* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67percent yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45percent yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
Reference：
[1] Pharmaceutical Chemistry Journal, 1997, vol. 31, # 9, p. 471 - 473
[2] Patent: US2007/292352, 2007, A1, . Location in patent: Page/Page column 45
[3] Patent: US2324013, 1941, ,
[4] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
[5] Patent: US2324014, 1941, ,
[6] Rum. Med. Rev., 1957, vol. 2, p. 96
[7] Patent: US2391853, 1942, ,
[8] Rum. Med. Rev., 1957, vol. 2, p. 96
[9] Patent: CH242247, 1944, ,
[10] Patent: CH242247, 1944, ,
14
[ 72-14-0 ]
[ 116-43-8 ]
Reference：
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
[2] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
15
[ 110-15-6 ]
[ 72-14-0 ]
[ 116-43-8 ]
Reference：
[1] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
triethylamine; In tetrahydrofuran; at 20℃; for 6.0h;
Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67% yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45% yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
A stirred methanolic solution (20 mL) of <strong>[72-14-0]Sulfathiazole</strong> (1 mmol,0.255 g) was added to the methanolic solution (10 mL) salicylaldehyde(1 mmol, 0.122 g), along with two drops of sulfuric acid.Thereafter, the reaction mixture was refluxed for 16 h and filteredand left standing at room temperature. By slow evaporation, orangecrystals of were formed after one week.C16H13N3O3S2. Orange crystals. Mol. Wt.: 359.42 g/moL. FT-IR:numax cm-1 (KBr):1616 (s, C=N). UV-Vis: lambdamax (nm) (epsilon.M-1 cm-1)(MeOH): 232 (92500), 275(104400), 345 (57600). 1HNMR (CD3OD,300 MHz): 6.71e7.96 (m, 10H), 8.82 (s, 1H).
In ethanol;Reflux;
To a stirred ethanolic solution of 4-amino-N-(1,3-thiazol-2-yl)benzenesulfonamide (0.01 mol), ethanolic solution of 2-hydroxybenzaldehyde(0.01 mol) was added and the mixture wasrefluxed for 4-5 h. A dark orange coloured solid mass separated outon cooling is filtered, washed and dried over anhydrous CaCl2 indesiccator.
With ammonium formate;palladium 10% on activated carbon; In methanol; at 23℃; for 8h;
To 1 eq of a 4-nitrobenzenesulfonamide as a 0.1 M solution in MeOH is added 0.1 wt. equiv. of 10% Pd/C and 5 equiv. of ammonium formate and the mixture is stirred at 23 C. for 8 h. Filtration through celite and evaporation gives the title compound as an off-white solid or a colorless oil.
With palladium on activated charcoal; hydrogen; In methanol; at 30℃; under 1551.49 Torr; for 24h;
Step 2 - 4-Amino-N-thiazol-2-yl-benzenesulfonamide (Intermediate Q) (0404) [00283] To a mixture of 4-nitro-N-thiazol-2-yl-benzenesulfonamide (6.00 g, 21.0 mmol) in methanol (50 mL) was added Pd/C (1.00 g, 21.0 mmol). The mixture was then stirred at 30 C for 24 hrs under hydrogen atmosphere (30 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound. The solid was used to the next step directly without further purification.1H NMR (400MHz, DMSO-d6) delta = 7.43 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 4.5 Hz, 1H), 6.75 (d, J = 4.5 Hz, 1H), 6.56 (d, J = 8.8 Hz, 2H).
General procedure: 4-Aminobenzenesulfonamide(1a-e) (10mmol) was suspended in water (50 mL). HCl (10 mL, 36.5%) was added dropwise to this solution with stirring. The mixture was gradually heated up to 70C till a clear solution was obtained. The solution was cooled to 0-5C in an ice bath. A sodium nitrite solution (0.5 g in 5mL H2O) was then added over a period of 5 min with stirring. Resorcinol (1.1 g, 10 mmol) was dissolved in 10% of the NaOH solution and kept at 0-5C. Subsequently, the diazonium salt solution was added with the occasional slow stirring to the resorcinol solution for 15-30 min. After acidification, the formed precipitate was filtered, dried, and recrystallized from absolute ethanol to give the pure products 3a-e.
