Benzocaine ethyl p-aminobenzoate

Benzocaine (or anaesthesine) is conveniently prep ared from p-nitrobenzoic acid by either of the following methods  

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 

Method 2. Ethyl p-nitrobenzoate. Place 21 g. of p-nitrobenzoic acid (Section IV,154), 11-5 g. of absolute ethyl alcohol, 3 8 g. of concentrated sulphuric acid, and 30 ml. of sodium-dried A.R. benzene in a 250 ml. round-bottomed flask, fit a reflux condenser, and heat the mixture under reflux for 16 hours. Add 50 ml. of ether to the cold reaction mixture, wash the extract successively with sodium bicarbonate soiution and water, dry with anhydrous magnesium sulphate or calcium chloride, and distil off the solvent on a water bath. Remove the last traces of benzene either by heating in an open evaporating dish on a water bath or in a bath at 100-110°. The residual ethyl p-nitrobenzoate (21 g.) solidifies completely on cooling and melts at 56°. 

---

Benzocaine (ethyl p-aminobenzoate) is used topically by itself or in combination with menthol or phenol in nonprescription dosage forms such as gels, creams, ointments, lotions, aerosols, and lozenges to relieve pain or irritation caused by such conditions as sunburn, insect bites, toothache, teething, cold sores or canker sores in or around the mouth, and fever blisters. Benzocaine is a lipophilic local anesthetic agent with a short duration of action. 

Devise a synthesis of benzocaine, ethyl p-aminobenzoate (H2NC6H4CO2CH2CH3), from benzene, organic alcohols, and any needed organic or inorganic reagents. Benzocaine is the active ingredient in the topical anesthetic Orajel (Section 18.14C). 

A. Ethyl 4-Amino-3-(methylthiomethyl)benzoate [Benzoic acid, 4-amino-3-[(methylthio)methyl]-]. A 1-1., three-necked, round-bottomed flask is fitted with a mechanical stirrer, a condenser topped with a gas-inlet tube, and a two-neckcd adapter holding a low-temperature thermometer and a 100-ml., pressure-equalizing dropping funnel. The flask is charged with 10.50 g. (0.10 mole) of ethyl p-aminobenzoate [Benzocaine Benzoic acid, 4-amino-, ethyl ester] (Note 1), 300 ml. of acetonitrile, and 100 ml. of dichloromethane, is flushed with nitrogen, and is then immersed in a 40% aqueous methanol-dry ice bath maintained between... 

A somewhat different mechanism was deduced by Baker and Bailey 4f) from their own studies of the systems phenyl isocyanate and ethyl p-aminobenzoate (benzocaine) cyclohexyl isocyanate and aniline phenyl isocyanate and aniline p-methoxyphenyl isocyanate and aniline. While Craven postulates one complex. Baker and Bailey assume two complexes of the isocyanate one with the amine, and one with the product urea. 

It should be mentioned that several more drastic simplifications of cocaine appeared on the scene even earlier. The only survivor is ethyl p-aminobenzoate (benzocaine, Table 13-6, No. 5). The others of interest were methyl p-amino-m-hydroxybenzoate (ortho-form), which, like benzocaine, was nontoxic, highly insoluble, and therefore not suitable for parenteral administration. Orthoform has no activity on intact skin, but it was useful as a powder on painful wounds. It was superseded commercially by the position isomer p-hydroxy-m-aminobenzoate methyl ester for reasons of cost since large-scale production of orthoform (as the pure, correct isomer) presented difficulties at the time. It should be pointed out that water-soluble hydrochlorides of the aminobenzoates can be prepared however, their solutions are much too acidic to inject. 

The acid dissociation constant of benzocaine has been given as pXa 2.5 (12). Estimation of microequilibrium constant of ethyl p-aminobenzoate was done spectrophotometrically and a K value of 0.00417 (NB pK = 2.38) was obtained. Spectrophotometric method applied for estimating microequilibrium constants is simpler, faster, and more accurate than the conventional method employing the dissociation constant of the alkylated derivative (13)."... 

Benzocaine. See Ethyl-p-aminobenzoate Benzochinamide. See Benzoguanamine Benzo dark green. See Direct green 1 1H,3H-Benzo(1,2-c 4,5-c ) difuran-1,3,5,7-tetrone. See Pyromellitic dianhydride Benzodihydropyrone 1,2-Benzodihydropyrone. See Dihydrocoumarin... 

Ethyl o-aminobenzoate. See Ethyl anthranilate Ethyl-p-aminobenzoate CAS 94-09-7 EINECS/ELINCS 202-303-5 Synonyms 4-Aminobenzoic acid ethyl ester p-Aminobenzoic acid ethyl ester Benzocaine Benzoic acid, 4-amino-, ethyl ester Benzoic acid, p-amino-, ethyl ester 4-Carbethoxyaniline 4-(Ethoxycarbonyl) aniline Ethylaminobenzoate Ethyl-4-aminobenzoate Ethyl p-aminophenylcarboxylate Ethyl PABA (INCI)... 

In the procedure described in this section, you will perform the Fischer esterification of p-aminobenzoic acid (16) with ethanol to give ethyl p-aminobenzoate (17), more commonly known as benzocaine, according to Equation 20.4. Benzocaine is a useful topical anesthetic, and the discovery of its anesthetic properties represents an interesting example of "rational drug design" as described in the Historical Highlight at the end of this chapter. 

For example, reduction of ethyl p-nitrobenzoate with H2 and a palladium catalyst forms ethyl p-aminobenzoate, a local anesthetic commonly called benzocaine. 

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. 

---