HSA- 3(Mahidol University)

A simplified synthetic approach involving sulfonylation followed by amino group alkylation produced new 2-aminothiazole derivatives. UV/Vis, infrared, and NMR spectroscopies confirmed their structures. Compounds 36, 22, 34, and 35 showed strong inhibition against Jack bean and Bacillus Pasteurii urease, with IC₅₀ values from 14.06 to 20.21 μM/mL. Compounds 20, 26, 21, 29, 30, 31, and 32 exhibited potent inhibitory effects against α-glucosidase and α-amylase, with IC₅₀ values between 20.34 and 37.20 μM/mL. Compounds 33, 26, and 27 demonstrated potent DPPH scavenging, with IC₅₀ values around 34.4-39.2 μM/mL. FMO analysis showed compounds 21, 22, 24, and 25 having parallel aromatic ring systems due to π cloud interactions, while compounds 32 and 38 had distinct electronic density distributions. Compound 22 had HOMO and LUMO energy gaps of 5.805 eV, with bromo and fluoro substitutions in compounds 21 and 24 slightly increasing the gaps to 6.089 eV and 6.078 eV, respectively. Nitro groups in compounds 25 and 32 reduced the gaps to 0.384 eV and 1.187 eV. All compounds demonstrated high gastrointestinal absorption, non-permeability to the blood-brain barrier, and optimal skin permeation (Log Kp between -5.83 and -6.54 cm/s). Compounds 22, 24, and 38 had promising QED scores of 0.719, 0.707, and 0.860, respectively, with synthetic accessibility scores from 2.057 to 2.517. ADMET predictions indicated minimal toxicity, cardiovascular safety, and significant inhibitory potential for CYP enzymes. Strong in silico binding affinities (binding energies -5.75 to -7.63 kcal/mol) and metabolic stability suggest these derivatives are promising candidates for further drug development.

N-Heterocyclic derivatives of p-HOC₆H₄SO₂NH₂ and p-halobenzenesulfonamides were synthesized for screening as chemotherapeutic agents.C₈H₁₇COCl (243.9 g.) added to 91 g. NH₂NHCSNH₂ at 100° (temperature kept below 110°), the mixture refluxed 30 min., cooled, 400 g. ice added, then NH₄OH to pH 8-8.5 yielded 77.4 g. 2-amino-5-heptyl-1,3,4-thiadiazole (I), m. 189.4-90.4° (from alc.).Method A: NaNO₂ (7 g.) in solution added to 0.1 mol of the sulfanilamide in 10-20% H₂SO₄, the mixture stirred cold 1 h., heated rapidly on the steam bath (internal steam addnl.), cooled, and recrystallized yielded the sulfonamide.Concentrated H₂SO₄ (100 cc.), then 1 kg. ice and 35 g. NaNO₂ in 200 cc. water added to 127.5 g. sulfathiazole in 2 l. water containing 100 cc. concentrated H₂SO₄, the solution heated 30 min. on the steam bath, decanted from the tar, let stand overnight, the product filtered off, added to 300 cc. water and NaOH at pH 8-9, 90 g. salt added, then NaOH to pH 12, the solution cooled to 5°, the Na salt filtered off, dissolved in 2 l. water at 90°, HCl added to pH 7.0, the solution clarified with C, HCl added to pH 3-4, and the solution cooled to 20° and filtered yielded 32 