Synthesis of Lidocaine

Lidocaine Lidocaine is 2-diethylamino-2, 6 -dimethylacetanilide (2.2.3). Synthesis of lidocaine is described in Chapter 2. 

The present synthesis of lidocaine (25) from 2,6-dimethylnitrobenzene (35) requires three steps, as shown in Scheme 21.5. Some of the details of each step in the sequence are discussed in the following paragraphs. 

The clinical success of hindered acetanilide derivatives, such as lidocaine, of course, resulted in the synthesis of many analogues. Branching in the acid moiety is consistent with activity as demonstrated by the local anesthetic properties of etidocaine (48)... 

This reaction is the first step in a synthesis of the drug lidocaine. 

Synthesis of[ 1-11C]-labelled ethyl, propyl, butyl and isobutyl iodides, and N-[1-11 C-ethyl]lidocaine, 178, N-[1-11C-butyl]bupivacaine, 179, and 3-nitrophenyl [1-11C]propyl ether, 180... 

Modulation of epidermal hpid biosynthesis has been reported to boost dmg delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum corneum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-dermal delivery of lidocaine or caffeine. Alteration of barrier function was produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-fiirancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (33). 

Triazole Derivatives. Triazole derivatives are known to possess tumor necrosis factor-a (TNF-a) production inhibitor activity. The synthesis of triazole derivatives can be achieved from alkynes or diynes by a tandem cascade reaction involving 1,3-dipolar cycloaddition, anionic cyclization and sigmatropic rearrangement on reaction with sodium azide. Some of the benzoyl triazole derivatives were considered to be potent local anaesthetics and are comparable with Lidocaine. The triazoles can also be prepared from benzoyl acetylenes,triazoloquina-zoline derivatives, 2-trifluoromethyl chromones, aliphatic alkynes, 2-nitroazobenzenes, ring opening of [ 1,2,4]triazolo [5,1-c] [2,4]benzothiazepin-10 (5//)-one, alkenyl esters and dendrimers. A number of these reactions are outlined in eqs 44 8. 

The compound 4-amino-5-nitrosalicylic acid is one of the building blocks needed for the synthesis of propoxycaine, one of the family of "caine" anesthetics. Some other members of this family of local anesthetics are procaine (Novocaine ), lidocaine (Xylocaine ), and mepiv-icaine (Carbocaine ). 4-Amino-5-nitrosalicylic acid is synthesized from salicylic acid in three steps (See Example 10.9)... 

After determining cocaine s structure, chemists could ask, "How is the structure of cocaine related to its anesthetic effects Can the anesthetic effects be separated from the habituation effect " If these questions could be answered, it might be possible to prepare synthetic drugs with the structural features essential for the anesthetic activity but without those giving rise to the undesirable effects. Chem -ists focused on three structural features of cocaine its benzoic ester, its basic nitrogen atom, and something of its carbon skeleton. This search resulted in 1905 in the synthesis of procaine, which almost immediately replaced cocaine in dentistry and surgery. Lidocaine was introduced in 1948 and today is one of the most widely used local anesthetics. More recently, other members of the "caine" family of local anesthetics have been introduced (e.g., etidocaine). All of these local anesthetics are administered as their water-soluble hydrochloride salts. 

With the development of DESs, they have been applied on some polymerization reactions that are carried out at relatively high temperatures. In these synthetic processes, the eutectic mixtures can act as true solvent-template reactant systems, and thus the DES is at the same time the precursor, the template, and the reactant medium for the fabrication of the desired polymeric material with a defined morphology or chemical composition. Monte and co-workers have reported i) the frontal polymerizations carried out in the eutectic mixtures ChCl/Acrylic acid and ChCl/Mac, " ii) the synthesis of poly(octane-diol-co-citrate) elastomers using eutectic mixtures of 1,8-octanediol and lidocaine at temperatures below 100 C (see Figure 20.3.4), " and iii) the synthesis of poly(acrylic acid)-carbon nanotube composites in the eutectic mixture ChCl/Aciylic acid. " ... 

Valenti, R, Montanan, R, Da Re, R, Soldani, G., Bertelli, A. Synthesis and pharmacological properties of three lidocaine cyclovinylogues. Arch. Pharm. 1980, 313, 280-284. 

The stratum comeum basically contains a mixture of cholesterol, free fatty acids, and ceramides, placed in multilayers. They mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Smdies have shown that each of the three key lipid classes is required for normal barrier function (37). These reports also show the potential of certain inhibitors of lipid synthesis to enhance the transdermal delivery of drugs like lidocaine or caffeine. Thus, the modulation of stratum cor-neum lipids is an important determinant of the barrier permeability to both hydrophobic and hydrophilic compounds transport and drag penetration. It has been reported that an inverse correlation exists between solute penetration and stratum comeum hpid content (38). 

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