348 3-Aminopyridine

Lloyd GK et al Assessment of the acute toxicity and potential irritancy of hair dye constituents. Food Cosmet Toxicol 15 607, 1977 

p-Aminophenol. Toxikologische Bewertung. Heidelberg, Berufsgenossenschaft der chemischen Industrie, pp 1-41, 1995 

Bio/Tox data on p-aminophe-nol from 1980. Washington, DC, Office of Toxic Substances, US Environmental Protection Agency, 1983 

Briggs D, Calder I, Woods R, Tange J The influence of metabolic variation on analgesic nephrotoxicity. Experiments with the Gunn rat. Pathology 14 349, 1982 

Klos C, Koob M, Kramer C, et al p-Aminophenol nephrotoxicity biosynthesis of toxic glutathione conjugates. Toxicol Appl Pharmacol 115 98-106, 1992 

In a 2-1. beaker equipped with a mechanical stirrer and immersed in an ice-salt bath is placed a solution of 75 g. (1.87 moles) of sodium hydroxide in 800 ml. of water. To the solution is added, with stirring, 95.8 g. (30.2 ml., 0.6 mole) of bromine. When the temperature of the solution reaches 0°, 60 g. (0.49 mole) of nicotinamide (Note 1) is added all at once with vigorous stirring. After being stirred for 15 minutes, the solution is clear. The ice-salt bath is replaced by a bath containing water at 75°, and the solution is stirred and heated at 70-75° for 45 minutes. 

The solution is cooled to room temperature, saturated with sodium chloride (about 170 g. is required), and extracted with ether in a continuous extractor (Note 2). The extraction time is 15-20 hours. The ether extract is adjusted to a volume of 1 1., dried over 4-5 g. of sodium hydroxide pellets, and filtered, and the ether is removed by distillation from a steam bath. The residue crystallizes on cooling. The yield of dark red crystals melting at 61-63° is 39-41 g. (83 -89%). 

The crude product is dissolved in a mixture of 320 ml. of benzene and 80 ml. of ligroin (b.p. 60 90°) and heated on a steam bath with 5 g. of Norit and 2 g. of sodium hydrosulfite for 20 

The nicotinamide should be finely powdered to facilitate rapid solution. 

The continuous extractor described by Pearl1 was used. If the material is extracted in a separatory funnel, four 800-ml. portions and ten 500-ml. portions of ether are required to give the above yield. 

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Aminopyridine (I) is converted by diazotisation in the presence of bromine and concentrated hydrobromic acid Into 2 broraopyridine (II) the latter upon treatment with copper powder in the presence of p-cymene yields 2 2 -dipyridyl (III). 

The important drug sulphapyridine (or M. B. 693 or 2-sulphaniIyl-aminopyridine) may be readily synthesised from 2-aminopyridine and p-acet-amidobenzenesulplionyl chloride (Section IX,9) as follows ... 

Aminopyridine. In a 1 litre three-neoked flask, equipped with a sealed mechanical stirrer, reflux condenser, thermometer and inlet tube for nitrogen, place 300 ml. of dry toluene (1) aud 75 g. of fine granular sodamide (2) bubble a steady stream of nitrogen thi ough the toluene. Stir the mixtiue vigorously and heat the flask in an oil bath until the internal temperatime is 110° (the bath temperatime required is approximately 130°). Add 100 g. of pure dry pyridine (compare Section 11,47,22)... 

Sulphapyridine. Dissolve 18-8 g. of 2-aminopyridine in 40 ml. of dry pyridine (Section 11,47,22) in a 250 ml. flask and add 48 0 g. of p-acetamidobenzenesulphonyl chloride (4) the temperature rises to about 70°. Cool, add excess of water, filter the precipitated 2-(p-acet-amidobenzonesulphonamido)p3Tidine (s acetyl-sulphapyridine) at the pump and recrystallise it from 50 per cent, acetic acid. The yield of pm product, m.py. 224°, is 46-5 g. 

