Iodoanthranilic Acid

The electrochemical reduction of 3-nitrophthalic acid at controlled potentials gave 2,1-benzisoxazole-3-carboxylic acid. Cyclization is presumed to proceed via an intermediate oxime (67AHC(8)277). Treating 5-iodoanthranilic acid with acetic anhydride gave 3-acetoxy-5-iodo-2,l-benzisoxazole (596) (65JMC550). 

The iodine monochloride solution at 5° is stirred rapidly into the anthranilic acid solution at 20°. 5-Iodoanthranilic acid separates almost immediately as a granular, tan to violet precipitate, and the reaction temperature rises to 18-22°. The mixture is stirred for an hour, while wanning to room temperature, then filtered on a 13-cm. Buchner funnel. The acid is pressed as dry as possible, washed with three loo-cc. portions of cold water, and then dried at 90-100°. There is obtained 185-189 g. (88-90 per cent yield) of brown to purple acid which melts at 185-190°, with decomposition (Note 2). 

Iodoanthranilic acid is best purified by recrystallization of its ammonium salt, as follows To 100 g. of the acid in a 400-cc. beaker is added 200 cc. of hot water, and the acid is dissolved by stirring in concentrated ammonia (sp. gr. 0.9) until solution is... 

The ammonium salt is not stable under the drying conditions. The dry product is a mixture of 5-iodoanthranilic acid and its ammonium salt. Contact with air may change its color from yellow to violet. 

Iodoanthranilic acid has been prepared by the reduction of 2-nitro-s-iodobenzoic acid, by treatment of anthranilic add with iodine in potassium hydroxide solution, by treatment of the anhydride of s-hydroxymercurianthranilic acid with iodine in aqueous potassium iodide solution, and by iodination of anthranilic acid in glacial acetic acid solution with iodine mono-chloride. ... 

The ammonium salt is dissolved in three parts of hot water, ammonia is added if necessary to effect complete solution at 60°, the solution is again treated with sodium hydrosulfite and 3-4 g. of decolorizing charcoal, filtered hot, and the 5-iodoanthranilic acid is precipitated by adding C.P. hydrochloric acid in 3- to 5-cc. portions, stirring thoroughly after each addition, imtil the reaction mixture is just faintly acid to Congo red. Ice is then added until the temperature is reduced to 20°, and the precipitated add is removed by suction filtration, washed freely with cold water, and dried at loo-i 10° (Note 5). 5-Iodoanthranilic acid is almost quantitatively precipitated from its ammonium salt solution and is obtained as a yellow powder, m.p. 190-195° (decomp.) (Note 6). 

In a i-l. flask 132 g. (0.5 mole) of s-iodoanthranilic acid (p. 52) and 35 g. (0.5 mole) of sodium nitrite are dissolved in a mixture of 500 cc. of warm water and 60 cc. of 30 per cent sodium hydroxide solution. After cooling to 20 the solution is added from a dropping funnel, over a period of fifteen to twenty minutes, to a well-stirred mixture of 250 cc. of concentrated hydrochloric acid (sp. gr. 1.18) and 250 g. of ice in a 2-I. beaker more ice is added, as required, to keep the temperature below 20°. The insoluble, yellow diazonium compound separates before completion of the diazotization. After all the solution has been added from the dropping funnel, the reaction mixture is stirred for five minutes and tested for excess nitrous acid with starch-iodide paper. If required, small amounts of solid sodium nitrite are added and the test is repeated at three-minute intervals until a slight excess is definitely established. The diazonium compound is allowed to settle and as much as possible of the... 

Proquinazid can be prepared starting from 5-iodoanthranilic acid (Scheme 22.3) [27, 32, 33]. Cyclization with n-propyl isothiocyanate affords 2,3-dihydro-6-iodo-3-propyl-2-thioxo-4(lH)-quinazolinone. Alternatively, this key intermediate can be obtained by reaction of an appropriate anthranilate with thiophosgene and n-propylamine. Subsequent introduction of the propoxy substituent via a methyl-ation displacement sequence concludes the synthesis. 

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