24.B Step B.
Step B. Preparation 6-[4-(2-Thiazolylsulfamoyl)phenylazo]-pyridoxal-5-phosphate The title material was prepared from 4-amino-N-thiazol-2-yl-benzenesulfonamide (step A) and pyridoxal-5-phosphate as described in general procedure D, method A. The final productproduct was obtained in 29% yield. 1H NMR (D2O): δ 2.31 (s, 3H), 5.55 (s, 2H), 6.46 (s, 1H), 6.97 (s, 1H), 7.88 (s, 4H), 10.26 (s, 1H). 31P NMR (D2O): δ 7.02 (s).
With potassium hydroxide; In water; at 20℃; for 1h;
The silver(I) complex with sulfathiazole (Ag-SFT) was synthesized by the reaction of 7.0mL of an aqueous solution containing 5.0×10-4mol (0.1279g) of the sulfathiazole (SFT) and 1.0×10-3mol (0.0549g) of KOH with 2.0mL of an aqueous solution containing 5.0×10-4mol (0.0854g) of AgNO3. The synthesis was carried out with stirring at room temperature. After 1h, the white solid obtained was vacuum filtered, washed with cold water and dried in a desiccator under vacuum. Anal. Calc. for AgC9H8N3O2S2: C, 29.6; H, 2.76; N, 11.5. Found: C, 29.5; H, 2.30; N, 11.4%. The yield of the synthesis was 90%. The Ag-SFT is insoluble in dichloromethane, chloroform, acetonitrile, hexane, acetone, ethanol, methanol and water. It is soluble in DMSO and is stable in this solvent. The Ag-SFT complex shows a band centered at 290nm in the UV-Vis spectrum with molar absorptivity coefficient of 15210 L mol-1cm-1 in DMSO.
General Procedure 3 To a stirring suspension of the aniline (1.3 mmol) and CH2Cl2 (5.5 mL) under N2, at 0 C., was added trimethylaluminum (1.3 mmol) dropwise over 20 minutes. The solution was stirred at ambient temperature for 30 minutes. The solution was cooled to 0 C. followed by the dropwise addition of (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (1 mmol) in CH2Cl2 (1.0 mL) over 30 minutes. The solution was stirred at ambient temperature for 19 hours. The solution was cooled to 0 C. and aqueous 1.0 M HCl was added dropwise over 1.5 hours. The organic portion was washed with 1.0 N aqueous HCl (2×1.0 mL) and evaporated to dryness under reduced pressure. The residue was purified via silica gel using MeOH in CH2Cl2 to obtain the desired amide as a white solid.(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide The reaction was set up with sulfathiazole (122 g, 477 mmol), CH2Cl2 (1.5 L), trimethylaluminum (2.0 M in hexanes, 239 mL, 477 mmol), and (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367 mmol) in CH2Cl2 (250 mL). The reaction was purified via silica gel using 10% MeOH in CH2Cl2 to obtain the desired amide as a white solid (207 g, 348 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
95%
(R)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)butanamide Synthesised according to General procedure 3. The reaction was set up with sulfathiazole (122 g, 477 mmol), CH2Cl2 (1.5 L), trimethylaluminum (2.0 M in hexanes, 239 mL, 477 mmol), and (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (125 g, 367 mmol) in CH2Cl2 (250 mL). The reaction was purified via silica gel using 10% MeOH in CH2Cl2 to obtain the desired amide as a white solid (207 g, 348 mmol, 95% yield). 1H NMR (400 MHz, DMSO-d6) delta 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
To a stirred suspension of the aniline (1.3 mmol) and DCM (5.5 mL) under N2, at 0 C., was added a solution of trimethylaluminum in hexane (2.0 M, 1.3 mmol) dropwise over 20 minutes. The solution was stirred at ambient temperature for 30 minutes. The solution was cooled to 0 C. followed by the dropwise addition of 3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (1 mmol) in CH2Cl2 (1.0 mL) over 30 minutes. The solution was stirred at ambient temperature for 19 hours. The solution was cooled to 0 C. and aqueous 1.0 M HCl was added dropwise. The organic portion was washed with 1.0 M aqueous HCl (2×1.0 mL) and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatographyy to obtain the desired amide.(S)-2-(tert-Butyldiphenylsilyloxy)-4-hydroxy-N-[(4-(N-thiazol-2-ylsulfamoyl)phenyl)]butanamide Synthesized according to General Procedure 5. The reaction was set up with sulfathiazole (11.2 g, 44 mmol), CH2Cl2 (150 mL), trimethylaluminum (2.0 M in hexanes, 22 mL, 44 mmol), and (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (12.6 g, 37 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (10% MeOH in DCM) afforded the desired amide as a white solid (22 g, 84% yield). 1H-NMR (400 MHz, DMSO-d6) delta 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59(m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
