P-Aminobenzoic acid esters

Halogen-substituted T,2, 3, 4 -tetrahydro-l-naphthyl-1,4,5,6-tetrahydropyri-midines, such as (XCVll), and their non-toxic water-soluble salts, are useful as hypotensive agents [681] 2-(p-Aminophenyl)-l,4,5,6-tetrahydropyrimidines (XCVlll), prepared from p-aminobenzoic acid ester and a,co-diaminoalkanes, are active as local anaesthetics over a wide pH range [682]. 

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. 

Molecular shape also affects ahgnment in the crystal. Molecules with A-type structure, which is produced by two / NA or p-aminobenzoic acid ester molecules linked by a methylene group, tend to stack hke piled shuttlecocks, and formation of a polar array was expected. Actually, many SHG-active crystals represented by NJ< -bis(4-ethoxycarbonylphenyl)diaminomethane (ECPMDA) were reported. ... 

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. 

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). 

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. 

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. 

Finally, the zwitterion is not the major form for all amino acids. For both o-aminobenzoic acid (anthrani-lic acid) and p-aminobenzoic acid, the uncharged species is the more prevalent form whereas the zwitterion/uncharged ratio for m-aminobenzoic acid is about 2.31. This behavior arises primarily from the low pK values for the aromatic ring s amino group e.g., the pi i and pKi values for anthranUic acid are 2.05 and 4.95 and the pA"a value for the ester is only 2.09). 

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]. 

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. 

First convert p-aminobenzoic acid to its ethyl ester by Fischer esterification, and then treat the... 

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. 

The ester-containing local anesthetics become metabolized to p-aminobenzoic acid derivatives, which have a potential for causing hypersensitivity reactions. Allergic reactions to amide are... 

SYNS AMERICAINE p-AMINOBENZOIC ACID ETHYL ESTER 4-AMINOBENZOIC ACID ETHYL ESTER ANESTHESIN ANESTHONE BENZOCAINE ETHYL AMINOBENZOATE ETHYL-p-AMNOBENZOATE KELOFORM NORCAIN ORTHESIN PARATHESIN TOPCAINE... 

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. 

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

Acetoxymercuri-p-aminobenzoic ethyl ester.—A mixture of 3 grams of the ethyl ester and 6 3 grams of mercuric acetate is heated in a glycerine bath. At 180° C. the mass becomes liquid and acetic acid is evolved, and as the temperature rises to 160° C. the melt solidifies. The product is cooled, pulverised, and extracted with methyl alcohol, the solution partly evaporated and diluted with hot water. The acetate crystallises in shining, bushy needles as the solution cools. Yield 2 3 grams. 

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]. 

Another possibility for obtaining imide modified thermoplastic polyesters was to use as a monomer the hydroxy acid made from trimellitic anhydride and aminoethanol. Such a poly(ester-imide) was claimed for injection molding [240]. For the same use, poly(ester-imide)s containing aminophenol/trimellitic anhydride [241],imidised polyfbutylene terephthalate) [242] and a wholly aromatic poly(ester-imide) made from trimellitic anhydride, p-aminobenzoic acid, p-acetoxybenzoic acid, diacetoxybiphenyl and terephthalic and isophthalic acids are known, which showing optical anisotropy [243]. 

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