Acetyl aminophenol

Phenacetin may be conveniently prepared in the laboratory from p-amino-phenol. The latter is readily acetylated with acetic anhydride to give p-acetyl-aminophenol this Is ethylated in the form of the sodio derivative to yield acetyl p-phenetidine (phenacetin) ... 

Obtained by reaction of propionyl chloride with 2-acetyl-aminophenol in DMF in the presence of aluminium chloride at 85° for 5 h [6913]. 

A) Benzoyl Derivative. Since acetylation and benzoylation do not always proceed smoothly with nitrophenols, it is best to reduce them to the aminophenol as in (3) above. Add an excess of 20% aqueous sodium hydroxide to the reaction mixture after reduction, cool and then add a small excess of benzoyl chloride, and shake in the usual way. The dibenzoyl derivative wiU separate. Filter, wash with water and recrystalUse. (M.ps., p. 551.)... 

Suspend 11 g. of p-aminophenol in 30 ml. of water contained in a 250 ml. beaker or conical flask and add 12 ml. of acetic anhydride. Stir (or shake) the mixture vigorously and warm on a water bath. The solid dissolves. After 10 minutes, cool, filter the solid acetyl derivative at the pump and wash with a little cold water. Recrystallise from hot water (about 75 ml.) and dry upon filter paper in the air. The yield of p-acetylaminophenol, m.p. 169° (1), is 14 g. 

Acylation. Reaction conditions employed to acylate an aminophenol (using acetic anhydride in alkaU or pyridine, acetyl chloride and pyridine in toluene, or ketene in ethanol) usually lead to involvement of the amino function. If an excess of reagent is used, however, especially with 2-aminophenol, 0,A/-diacylated products are formed. Aminophenol carboxylates (0-acylated aminophenols) normally are prepared by the reduction of the corresponding nitrophenyl carboxylates, which is of particular importance with the 4-aminophenol derivatives. A migration of the acyl group from the O to the N position is known to occur for some 2- and 4-aminophenol acylated products. Whereas ethyl 4-aminophenyl carbonate is relatively stable in dilute acid, the 2-derivative has been shown to rearrange slowly to give ethyl 2-hydroxyphenyl carbamate [35580-89-3] (26). 

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80°C (191), with acetic acid anhydride in pyridine at 100°C (192), with acetyl chloride and pyridine in toluene at 60°C (193), or by the action of ketene in alcohoHc suspension. 4-Hydroxyacetanihde also may be synthesized directiy from 4-nitrophenol The available reduction—acetylation systems include tin with acetic acid, hydrogenation over Pd—C in acetic anhydride, and hydrogenation over platinum in acetic acid (194,195). Other routes include rearrangement of 4-hydroxyacetophenone hydrazone with sodium nitrite in sulfuric acid and the electrolytic hydroxylation of acetanilide [103-84-4] (196). 

Thus, acetylation of aniline affords acetanilide (20), an analgesic widely used in proprietary headache remedies. A similar transformation on p-aminophenol gives the analgesic, acetaminophen (21). It is of interest that the latter is also formed in vivo on administration of 21. An interesting preparation of this drug involves Schmidt rearrangement of the hydrazone (24) from p-liydroxyacetophenone. ... 

The key to clinical agents in this series, the secondary amine, 65, is obtained by a sequence analogous to that used to obtain desmethymorphine. Thus, the phenol (63) is first acetyl-ated (64), and then demethylated by treatment with cyanogen bromide hydrolysis gives the desired aminophenol (65). Alkylation... 

To the filtrate obtained, there are then added about 0.2 gram of sodium hydrosulfite or sodium sulfite and 15.0 grams of anhydrous sodium acetate in about 27 grams of acetic anhydride at 40°C. The reaction mixture formed is cooled to 8° to 10°C with stirring and held at this temperature for 60 minutes. A crystalline precipitate of about 27 grams of N-acetyl-p-aminophenol is obtained melting at 169°-171°C. This is equivalent to a yield of 85%. 

Example 1 65 grams of N-acetyl-p-aminophenol were slurried with 400 ml of water and cooled to 10°C. 125 ml of 20% sodium hydroxide were slowly added to the mixture with... 

Example 2 65 grams of sodium N-acetyl-p-aminophenol were slurried with 500 grams of dry benzene and 80 grams of acetyl salicoyl chloride added. The mixture was heated under reflux for four hours and filtered hot. The excess benzene was removed under vacuum and the crude acetyl salicyclic acid ester of N-acetyl-p-aminophenol crystallized from ethanol. 