g. N-(2-thiazolyl)-1-phenol-4-sulfonamide (IA), m. 229-30.5°.Sulfadiazine (125 g.) by a similar procedure yielded 19 g. N-(2-pyrimidyl)-1-phenol-4-sulfonamide (IB), m. 230.5-32°.Sulfaguanidine (106 g.) yielded 46 g. bis(N-guanyl-1-phenol-4-sulfonamide) sulfate colorless, sandy crystals from 30% EtOH, m. 219.8-20.3°.Sulfonylchloride methods.Method B: ClCO₂Et (427cc.) added to the di-Na salt from 780 g. 4-HOC₆H₄SO₂Na in 2 l. water, the mixture stirred until a precipitate formed, 200 cc. 50% NaOH added, and the mixture cooled and filtered yielded 500 g. Na p-carbethoxyoxybenzenesulfonate (II).II (400 g.) and 400 g. PCl₅ mixed by alternate portion-wise addition, the mixture stirred 1 h., 75 cc. C₆H₆ added, and the precipitate filtered off yielded 330 g. acid chloride (III), m. 69.9-71.0°.III (150 g.) added to 150 cc. dry pyridine and 71 g. 2-aminothiazole (IV), the temperature kept 15 min. at 50-5° and 30 min. at 65-70°, and 600 cc. water added, then concentrated HCl to pH 4, yielded N-(thiazolyl)-p-carbethoxyoxybenzene sulfonamide (V), m. 155.6-6.5°(from EtOH).V(12g.)and 52 cc. water containing 12 g. NaOH heated 30 min. at 85-90°, and the mixture adjusted to pH 4 with concentrated HCl yielded IA.Method C: IV (10 g.) added to 68 cc. pyrimidine and 30 g. p-BzC₆H₄SO₂Cl, the mixture heated 15 min. at 50-60°, diluted with 200 cc. water and acidified with HCl, the gum in 55 cc. water containing 20 cc. 50% NaOH heated 30 min. at 85-95°, and the solution filtered with C and acidified yielded IA.Method D: 2-Aminopyridine (VA) (3.1 g.) in 15 cc. dry pyridine treated at 0-5° with 7 g. p-AcOC₆H₄SO₂Cl, let stand overnight at room temperature, and poured into ice water gave 7.1 g. crude acetate, m. 196-7° (from EtOH), of N-(2-pyridyl)-1-phenol-4-sulfonamide, m. 224.5-6.5° (VIA).Method E: p-(p-Tosyloxy)benzenesulfonyl chloride (VI), m. 82.5-3.5° (35 g.), added to 10 g. VA in 50 cc. pyridine, and the mixture heated 20 min. at 50° and poured into 500 cc. cold water yielded p-toluenesulfonate, minute white plates from AcOH, m. 202.5-4.5°, of VIA.VI and 2-methylaminothiazole yielded the toluenesulfonate derivative, m. 116-18°, of N-methyl-N-(2-thiazolyl)-1-phenol-4-sulfonamide, m. 141-2.5°.Method F: 2-Amino-4,5-dimethylthiazole (26 g.) in 200 cc. pyridine treated with 46 g. p-ClC₆H₄SO₂Cl heated 30 min. on a water bath, poured into 2 l. water (a red gum separated), acidified to about pH 2, the gum (which crystallized on standing) filtered, washed, suspended in 500 cc. water, dissolved by addition of NaOH, treated with Darco G-60, filtered, and precipitated with HCl gave 45 g. crude N-(4,5-dimethyl-2-thiazolyl)-p-chlorobenzenesulfonamide, m. 206.7-7.9° (from AcOH).Method G: 2-Amino-5-methyl-1,3,4-thiadiazole (57.5 g.) slurried in 200 cc. pyridine at 20-30°, treated with 103.3 g. p-MeOC₆H₄SO₂Cl, heated 2 h. at 50°, let stand overnight, poured into 400 cc. water, and made up to pH 3 with HCl gave 110.4 g. crude