Preparation of (lr,4r)-4-((4-(benzylamino)-6-(2,3-dimethylbenzylamino)-l,3,5- triazin-2-ylamino)methyl)-Lambda^-(4-(Lambda^-thiazol-2- ylsulfamoyl)phenyl)cyclohexanecarboxamideA solution of (lr,4r)-4-((4-(benzylamino)-6-(2,3-dimethylbenzylamino)-l,3,5- triazin-2-ylamino)methyl)cyclohexanecarboxylic acid (40 mg, 0.084 mmol, 1 equivalent), 4-amino-N-(thiazol-2-yl)benzenesulfonamide (24.5 mg, 0.096 mmol, 1.14 equivalents) and DMAP (2.1 mg, 0.017 mmol, 0.2 equivalent) in dichloromethane (1 ml) was cooled with stirring in an ice bath. l-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 20.2 mg, 0.105 mmol, 1.25 equivalents) was added. The reaction mixture was stirred at 00C for 30 minutes and at room temperature overnight. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The solvent was removed in vacuo to give the crude which was further purified by RP-HPLC (Luna, 5mu C8(2), 100x21mm, 5-80% CH3CN/H2O, 0.1% TFA, 25 min) to give the desired product (45.6 mg, yield 76%). MS: calcd for C36H41N9O3S2+H+ 712.28, found 712.4.
General procedure: Compound 12a (1 g, 3.56 mmol) and the appropriate sulfonamide (3.56 mmol) were stirred in dry acetone (50 ml) in the presence of anhydrous potassium carbonate (1 g, 4.83 mmol) for 10 h. The reaction mixture was then filtered while hot. Upon cooling, crystals separated out and were filtered and recrystallized from absolute ethanol.
General procedure: The compounds were prepared through condensation reaction between 0.001 mol phthalic anhydride and 0.001 mol sulfonamides in 10 mL acetic acid under reflux at 120 C for 3-4 h. Then 20 mL distilled water was added into the reaction media. The compounds were filtered and recrystallized in ethanol.30
4-(4,5,6,7-tetrafluoro-1,3-dioxo-isoindolin-2-yl)-N-thiazol-2-yl-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.2%
With acetic acid; at 120℃;
General procedure: The compounds were prepared through condensation reaction between 0.001 mol tetrafluorophthalic anhydride and 0.001 mol sulfonamides in 5 mL acetic acid under reflux at 120 C for 3-4 h. Then 20 mL distilled water was added into the reaction media. The compounds were filtered and recrystallized in ethanol.
With pyridine; In tetrahydrofuran; at 20℃; for 12h;
The sulfathiazole (0.255g, 1mmol) was dissolved in 10mL of acetone was added 0.12 mL of pyridine, was added dropwise 4- (4-benzoylamino) benzyl chloride (1 mmol of, prepared according to Example 1d) in acetone 5mL, stirred for 12 hours at room temperature, acetone was distilled off under reduced pressure, was added 20mL of saturated Na2CO3The solution was stirred at room temperature for 10 min, extracted with ethyl acetate, the aqueous layer with 10% HCl solution was adjusted to about pH 2, a white precipitate was filtered washed with water, and dried to give a white solid 0.37g, 68% yield.mp: 239 ~ 241C .
59%
With triethylamine; In tetrahydrofuran; at 20℃;
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
52%
With triethylamine; In tetrahydrofuran; at 20℃; for 12h;
The sulfathiazole (0.255g, 1mmol) was dissolved 15mL THF added 0.14 mL of triethylamine, was added dropwise 4- (4-nitrile benzoylamino) benzoyl chloride (1.2 mmol, prepared as described in Example 1d) in THF solution 5mL, was stirred room temperature for 12 hours, poured into 20mL 10% hydrochloric acid solution, filtered, the filter cake was washed successively with 10% HCl solution, saturated NaHCO3Solution, H2O and washed with methanol, and dried to give a pale yellow solid 0.264 g, 52% yield.mp: 301 ~ 304 .
