Methyl anthranilate, synthesis

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

An extension of Kametani s earlier synthesis has afforded a neat synthesis of rutaecarpine (24) and hortiacine (10-methoxyrutaecarpine).22" In this modification, the presence of a trifluoromethyl group in (23) (instead of hydrogen, as in Kametani s synthesis) increases the electrophilicity of the protonated form, and also provides a useful leaving group for the final stage of the synthesis a dehydrogenation step is therefore unnecessary (Scheme 3). Rutaecarpine has also been synthesized.226 11-Methoxyrutaecarpine has been simply synthesized by condensation of 7-methoxy- 1-oxo-l,2-dihydro-/ -carboline with methyl anthranilate and phosphorus oxychloride.22c... 

A cyclodimerization, analogous to that of methyl anthranilate, was exhibited by 2-aminothiophenes bearing a carboxylic portion in position 3 to give the dithienodiazocines. In that patent, the procedures for the synthesis of unsymmetrical dithienodiazocines, thienobenzodiazocines and tetracyclic diazocines were also described <2004W0010136>. 

A readily realizable synthesis of the quinazolin-4(3//)-one ring system 22 is the reaction of anthranilic acid or methyl anthranilate and their derivatives 20 with 1,3,5-triazine. The reaction proceeds via the intermediacy of 21 which results from the nucleophilic attack of the amino group of 20 on an electrophilic carbon atom of 1,3,5-triazine. ... 

A further solution to the problem of isomer formation in the synthesis of oxoacridine carboaylic acids is to mask one of the two carboxyl groups. The requisite 2-(2-metho carbonylphet lamino)benzoic acids are available from methyl anthranilates reaction with diphenyliodonium carboxylates. The esters which result after cyclisation with polyphosphoric ethyl ester undergo ready alkaline l drolysis to the acid (G.W. Rewcastle and W.A. Denny. Synthesis. 1985. 220). 

Kim and co-workers used dithiazoles to prepare 3-substituted 2-cyanoquinazolinones. Treatment of methyl anthranilate with Appel s salt in the presence of two equivalents of pyridine fiimished the corresponding methyl-A -(4-chloro-5//-1,2,3-dithiazol-5-ylidene)anthranilate (not shown). Further reaction of the ylidene with methyl amine provided the desired cyanoquinazoline in 73% yield. This work set the framework for Besson and co-workers synthesis of a tricyclic congener of desoxyvasicinone, a compound with cytotoxicity against a murine leukemia P-388 cell line. 

The use of methyl anthranilate (26) in the Niementowski reaction was reported by Meyer and Wagner in 1943. One of the factors limiting the usefulness of the Niementowski synthesis under conventional conditions is the propensity of anthranilic acid to undergo thermal decarboxylation at sustained heating of 150 °C or above. Methyl anthranilate, however, is stable at temperatures approaching its boiling point of 260 °C. Moreover, it was found to react with formamide at about 200 °C to form the expected 4-quinazolone product in 49% yield. Extension of this procedure to amides larger than acetamide, however, did not result in improved yields compared to the use of anthranilic acid. 

In this area, Yadav and Krishnan have investigated the use of polymeric supported acids as catalysts in the large-scale synthesis of a known perfumery and flavoring agent, methyl anthranilate (2), derived from the corresponding carboxylic acid 1 and an excess of methanol (eq 13). They have shown that Amberlyst 15 was the most efficient polymeric supported acid screened and was far superior to related polymeric acids such as Indion-130, Bayer K-24, Amberlyst 18, and Dowex M-32. 

The historical condensation of anthranilic acid (3) with phloroghicinol (206) to give 1,3-dihydroxyacridone (22) by Baczynski and von Niementowdd should be considered as Ae first biomimetic synthesis of an acridone alkaloid (284). The yield of the reaction was initially very poor, but was increased by subsequent modifications by Beck et al. (28S) and by Hlubucek et al. (286). More rec y. Smolders et al. described an efficient condensation of methyl anthranilate (207) with phloroglucinol, in the presence of 4-toluenesulfonic acid in l-hqitanol, which gave 22 in 80% yield (287). 

Synthesis of the title compounds (e.g. 316) from 1,2,4-triazole precursors was reported as early as 1930, when anthranilic acid was condensed with 4,5-dihydro-3-methyl-l-(4-nitrophenyl)-5-oxo-l, 2,4-triazole (315, R = 4-N02-C6H4) (30JIC899). 

In the diaryl amine series 191 (Scheme 47), additional, synthetically valuable, anionic pathways provide routes to anthranilates 190, oxindoles 192, and dibenzazepinones 194. Although not explored in terms of its scope [75c], the lateral metalation-cydization, 191 -> 192, is extensively precedented [69] but harbors intriguing potential for subsequent DreM chemistry. The rearrangement 191 —> 190 is an N —> ortho C anionic Fries equivalent of the aryl O-carbamate migration (Scheme 3E) [75c] and after N-methylation, 190 may be transformed into 1,2,3-trisubstituted systems 193 [76]. In another appealing manifestation of CIPE, the efficient conversion of 191 into dibenzazepinone 194 has been applied in an effective synthesis of the antiepileptic drug oxcarbazepine (Trileptal ) 195 [77] and may also be... 

Fig. 4. (a) Degradation of anthramycin-11-methyl ether (25) and tomaymycin ethyl ether (28) to anthranilic acid derivatives (28). (b) Formation of the trioxo compound (33) by degradation of tomaymycin (12) and by total synthesis (26). 

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