Anthranilic ester, condensation with

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. 

A somewhat different approach is used for the preparation of the analogue that contains a trifluoromethyl group. The scheme involves first the conversion of ort/zo-trifluoromethyl aniline (27-1) to a quinolol. The compound is thus condensed with EMME and cyclized thermally (27-2). That intermediate is then saponified the resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (27-3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (27-4) then affords the coupled intermediate (27-5). An ester interchange of that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID flocatfenine (27-6) [31]. 

A quinazolone moiety also provides the nucleus for a highly simplified leukotriene antagonist (compare this compound with verlukast (29-6), discussed earlier in this chapter). Condensation of the anthranilate ester (85-1) with formamide leads to the formation of the quinazolone (85-2). Reaction of the salt from the reaction of this product with a strong base with ethyl 3-bromoacrylate leads to vinylation on nitrogen by what is probably an addition-elimination sequence the product is largely the E isomer (85-3). Saponification then affords tiacrilast (85-4) [95]. 

An efficient method for the synthesis of 2-substituted benzoxazin-4-ones was performed by the condensation of anthranilic acid (436) with various orthoesters by classical heating for 1 2h to give 75 91% yields. But under MWI in an open vessel, a rapid formation of benzoxazin-4-ones 439 in high yields (76-94%) took place within 1-5 min (Scheme 86). The reaction may proceed through the imidic ester intermediate 437, which upon nucleophilic attack by the carboxyl oxygen produced the cycKzed intermediate 438 that then eliminated a molecule of alcohol to give 439 (97JCR(S)286). 

Analogously, anthranilonilrile 79 was also used as starling material for the preparation of quinazolinones. Chowdhury and co-workers reported the synthesis of ting fused thioquinazolinone 82 by condensing anthranilonilrile 79 with JV-melhylsulfanylthiocarbonyl-glycine ester 81 <01H1747>. In comparison, reaction of 81 with anthranilate ester 80 led to 83. 

The cyclic dipeptide cyclopenin (12) has been neatly synthesised by condensation of a modified anthranilic acid moiety with phenylpyruvic acid. The reaction strategy (Scheme 2) was patterned on biogenetic considerations. 2-Nitrobenz-amide (13) condensed with phenylpyruvic acid to give the hippuric acid (14) the ester (15), upon iV-methylation, reduction, and cyclisation, gave the 3,10-dehydro-derivative (18), which had been converted previously into cyclopenin. 

Langer and co-workers generated 2,2 -bis-quinazolin-4-ones by condensing substituted anthranilic esters with substituted bis(imidoyl)-chlorides. These compounds, which are structurally similar to the quinazoline alkaloid febrifUgine, have the potential to serve as anti-malarials. Treatment of methyl-2-amino-4,5-dimethoxybenzoate with bis(p-methoxyl-phenylimidoyl)chloride in the presence of two equivalents of TEA in refluxing toluene gave the desired product in 60% yield. 

It should be noted that the somewhat related Baumgarten method has not been successfully employed to produce 3-nitro-4-cinnolones. In this method, an ortho-ammo acetophenone (or benzaldehyde, Ri = H) is diazotized, and the resulting diazonium salt is intercepted with the sodium salt of nitromethane to afford a nitroformaldehyde phenylhydrazone (5), which may be isolated. Cyclization of 5 may be viewed as occurring by a Knoevenagel condensation between the methylene group and the ketone carbonyl. However, attempts to extend this chemistry to anthranilate esters were not successful. 

Altanserin (100) is a representative of the thiaquinazolinones. This serotonin antagonist is said to prevent gastric lesions. One method for preparation of this compound involves first preparation of isothiocyanate derivative 99, by reacting 4-fluorobenzoylpiperidine with 2-bromoethylamine and then converting the intermediate to the isothiocyanate with thionyl chloride and base. Condensation of 99 with methyl anthranilate (98) probably proceeds initially to a thiourea. Cyclization by ester-amide interchange leads to altanserin (100) [28]. 

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). 

Condensation of anthranilic acid or its methyl ester with the 2,3-benzoxazine imidoyl chloride or imidate ester (569) gave the 5H, H-quinazo ino[3,2-c]2,3-benzoxazin-9-one (570) [74CI(M)492]. 

Condensation of anthranilic acid with various ort/zo-esters and reaction of semicarbazides, gave 2-substituted benzoxazin-4-ones and also by the reaction of hydrazones with aryl-/alkyl-ureas and by salicylaldehyde or 2-hydroxyacetophenones with 4-aryl-/alkyl-semicarbazides. Hydrolysis of o-aminoesters and subsequent treatment with phosgene gave 40. Fused oxazine with bridge head nitrogen 41 and triazolo[3,4-Z>]thiazines 42 were also prepared . The 2,3-dihydrobenzoxazine 43, thiomorpholines 44 and phenothiazines 45 were prepared. ... 

The derivatives of anthranilic acid 179 (the products from the condensation of primary amines and the respective isatoic anhydrides) were treated with orthocarbonic ester, and the obtained compounds 180 were cyclized to the derivatives of 2,4-quinazolinedione 181 by the action of an alcohol solution of potassium hydroxide [67, 96, 104, 105],... 

The derivative of anthranilic acid 231, formed with a yield of 88% as a result of the condensation of the anhydride 232 with glycine methyl ester hydrochloride, undergoes cyclization to benzothiadiazinone S-oxide 233 when heated with thionyl chloride [111]. 

Euxylophoricine F (90) exhibits the same uv spectrum as the other euxylophoricines. Methylation with methyl iodide and potassium carbonate yields Ni3-methyleuxylophoricine A, indicating that euxylophoricine F is a 2,3-disubstituted rutaecarpine derivative. The structure was confirmed by synthesis. Condensation of 4-benzyloxy-5-methoxy-anthranilic acid methyl ester with 1,2,3,4-tetrahydro-l-keto-p-carboline in the presence of phosphorus oxychloride and subsequent hydrogenolysis gave (90). 

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