Synthesis of local anesthetics derived from benzoic acid

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

      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.

Local anesthetics are drugs that, when applied to a specific 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)       Esters of m-aminobenzoic acid :

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.

Next, the synthesis of several of them will be presented in detail, as an example of the application of the synthesis methodology, known as the disconnection or synthon method. The order of exposure has no relation to the greater or lesser their 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.

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.

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

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 leads to obtaining it from the reduction of another ester group and preparing this last molecule by the Michael reaction between an α, β-unsaturated carbonyl compound and the α nucleophile . -methylpiperidine.

Synthesis of Piperocaine :

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.

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 (–CH ₂ -).

Retrosynthetic analysis : The disconnection begins by 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 :

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 egnonin is formed, 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 :