With triethylamine; In tetrahydrofuran; at 20℃; for 12h;
The sulfathiazole (0.255g, 1mmol) was dissolved 15mLTHF added 0.17 mL of triethylamine, was added dropwise 4- (4-fluoro-benzoylamino) benzoyl chloride (1 mmol of, prepared as described in Example 1d) in THF 5mL the mixture was stirred at room temperature for 12 hours and complete reaction was monitored by TLC, was filtered, 10% NaHCO3Solution, 10% HCl solution, H2O and washed with small amount of acetone, and dried to give a white solid 0.345g, yield 69.6%.mp: 307 ~ 309 C (300 decomposition starting).
70%
With triethylamine; In tetrahydrofuran; at 20℃;
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
15.9%
With triethylamine; In tetrahydrofuran; at 20℃; for 12h;
The sulfathiazole (0.306g, 1.2mmol) was dissolved 15mLTHF suspension was added 0.2 mL of triethylamine, a solution of 2-hydroxy-4- (4-methoxy benzoylamino) benzoyl chloride (1.2 mmol, as described in preparation Example 1d) in THF 5mL, was stirred at room temperature for 12 hours and filtered, 10% HCl solution, H2O and the filter cake was washed with small amount of acetone to give crude product, which was dissolved in a small amount of DMF, heated to dissolve, add appropriate amount of acetone, and the precipitated white solid was filtered, washed with a little water and acetone, and dried to obtain a white powder 0.1g, yield 15.9%.mp: 309 ~ 311 C (309 C decomposition).
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
76.1%
With pyridine; In acetone; at 20℃; for 4h;
The sulfathiazole (0.306g, 1.2mmol) suspended in a 10mL of acetone was added 0.12 mL of pyridine, was added dropwise 4- (4- (methoxycarbonyl) benzoylamino) benzoyl chloride (1 mmol of, as prepared in Example 1d ) in acetone 10mL, stirred at room temperature for 4 hours to produce a gray precipitate, complete reaction was monitored by TLC, filtered cake was washed with 10% HCl solution, saturated NaHCO3H2O wash, a small amount of acetone and ethanol, and dried to give 0.408 g of a white powder, yield 76.1%.mp:> 350 C.
General procedure: In the presence of catalytic amount DMF, a solution of oxalyl chloride (1.2 equiv) in dichloromethane was added dropwise to a solution of 17, 19 or 20 (1 equiv) in dichloromethane. The mixture was stirred for 12 h at room temperature and the solvent was evaporated in vacuo. The residue was dissolved in dried tetrahydrofuran and added dropwise to a solution of sulfathiazole or 4-(methylamino)-N-(thiazol-2-yl)benzene-sulfonamide (1 equiv) in tetrahydrofuran or acetone, respectively. A solution of triethylamine or pyridine (1 equiv) in tetrahydrofuran was added to the reaction mixture, which was then stirred overnight at room temperature followed by filtration. The filter cake was washed with 5-10% hydrochloric acid, saturated sodium bicarbonate, and water in sequence to give the target compounds 2-9.
With triethylamine; In dichloromethane; at 20℃; for 4h;
General procedure: To a suspension of aryl acid (23a-c, 24) in dried dichloromethane were added 1 drop of DMF followed by a solution of oxalylchloride (1.2 equiv) in dichloromethane dropwise and the mixture was stirred for about 2 hours. The solvent was evaporated and the residue was resolved in dried dichloromethane. To the reaction mixture were added sulfathiazole (1 equiv) and triethylamine (1 equiv) dropwise. The mixture was stirred overnight at room temperature, and evaporated. The residue was dispersed in methanol, and refluxed for about 2 hours. After cooling to the room temperature, the suspension was filtered, washed with cold methanol, and dried to yield 13-16.