N-(5-methyl-1,3,4-thiadiazol-2-yl)-p-methoyxbenzenesulfonamide; solution in the min. amount of boiling AcOH, precipitation by gradually adding 1 volume of water, cooling to 10°, and repeating the process 3 times gave 86.2 g. product m. 171-3°.The N-heterocyclic radicals, R', in Table I are: (1) 2-thienyl, (2) 6-methyl-2-pyridyl, (3) 5-methyl-2-pyridyl, (4)4-methyl-2-pyridyl, (5) 3-methyl-2-pyridyl, (6) 5-chloro-2-pyridyl, (7) 2-quinolyl, (8) 2-benzimidazolyl, (9) 2-pyrimidyl, (10) 4-methyl-2-pyrimidyl, (11) 5-chloro-2-pyrimidyl, (12) 4-methoxy-2-pyrimidyl, (13) 4,6-dimethyl-2-pyrimidyl, (14) 4,6-dimethoxy-2-pyrimidyl, (15) 2-pyrazinyl, (16) 5,6-dimethyl-2-pyrazinyl, (17) 2-quinoxalyl, (18) 6-methyl-3-pyridazinyl, (19) 1,2,4-triazol-4-yl, (20) 5-phenyl-1,2,4-triazol-3-yl, (21) 4,6-diamino-2-triazinyl, (22) 2-benzoxazolyl, (23) 3-phenyl-5-isoxazolyl, (24) 2-thiazolyl, (25) 4-methyl-2-thiazolyl, (26) 5-methyl-2-thiazolyl, (27) 5-amyl-2-thiazolyl, (28) 4-phenyl-2-thiazolyl, (29) 5-carboxy-2-thiazolyl, (30) 4,5-dimethyl-2-thiazolyl, (31) 5-carbethoxy-2-thiazolyl, (32) 2-benzothiazolyl, (33) 4(5H)-thiazolon-2-yl, (34) 5-methyl-4(5H)-thiazolon-2-yl, (35) 5-ethyl-4(5H)-thiazolon-2-yl, (36) 5-methyl-1,2,4-oxadiazol-3-yl, (37) 1,3,4-thiadiazol-2-yl, (38) 5-methyl-1,3,4-thiadiazol-2-yl, (39) 5-heptyl-1,3,4-thiadiazol-2-yl, (40) 5-phenyl-1,3,4-thiadiazol-2-yl, (41) 5-amino-1,3,4-thiadiazol-2-yl.For R, Cb = EtO₂C, P = p-HOC₆H₄SO₂, T = p-MeC₆H₄SO₂.Table I; N-Heterocyclicbenzenesulfonamides, RSO₂NHR'; R, R', Method, Yield (%), Recrystallization solvent, M.p. °C; Cl, (1), F, 19, Dilute alc., 116.0-17.0; OH, (2), E, 41, Water, 190.5-2.0; OH, (3), E, 54, Alc., 208.0-10.0; OH, (4), E, 57, Alc., 254.5-6.0; OH, (5), E, 44, Alc., 216.0-17.0; Cl, (2), F, 70, DiluteAcOH, 101.5-3.0; Cl, (3), F, 34, AcOH, 210.5-12.5; Cl, (4), F, 53, AcOH, 242.5-4.5; Cl, (5), F, 46, Alc., 142.5-4.5; OH, (6), E, 74, Water, 197.5-9.0; OH, (7), C, 37, MeOH, 241.0-3.0; OBz, (7), C, 47, Alc., 181.0-2.0; OH, (8), E, 8, Alc., 333.0-4.0; I, (9), A, 9, Dilute alc., 219.0-20.5; OCb, (9), B, 59, Alc., 190.5-1.7; OH, (10), B, C, -, Water, 224.0-5.0; OCb, (10), B, -, Alc., 190.8-2.9; OH, (11), A, 74, 50% alc., 240.5-2.0; OH, (12), B, 6, 70% alc., 243.9-4.5; OMe, (12), G, 46, Water, 198.6-9.2; OH, (13), C, E, 57, Alc., 197.5-9.5; OMe, (13), G, 45, Alc., 165.0-7.0; OT, (13), E, 74, Alc., 179.1-80.5; F, (13), F, 25, Dilute alc., 179.0-80.0; Cl, (13), F, 46, Alc., 181.0-2.5; Br, (13), F, 52, Alc., 178.0-9.5; OH, (14), E, 20, 50% alc., 190.1-90.9; Cl, (14), F, 18, CCl₄, 152.6-3.9;OH, (15), B, E, 26, AcOH, 243.0-4.0; OH, (16), E, 71, Alc., 226.7-7.8; OH, (17), E, 31, MeOH, 232.5-4.5; OT, (17), E, 54, MeOH, 178.5-9.5; OH, (18), E, 82, Water, 171.0-2.0; OT, (18), E, -, Alc., 188.0-8.5; OH, (19), C, 56, Water, 283.0-4.0; OH, (20), D, -, -, 149.0-51.0; Cl, (20), D, 86, Dilute alc., 209.0-10.0; OH, (21), A, -, Water, >360; OT, (22), E, 93, Alc., 