Chlorination of anthranilic acid

As a structure proof, the compound was prepared by an alternate route 5-chloroanthranilic acid, prepared by the chlorination of anthranilic acid, according to J. Am. Chem.Soc. 68, 1303 (1946) was converted into 5-chloro-2-mercaptobenzoic acid by the method described in J. Org. Chem., 18, 1380 (1953), and the latter was condensed with benzene by means of sulfuric acid to yield 10-(2-chloro)thiaxanthenone, identical with that obtained by the first method. 

Dichloro-2-aminobenzoic acid can be prepared by the chlorination of anthranilic acid in glacial acetic acid solution J and by the action of sulfuryl chloride on anthranilic acid.4-5 The above procedure is derived from a more recent detailed study of the chlorination reaction.2... 

Carboxy-3,5-dichlorophenyl diazo-nium chloride, 31, 97 Catalyst, ammonium acetate, 31, 25, 27 copper chromite, 31, 32 ferric nitrate, hydrated, 31, 53 piperidine, 31, 35 piperidine acetate, 31, 57 Chlorination of anthranilic acid, 31, 96 Chlorine, 30, 24 31, 96 Chloroacetamide, 30, 22 Chloroacetonitrile, 30, 22 o-Chloroaniline, 31, 21... 

The diazonium salts usually decompose when warmed with water to give a phenol and nitrogen. When treated with CuCl, CuBr, KI, the diazo group is replaced by chlorine, bromine or iodine respectively (Sandmeyer reaction). A diazonium sulphate and hydroxyl-amine give an azoimide. The diazonium salt of anthranilic acid (2-aminobenzoic acid) decomposes to give benzyne. ... 

Condensation of anthrandic acid (77-1) with an iminoether represents another method for preparing quinazolones. The reaction with the iminoether (77-2) from 2-cyano-5-nitrofuran and ethanohc acid can be visualized as proceeding through the formation of the amidine from addition-elimination of anthranilic acid cycliza-tion then affords the observed product (77-3). This is then converted to chloride (77-4) in the usual way. Displacement of the newly introduced chlorine with diethanolamine leads to the formation of nifurquinazol (77-5) [86], one of the antibacterial nitrofmans (see Chapter 8). 

A. 3,5-Dicfdoro-2-aminobenzoic acid. A solution of 45 g. (0.33 mole) of anthranilic acid, 150 ml. of concentrated hydrochloric acid, and 850 ml. of water is placed in a 2-1. three-necked flask in a hood and weighed. While the solution is rapidly stirred, chlorine is introduced until the reaction mixture gains 45 g. (0.63 mole) in weight (Note 1). The flask is surrounded by a water bath to maintain the temperature of the reaction mixture below 30° during the chlorination procedure. The reaction mixture is filtered by suction, using a large (10-12 in.) Buchner funnel the crude product is washed with water and then dried at room temperature (Note 2). There is obtained 55 -65 g. of... 

In an I.G. Farben patent [180] the use of disulfur dichloride is described in place of sulfur (method BJ. Possibly the intermediates here are 1,3,2-benzothiazathiolium chlorides (CV) which react with carbon disulfide to give benzothiazoline-2-thiones (CIII). In some instances, the cycUzations are carried out in the presence of sodium hydrosulfite or sodium sulfide. A peculiarity of this reaction is that, simultaneously with the cyclization, chlorination of the arylene ring occurs. Thi.s is not a general rule though. It happens with aniline, o-toluidine, o-anisidine and oc-naphthylamine but not with /)-phenetidine, )S-naphthylamine or benzidine. It seems quite clear therefore that the para position of the aniline must be free if chlorination is to take place, since it is in this position that the chlorine atom is brought in. With anthranilic acid there is formed 4-carbox -6-phenylaminobenzothiazoline-2-thione which shows that the chlorine atom, which is substituted during the reaction, is replaced by a second molecule of anthranilic acid and that decarboxylation occurs at the same time. 

The only practical methods of preparing o-chlorobenzoic acid consist in the oxidation of o-chlorotoluene and the replacement of the amino group in anthranilic acid by a chlorine atom. Both of these methods have been fully discussed by Graebe,1 who recommends the former for the preparation of relatively large quantities. The oxidation of o-chlorotoluene by permanganate was originally described by Emmerling.2... 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

Chlorination of the known triazinone 304 <1989IJB647>, followed by reaction with anthranilic acid, gave the benzopyrido[2, 3 5,6]-l,2,4-triazino[4,3-f]quinazolinone 306 (Scheme 51) <1996IJB1026>. 

Many other industrial methods are now employed e.g. one starts (22) with anthranilic acid which is diazotised and treated with liquid sulfur dioxide in presence of copper as catalyst. The sulphinic acid derivative thereby obtained is treated with chlorine in alkaline solution and sulfonyl chloride so obtained is treated with ammonia and heated. 

Synthesis from Phthalic Acid and Naphthalene.— This was found when anthranilic acid was synthesized from ortho-phthalic acid which, as has been stated, may in turn be synthesized from naphthalene, a cheap abundant compound. The conversion of naphthalene into or//fo-phthalic acid we have given (p. 689) as resulting from chlorination and subsequent oxidation. 

The reaction is accomplished by simply heating together phthalic anhydride and ammonium carbonate. Phthalimide then hydrolyzes with potassium hydroxide yielding the potassium salt of phthalamidic acid and this acid amide compound undergoes the Hofmann reaction (pp. 148, 685) with bromine (or chlorine) and potassium hydroxide by which one of the carboxyl groups is replaced by the amino group yielding amino benzoic acid or anthranilic acid. 

The oxide is in general very stable towards acids and alkalies, but when boiled with 20 per cent, hydrochloric acid it is transformed into anthranil. Treatment with chlorine in presence of an excess of hydrochloric acid gives o-nitrobenzylmercuric chloride, and bromine and iodine yield the corresponding halides. 

The glutaconic aldehyde formed in the reaction of cyanogen bromide with pyridine has been condensed with anthranilic acid [12]. In the determination of cyanide, use has also been made of the polymethine dye which is formed in the reaction of cyanogen chloride with pyridine and barbituric acid. Chloramine T has been used for the chlorination of cyanide. This highly sensitive method (e = 1.0-10 at 580 nm) has been studied in detail [13—16]. 4-Methylpyridine has been suggested instead of pyridine [17]. 

A number of methods are available for the synthesis of saccharin. For many years, the most popular process was one developed by the Maumee Chemical Company of Toledo, Ohio, in 1950. This method begins with anthranilic acid (oaminobenzoic acid C6H4(NH2)C00H), which is treated successively with nitrous acid (HN02), sulfur dioxide (S02), chlorine (Cl2), and ammonia (NH3) to obtain saccharin. Another process discovered in 1968 starts with o-toluene, which is then treated with sulfur dioxide and ammonia to obtain saccharin. 

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