57.8%
With triethylamine; In dichloromethane; at 20℃; for 4h;Cooling with ice;
The above-described light yellow solid was dissolved in 20ml of dry dichloromethane, and 510mg sulfathiazole is dissolved in 14ml of dry dichloromethane, was added dropwise under ice-cooling the reaction mixture, the reaction mixture was added dropwise triethylamine (0.28 ml) in dry dichloromethane, stirred at room temperature 4h, TLC detection, starting material the reaction was complete, the reaction was stopped, the solvent was evaporated under reduced pressure, the residue was added 20ml of methanol, heated to reflux, filtered, and the filter cake was washed several times with methanol to give a yellow solid 0.6g, 57.8% yield.
With triethylamine; In dichloromethane; at 20℃; for 4h;
General procedure: To a suspension of aryl acid (23a-c, 24) in dried dichloromethane were added 1 drop of DMF followed by a solution of oxalylchloride (1.2 equiv) in dichloromethane dropwise and the mixture was stirred for about 2 hours. The solvent was evaporated and the residue was resolved in dried dichloromethane. To the reaction mixture were added sulfathiazole (1 equiv) and triethylamine (1 equiv) dropwise. The mixture was stirred overnight at room temperature, and evaporated. The residue was dispersed in methanol, and refluxed for about 2 hours. After cooling to the room temperature, the suspension was filtered, washed with cold methanol, and dried to yield 13-16.
74.6%
With triethylamine; In dichloromethane; at 20℃; for 4h;Cooling with ice;
The above light yellow solid was dissolved in 20 ml of dry methylene chloride solution,510 mg sulfathiazole was dissolved in 14 ml dry dichloromethane,Cooled in an ice bath and added dropwise to the reaction solution,Considering the reaction solution was added dropwise triethylamine (0.28ml) in dry dichloromethane, stirred at room temperature for 4h, TLC detection,The reaction was complete, the reaction was stopped, the solvent was evaporated under reduced pressure, the residue was added 20ml methanol, heated to reflux, filtered, washed with methanol several times to give a pale yellow solid 0.75g, yield 74.6%.
With triethylamine; In dichloromethane; at 20℃; for 4h;
General procedure: To a suspension of aryl acid (23a-c, 24) in dried dichloromethane were added 1 drop of DMF followed by a solution of oxalylchloride (1.2 equiv) in dichloromethane dropwise and the mixture was stirred for about 2 hours. The solvent was evaporated and the residue was resolved in dried dichloromethane. To the reaction mixture were added sulfathiazole (1 equiv) and triethylamine (1 equiv) dropwise. The mixture was stirred overnight at room temperature, and evaporated. The residue was dispersed in methanol, and refluxed for about 2 hours. After cooling to the room temperature, the suspension was filtered, washed with cold methanol, and dried to yield 13-16.
77.8%
With triethylamine; In dichloromethane; at 20℃; for 4h;Cooling with ice;
The above light yellow solid was dissolved in 20ml of dry dichloromethane solution, 255mg sulfathiazole dissolved in 10ml of dry dichloromethane, was added dropwise to the reaction mixture under ice cooling, and then thought the reaction solution was added dropwise triethyl Amine (.14ml) in dry dichloromethane, stirred at room temperature for 4h, TLC detection, the reaction was complete, the reaction was stopped, the solvent was evaporated under reduced pressure, the residue was added 10ml of methanol, heated to reflux, filtered, the filter cake was washed with methanol Over, white solid 0.40g, 77.8% yield.
With triethylamine; In dichloromethane; at 20℃; for 4h;
General procedure: To a suspension of aryl acid (23a-c, 24) in dried dichloromethane were added 1 drop of DMF followed by a solution of oxalylchloride (1.2 equiv) in dichloromethane dropwise and the mixture was stirred for about 2 hours. The solvent was evaporated and the residue was resolved in dried dichloromethane. To the reaction mixture were added sulfathiazole (1 equiv) and triethylamine (1 equiv) dropwise. The mixture was stirred overnight at room temperature, and evaporated. The residue was dispersed in methanol, and refluxed for about 2 hours. After cooling to the room temperature, the suspension was filtered, washed with cold methanol, and dried to yield 13-16.
