3-Iodobenzoic acid

Another method of removing most of the mercuric iodide is to grind the crystals, suspend them in a little water, and pour off the lighter suspension of iodobenzoic acid, leaving the heavy mercuric iodide behind. Washing with iodide solution is necessary to remove the last of the mercuric iodide. 

CH3C0CHC02C2H5+Na0II - CIl3C0CHC02Na+C2IIs0H (CH2)3CH3 (CH2)3CH3 

In a 12-I. round-bottom flask, fitted with an efficient mechanical stirrer, is placed 5 l. of a 5 per cent solution of sodium hydroxide (6.25 moles). To this is added the crude ethyl w-butylaceto-acetate (about 925 g.) (p. 36) obtained from 5 moles of ethyl acetoacetate. The mixture is stirred at room temperature for four hours, during which time the mono-substituted acetoacetic ester is completely saponified and passes into solution. The mixture is then allowed to stand until the unsaponified material separates completely as an oily layer. The aqueous layer is separated (Note r) and transferred to a flask provided with a stopper fitted with a separatory funnel and a large bent glass tube leading to a condenser set for distillation. 

Through the separatory funnel is added slowly 500 cc. of 50 per cent (sp. gr. 140) sulfuric acid (3.6 moles), which is somewhat more than the amount required to neutralize the alkali (6.25 moles) used in the saponification of the ester. When the evolution of carbon dioxide ceases to be vigorous, the reaction mixture is heated slowly to boiling, and from one-third 

In the distillate the ketone layer is separated from the water, and the latter is distilled until one-third has been collected. The ketone layer in this distillate is separated, and the water layer is again distilled. This procedure is repeated as long as any considerable amount of ketone is obtained in the distillate (Note 3). The combined ketone fraction is washed four times with one-third its volume of a concentrated solution of calcium chloride (sp. gr. 1.3 or greater) to remove alcohol (Note 4), then dried over 50 g. of solid calcium chloride, filtered and distilled. The yield of methyl M-amyl ketone boiling at 148-151° at 750 mm. is 300-350 g. (52-61 per cent of the theoretical amount, based upon the original ethyl acetoacetate) (Note 5). 

A solution of 13.7 g. (0.1 mole) of anthranilic acid in dilute sulfuric acid is diazotized in customary fashion [Org. Syntheses Coll. Vol. 1, 374 (1941)] at 0-10° with an aqueous solution of 7.5 g. (0.11 mole) of sodium nitrite. The resulting clear solution is added with agitation to a solution of 25 g. (0.15 mole) of potassium iodide in dilute sulfuric acid. The mixture is heated to boiling for a few minutes, and then cooled, the o-iodobenzoic acid is removed by filtration. Recrystallization from hot water gives a product melting at 162°. The yield is nearly quantitative. 

A solution of 43.5 g. (0.21 mole) of o-aminodiphenyl hydrochloride in dilute hydrochloric acid is diazotized at 0-10° by careful addition of an aqueous solution of 14.5 g. (0.21 mole) of sodium nitrite. To the resulting solution of the diazonium salt, there is added slowly with continuous stirring a solution of 100 g. (0.60 mole) of potassium iodide in 150 ml. of water. After standing for 1.5 hours, the pasty mixture 

Submitted by V. H. Wallingford and Paul A. Krueger. Checked by F. C. Whitmore and L. H. Sutherland. 

In a i-I. flask 132 g. (0.5 mole) of 5-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 2-1. beaker more ice is added, as required, to keep the temperature below 200. 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 

In a 3-I. beaker are placed 750 cc. of 95 per cent ethyl alcohol and 1.5 g. of finely ground copper sulfate, and the mixture is heated on a hot plate or steam bath to 70°. The diazonium slurry is added in about 30-cc. portions to the well-stirred alcohol the temperature is kept between 6o° and 70°, and the nitrogen evolution is allowed to subside considerably between additions. The final traces of diazonium slurry are washed into the alcohol with small amounts of the decanted solution, the remainder of which is then added to the alcohol in 100-cc. portions. The reaction mixture is heated and stirred at 65-70° for half an hour, and then cooled without agitation to 50. The m-iodobenzoic acid which separates is filtered with suction on a Buchner funnel, washed with three 50-cc. portions of cold water, and dried at 90-110°. There is obtained 107-116 g. of crude, brown m-iodobenzoic acid (86-93 per cent of the theoretical amount) (Note 1). 

The ammonium salt thus obtained is recrystallized until white by dissolving it in an equal weight of water at 80° and cooling to 50. The recovery in this purification averages 75-85 per cent (Note 3). 

Evaporation of the mother liquors to incipient turbidity and cooling the concentrate to 50 will produce a few grams of acid, but this is usually very impure and tarry. 

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Iodobenzoic acid [88-67-5] M 248.4, m 162 , pK 2.93. Crystd repeatedly from water and EtOH. Sublimed under vacuum at 100 . 

Iodosalicylic acid (2-hydroxy-5-iodobenzoic acid) [119-30-2] M 264.0, m 197 pKj 2.65, pK 13.05. Crystd from water. 

Cyclocondensation of 2-chloronicotinic acid with 2-amino-5-iodobenzoic acid and methyl 2-amino-4-bromobenzoate in boiling EtOH in the presence of cone. HCl for 18 h gave the 2-iodo and 3-bromo derivatives of 11-0X0-1 l/f-pyrido[2,l-6]quinazoline-6-carboxylic acid (98MIP1, 98MIP2, 99USP5908840, 99USP5914327). 

Ullman condensation of m-trifluoromethylaniline (13) with o-iodobenzoic acid in the presence of copper-bronze affords flu-fenamic acid (14). An analogous reaction of o-chlorobenzolc acid with 2,3-dimethylaniline (15) gives mefenamic acid (16) meclofenamic acid (18) is obtained by Ullman condensation employing 2,6-dlchloro-3-methylaniline (17). 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

The nucleophilic displacement of the iodine moiety in 2-iodoben-zoates mediated by triphenyltin hydride and di-n-butyltin dichloride in aqueous solution has been demonstrated (Eq. 6.16).33 For example, 2-iodobenzoic acid reacts with a toluene solution of Ph3SnH/l,3-(N02)2 C6H4/aq. NaHC03 to give 89% yield of salicylic acid. 

Reaction of the sodium salt of 2 with 2-iodobenzoic acid results in formation of the corresponding bis-arylsulfide via nucleophilic aromatic substitution. 

The same authors performed a microwave assisted Stille reaction on the Rink amide (RAM) Tentagel polymer-tethered 4-iodobenzoic acid [5 b]. Successful palladium-catalyzed coupling of heteroaryl boronic acid with anchored 4-iodobenzoic acid enabled both >99% conversion of the starting material within 3.8 min (45 W) and a minimal decomposition of the solid support. The coupling reactions were realized in a mixture of polar solvents (H20-EtOH-DME, 2.5 1.5 6). 

Interestingly, the Suzuki reaction worked smoothly on solid supports and high yields of a variety of products were reported under these reaction conditions (Eq. 11.22) [36]. 4-Bromo- and 4-iodobenzoic acid linked to Rink-amide TentaGel re-... 

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