215.8-17.1; Cl, (22), F, 52, Dilute alc., 216.0-17.5; OH, (23), E, 15, Dilute alc., 90.0-1.0; OT, (23), E, 19, Alc., 136.5-8.5; Cl, (23), F, 24, Alc., 142.0-4.0; OMe, (24), G, 31, Water, 178.0-8.8; F, (24), F, 38, Dilute alc., 174.0-5.0; Cl, (24), F, 69, Dilute alc., 203.5-4.0; OH, (25), E, 57, Water, 209.5-10.5; OH, (26), E, 46, AcOH, 233.1-3.6; OH, (27), E, 40, Alc., 223.2-4.0, OH, (28), E, 84, Water, 251.0-2.0; OH, (29), B, 6, Water, 212.5-13.9; OH, (30), E, 74, Water, 243.8-4.6, NHP, (24), E, 46, Water, 136.0-8.0; , , , , , (- water); Cl, (29), F, 38, Dilute alc., 238.0-41.0; Cl, (31), F, 57, Dilute alc., 204.0-5.0; OH, (32), E, 57, Alc., 297.0-300.0; OT, (32), E, 85, DiluteMe₂CO, 234.0-5.0; Cl, (33), F, 52, Alc., 244.5-5.5; OH, (34), D, 12, Water, 200.0-2.0; OMe, (34), D, 29, Alc., 171.0-2.0; Cl, (34), F, 20, Alc., 161.0-2.0; OH, (35), D, 13, Water, 199.5-200.0; Cl, (35), F, 38, Dilute alc., 173.5-4.5; OH, (36), A, 50, Alc., 230.0-3.0; OH, (37), A, 35, Water, 241.5-3.0; Cl, (37), F, 20, Alc., 212.0-13.0; Br, (37), F, 17, Alc., 230.0-1.0, I, (37), A, 8, Dilute alc., 248.0-9.0; OH, (38), C, 25, Water, 224.5-6.0; F, (38), D, 32, Dilute alc., 177.0-8.0; Cl, (38), D, 39, Alc., 193.0-4.0; Br, (38), D, 40, Alc., 204.0-5.0; OH, (39), E, 24, DiluteAcOH, 130.0-2.0; OH, (40), E, 23, DiluteAcOH, 283.0-4.0; OH, (41), E, 28, DiluteAcOH, 262.0-4.0; Di-Na N-heterocyclic-1-phenol-4-sulfonamide sulfates were prepared by treating 0.1 mol. N-substituted phenolsulfonamide, dissolved or suspended in 200 cc. water, with 0.2 mol. NEt₃SO₃, heating until a clear solution resulted (usually about 2 h.), making strongly alk. with 50% aqueousNaOH, boiling until practically all the Et₃N had been removed, clarifying with charcoal, cooling to 5-10°, seeding with Na₂SO₄.10H₂O crystals, refrigerating overnight, filtering off the Na₂SO₄, saturating with NaCl, refrigerating until crystallization of the Na salt of the sulfuric ester was complete, and recrystallizing the product (Table II).Table II; N-Heterocyclic-1-phenol-4-sulfonamide sulfate esters NaOSO₂OSO₂NNaR'; R' (from Table I), Yield (%), Recrystallization solvent, M.p., °C.; (24), 55, Water, alc., 275-8 (decomposition); (24), -, 90% alc., 125 (- water), mono-Na salt; (24), 69, 80% alc., 200-50 (decomposition) di-K salt; (30), 88, Water, 90% alc., 295-300 (decomposition); (9), 50, Water, 90% alc., 260-5 (decomposition); (11), 32, Water, 90% alc., 332-5 (decomposition); (13), 60, Water, 90% alc., 315-18 (decomposition); (38), 26, Water, 90% alc., 280-2 (decomposition); Guanidine derivs: General method: Guanidine nitrate (VII) (0.1 mol) in 50 cc. water containing 20 cc. 5 N NaOH shaken a few hrs. with 0.05 mol RC₆H₄SO₂Cl in 50 cc. C₆H₆, the emulsion let stand 1-5 days at room temperature, the mass broken up, washed, filtered, and recrystallized from alc. or dilute alc. 1-Tosyloxy-4-benzenesulfonyl chloride and VII yielded 50% N-guanyl-1-tosyloxy-4-benzenesulfonamide, m. 