Anthranilic acids, condensation

Path A involves N-formylation of anthranilic acid, condensation of the resultant 2-formaminobenzoic acid with the amine followed by intramolecular amidation of the intermediate amidine to form the product. On the other hand, the amine instead of anthranalic acid may be formylated and go through the known Niementowski reaction (path B). When the reaction of 2-formamidobenzoic acid with aniline and the condensation of formanilide with anthralic acid were conducted under microwave irradiation, the desired 3-phenylquinazolin-4(3 JT)-one was obtained in both cases in a few minutes in 68-87% yield. 

Phenylglycine-o-carboxylic acid. In a 750 ml. round-bottomed flask, fitted with a reflux condenser, place 14 g. of anthranilic acid (Section IV,170), 10 g. of chloroacetic acid, 20 g. of anhydrous sodium carbonate and 200 ml. of water. Reflux the mixture for. 3 hours, then pour into a beaker, cool, render shghtly acid with concentrated hy dro-chloric acid, and allow to stand overnight. Filter off the crude acid and wash it with water. Recrystalhse from hot water with the aid of a little decolourising carbon, and dry the acid at 100°. The yield of phenyl-glycine-o-carboxyhc acid, m.p. 208°, is 12 g. 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

Flufenamic acid (162) is a reasonably well-established NSAID (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassiuni salt with the hydroxyethyl ethyl ether of ethylenechlo-rohydrin affords the latendated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

N-(m-methylmercapto-phenyl)-aniline (MP 59° to 61°C) is prepared by condensing m-methyl-mercapto-aniline (BP 163° to 165°C/16 mm Hg) with the potassium salt of o-chloro-benzoic acid and decarboxylating the resultant N-(m-methylmercapto-phenyl)-anthranilic acid (MP 139° to 141°C) by heating, and then distilling. 

Most condensations of this type start with 2-aminobenzoic acid (anthranilic acid) derivatives. In an early, extensive work on the synthesis and chemistry of dianthranilides", acid chlorides 1 were used as starting materials.2... 

Table 3. Benzannulated 1,5-Diazocines by the Condensation of Anthranilic Acid Derivatives...

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. 

The first anthraquinone vat dye containing an acridone ring system was synthesised in 1909 by Ullmann. The parent compound (6.89) can be made by condensation of 1-chloroanthraquinone with anthranilic acid in the presence of copper, followed by cyclodehydration in concentrated sulphuric acid (Scheme 6.17). 

Quinacridones are not the only industrially significant products. The list may be extended to include the derivative mentioned in Section 3.2.1.4, the linear trans-quinacridone quinone. There are two other synthetic pathways besides the hydroquinone method. The older method involves cyclization of the 2,5-bis-(2 -carboxyanilino-)-l, 4-benzoquinone 63 with concentrated sulfuric acid or polyphos-phoric acid at 150 to 200°C. The starting material 63 is obtained through condensation of 1,4-benzoquinone with anthranilic acid ... 

One of the early steps in an allergic reaction consists in the release of a series of endogenous compounds referred to as mediators from sensitized cells. The finding in the early 1960s that cromolyn sodium, still the only approved drug of this class, blunts this reaction has led to an intense search for additional examples. It is of interest that a relatively simple anthranilic acid derivative has shown mediator-release inhibiting activity. Reaction of 3,4-dimethoxybenzalde-hyde (167) with isatoic anhydride 168 gives the condensation product 169, which, upon hydrolysis, affords tranilast (170) (43]. 

In the condensations of o-aminohenzyl alcohol 376 or anthranilic acid 401 with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) 402, imino-l,2,3-dithiazoles 403 were formed. Heating of the imino alcohol 403 (X = H2) in THE in the presence of NaH afforded an 11 1 mixture of 3,1-benzoxazine 404 and 3,1-benzothiazine 405 in moderate yield. Thermal cyclization of imino acid 403 (X = 0) resulted nearly quantitatively in formation of 3,1-henzoxazin-4-one 406 (Scheme 76) <1995CC1419, 1995J(P 1)2097, 1997SL704>. 

The gallium(lll) triflate-mediated condensation of anthranilic acid with fluorinated ketones gave the corresponding 2,2-disubstituted l,2-dihydro-4//-3,l-benzoxazin-4-ones in high yields <20070L179>. 

Aryl-5-mercapto-1,2,4-triazoles condense with anthranilic acid forming 3-ary 1-5,6-benzo-7-oxo-TPs [82IJC(B)377],... 

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). 

Condensations of anthranilic acid derivatives lead to the 6,12-diamino- and 6,12-dioxo-dibenzodiazocines, and the dichloro compound (279) is available from the latter (54JCS3429). Reduction of (279) via the dihydrazino compound was used to prepare the parent dibenzo[6,/][l,5]diazocine (280) (67CC1077). The NMR value (5 8.53 p.p.m.) of the 6(12) proton is indicative of the diazocine structure, presumably in a tub form, rather than the valence isomeric dibenzodiazapentalene (281). 

Pyrrolo[2, l-b]quinazolines (49) were obtained through the formation of their diazine ring by condensation of an anthranilic acid derivative with a pyrrole derivative such as O-alkylbutyrolactimes (48) [60GEPI088968 ... 

Laser irradiation of isatin (70) gave 71 as a result of bimolecular condensation (78TL3007). The diazine ring of 73 was formed during the cyclocondensation of anthranilic acids with the imidate esters derived from indolinone (72) (81AP271). 

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