80.6%
With triethylamine; In dichloromethane; at 20℃; for 20h;Cooling with ice;
The above yellow solid was dissolved in 20 ml of dry dichloromethane, sulfathiazole (3.825 g, 15 mmol) was dissolved in 50 ml of dry dichloromethane, and added dropwise to the above reaction solution while cooling in an ice bath, and then added to the reaction liquid A solution of triethylamine (2.5 ml) in dry dichloromethane was added dropwise and the mixture was stirred at room temperature for 20 h. The reaction was complete by TLC. The reaction was stopped and the solvent was evaporated under reduced pressure. The residue was added to 200 ml of methanol and heated to reflux. Methanol washed several times, pale yellow solid 6.3g, 80.6% yield.
With N,N'-dimethylpiperazine; In tetrahydrofuran; at 55 - 60℃;
General procedure: The synthesis of diphenyl N-substituted carbamimidoylphosphoramidate wasachieved in two steps. In the first step, diphenylphosphorochloridate (1) was reacted withcyanamide (2) in the presence of 1,4-dimethylpiperazine (DMP) as a base in THF at50-55 C to form the intermediate diphenylcyanophosphoramidate (3). Formation of 3was ascertained by TLC analysis run in 3:7 mixture of ethyl acetate and hexane. In thesecond step, 3 was treated with aromatic/heterocyclic amines 4(a-k) in the presence of1,4-dimethylpiperazine at 55-60 C to obtain the title products, diphenyl N-substituted carbamimidoylphosphoramidates 5(a-k). Identification of the products and completion ofthe reaction was monitored by TLC using ethyl acetate: hexane (3:2). After completionof the reaction, the hydrochloride salt was filtered off and the solvent was removed ina rota-evaporator and the residue was purified by column chromatography on silica gel(100-200 mesh) using petroleum ether-ethyl acetate (3:7) as eluent. The resulting titlecompounds 5(a-k) were obtained in high yields (68-78%). The structures of the titlecompounds 5(a-k) were established by spectral and elemental analysis. Representativespectra (1H, 13C, and 31P) for compounds 5a and 5f are presented in the SupplementalMaterials (Figures S1-S6).
General procedure: A mixture of 1 (2.31 g, 0.01 mol) and the corresponding sulfadrugs (0.012 mol) in dry DMF (20 mL) was refluxed for 12 h. The solid obtained after concentration was filtered and crystallized from dioxane to give 2-14, respectively.
4-isothiocyanato-7-(triflouromethyl)quinoline[ No CAS ]
[ 72-14-0 ]
[ 1491007-14-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With triethylamine; In N,N-dimethyl-formamide; for 24h;Reflux;
General procedure: A mixture of 18 (0.43 g, 0.001 mol) and the appropriate sulfadrugs (0.0012 mol) in dry DMF (30 mL) containing a catalytic amount of triethylamine was heated under reflux for 24 h. The obtained solid was filtered and crystallized from dioxane to give 19-30, respectively.
6, 8-ditertbutyl-4-chloro-2-oxo-2H-chromene-3-carbaldehyde[ No CAS ]
4-((6,8-di-tert-butyl-4-chloro-2-oxo-2H-chromen-3-yl)methyleneamino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
In ethanol; acetic acid; at 20℃; for 3h;
General procedure: To a solution of compounds 4a-4c (7.6 mmol) in ethanol (15 mL) was added different substituted sulfonamide (7.6 mmol) and acetic acid (0.5 mL). The mixture was heated at room temperature for 3 h. A solid product was immediately formed which was filtered, washed with water. And the crude products were purified by recrystallization with ethanol, ethyl acetate and acetone(1:1:0.5) washed by ice-water (25 mL) for three times and dried to give a yellow solid product 5a-5r.
