, Park developed a continuous flow photoredoxamination of aryl halides using Ni (II) salts and Ru(bpy)3(PF6)2 ascatalysts. The authors obtained tetracaine (24) in 84% yield in onestep, starting from 2-(dimethylamino)ethyl 4-bromobenzoate (21)(Scheme 21) [87]; the residence time is short - only 10min - and thesmall amount of Ru catalyst needed - only 0,02% - argues for itseconomic viability.

6.5. Limitations of tetracaine

Tetracaine was the only option in long-duration surgeries foralmost fifteen years. The discovery of novel local anesthetics thatshared only the positive aspects of procaine and tetracaine waschallenging and would require radical structural modifications. The

Scheme 21. Continuous flow photoredox amination of 2-(dimethylamino)ethyl 4-bromobenzoate (21) affording tetracaine (24).

8

drug that would eventually overcome both procaine and tetracainehad its development marked by serendipity and systematic work.

7. Lidocaine

7.1. The invention of lidocaine

The Swedish chemists’ Nils L€ofgren and Bengt Lundqvistinvented lidocaine in 1943 and it had an unprecedented chemicalstructure for a local anesthetic. At the time, the chemists weresynthesizing analogs of isogramine - casually reported as a mildlocal anesthetic after a researcher prepared it by mistake [88,89].After a systematic selection of drug candidates, L€ofgren andLundqvist identified lidocaine, an amino-amide derivative from2,6-xylidine, as their best local anesthetic [90,91]. Lidocaine wassuperior to procaine in safety and comparable to tetracaine induration [84]; it was so valuable that the company that launchedlidocaine, Astra AB, became one of the biggest pharmaceuticalcompanies in the world [88,92].

7.2. The original synthesis

Originally, L€ofgren and Lundqvist obtained lidocaine (30) in twosteps: the first step was the acylation of 2,6-xylidine (31) using 2-chloroacetyl chloride (32) to afford the intermediate 2-chloro-N-(2,6-dimethylphenyl)acetamide (33) in 70e80% yield; the next stepwas the amine alkylation between the 33 and diethylamine (34),furnishing lidocaine (30) in quantitative yields (Scheme 22) [91].

7.3. Ugi tricomponent reactions

Adolph and co-workers developed a photo catalyzed tri-component Ugi reaction using a 100 W Hg lamp and Pt/TiO2 as aphotocatalyst; this methodology used 2-isocyano-1,3-dimethyl(35) benzene and diethylamine (34) as starting materials andafforded lidocaine (30) in 82% yield after a 24 h reaction (Scheme23) [93].

The describedmethod is a photocatalyzed version of the original

Scheme 22. Original synthesis two-step synthesis of lidocaine; firstly, the acylation of 2,6-xylidine; then, the amine alkylation of 2-chloro-N-(2,6-dimethylphenyl)acetamide (33).

Scheme 23. Photocatalized tricomponent Ugi reaction starting from 2-isocyano-1,3-dimethyl (35) to produce lidocaine (30).

M.M. Bezerra, R.A.C. Le~ao, L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Ugi’s lidocaine synthesis, which obtained the local anesthetic in a78% yield after 70 h [94]. The Ugi reaction is a useful way to producelidocaine under mild conditions; this strategy shifts the complexityof the synthesis to the preparation of the isonitrile.

7.4. Transamidation methods

Srinivas and co-workers developed an efficient, simple, andsustainable method for the synthesis of various amides via trans-amidation. The methodology required a stoichiometric amount ofK2S2O8 in aqueous media, heating the reagents at 100 �C for 10 minwith microwave irradiation or conventional thermal conditions.The authors used 2,6-xylidine (31) and 2-(diethylamino)acetamide(36) as starting materials furnishing lidocaine (30) in a 95% yield(Scheme 24) [95].

Another transamidation was reported by Guangchen and co-workers, who synthesized lidocaine (30) and a broad scope ofamides under mild conditions. The authors started from 2,6-xylidine (31) and phenyl diethylglycinate (37), using LiHMDS toproduce lidocaine (30) in 91% yield (Scheme 25) [96]. The pro-cedure is transition-metal-free, operationally simple, and carried atroom temperature.

