4-chloro-6-methyl-anthranilic acid

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. 

Tolfenamic acid is used as an injectable formulation in cattle and swine. In rats and target animals, tolfenamic acid is metabolized by hydroxylation either of the methyl or the methylchlorophenyl group producing two metabolites further oxidation of the hydroxymethyl group to the corresponding aldehyde or carboxylic acid can produce two additional metabolites. The two hydroxylated metabolites of tolfenamic acid, N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid, are much less potent than the parent compound in terms of anti-inflammatory and analgesic... 

Disposition in the Body. Readily absorbed after oral administration bioavailability about 60%. It is metabolised by hydroxyla-tion to V-(2-hydroxymethyl-3-chlorophenyl)anthranilic acid and V-(2-methyl-3-chloro-4-hydroxyphenyl)anthranilic acid, which are the major metabolites. About 50% of an oral dose is excreted in the urine in 48 hours mainly as glucuronide conjugates of the two hydroxylated metabolites. Less than 10% of a dose is excreted in the urine as unchanged drug or its glucuronide conjugate. Tolfenamic acid and its metabolites are excreted in the bile. 

Chlorosulphonation of 4 -chloro-o-acetotoluidine yields the eorresponding sulphonyl chloride derivative whieh on amination forms the sulphonamide derivative. Oxidation of the methyl moiety gives the respeetive anthranilamide derivative whieh on hydrolysis eliminates the acetyl group to yield the substituted anthranilic acid. Fusion of this amino acid with propionamide first gives rise to an intermediate by the loss of a mole of water and ultimately helps in the closure of the ring to generate the quinazoline ring system. Catalytic reduction of this finally produces the official compound. 

To a solution of NaOEt prepared from 0.11 g sodium (4.7 mmol) and 10 mL absolute ethanol, cooled in an ice bath, was added in rapid succession 0.88 g methyl 2-chloro-6-hydroxybenzoate (4.7 mmol) and a solution of 1.14 g A-4-methoxyphenylbenzimidyl chloride (4.7 mmol) in 30 mL dry ether. The reaction mixture was shaken vigorously, whereupon a precipitate of sodium chloride began to form. The mixture was allowed to stand at room temperature for 48 h, the solvent was evaporated, and the residue was diluted with water. The resulting oily solid was removed by extraction with ether, the ethereal solution was dried, and the ether was distilled. The crude imido ester was heated in a nitrogen atmosphere at 210-215 C for 70 min, then dissolved in 10.8 mL ethanol the alcoholic solution was diluted with 5.4 mL water and 5.4 mL of a 1 M ethanolic sodium ethoxide. The solution was refluxed for 1.5 h, the alcohol was evaporated on a steam bath, and the aqueous solution was acidified with dilute HCl. The dark oil that formed was separated by decantation, and the crude benzoate of the substituted anthranilic acid was dissolved in 22 mL ethanol. A solution of 7.2 g sodium hydroxide in 7.2 mL water was added, and the mixture was refluxed for 1 h. The alcohol was evaporated, and the solution was then acidified. The brown solid was extracted exhaustively with boiling water to remove the benzoic acid, and the remaining brown solid was recrystallized from aqueous ethanol. The yellow needle-like crystals of A-(4 -methoxyphenyl)-6-chloroanthranilic acid, in a total amount of 0.36 g, was obtained, in a yield of 27.7%, m.p., 139.5-140.5°C (dec). 

Another q>pToach to the aoidone skeleton, developed by Watanabe et al. 314), was based on an earlio- obsravation that small amounts of aoidones woe formed when benzynes were generated by diazotization of anthranilic acids 315-317). The acridones result in these cases from the reaction of benzynes with undiazotized anthranilic acids. Therefore, a new route was developed through tandem metallation synthesis. The lithium salt of methyl iV-methylanthranilate (250) could be easily coupled with the benzynes 251, 252, and 253, generated by treatment of chlorobenzene, 1 -bromo-2-methoxybenzene, and l-chloro-3,5-... 

Aryl-5H-l,3,4-thiadiazolo[2,3-b]quinazolin-5-ones (216) are accessible in moderate yield by the condensation of 2-chloro-l,3,4-thiadiazoles and methyl anthranilate in boiling acetic acid. ... 

Hydroxy-3-methylanthranil is methylated normally with methyl iodide and sodium carbonate to give the 7-methoxy derivative.135 Anthranil carboxylic acids are converted into their acid chlorides by thionyl chloride,208 and their methyl esters by diazomethane.169 The acid chloride of 5-chloro-3-phenylanthranil-6-carboxylic acid participates in the Friedel-Crafts acylation of benzene to give 6-benzoyl-5-chloro-3-phenylanthranil (67%).208... 

---