Supplement 1953 3242-3457 Hydroxy-carboxylic acids, 190 In i doxylic acid, 226. Carbonyl-carboxylic acids, 284. i Sulphonic acids, 386 Quinoline sul-phonic acid, 390. Amines, 419 2-Aminopyridine, 428. Amino-carboxylic acids, 541 Tryp- tophane, 545. Hydrazines, 563. Azo. compounds, 572. Diazo compounds, 590. ... 

This reaction, thoroughly studied for 2-aminopyridine (14, 15), has received less attention in the case of the thiazole nucleus. 2-Amino-4-methylthiazole is formed when 4-methylthiazole is heated with sodium amide for 15 hr at 150°C (16). This reaction was used to identify 2-amino-4-butylthiazok (17). 

When carried out in dilute acid, diazotization of 2-aminothia2ole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

Treating 5.5 g of 2-amino-4,5-dimethylthiazole HCl with 0.66 g of solid sodium hydroxide 15 min at 220°C yields 53% of 4.4. 5.5 -tetramethyT 2,2 -dithiazolylamine, whose structure w as proved by identification with the produa obtained from the reaction between dithiobiuret and 3-bromo-2-butanone (467). This result is comparable to the reaction between 2-aminopyridine and its hydrochloride to yield bis(pyridyl-2)amine (468). Gronowitz applied this reaction to 2-aminothiazole, refluxing it with its hydrochloride 4 hr in benzene and obtained the dimeric 2-aminothiazole (236). He proposed a mechanism (Scheme 143) that involves the addition of a proton to the 5-position of the ring to give 234. The carbocation formed then reacts on the 5-position of a second... 

The reaction of C2S2 with 2-aminopyridine and /V-pbenylbensamidine yields the higher condensed derivatives C2S2 also reacts with p-aminocrotonate to yield H2NC(CH2)=C(COOC2H2)]2S (7). 

Dihydropyrido[2,3- /]pyrimidines have also been prepared from 3-acylaminomethyl-2-aminopyridines (53JA656). 

One of the most elegant of these involves the reaction of two moles of 2-aminopyridine with two moles of carbon dioxide under high temperature and pressure to give the 3-pyridyl-2,4-dione (279) (54USP2680741). 

The historieal aspeets of synthesis, study and applieation of heteroeyelie azoeompounds (HAC) pyridynie of a line in airalytieal ehemistry are eonsidered. Works of A.E. Chieibabin on diazotation of 2-aminopyridine and it azoeopulation with resoreinol (PAR) and 2-naphthol (PAN-2). 

In a 5-1, 3-necked flask fitted with a mechanical stirrer (Note 1), a dropping funnel, and a thermometer for reading low temperatures is placed 790 ml. (7 moles) of 48% h drobromic acid. The fl.ask and contents are cooled to 10-20 in an ice-salt bath, and 150 g, (1.59 moles) of 2-aminopyridine (Note 2) is added over a period of about 10 minutes. While the temperature is kept at 0° or lower, 240 ml. (4.7 moles) of bromine is added dropwise (Note 3). A solution of 275 g. (4 moles) of sodium nitrite in 400 ml. of water is added dropwise over a period of 2 hours, the temperature being carefully maintained at 0° or lower (Note 4). After an additional 30 minutes of stirring, a solution of 600 g. (15 moles) of sodium hydroxide in 600 ml. of water is added at such a rate that the temperature does not rise above 20-25° (Note 5). The nearly colorless reaction mixture is extracted with... 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

Thiophenealdehyde has been used in the reductive alkylation of 2-aminopyridine and 2-aminopyrimidine. 2-Arylamino-4- (2-thienyl )thiazoles have been prepared by the reaction of 2-acetylthio-phene with A-arylthioureas in the presence of iodine, ... 

The second group of chemical methods is based on a comparison of the structure (s) of the reaction product(s) with that of the starting material. These methods can be illustrated by the observation that l-methylpyrid-2-onimine (38) is formed when 2-aminopyridine (37) is allowed to react with methyl iodide followed by treatment with alkali. From these data it was incorrectly concluded that 2-aminopyridine reacted, or existed, in the imino form. Actually, the... 

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