7.5. Batch and continuous flow processes

Monbaliu and co-workers designed a pharmaceuticalmanufacturing platform for the synthesis of lidocaine hydrochlo-ride. The authors used the classic synthetic strategy - using 2,6-xylidine, 2-chloroacetyl chloride, and diethylamine as startingmaterials - and developed an advanced end-to-end purification,extraction, reactive crystallization, antisolvent cooling crystalliza-tion, and aqueous liquid formulation processes. The manufacturing

Scheme 24. Transamidation of 2-(diethylamino)acetam

9

platform could produce 810 doses per day of a 2% lidocaine hy-drochloride solution [97].

The compact continuous-flow platform developed by Adamoand co-workers produced the same 810 lidocaine doses per day asthe previously mentioned manufacturing platform. Therefrigerator-sized factory was able to alternate the production oflidocaine hydrochloride, diphenhydramine hydrochloride, diaz-epam, and fluoxetine hydrochloride by reconfiguring the synthesismodules. The processes were carried out via a multi-step contin-uous-flow synthesis followed by isolation, crystallization, andformulation systems, able to deliver the medicine on-demand. Theauthors also chose the classic synthetic strategy, using 2,6-xylidine,2-chloroacetyl chloride, and diethylamine as startingmaterials. Thereaction follows through two tubular reactors: the acylation stepoccurs in the first one, in 18.4 min residence time; the substitutionstep occurs in the second one, in 17.7 min, furnishing lidocaine in90% yield (Scheme 26) [98].

7.6. Across-the-world automated synthesis of lidocaine

Fitzpatrick and co-workers developed a delocalized synthesis oflidocaine. Using the cloud, servers located in Tokyo, Japan auton-omously optimized the synthesis conditions in laboratories inCambridge, UK; A researcher controlled the process from LosAngeles, USA via an internet connection. This work opened newpossibilities in the API synthesis; this approach frees the researcheror producer from the obligation of having a fixed location, and thetime can be spent more efficiently, once the system is autono-mously optimized, with minimal researcher intervention [99].

7.7. Challenges involving the discovery of new local anesthetics

The modern approaches that use lidocaine as a target reflect theimportance of this local anesthetic. Even nowadays it is extremelypopular due to its safety and versatility. The high standardsestablished by lidocaine demanded that the next generation of localanesthetics should be even more efficient.

8. Mepivacaine family

8.1. Invention of the mepivacaine family

The next family of local anesthetics arose, once again, in Swe-den. Bo af Ekenstam synthesized Mepivacaine and Bupivacaine,both launched as racemic mixtures; as well as levobupivacaine and

ide (36) and 2,6-xylidine (31) promoted by K2S2O8.

Scheme 25. Transamidation of phenyl diethylglycinate (37) and 2,6-xylidine (31) promoted by LiHMDS.

Scheme 26. Multi-step continuous flow synthesis of lidocaine (30) in a compact and reconfigurable system.

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ropivacaine, launched as enantiomerically pure products[100e102]. These local anesthetics are amino-amides derivativesfrom 2,6-xylidine, like lidocaine. However, the free amino group inthe mepivacaine family is an alkylated piperidine ring; The lengthof the alkyl chain indicates the local anesthetic - mepivacaine has amethyl group, ropivacaine an n-propyl group, and bupivacaine/levobupivacaine an n-butyl group. Mepivacaine is similar to lido-caine concerning potency and duration [100]; Bupivacaine, though,is three times more potent than mepivacaine and offers a muchlonger effect [103]. Ropivacaine and levobupivacaine gained spaceafter the discovery that (R) enantiomers of the mepivacaine familyare related to a higher incidence of cardiac arrest [104,105], so the(S) enantiomers were presented as a safer option [106].

