Esters of p-Aminobenzoic Acid

Mannich, C. Krosche, W. Arch. Pharm. 1912, 250, 647. Carl U. F. Mannich (1877-1947) was bom in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Gottingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics. 

A similar set of reactions has been carried out with the ethvl ester of p-aminobenzoic acid, but in addition a mercuric acetate salt of aeetoxy-mercuri-p-aminobenzoic acid has been obtained, and the mono and diacetoxymercuri derivatives may be isolated from this under suitable conditions. Also in the case of this ester only the diacetoxymercuri compound has been obtained directly from the N-isodiaeetoxymercuri derivative, direct mercuration being used to obtain the monoaeetoxy-inercuri product. 

In 1896 and 1897 Eucaine A and Eucaine B were prepared and came into general use as a result of their potent action. These compounds indicated that the entire condensed ring system of cocaine was not necessary for activity. The common denominator in all of the compounds so far found active was that they were amino esters. Shortly after 1900 Einhorn foimd that alkyl esters of p-aminobenzoic acid were active anesthetics, and a little later he found that the dialkylaminoalkyl esters were more active... 

Figure 5.2 Cumulative flux of alkyl esters of p-aminobenzoic acid through a synthetic dimethylpolysiloxane membrane. [Reproduced from G. L. Flynn and S. H. Yalkowsky, J. Pharm. Set, 61, 838. Copyright 1972. This material is used by permission of Wiley-Liss Inc., a subsidiary of John Wiley Sons, Inc.]...

TABLE 5.1 Steady-State Flux of Esters of p-Aminobenzoic Acid across a Dimethylpolysiloxane Membrane... 

Mackay and Hughes (1984) reported that narcosis in goldfish acutely exposed to a series of alkyl esters of p-aminobenzoic acid appeared to occur at an internal body concentration of about 4.36 mol m (4.36 mmol L" ) irrespective of the ester. The mean acute toxicity constant for narcotics calculated herein, 2.0 mmol L is in close agreement. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

Procaine is a derivative of p-aminobenzoic acid, and is a one of the oldest used ester-type local anaesthetic agents [1], The compound was originally developed by Einhom [2,3], and later with and Uhlfelder [4]. This anti-arrhythmic drug itself has a short half-life, but is able to form salts with other drugs which causes an increase in the duration of action [5]. 

Ethyl p-aminobenzoate. Saturate 80 ml (63.2 g, 1.37 mol) of absolute ethanol with dry hydrogen chloride, add 12 g (0.088 mol) of p-aminobenzoic acid and heat the mixture under reflux for 2 hours. Upon cooling, the reaction mixture sets to a solid mass of the hydrochloride of ethyl p-aminobenzoate. It is better, however, to pour the hot solution into excess of water (no hydrochloride separates) and add sodium carbonate to the clear solution until it is neutral to litmus. Filter off the precipitated ester at the pump and dry in the air. The yield of ethyl p-aminobenzoate, m.p. 91 °C, is 10 g (69%). Recrystallisation from rectified spirit does not affect the m.p. 

Fife et al. have reported intramolecular GB-assisted ester hydrolysis. The pseudo-first-order rate constants (k bj.) are pH-independent from pH 8 to pH 4. The triflnoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid hydrolyze with similar rate constants in the pH-independent reactions, and the rates of these water reactions are twofold slower in D2O than in HjO. The most likely mechanism involves the intramolecular GB assistance by the neighboring amino group. The rate enhanc ents in the pH-independent reaction in comparison with the pH-indepen-dent hydrolysis of the corresponding para-substituted esters are 50- to 100-fold. 

Dialkylphosphonoacetic acid esters react with p-aminobenzoic acid to anilides. The potassium salt of the diamyl ester is said to be surface-active [126]. Phosphorus organic carbonic acid amides can also be obtained by the following reaction [127] see Eq. (76). 