Multi-step reaction with 2 steps
1: ethanol / 100 °C / Sealed tube
2: sodium tetrahydroborate / 0.5 h / 20 °C
Stage #1: Sulfathiazole; 3-methoxy-2-hydroxybenzaldehyde In ethanol at 100℃; Sealed tube;
Stage #2: With sodium tetrahydroborate; ethanol at 20℃; for 0.5h;
4-(2-hydroxy-3-methoxybenzylamino)- V-(thiazol-2-yl)benzenesulfonamide (1)
General procedure: 4-(2-hydroxy-3-methoxybenzylamino)- V-(thiazol-2-yl)benzenesulfonamide (1): Method A: using 2-hydroxy-3-methoxybenzaldehyde; 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.44-7.33 (m, 2H), 7.00 (d, J= 4.20 Hz, 1H), 6.85-6.62 (m, 3H), 6.60-6.45 (m, 4H), 4.19 (d, J= 5.91 Hz, 2H), and 3.77 (s, 3H); LC-MS retention time (Method 2): 4.394 min; HRMS: m/z (M+H)+ = (Calculated for Ci7Hi8N304S2392.0733) found, 392.0726. General Synthetic Procedures. (Scheme 1, Method A): 4-amino-N-(thiazol-2- yl)benzene sulfonamide (0.39 mmol) (2), and required benzaldehyde (0.67 mmol) were combined in ethanol (2 mL) in a sealed tube and heated to 100 °C for 4-18 h. The solid was allowed to cool to room temperature and sodium borohydride (0.80 mmol) was added and stirred for 30 min, during which time the reaction turned clear and then cloudy. The resulting solids were filtered, washed with ethanol, and purified using a prep-HPLC (gradient 10-100% acetonitrile w/ 0.1% TFA in water w/ 0.1 %> TFA) to give the desired product.
With acetic acid; In ethyl [2]alcohol; for 3h;Reflux;
4-(2-Hydroxy-3-methoxy benzylidenamine)-N-(thiazole-2-yl)benzene sulfonamide, (HL2) (2) was prepared in a similar procedureof the Schiff base (1) by the addition of (0.51 g, 2 mmol) of sulfathiazole(STZ) to (0.30 g, 2 mmol) of o-vanillin in 25 mL of absoluteethanol. The solution was acidified by adding 2 drops of glacialacetic acid and refluxed for 3 h. The precipitate was filtered,washed with cold ethanol, and then dried in air. Recrystallizationfrom ethanol afforded the purified yellow crystal Schiff base.
4-(1,3-dioxo-hexahydro-1H-isoindol-2(3H)-yl)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
at 150℃; for 0.0333333h;Microwave irradiation;
General procedure: Sulfathiazole (6a; 255mg;1mmol) and furan-2,5-dione (98mg; 1mmol) were mixedthoroughly and subjected to focused microwave irradiationat 150 C for 5 min. TLC of reaction mixture over silicagel G using CHCl3: MeOH (9:1) as mobile phase showedabsence of starting materials and hence completion of thereaction. This crude product was purified by crystallizationfrom methanol to give pure product 7a.
4-((2-phenylquinazolin-4-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
In N,N-dimethyl-formamide; for 22h;Reflux;
General procedure: A mixture of 4-chloro-2-phenylquinazoline (1, 2.42 g, 0.01 mol) and sulfonamides (0.012 mol) in dry dimethylformamide (10 mL) was refluxed for 22 h., then left to cool. The solid product formed upon pouring onto ice/water was collected by filtration and recrystallized from ethanol-dimethylformamide to give 2-18, respectively.
67%
In isopropyl alcohol;Reflux;
General procedure: To a stirred solution of 4-chloroquinazolines 2a-h (1 mmol) in refluxing 2-propanol (15 mL), a solution of sulfanilamide or sulfathiazole (1 mmol) in 2-propanol was added. The reaction mixture was refluxed for 3 h. The precipitate formed was collected by filtration while hot and washed with hot 2-propanol and then with water and crystallized from ethanol to give compounds 3a-p, respectively.
4-((2-(4-chlorophenyl)quinazolin-4-yl)amino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
In isopropyl alcohol;Reflux;
General procedure: To a stirred solution of 4-chloroquinazolines 2a-h (1 mmol) in refluxing 2-propanol (15 mL), a solution of sulfanilamide or sulfathiazole (1 mmol) in 2-propanol was added. The reaction mixture was refluxed for 3 h. The precipitate formed was collected by filtration while hot and washed with hot 2-propanol and then with water and crystallized from ethanol to give compounds 3a-p, respectively.