8.2. The original syntheses

Originally, Ekenstam proposed a two-step synthesis startingfrom 2,6-xylidine (31) and racemic piperidine-2-carboxylic acid(38), or the optical isomer (S)-piperidine-2-carboxylic acid ((S)-38),to produce mepivacaine (39), bupivacaine (40), ropivacaine ((S)-41), and levobupivacaine ((S)-40). The strategy involves the amidecoupling via acid chloride between 2,6-xylidine (31) and theracemic 38 or optically pure carboxylic acid (S)-38, furnishing theintermediate N-(2,6-dimethylphenyl)piperidine-2-carboxamide(42) or the (S)-enantiomer (S)-42; then, the racemic or opticallypure intermediate is N-alkylated with the suitable alkyl halide toafford the correspondent local anesthetic (Scheme 27) [101,102].

8.3. The a-C-H carbamoylation method

Yoshimitsu and co-workers developed the synthesis of mepi-vacaine via a-C-H carbamoylation; The authors mixed the readilyavailable N-methylpiperine (43) with 2,6-dimethylpheylisocyanate(44) and Et3B at room temperature for 42 h, obtaining 52% yield ofmepivacaine (39) (Scheme 28). This approach presented onlymoderate yields, but it shifts the complexity of the synthesis to thexylidinemoiety, avoiding the amidation/alkylation steps, present inthe classic strategy [107].

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8.4. Stereospecific synthesis of levobupivacaine

Adger and co-workers reported a five-step synthesis of levo-bupivacaine, starting from the protected L-Lysine. Firstly, the Cbz-L-Lysine (45) was treated with NaNO2 and NaOAc in acetic acid,yielding the intermediate (S)-6-acetoxy-2-(((benzyloxy)carbonyl)amino)hexanoic acid (46); The second step was the amide couplingvia carbodiimide between 46 and 2,6-xylidine (31), furnishing theintermediate (S)-5-(((benzyloxy)carbonyl)amino)-6-((2,6-dimethylphenyl)amino)-6-oxohexyl acetate (47); then, occurredthe acetoxy hydrolysis followed by tosylation affording the tosy-lated intermediate (S)-5-(((benzyloxy)carbonyl)amino)-6-((2,6-dimethylphenyl)amino)-6-oxohexyl 4-methylbenzenesulfonate(48); in the fourth step, the 48 suffered a one-pot deprotection/cyclization via catalytic hydrogenation promoted by H2 and Pd/C,furnishing (S)-42; Lastly, the authors reacted (S)-42 with 1-bromobutane, furnishing levobupivacaine ((S)-40) in 38% overallyield (Scheme 29) [108].

This work applied simple chemical transformations and low-cost starting materials to stereospecifically produce levobupiva-caine; The number of steps could be a downside of this strategy.

8.5. The asymmetric synthesis of mepivacaine family via a “cation-pool” strategy

Shankaraiah and co-workers developed a “cation-pool” strategyfor the asymmetric synthesis of (S)-mepivacaine ((S)-39), levobu-pivacaine ((S)-40), and ropivacaine ((S)-41). The authors appliedanodic oxidation and soft nucleophiles to prepare an (S)-pipecolicacid precursor, tert-butyl (S)-2-(2-cyanopiperidin-1-yl)-2-oxoacetate (49), used in the synthesis of the local anesthetics. Thefirst step is the telescoped acidic hydrolysis followed by amidationwith 2,6-xylidine (31) via EDC/HOBt, affording the intermediate(S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide ((S)-42); thealkylation of the piperidine ring with formaldehyde/NaCNBH3, 1-bromopropane or 1-bromobutane leads to (S)-mepivacaine ((S)-39), ropivacaine ((S)-41) or levobupivacaine ((S)-40), respectively,in yields between 80 and 85% (Scheme 30) [109].

Scheme 27. Original synthesis of mepivacaine (39), bupivacaine (40), ropivacaine ((S)-41) and levobupivacaine ((S)-40) described by Ekenstam.

Scheme 28. Synthesis of mepivacaine (39) via a-C-H carbamoylation using N-meth-ylpiperine (43) and 2,6-dimethylpheylisocyanate (44) as starting materials.

Scheme 29. Stereospecific synthesis of levobupi

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11

8.6. Continuous flow telescoped hydrogenation

Suveges and co-workers developed a fast method to synthesizethe mepivacaine (39), bupivacaine (40) and rac-ropivacaine (41)using continuous flow technology. The authors accomplished atelescoped catalytic hydrogenation/reductive amination using acontinuous-flow H-Cube reactor; the methanolic solution of N-(2,6-dimethylphenyl)picolinamide (50) in the presence of a suit-able aliphatic aldehyde e formaldehyde, propionaldehyde or

vacaine ((S)-40) starting from L-lysine (45).