It is noteworthy that cyanoguanidine and p-aminosalicylic acid react in acidified boiling water with simultaneous decarboxylation [608), giving m-hydroxyphenylbiguanide instead of the expected l-(3-hydroxy-4-carboxyphenyl)biguanide. The decarboxylation under such mild conditions appears to be anomalous, since p-aminobenzoic acid [100) and its esters [97) do give the expected biguanides. 

The ester-type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a small percentage of the patient population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to amide local anesthetics are extremely rare. 

Topical medications useful in protecting against sunlight contain either chemical compounds that absorb ultraviolet light, called sunscreens, or opaque materials such as titanium dioxide that reflect light, called sunshades. The three classes of chemical compounds most commonly used in sunscreens are p-aminobenzoic acid (PABA) and its esters, the benzophenones, and the dibenzoylmethanes. 

Mercuric acetate salt of acetoxymercuri-p-aminobenzoic acid ethyl ester,... 

Description and classification of substances is of course not always easy, and the information provided in a UV spectrum is not always sufficient for identification, but it should be possible with the aid of this type of picture and information to classify quite rapidly some substances not included in the selection from their UV spectra, according to the chemical (and sometimes also the therapeutic) group defined by their chromophores. For example, it is logical to assume an analgesic/antipyretic classification from a pyrazolone spectrum, while conversely if a substance is thought to be a local anaesthetic, the analyst will consider p-aminobenzoic acid esters or base-substituted anilides, and will read the spectrum from this aspect. 

Local anesthetics make use of the lipophobic property of an aromatic amine moiety, or its acyl derivative, that links with a hydrophilic amino acid. The products include the anilide lidocaine, or 2-(diethylamino)-A-(2,6-dimethylphenyl)acetamide (153), the toluidine derivative prilocaine and the century-old procaine, 2-diethylaminoethyl 4-aminobenzoate (154)84. The ester is prepared by reacting p-aminobenzoic acid with ethylene chlorohydrin and diethylamine. 

In the body, the ester link of procaine is hydrolyzed, yielding p-aminobenzoic acid (PABA) and N,h/-diethyl-aminoethanol (DEAE), an analog of DMAE. It is PABA (Figure 3.11) that is responsible for the large majority of allergic reactions to procaine it is excreted rapidly by the kidneys. PABA is most often used as a sunscreen, but is sometimes called vitamin B-x , although it is not essential for humans and the body cannot synthesize folate from PABA. According to some authors, the Aslan method relies solely on the combined action of PABA and DEAE/DMAE. It is assumed that the action of PABA is due to its anti-free-radical properties. 

A further possible use is in the field of synthetic lubricants. The most likely use for the pyromellitate esters are as viscosity improvers(45), as the esters have quite high viscosities. They cannot be used at high temperatures, however, as at elevated temperatures they pyrolyse to form PMDA. There is an alternative use for PM LA in high temperature greases where pyrolysis is prevented by the formation of diimides, e.g. by reacting PMDA with p-aminobenzoic acid(46) and subsequently forming esters. Extreme pressure greases have also been claimed with the use of diimide derivatives(47). 

Aromatic monoamines, having a minimum one additional functional group, and being found in the patent literature of poly(ester-imide)s, are the aforementioned p-aminobenzoic acid [48, 77], the p-aminophenol [78], the aminoth-erephthalic acid [79] and the p-aminobenzenesulfonic acid [80], but probably none of these monomers were ever used for large scale production. Also the di-aminobenzenes had no economical success as wire enamel raw materials, probably because they were too expensive, too toxic and because they have, in bulk, insufficient storage stability. 3,5-Diaminotriazole-(l,2,4) was claimed as raw material for wire enamel resin yielding films with improved hardness [81]. 

A very recent synthesis of a thermotropic copolyimide contains an AT-(car-boxyphenyl) trimellitimide ester unit linked to a p-aminobenzoic acid via an amide linkage, which in turn is linked by an alkane diol unit back to the trimellitimide unit [86]. This is probably the first example of a copoly(ester-amide-im-ide) with mesogenic properties identified. Its MI score is 9.6. 

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