sodium 3-(acetylamino)-2,4,6-triiodo-5-[(methylamino)carbonyl]benzoate

Angio-Conray,Mallinckrodt Inc.,USA

Diagnostic aid (radiopaque medium).

Normal aqueous sodium hydroxide (0.02 eq) was added at room temperature with rapid swirling to a solution of 5-nitroisophthalic acid, dimethyl ester, (4.8 g, 0.02 mole) in acetone-methanol (100 ml each). The clear solution immediately assumed a deep red-purple color which gradually lightened to a brown color over a 25-minute period. On standing overnight the solution lightened in color to a pale pink.
The solvent was evaporated, and the residue extracted with warm water (50 ml). The residue of unsaponified diester (0.23 g), 4.2%; m.p. 115°-117°C was filtered off, and the filtrate was acidified toprecipitate the crude monomethyl ester of 5-nitroisoftalic acid. Yield 3.4 g (75%). M.p. 170.5°- 175.5°C.
The preparation was repeated on a larger scale with certain variations. Methanolic potassium hydroxide was substituted for the aqueous sodium hydroxide, and acetone was used as the solvent for the 5-nitroisophthalic acid, dimethyl ester. Yield, 78%. M.P. 175°-179°C (corrected).
Crude 5-nitroisophthalic acid, monomethyl ester (46.3 g, 0.21 mole) was dissolved in 35% aqueous methylamine solution (500 ml). On standing, the orange solution became blood red. The reaction mixture was evaporated overnight on the steam bath, the cool residue was treated with 50 ml of water and the solution was acidified with hydrochloric acid. A yellow precipitate of crude N-methyl-5-nitroisophthalamic acid was separated and dried (yield 41.5 g). This acid was redissolved in dilute ammonia solution and the resulting solution (pH 5.2) was treated with charcoal. Acidification of the treated solution yield a pale yellow product of neutral equivalent 213. A small portion (10 g) was recrystaliized from 1:1 water-ethanol (300 ml) to yield orange Nmethyl-5-nitroisophthalamic acid. M.p. 251°-252.5°C.
Crude N-methyl-5-nitrosophthalamic acid (11.2 g, 0.05 mole) was reduced with hydrogen in a low pressure hydrogenator. The solvent was anhydrous methanol (250 ml) and the catalyst was 5% palladium on charcoal slurried in 10 ml of water. After the theoretical quantity of hydrogen for reduction of the nitro group had been absorbed the solution was filtered to remove the catalyst and the solvent was evaporated under reduced pressure, leaving a white residue of crude 5-amino-N-methylisophthaIamic acid. M.p. 227°-230°C (corrected).
The crude 5-amino-N-methylisophthalamic acid was dissolved in hydrochloric acid (100 ml concentrated acid and 100 ml of water) and this solution was diluted to 1 liter with water. Iodine monochloride (27.4 g of 95% ICI, 0.16 mole) in concentrated hydrochloric acid (30 ml) was added in one portion to the stirred solution maintained at 54°C. The solution was heated on a steam bath. After 2 hours the solution was diluted to 1.5 liters and after 3 hours titration of an aliquot indicated that 50% of the iodine monochloride had been consumed. Precipitation of a solid began after 33/4 hours of reaction (75°C). Intermittent heating and stirring was continued for 4 days, 10 g of 95% iodine monochloride was added during the third day. After 4 days, titration of an aliquot indicated that 96% of the theoretical quantity of iodine monochloride had been consumed. The precipitated solid was filtered off, washed with water and dried at 75°C under reduced pressure. Yield of 5-amino-2,4,6-triiodo-N-methylisophthalamic acid 20.6 g. M.p. 266-268°C (dec.)
1.95 molar KICl2 a solution (1144 ml, 2.22 moles) was added during 0.5 hour to a stirred suspension of 5-amino-N-methylisophthalamic acid (196 g, 1.01 moles) in 2.5 liters of water. After three hours of additional stirring, a solution of sodium hydroxide (88 g, 2.2 moles of NaOH in 200 ml of water) was added. Then, additional 1.95 molar KICl2 solution (522 ml, 1.01 mole) was added during 0.5 hour. The reaction mixture was stirred overnight after which the crude product was collected and purified by conversion first to the ammonium salt, then to the free acid. Yield of 5-amino-2,4,6-triiodo-Nmethylisophthalamic acid, 310 g (53.6%).
Acetyl chloride (17 ml, 0.24 mole) was added in portions during 10 minutes to a stirred slurry of 5-amino-2,4,6-triiodo-N-methylisophthalamic acid (57.2 g, 0.1 mole) in dimethylacetamide (120 ml). Solution occurred in 0.5-1 hour and after a total of 1.5 hours 20 ml of water was added and the reaction mixture was evaporated to a thick slurry. The product was purified by twice dissolving it as a sodium salt and precipitating the free acid by the addition of mineral acid. The resulting nearly colorless 5-acetamido-2,4,6-triiodo-Nmethylisophthalamic acid decomposed at about 285°C but did not melt below 300°C. Yield, 47 g (76.5%).
5-Acetamido-2,4,6-triiodo-N-methylisophthalamic acid was slurried in water and dissolved by the addition of an equivalent quantity of sodium hydroxide. The solution was evaporated to dryness to yield the sodium salt of 5- acetamido-2,4,6-triiodo-N-methylisophthalamic acid. Its solubility in water at 25°C is approximately 85 g per 100 ml of solution. The acute intravenous LD50 of this salt in male albino mice is approximately 19.2 g/kg.

Conray (Mallinckrodt).

Diagnostic aid