Preparation and purification of antiviral disulfonic acid disodium salt

#This invention concerns methods for the preparation, purification and isolation of antiviral disulfonic acid, disodium salt, particularly 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid, as well as intermediates useful for its synthesis.

#Ellestad et al, J. Med. Chem. 41, 2671 (1998) and U.S. Pat. No. 5,852,015 describe a method for preparation and purification of 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid. The intermediates of this disclosed process, when used in subsequent steps lead to an approximately 70% product purity by HPLC, which requires extensive reverse phase chromatographies, followed by lyophilization to remove residual solvents. The process of Ellestad et al. may be summarized in the following Scheme I.

#The use of pure intermediates leads to a higher purity crude 4′,4-bis-{4,6-bis-[3-(bis-carbamoyl-methyl-1-sulfamoyl)-phenylamino]-[1,3,5]triazin-2-ylamino}-biphenyl-2,2′-disulfonic acid. Formation of impurities that require chromatography to remove can be further reduced by performing the last reaction step at a temperature range of 60-75° C. A purity of better than 80% can be obtained. It is desirable to have a process by which even greater purity can be achieved.

#Preparation of N-Acetamido-3-nitrobenzenesulfonamide

#Charge 3-nitrobenzenesulfonyl chloride (1000 g, 4.52 mol) followed by potable water (2250 g) to a 4-necked 12 L round-bottomed flask equipped with a mechanical stirrer, a temperature probe, a dropping funnel and an inlet for a pH probe. To the resulting amber colored slurry add glycinamide HCl (600 g, 5.42 mol). Stir the resulting slurry at 22° C. for 0.5 hour. To the slurry add, via the dropping funnel, Na2CO3 solution (prepared from 525 g Na2CO3, 10 mol, and 1850 g potable water), while maintaining a pH between 6.0 and 6.9. The pH prior to any base is 3.0. Once a pH of ˜6.5 is reached, the drop rate is set so that a pH of 6.5 to 6.9 is maintained. The pH is monitored continuously with the pH probe throughout the addition. Fast stirring in the reaction flask assures that the droplets of incoming base (pH=11) mix well. The addition requires a period of 2 hours. Rinse the dropping funnel with potable water (50 g). Stir at 22° C. for 20 h. Check for reaction completion by quantitative TLC or HPLC. If not complete add more glycinamide HCl followed by Na2CO3 solution. Filter the reaction mixture on a 27 cm diameter porcelain Buchner funnel. Wash the off-white cake with (4×2000 g) potable water and then with (2×1578 g, 2000 mL) ethanol. Dam the cake on the Buchner funnel until dripping stops and then dry in a vacuum oven at 50° C. for 20 h.

#Yield 83.4% Total Imp (HPLC) 0.96% Sgl Imp (HPLC) 0.3% Ethanol (GC) LT 0.01% Water (KF) 0.78%