223.5-4.5°. p-ClC₆H₄SO₂Cl (VIII) and VII yielded 25% N-guanyl-p-chlorobenzenesulfonamide, m. 198-200°.3,4-(O₂N)ClC₆H₃SO₂Na (225 g.) and 250 g. PCl₅ heated 30 min. on the steam bath, the mixture poured into ice and water, filtered, and the wet filter cake dissolved in 75 cc. hot PhMe yielded about 170 g. 3-nitro-4-chlorobenzenesulfonyl chloride (IX).IV (100 g.) in 300 cc. dry pyridine added to the solution of IX at 70-80° and the mixture poured into 1200 cc. water and HCl added to pH 2.5-3 yielded N-(2-thiazolyl)-3-nitro-4-chlorobenzenesulfonamide (X).About 0.75 of X in 300 cc. water and 120 cc. 5 N NaOH let stand overnight, 200 cc. 50% NaOH added, the mixture cooled and filtered, the cake dissolved in 250 cc. water at 60°, 150 cc. 50% NaOH added, and the mixture filtered, the cake dissolved in 500 cc. water at 80°, HCl added to pH 7-8, the solution clarified with C, and the filtrate treated with HCl to pH 3-4 yielded 35 g. N-(2-thiazolyl)-2-nitrophenol-4-sulfonamide (XI), yellow crystals, m. 204.1-5.0°.XI in alc. reduced with Pd-on-C at 40 lb./sq. in. at room temperature yielded the 2-amino compound, m. 230-1°. o-MeC₆H₄OH (225 g.) and 300 g. concentrated H₂SO₄ heated 16 h. on the steam bath, the solution added to 1 l. water, then 300 cc. NaCl added, the mixture cooled, 50% NaOH added to pH 12, then 300 g. more added, the mixture cooled to 20° and filtered yielded 275 g. di-Na 2-methylphenol-4-sulfonate (XII).XII in 1 l. water containing 37 g. 50% NaOH treated with 162 g. OC(OEt)Cl (the temperature kept. just below 50° by the addition of ice), 100 g. NaCl added, the mixture cooled to 20° and filtered yielded 250 g. Na 3-methyl-4-carboethoxyoxybenzenesulfonate (XIII).XIII and PCl₅ (250 g. each) mixed alternately and portion-wise, the mixture heated 30 min. at 80-90°, added slowly to ice and water, let stand 16 h. and filtered, the solid dissolved in C₆H₆ (water layer discarded), the acid chloride in C₆H₆ added to 100 g. IV and 250 cc. pyridine, the mixture heated 1 h. at 60-70°, poured into 800 cc. of hot water, heated 15 min. at 70°, cooled, 200 cc. concentrated HCl added, and the product let stand overnight yielded 192.7 g. N-(2-thiazolyl)-1-carbethoxy-2-methyl-4-benzenesulfonamide (XIV), m. 125.2-6.8° (from BuOH).XIV (191.7 g.) refluxed 1 h. with 600 cc. water and 165 cc. 50% NaOH, 245 cc. concentrated HCl added, the solution cooled to 10°, filtered, the precipitate dissolved in 400 cc. water and 50 cc. 50% NaOH, the Na salt precipitated by the addition of 120 g. of salt and 250 cc. 50% NaOH, filtered off, dissolved in dilute alkali, the solution treated with Na₂S₂O₄ and C, acidified, and the product filtered off yielded 39.2 g. N-(2-thiazolyl)-2-methyl-1-phenol-4-sulfonamide, m. 243.5-4.5°.Guaiacol (500 g.) and 400 cc. concentrated H₂SO₄ heated 16 h. on the steam bath, the mixture poured into 4 l. water, 400 g. lime added, the hot slurry filtered, 400 g. CaCl₂ added, the pH adjusted to 8-9 with NH₃, and the precipitate filtered at 20° yielded 290 g. Ca salt of 2-methoxy-1-carbethoxyoxy-4-benzenesulfonate (XV); the Ca salt slurried portion-wise into 400 cc. water at 85° with the addition of 150 g. K₂CO₃, the slurry filtered hot, and the filtrate brought to pH 3-4 yielded 175 g. mono-K salt of XV, which in 500 cc. water treated with 42 g. KOH, then with 94 g. OC(OEt)Cl and KOH to maintain the pH at 8-9, the slurry let stand overnight at 5° and filtered yielded 167 g. K salt, which heated 1 h. at 95-100° with 150 g. PCl₅, the mixture cooled, poured on ice, and extracted with 100 cc. C₆H₆ yielded the acid chloride (not isolated), which (in C₆H₆) condensed with IV (Method H) yielded N-(2-thiazolyl)-2-methoxy-1-phenol-4-sulfonamide, m. 131.2-2.5°.4-AcOC₆H₄SO₂Cl (106 g.) added during 2 h. to 92 g. 2-aminothiazoline in 225 g. pyridine at 0-10°, the mixture stirred 4 h. at room temperature, cooled to 10°, filtered, the filtrate poured into 1.5 l. water, the oil separated, washed with water, dissolved in 300 cc. alc., 375 cc. concentrated HCl added, the mixture let stand at room temperature overnight, neutralized with 50% NaOH to pH 3.0-3.5, concentrated in vacuo on the water bath to 300 cc., cooled, the supernatant liquid decanted, the residue heated with 3.5 l. water at 85°, the solution clarified, cooled, and fractionally recrystallized yielded 6% N-(2-thiazolinyl)-1-phenol-4-sulfonamide, m. 203-4° (from alc.); and 3-(p-hydroxyphenylsulfono)-2-(p-hydroxyphenylsulfonimido)thiazolidine {or 2-[bis(p-hydroxyphenylsulfonyl)amino]thiazoline}, m. 214-15° (structure not established).An attempt to prepare N-(2-thiazolinyl)-p-chlorobenzenesulfonamide yielded only the bis compound which could not be hydrolyzed to a mono compound 1,4-(HO)₂C₆H₃SO₂NH₄ (300 g.), 500 cc. Ac₂O, and 500 cc. pyridine let stand 3 days at room temperature, the mixture concentrated in vacuo at 70°, the residue treated with 500 g. PCl₅, the mixture heated 30 min. at 60°, poured into 6 l. water, the precipitate washed by decantation, filtered, extracted with 6 l. hot CCl₄, the extract concentrated to incipient crystallization, and cooled overnight yielded 318 g. 1,4-diacetoxy-3-benzenesulfonyl chloride (XVI).XVI (176 g.), 66 g. IV, and 200 cc. pyridine let stand 30 min. at room temperature, refrigerated overnight, the mush poured into 3 l. water, acidified with dilute HCl, and filtered yielded 172 g. crude N-(2-thiazolyl)-1,4-diacetoxy-3-benzenesulfonamide (XVII); XVI (143 g.) and 2 l. N NaOH stirred 10 min. at 20-5°, filtered, the cake (48 g.) washed with 200 cc. water, the filtrate heated 1 h. on the steam bath, cooled to 60°, adjusted to pH 9 with dilute HCl, treated with C, the filtrate adjusted to pH 2-3 and refrigerated 3 days yielded N-(2-thiazolyl)-1,4-dihydroxy-3-benzenesulfonamide, white crystals from water, m. 222-4°.XVI (146 g.), 52 g. VA, and 200 cc. pyridine