Methyl anthranilate, condensation with

Methyl anthranilate condensed with 646 to give 2-phenyl-4-imino-l,3, 5-triazino[2,l-6]quinazolin-6-one (647) [69JCS(D)1040]. Condensation of the cyanuric acid derivative 648 with methyl anthranilate gave 649 which, upon cyclization, afforded a mixture of the two isomeric 4(2)-ani-lino-4(2)-hydroxy-l,3,5-triazino[2,l- ]quinazolin-6-ones (650 and 651) (75USP3887554). 

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). 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

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. 

Substituted 2-mercapto-4(3i/)quinazolinones were prepared by condensing methyl anthranilate with isothiocyanates (see 7c). 

The alkaloid rutaecarpine (111) was synthesized from l-oxo-1,2,3,4-tetrahydro-)3-carboline (183 R = H) by condensation with methyl anthranilate in the presence of phosphorous chloride or by heating... 

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]. 

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]. 

Condensation of ethyl anthranHates with isothiocyanates provides entry to a closely related compound in which the carbonyl at the 2 position is replaced by a thione. The sequence starts with the alkylation of pyrrolidine nitrogen in (92-1) with 2-bromoethylamine. Reaction of the primary amine in the product (92-2) with thiophosgene leads to the isothiocyanate derivative (92-3). Reaction of that reactive intermediate with methyl anthranilate (92-4) leads initially to the transient... 

Performing a Vilsmeier-Haack reaction on 3-benzoyloxy-2-methyl-quinazolin-4-one (184) afforded the isoxazolo[3,2- ]quinazolinone (185) [86IJC(B)709]. This ring system (187) was also synthesized by cyclocondensation of anthranilic acids or isatoic anhydrides with the isoxazolin-3-ones (186) (77AF766 83MIP1), or by condensation of methyl anthrani-late with 3-chloropropanoyl chloride followed by cyclization with hydroxylamine hydrochloride (77AF766). 

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). 

A Schiff base is formed by the combination of an aldehyde and an amine (—NH2) usually in perfumery with methyl anthranilate. This is a condensation reaction in which water is produced. For example, aurantiol, the most widely used of the Schiff bases, is formed by the condensation of hydroxycitronellal and methyl anthranilate ... 

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... 

Diazotised anthranilic acid is condensed with an alkaline solution of o-carboxyphenylarsenoxide and the product recrystallised from methyl alcohol and finally from water. It melts at 256° C., and when reduced gives o-o -dicarboxydiphenylarsenious anhydride, M.pt. 251° to 255° C. The latter compound is insoluble in ether, benzene, chloroform, or carbon tetrachloride, but dissolves in methyl alcohol. When its solution in this solvent is treated with hydrogen chloride it gives o-o -dicarbomethotnydiiphenylehloroarsine, M.pt. 184° C. ... 

Reactions of piperazine-2,5-diones with phosphorus pentachloride and phosphorus pentabromide have been described in Sections V.ID and V.IF, respectively. Aromatic aldehydes condense with 3-methylpiperazine-2,5-dione in the presence of acetic anhydride to form mainly mono-A -acetyl derivatives of trans-3-arylidene-6-methylpiperazine-2,5-diones (e.g., 96, R = Ac) (1066). In these products the acetyl group was shown to be attached to position 1 and the 4,5-amide group was found to be sterically hindered. Photolysis formed the cis isomers. Both isomers were deacetylated with methanolic potassium hydroxide (1066). Condensation of 1,4-diacetylpiperazine-2,5-diones with aldehydes has been applied to the synthesis of unsymmetrical 3,6-diarylidenepiperazine-2,5-diones and the reaction has been extended to l,4-diacetyl-3,6-dimethylpiperazine-2,5-diones (1624). Treatment of (96, R = H) with triethyloxonium tetrafluoroborate in dichloromethane gave the monoimino ether, 5-benzylidene-6-ethoxy-3-hydroxy-2-methyl-2,5-dihydropyrazine (97) (1066). l-Methylpiperazine-2,5-dione similarly treated gave 5-ethoxy-l-methyl-2-oxo-l,2,3,6-tetrahydropyrazine (which was condensed with anthranilic acid at 150° to 2-methyl-l,2-dihydropyrazino[2,l-fi]quinazoline-3(4/0.6-dione (98) (1625), and l,4-dimethylpiperazine-2,5-dione gave 5-ethoxy-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrazine and 5,5-diethoxy-l,4-dimethylpiperazin-2-one (1626). 

Amino-2-hydroxy[4- C]butyric acid (the corresponding aldehyde has been condensed with o-aminobenzaldehyde to give vasicine 4-hydroxy-[2- C]glutamic acid (found with vasicine in Linaria yw/garis ), N-methyl-anthranilic acid, and N-formylanthranilic acid have been tested as vasicine precursors in A. vasica, without success. 

Cyclization of methyl anthranilates with sulfamyl chloride affords 2,1.3-benzothiadiazin-4-ones (Section 9.07.9.1.1). The less common l//-2,l>3-benzothiadiazine 2,2-dioxides were obtained in modest yield by reaction of 2-hydroxymethyl anilines with Burgess reagent (Section 9.07.9.1.1). A two-step process starting from t>/t, <7-iodosulfamides, via generation of a trianion, condensation with an aldehyde, and subsequent acid-catalyzed cyclization, led efficiently to 4-substituted-3,4-dihydro-l//-2,l,3-benzothiazine 2,2-dioxides (Section 9.07.9.2.2). 

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. 

However, the imidoyl chloride XXXIX could not be isolated, and it was therefore reacted in situ with methyl anthranilate to afford 6,7,8,9-tetrahydropyrido-[2,l-ft]-quinazole-ll-one (XLI). Since this condensation occurs in high yield ( ), the amount of XXXIX present in the original reaction mixture can be established in this manner. 

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. 

Condensation of glycosyl isocyanides with amines in the presence of mercuric or silver chloride gave formamidines (Gly-N=CH—NR2), but when methyl anthranilate was used with mercuric chloride, cyclization took place to give the nucleoside analogue (47). When silver chloride was used as catalyst only the intermediate formamidine was obtained... 

A solution of 90 g (0.59 mol) of methyl anthranilate in 265 mL of glacial acetic acid is placed in a 1-L round-bottomed flask equipped with a reflux condenser and a magnetic stirrer. The stirrer is started, and 78 g (0.59 mol) of... 

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