P-aminobenzoates

White crystals, m.p. 90-9 rC. Prepared fromp-nitrotoluene by way of p-aminobenzoic acid. It is used as a local anaesthetic on mucous surfaces internally and by injection, and is taken internally to relieve gastric pain. 

The action of the sulphonamides is antagonized by p-aminobenzoic acid and they act by inhibiting the uptake and utilization of 1-aminobenzoic acid by bacterial cells, which require this as a precursor of folic acid. 

Successful results have been obtained (Renfrew and Chaney, 1946) with ethyl formate methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and iso-amyl acetat ethyleneglycol diacetate ethyl monochloro- and trichloro-acetates methyl, n-propyl, n-octyl and n-dodecyl propionates ethyl butyrate n-butyl and n-amyl valerates ethyl laurate ethyl lactate ethyl acetoacetate diethyl carbonate dimethyl and diethyl oxalates diethyl malonate diethyl adipate di-n-butyl tartrate ethyl phenylacetate methyl and ethyl benzoates methyl and ethyl salicylates diethyl and di-n-butyl phthalates. The method fails for vinyl acetate, ieri.-butyl acetate, n-octadecyl propionate, ethyl and >i-butyl stearate, phenyl, benzyl- and guaicol-acetate, methyl and ethyl cinnamate, diethyl sulphate and ethyl p-aminobenzoate. 

The p-substituted amino ketones can be reduced readily to the more stable P-dialkylamino alcohols, many of which are useful local anaesthetics. Thus the local anaesthetic Tutocaine is made from the Mannich base derived from formaldehyde, methyl ethyl ketone and dimethylamine, followed by reduction and conversion into the p-aminobenzoate ... 

Amino-3 5-diiodobenzoic acid. In a 2 litre beaker, provided with a mechanical stirrer, dissolve 10 g. of pure p-aminobenzoic acid, m.p. 192° (Section IX,5) in 450 ml. of warm (75°) 12 -5 per cent, hydrochloric acid. Add a solution of 48 g. of iodine monochloride (1) in 40 ml. of 25 per cent, hydrochloric acid and stir the mixture for one minute during this time a yellow precipitate commences to appear. Dilute the reaction mixtiue with 1 litre of water whereupon a copious precipitate is deposited. Raise the temperature of the well-stirred mixture gradually and maintain it at 90° for 15 minutes. Allow to cool to room tempera-tiue, filter, wash thoroughly with water and dry in the air the yield of crude acid is 24 g. Purify the product by dissolving it in dilute sodium hydroxide solution and precipitate with dilute hydrochloric acid the yield of air-dried 4-amino-3 5-diiodobenzoic acid, m.p. >350°, is 23 g. 

Ethyl p-aminobenzoate (esterification of p-aminobenzoic acid). Place 80 ml. of absolute ethyl alcohol in a 250 ml. conical flask equipped with a two-holed cork and wash-bottle tubes. Pass dry hydrogen chloride (Section 11,48,2) through the alcohol until saturated—the increase in weight is about 20 g.—and transfer the solution to a 250 ml. round-bottomed flask. Introduce 12 g. of p-aminobenzoic acid, fit a double surface condenser to the flask, and reflux the mixture for 2 hours. Upon... 

Bacteria require p-aminobenzoic acid to biosyn thesize folic acid a growth factor Structurally sul fanilamide resembles p-aminobenzoic acid and is mistaken for it by the bacteria Folic acid biosynthesis IS inhibited and bacterial growth is slowed suffi ciently to allow the body s natural defenses to effect a cure Because animals do not biosynthesize folic acid but obtain it in their food sulfanilamide halts the growth of bacteria without harm to the host... 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

This interesting conversion of a five- into a six-membered heterocyclic ring was proven by the isolation of the enzyme GTP-cyclohydrolase from E. coli (71MI21600) and a similar one from Lactobacillus platarum (B-71MI21601) which catalyzes the reaction (300)(303). Dephosphorylation leads to 7,8-dihydro-D-neopterin (304), which is then cleaved in the side-chain to 6-hydroxymethyl-7,8-dihydropterin (305), the direct precursor of 7,8-dihy-dropteroic acid and 7,8-dihydrofolic acid (224). The alcohol (305) requires ATP and Mg " for the condensation with p-aminobenzoic and p-aminobenzoylglutamic acid, indicating pyrophosphate formation to (306) prior to the substitution step. 

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. 

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