Optimization and Comparison of Synthetic Procedures for a Group of Triazinyl-Substituted Benzene-Sulfonamide Conjugates with Amino Acids

Abstract

Sulfonamides incorporating 1,3,5-triazine moieties can selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII, and XIV over cytosolic isoforms I and II. In the present work, a highly effective synthetic procedure was proposed for this group of potent cancerostatic drugs and compared with previously used methods. The synthesis of triazinyl-substituted benzene-sulfonamide conjugates with amino acids can be easily carried out using sodium carbonate-based water solution as a synthetic medium instead of N,N-Diisopropylethylamine/Dimethylformamide. The benefits of this synthetic procedure include: (i) high selectivity of the creation of disubstituted conjugates; (ii) several times higher yield (≥95%) than that achieved previously; (iii) elimination of organic solvents by the use of an environmental friendly water medium (green chemistry); (iv) simple and fast isolation of the product. The synthesis and resulting products were evaluated using TLC, IR, NMR, and MS methods. The present work demonstrates a significant advantage in providing shortened routes to target structures.

Keywords: 1,3,5-triazine conjugates; amino acids; carboanhydrase inhibitors; sulfonamides; synthesis optimization.

Scheme 1

Synthesis of 4-(4′,6′-dichloro-1′,3′,5′-triazin-2′-ylamino)-benzene-sulfonamide precursor 1. Reagents and conditions: 4-aminobenzenesulfanilamide, cyanuric chloride, acetone, at 0 °C, was added to an aqueous solution of NaOH, stirred for 1 h, and the reaction was subsequently quenched by the addition of slush (100 mL), after which the solid was filtered off. The scheme is reprinted from [4], with permission of the publisher. Product yield: 95%.

Scheme 2

Synthesis of dimethyl 2′′,2′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)diacetate intermediate 2. Reagents and conditions: a mixture of methyl 2-aminoacetate hydrochloride, DMF, and DIPEA was stirred for 2 h at r.t. Then, 4-(4′,6′-dichloro-1′,3′,5′-triazin-2′-ylamino)-benzene-sulfonamide 1 dissolved DMF was added, and the mixture was stirred at 90 °C under an argon atmosphere overnight. Product yield: 37%.

Scheme 3

Hydrolysis of 2′′,2′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)diacetate intermediate 2 to product 3. Reagents and conditions: a mixture of 2′′,2′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)diacetate 2, MeOH, LiOH, and H₂O was stirred at r.t. for 3 h. Product yield: 64%.

Scheme 4

Synthesis of 2′′,2′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)diacetic acid 3. Reagents and conditions: 4-(4′,6′-dichloro-1′,3′,5′-triazin-2′-ylamino)-benzene-sulfonamide 1, glycine, NaOH, and H₂O were refluxed for 24 h. Product yield: 65%.

Scheme 5

Synthesis of 2′′,2′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)diacetic acid 3. Reagents and conditions: 4-(4′,6′-dichloro-1′,3′,5′-triazin-2′-ylamino)-benzene-sulfonamide 1, glycine, Na₂CO₃, and H₂O were refluxed for 24 h. Product yield: 96%.

Scheme 6

Synthesis of 3′′,3′′′-[6′-(4-sulfamoylphenylamino)-1′,3′,5′-triazine-2′,4′-diyl]-bis(azanediyl)dipropanoic acid 4. Reagents and conditions: 4-(4′,6′-dichloro-1′,3′,5′-triazin-2′-ylamino)-benzene-sulfonamide 1, β-alanine, Na₂CO₃, and H₂O were refluxed for 24 h. Product yield: 95%.