N-substituted phenylhydroxylamine derivatives, e.g. N-acetyl and N-sulphonic acid, also form the para-aminophenol", but more bulky groups prevent reaction, it is thought by steric hindrance to the approach of the hydronium ion. -substituted phenylhydroxylamines, on the other hand form only the ortho product, it is thought via an intramolecular rearrangement, e.g. 

Tylenol paracetamol N-acetyl-para-aminophenol para-acetyl-amino-phenol... 

Various hydroxyl and amino derivatives of aromatic compounds are oxidized by peroxidases in the presence of hydrogen peroxide, yielding neutral or cation free radicals. Thus the phenacetin metabolites p-phenetidine (4-ethoxyaniline) and acetaminophen (TV-acetyl-p-aminophenol) were oxidized by LPO or HRP into the 4-ethoxyaniline cation radical and neutral V-acetyl-4-aminophenoxyl radical, respectively [198,199]. In both cases free radicals were detected by using fast-flow ESR spectroscopy. Catechols, Dopa methyl ester (dihydrox-yphenylalanine methyl ester), and 6-hydroxy-Dopa (trihydroxyphenylalanine) were oxidized by LPO mainly to o-semiquinone free radicals [200]. Another catechol derivative adrenaline (epinephrine) was oxidized into adrenochrome in the reaction catalyzed by HRP [201], This reaction can proceed in the absence of hydrogen peroxide and accompanied by oxygen consumption. It was proposed that the oxidation of adrenaline was mediated by superoxide. HRP and LPO catalyzed the oxidation of Trolox C (an analog of a-tocopherol) into phenoxyl radical [202]. The formation of phenoxyl radicals was monitored by ESR spectroscopy, and the rate constants for the reaction of Compounds II with Trolox C were determined (Table 22.1). 

Aniline is rapidly and extensively metabolized following oral administration. In the pig and sheep, approximately 30% of a 50-mg/kg dose of 14C-labeled aniline was excreted in the urine, as measured by 14C activity, within 3 h after administration, whereas approximately 50% of the dose was excreted in rats. Within 24 h, more than half the administered dose was excreted by pigs and sheep and 96% of the dose was excreted by rats. Fecal radioactivity was low. A-acetylated metabolites accounted for most of the excretion—/V-acetyl-/>-aminophenyl glucuronide being the primary metabolite in sheep and pig urine and /V-acetyl-/>-aminophenyl sulfate being the primary metabolite in the rat (Kao et al. 1978). Biologic monitoring of workers exposed to aniline showed that /i-aminophenol constituted 15-55% of the parent compound in the urine the o- and ra-isomers were also formed (Piotrowski 1984). 

Acetal formation, microwaves in, 76 557 Acetalization, of PVA, 25 602-603 Acetal polymerization, 74 271 Acetal resins, 70 183-185 Acetal resins, formaldehyde in, 72 122 Acetals, 2 64 70 529 aroma chemicals, 3 253 inorganic pigment applications, 7 372t organic pigment applications, 7 368t typical soluble dye applications, 7 376t Acetaminophen, 4 701. See also AT-Acetyl-p-aminophenol (acetaminophen)... 

Acetylium tetrailuoroborate, 4 144t N-Acetyl-p-aminophenol (acetaminophen), acetic anhydride used in production of, 1 158. See also Acetaminophen Acetyl perchlorate, 1 157 Acetylsalicylic acid (aspirin), 22 17-21 acetic anhydride used in production of, 1 158... 

Phenazo- pyridine Analgesic HaN v) NHa 35 2 -, 4 - and 5-hydro-xylations cleavage to 4-aminophenol, followed by N-acetylation 4 -Hydroxylation and 4 -0-sulfate conjugation (Cunninghamella echinulata) [98]... 

The different reactivities associated with nucleophiles and leaving groups is nicely exemplified in the synthesis of the analgesic drug paracetamol (USA acetaminophen) from 4-aminophenol. If 4-aminophenol is treated with an excess of acetic anhydride, aeetylation of both amino and phenol groups is observed, and the product is the diacetate. Paracetamol is the A-acetate of 4-aminophenol, so how might mono-acetylation be achieved There are two approaches. 

Acetaminophen (APAP, N-acetyl-p-aminophenol) (Tylenol, other generic)... 

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