5-Methylanthranilic acid, preparation

N-Methylanthranilic acid is very readily prepared (p. 222). Prepare a sample of this acid and recr> stallise it 2 or 3 times from ethanol until it has m.p. 177" and is pure . 

A) Preparation of 4-Acetyl-7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-5H-1,4-Bemodiazepin-5-one A mixture of 68.5 g (0.37 mol) of 5-chloro-N-methylanthranilic acid, 51 g (0.51 mol) of calcium carbonate, 76 g (0.37 mol) of bromoethylamine hydrobromide and 2.5 liters of water was stirred and heated under reflux for 3 hours. A solution of 23.4 g (0.26 mol) of anhydrous oxalic acid in 250 ml of water was slowly added to the refluxing mixture. The precipitated calcium oxalate was filtered off, and the filtrate adjusted to pH 7 with concentrated ammonium hydroxide. The filtrate was then concentrated to dryness in vacuo and the residue heated on the steam bath with 400 ml of 6 N ethanolic hydrogen chloride until the residue was crystalline. Filtration gave 122 g of N-(aminoethyl)-5-chloro-N-methylanthranilic acid hydrochloride as a solid. 

Various 1-(1-naphthyl)-1,2,3-triazoles with electron-withdrawing groups at the 4- and/or 5-pos-itions (e.g. (135)) are synthesized from 1-azidonaphthalene and alkynes <87JCS(P1)413>. l-(Naphthyl)-benzotriazoles (127) are prepared by cycloaddition of the appropriate 1-azidonaphthalenes to benzyne or substituted benzynes, generated from 3-methylanthranilic acid. l-(l-Naphthyl)-naphthotriazole is similarly prepared by cycloaddition to 2,3-dihydronaphthalene. 1,3-Dipolar cycloadditions of 8-azidoquinolinone with benzyne and DMAD give benzotriazoles and triazoles (e.g., (130)), respectively <87JCS(Pi)403>. 

A convenient synthesis of quinazolines has been reported, and has been applied to the synthesis of representative alkaloids of the quinazoline group (Scheme 5).27 The procedure depends on the formation of sulphinamide anhydrides (23) from the reaction of anthranilic acids with thionyl chloride and the generation in situ of the iminoketens (24). Addition of the latter to the imine (25) or to 2-piperidone, for example, afforded alkaloid (27). Arborine (26) was prepared similarly from N-methylanthranilic acid application of the method to the synthesis of rutecarpine is described in Chapter 11. 

There are a few tetra- and pentacyclic analogues. Benzo analogues of 245 were prepared from pyridine-2,3-dicarboxylic acid anhydride and a tetralin derivative under conditions of the Friedel-Crafts reaction (85JCR(S)338). Pentacyclic compounds 258 (R = H or Me) were prepared from the bis adduct of anthranilic (or IV-methylanthranilic) acid to 1,4-benzoquinone, followed by cyclization in concentrated sulfuric acid (55JCS4440 66CB1991). 6-Methylquinoline-5,8-dione dimerized in the presence of ethanolic N-methyl-cyclohexylamine to 259 in very low yield and the dimerization is interpreted as two base-catalyzed addition reactions and three oxidation steps (71JCS(C)1253). 

The key intermediate 2-thioxo-3-phenylquinazohn-4(3H)-one was prepared by adding carbon disulfide and sodium hydroxide solution simultaneously to a vigorously stirred solution of aniline 7 in dimethylsulfoxide over 30 min stirring was then continued for an additional 30 min. Dimethylsulfate was added to the reaction mixture whilst stirring at 5-10°C after which it was stirred for another 2 h and then poured into ice water to obtain a soHd dithiocarbamic acid methylester 6. The compoimd 6 and methylanthranilate 5 when refluxed in ethanol for 18 h yielded the desired 2-thioxo-3-substituted quinazolin-4(3H)-one 4. The product obtained was cycUc and not an open chain thiourea 5a. It was confirmed by its value, high melting point, and its... 

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