Scheme 30. Synthesis of (S)-mepivacaine ((S)-39), ropivacaine ((S)-41) or levobupivacaine ((S)-40) via ‘cation-pool’ strategy.

Scheme 31. Continuous flow telescoped catalytic hydrogenation/reductive amination for the synthesis of mepivacaine (39), bupivacaine (40) and rac-ropivacaine (41).

M.M. Bezerra, R.A.C. Le~ao, L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

butyraldehyde - was pumped through a 10% Pd/C cartridge, underhydrogen pressure - the H-Cube system generates hydrogen in-situ,providing a safer and more convenient reaction setup. The racemiclocal anesthetics were obtained in yields between 80 and 89%(Scheme 31) [110].

8.7. Perspectives on the synthesis of mepivacaine family

The mepivacaine family is widely used in modern surgery,especially in long-duration procedures. The major challenges pre-sent in the synthesis of these local anesthetics are the developmentof methods for the amide bond formation that are milder, safer,more sustainable; the study of new methods to the asymmetricsynthesis of (S)-piperidine-2-carboxylic acid; and the explorationof novel synthetic strategies and technologies that could allowdifferent or more efficient routes. The previously depicted worksaddressed some of these challenges, but there is still room for newideas.

9. Conclusion

After the isolation of cocaine and the experiments of Carl Koller,humanity was faced with local anesthesia, a tool that could nolonger be left out. Local anesthetics are a disruptive technology thathas enabled the medical practice to effectively perform varioussurgical procedures, such as ophthalmic, obstetric, dental opera-tions, among others. Cocaine served as a model for the posteriorlocal anesthetics. The new molecules should be more effective and

12

safer than cocaine.The discovery of new technologies for the synthesis of these

molecules can be analyzed in parallel to the history of local anes-thesia. The growing concern with sustainability, automation, andmachine learning highlights the importance of tools such ascatalysis, flow chemistry, and cloud-based servers to the improve-ment of organic synthesis processes. These approaches associatedwith the study of novel transformations can revolutionize the waylocal anesthetics are produced and delivered to the patients.

Declaration of competing interest

The authors declare that they have no known competingfinancial interests or personal relationships that could haveappeared to influence the work reported in this paper.

Acknowledgement

Authors thanks CAPeS, CNPq and FAPERJ for financial support.

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Prof. Rodrigo O. M. A. de Souza has a degree at thePharmacy School of Federal University of Rio de Janeiro(UFRJ) and PhD at the Institute of Natural ProductsResearch. He is coordinating the Biocatalysis and OrganicSynthesis group at the Chemistry Institute of UFRJ since2010 with Prof. Leandro S. M. Miranda, and have beenworking on process development for API synthesis as wellas introducing continuous-flow methodologies on bio-catalytic process.

Prof. Leandro S. de M. Miranda has a degree at thePharmacy School of Federal University of Rio de Janeiro(UFRJ) and PhD at the Institute of Natural ProductsResearch He is coordinating the Biocatalysis and OrganicSynthesis group at the Chemistry Institute of UFRJ since2010 with Prof. Rodrigo O. M. A. de Souza and have beenworking on the development of synthetic organicmethods towards API synthesis.

M.M. Bezerra, R.A.C. Le~ao, L.S.M. Miranda et al. Tetrahedron xxx (xxxx) xxx

Dr. Raquel A. C. Le~ao has a PhD in chemistry from Flu-minense Federal University and have been working asstaff scientist at the Biocatalysis and Organic Synthesisgroup since 2013. Her main research focus is on applyingcontinuous-flow chemistry to API synthesis, on single andmulti-step processes.

15

Msc Marco Macena has a degree at the Pharmacy Schoolof Federal University of Rio de Janeiro and is actuallyworking to obtain his PhD on new strategies towards thesynthesis of cheap anesthetics compounds.