Synthesis of local anesthetics derived from benzoic acid

The properties of the alkaloids isolated from the leaves of the coca plant were first discovered by Gaediche in 1855, the purification and isolation of the active ingredient called cocaine by albert nieman in 1860, he practically kicked off the history of local anesthetics. Subsequently, einhorn introduced in 1904 the procaine (novocaine) As a local anesthetic in medicine.


Since then, humanity has witnessed a continuous and sustained development of the synthesis of new molecules with anesthetic active ingredients:

*      In 1925 Niescher synthesized nupercaine.

*      In 1928 Von Eisleb tetracaine (pantocaine) and

*      In 1946 Lofgren and Lundquist synthesized lognicaine (xylocaine or lidocaine).

*      Then in 1954 Af Ekenstam and Egner obtained the synthesis of mepivacaine (scandicaine).

*      Later in 1960 and 1964 they were introduced in clinical medicine prilocaine (citanest), and marcaine (carbosterine).

*      Finally, in the following years, new anesthetics have been incorporated into medicine.

The local anesthetics, are the drugs that, when applied to a certain area of ​​the body, produce a temporary and reversible loss of sensitivity (thermal, painful and tactile), without inhibition of the patient's consciousness.  The duration of the effect of the drug depends on the dose used, its chemical structure, the formulation and the pharmaceutical form of the drug.

In general, local anesthetic drugs respond to different chemical structures, but all of them have similar effects or different intensities of the anesthetic effect. However, an attempt can be made to group them into benzoic acid esters, aminobenzoic acid esters, Amides, etc.

1. Chemical structure of local anesthetics

Local anesthetics are predominantly weak bases and are formed by an arene group,  ester or amide, which gives the molecule lipophilic properties (which mainly determine the potency of the drug), an aliphatic tertiary amino group (alkyl or alicyclic), which gives the molecule its hydrophilic character, and an alkyl intermediate chain that joins the parts of the arene with the amine and is responsible for the level of toxicity  of the drug.

Thus, the main local anesthetics used in the different medical disciplines can be found in the following groups:

to)      Amino esters of benzoic acid:

b)      m-aminobenzoic acid esters:

c)      Esters of p-aminobenzoic acid:

d)      Amides:

and)      Ketones:

F)        other groups 

2. Synthesis of local anesthetics derived from amino esters of benzoic acid

The most representative drugs of this group are cocaine, hexylcaine, piperocaine, ethyl aminobenzoate, meprilcaine, amylocaine, cyclomethicaine and propanocaine. These names respond to The denomination Common International (DCI), and do not necessarily correspond to the respective trade names. It is worth emphasizing that, in general, local anesthetics in their different pharmaceutical forms are found as the corresponding hydrochloride salt, a detail that should be understood when mentioning the chemical structure of the drugs that will be synthesized as   example.

The detailed synthesis of several of them will be presented below, as an example of the application of the synthesis methodology, known as the disconnection or tuning method, The order of exposure has no relation to their greater or lesser importance, since the objective sought is to delve into the study of the chemical synthesis of these drugs. exist   specialized treatises on the pharmacokinetics and pharmacodynamics of these molecules.

Mob 01:Hexylcaine hydrochloride , also called cyclaine (Merck) or osmocaine, is a short-acting local anesthetic.  Propose a synthesis design, from simple and affordable materials, for this drug.


retrosynthetic analysis: The presence of the secondary amine in the structure of the mob, makes the possibility of initiating the disconnection process by the acyl-oxygen bond unfeasible, which is the most common in esters, since in the corresponding reaction the formation of the ester and/or the amide would be in competition. which is used to disconnect the alkyl-oxygen bond, which originates a carboxylate nucleophile and a halogenated derivative as synthetic equivalents to be used and whose synthesis does not require extraordinary chemical reactions.


Hexylcaine synthesis: The aminoalcohol required as an intermediate is prepared by the  opening of the appropriate epoxide with the corresponding primary (nucleophilic) amine.


mob 02. The piperocaine is a local anesthetic drug used as its hydrochloride salt. Propose a synthesis plan for this drug.


retrosynthetic analysis: The structure of the mob 02, allows to initiate the disconnection by the oxygen acyl bond of the ester. Which gives rise to an acyl chloride and an amino alcohol as synthetic equivalents. This reaction presents a higher yield than that of carboxylic acid and alcohol (Fischer synthesis), which is an equilibrium reaction. On the other hand, the length of the alkyl group in the amino alcohol, guides to obtain it from the reduction of another ester group and this last molecule is prepared by the Michael reaction between a compound α,β- unsaturated carbonyl and the nucleophile α-methylpiperidine.


Synthesis of Piperocaine:


Mob 03: The meprilcaine, also known as epirocaineIt is a local anesthetic of moderate duration. Propose a synthesis design for this molecule from simple and affordable materials.


retrosynthetic analysis: The structure of the mob 03, requires a previous functionalization, to proceed with the disconnection of the alkyl-oxygen bond, for the reasons explained in the synthesis of the mob 01.

The disconnection of the two precursor molecules is then continued, the CN bond of the amide is disconnected and this operation is continued until reaching ethyl acetate and toluene as starting materials.


Synthesis of Meprilcaine: The preparation of nitro tertbutyl must be carried out by condensation reactions of the aldol type, to avoid the competition of elimination reactions in the substitution reactions, for example if one wishes to use a halide or tertbutyl alcohol as an intermediate.



Mob 04:Amylocaine design for this molecule, from simple and affordable materials


retrosynthetic analysis: The disconnection process begins by the acyl-oxygen bond, the subsequent disconnection of the NC bond of the amino alcohol, discovers the structure of a substituted epoxide and dimethylamine as precursor molecules. The epoxide can be formed from a ketone with sulfur ylide.


Amylocaine synthesis: The required 2-butanone precursor molecule can be prepared from acetic acid and the corresponding Gillman's reagent. Which leads to preparing the epoxide from the same ketone, using the respective sulfur ylide, to introduce the group   methylene (–CH2-).


mob 05: The cyclomethicaine is another important local anesthetic. Propose a synthesis plan for this drug, starting from simple and affordable materials.


retrosynthetic analysis: The disconnection begins with the acyl-oxygen bond of the ester group and then continues with the disconnections of the two precursor molecules generated, until arriving at benzene, toluene, ketone and acetic acid as starting materials.


Cyclomethicaine synthesis:


mob 06: The cocaine It is the first local anesthetic of natural origin, obtained from coca leaves, and unfortunately it has been used mostly unscrupulously due to its hallucinogenic effects.

Despite this, several cocaine derivatives have been obtained, all of them used as local anesthetics, such as ecgonine, B-eucaine, tropanone and pseudotropanol.











With essentially medical and therapeutic purposes, cocaine has been synthesized in chemistry laboratories. Describe a possible chemical synthesis route for cocaine from simple materials.

retrosynthetic analysis: The disconnection is initiated by the acyl oxygen bond of the ester directly attached to the bicyclic compound, an aspect that greatly simplifies the structure and forms precursor molecules, much easier to deal with in their disconnections. Then the egnonina, the same one that is disconnected by a Claisen retro-condensation, to continue with a Knoevenagel retro. Subsequent disconnections originate precursor molecules that go as far as acetylene and formaldehyde as starting materials.


Synthesis of cocaine:

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