yielded 139 g. N-(2-pyridyl)-1,4-diacetoxy-3-benzenesulfonamide, m. 238-9° (from Me₂CO); the 1,4-dihydroxy compound decomposed 203-5°.4-Methyl-1-phenol-2,6'-bis-(sulfonyl chloride) added during 15 min. at 15-20° to 29.1 g. VA in 120 cc. pyridine, the mixture let stand 1 h. at room temperature, refrigerated 23 h., poured into 800 cc. water, acidified to pH 3.5-4.0 with 5 N HCl, heated 15 min. at 70°, the product filtered off, washed with hot water, dissolved in 760 cc. 0.5 N NaOH, treated with C, the filtrate treated with 240 cc. 50% NaOH, the precipitate filtered off at 5°, dissolved in 1.5 l. water, treated twice with C, the solution acidified with dilute HCl, and filtered yielded 47 g. 4-methyl-1-phenol-2,6-bis[N-(2-pyridyl)sulfonamide]; recrystallization through the Na salt gave a product m. 246-50°.VA (52 g.), 146 g. 1,2-diacetoxy-4-sulfonyl chloride, and 200 cc. pyridine let stand 1 h. at 25-30°, refrigerated overnight, poured into water, acidified with concentrated HCl (a heavy gum settled out and beads formed above), and the beads recrystallized from sec-BuOH yielded 13 g. N-(2-pyridyl)-1,2-diacetoxy-4-benzenesulfonamide, white needles, m. 166-7°; 1,2-dihydroxy compound m. 225-6° (from water).K₂CO₃ (17.2 g.), 26 g. 4-HOC₆H₄SO₂NH₂ (m. 175-6°), and 11.5 g. 2-chloropyrazine (b. 152.6-3.6°) refluxed 5 h., the mixture cooled, dissolved in 200 cc. water, made strongly alk. with dilute NaOH, steam distilled, the residue clarified with C, adjusted to pH 10 with dilute HCl, and cooled (ice bath) yielded 9 g. O-(2-pyrazinyl)-1-phenol-4-sulfonamide, small, white plates from alc., m. 150.6-1.4°.Na p-tosyloxybenzenesulfinate (XVIIA) (159 g.) in 825 cc. water containing 64 g. 2-amino-5-chlorothiazole and 40 g. NaHCO₃ heated 2 h. at 80° and the solid filtered off after cooling yielded 2-amino-5-(p-tosyloxyphenylsulfonyl)thiazole (XVIII), m. 157.5-8.5° (from alc.).The crude XVIII slurried in 800 cc. 10% NaOH, the mixture heated 10 min. on the steam bath, filtered hot, adjusted to pH 6.0-6.5, and filtered yielded 59 g. crude product; the product extracted 1.5 l. alc., filtered, the filtrate clarified and diluted with 1 volume water, and the product filtered off yielded 2-amino-5-(p-hydroxyphenylsulfonyl)thiazole, shiny white crystals from 50% alc., m. 275-6°.2-Chlorothiazole (50 g.), 140 g. XVIIA, and 250 cc.Di-Et Carbitol refluxed 4 h., the mixture cooled, poured into 1 l. water, cooled to 5-10°, and filtered yielded 56 g. 2-(p-tosyloxyphenylsulfonyl)thiazole (XIX), m. 146-7° (from alc.).XIX in 700 cc. 10% NaOH containing 150 cc. alc., heated 40 min. on the steam bath, the solution clarified, cooled, and precipitated yielded 23.1 g. 2-(p-hydroxyphenylsulfonyl)thiazole, m. 162.5-3.5° (from 20% alc.).For some compounds from Table I R', [pK₁, pK₂, (R = OH)], pK_a (R = NH₂) are: (9), 6.37, 9.0, 6.48; (11) 5.59, 8.84, -; (13), 7.52, 9.16, 7.37; (24), 7.29, 9.05, 7.12; (38), 5.37, 8.81, 5.45.