With sodium hydroxide; In methanol; ethanol; for 3h;pH 7.8 - 8;Reflux;
General procedure: A general procedure was followed for the preparation of thecomplexes using metal acetate and the Schiff base. An ethanolicsolution (20 mL) of sulfa drug (2 mmol) was mixed with (0.22 g,2 mmol) of o-vanillin in 20 mL of methanol. Then, (1 mmol) metalacetate was dissolved in hot methanol and added to the mixture.Then, a few drops of sodium hydroxide (1 M) were added to resultingsolution to adjust the pH to 7.8-8.0. Then, the solution washeated under reflux for 3 h. The reaction mixture was concentratedby evaporation, and the precipitate of metal complexes were collectedby filtration, washed with hot water, ethanol and finallywith small portion of diethyl ether to extract all organic impurities.
N-cantharidinimido-N’-(2-thiazolyl)sulfanilamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With triethylamine; In toluene; at 200℃; for 2h;Sealed tube; High pressure;
General procedure: General procedures were followed for the reaction of ammonia with cantharidine and the other acid anhydride. These compounds were prepared according to similar procedures, and the reactions took place in high-pressure tubes (Buechi Glasuster 0032, Zuerich, Switzerland). Cantharidin or acid anhydrides were added to a tube containing 3 mL of dry toluene and triethylamine (TEA), and the solution was stirred and heated to ca. ~200C. After being stirred for 2 h, the mixture was evaporated, and the residual mass was purified by column chromatography on silica gel and recrystallized from methanol.
N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)cinnamamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
3-phenyl-N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)propanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
4-(3-cyano-6-methylpyridin-2-ylamino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With triethylamine; In N,N-dimethyl-formamide; for 18h;Reflux;
General procedure: A mixture of 2-chloro-6-methylnicotinonitrile (II)(1.52 g, 0.01 mol) and corresponding sulfonamide derivatives (0.012 mol) in dry dimethylformamide(10 mL) containing 3 drops of trimethylamine was refluxed for 18 h then left to cool. The solid productformed upon pouring onto ice water was collected byfiltration and recrystallized from ethanol-dimethylformamide to give (III-XX), respectively.
N,N-bis(4-acetamidobenzenesulfonyl)-2-aminothiazole[ No CAS ]
[ 72-14-0 ]
Yield
Reaction Conditions
Operation in experiment
75%
With water; sodium hydroxide; at 75℃; for 0.75h;Reflux;
General procedure: A round-bottom flask (10 mL volume) was charged with the disulfonylated compound (3f-3h) (1 mmol) and 10% aqueous sodium hydroxide (5 mL). The mixture was then immersed in a preheated oil bath, heated to 75C, and simultaneously stirred for 45 min. After reaction completion, the resulting mixture was cooled to room temperature and acidified by HCl aqueous solution (10%) until the mixture had pH 5. The pH of the mixture was subsequently adjusted to just basic (checked by litmus) by adding solid sodium acetate, and then this mixture was heated to boiling and filtered. The resulting filtrate was cooled slowly first to room temperature and then further to 0C in an ice bath. The final product (4f-4h) was isolated by filtration as a yellowish solid and purified by re-crystallization in ethanol/water or by flash column chromatography (7-8 g silica gel, Davisil, grade 710,4-20mum, 6 A, 99%) using as eluent a mixture of dichloromethane and ethyl acetate (5:5 v/v).
Z-4-(3-(3,4-dimethoxyphenyl)-3-oxoprop-1-enylamino)-N-(thiazol-2-yl)-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With acetic acid; In ethanol; for 22h;Reflux;
General procedure: General ProcedureA mixture of 2 (2.35 g, 0.01 mol) and sulfa drugs (0.012 mol) in absolute ethanol (10 mL) and glacial acetic acid (5 mL) was refluxed for 22h, and subsequently left to cool. The solid product formed was collected by filtration and recrystallized from acetic acid to give compounds 3-19.
General procedure: Secondary sulfonamides were synthesized using naturally available 4-hydroxy and3,4,5-trihydroxy benzoic acids (gallic acid) in various plants and fruits, which were reacted with aceticanhydride to obtain 4-acetoxy and 3,4,5-triacetoxy benzoic acids for the protection of hydroxyl groups.Then, they were converted to their corresponding chloride derivatives by treating with thionyl chlorideto produce benzoyl chlorides, which underwent reactions with secondary sulfonamides having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups to obtain secondary sulfonamidederivatives of acetoxybenzamides and triacetoxybenzamides as one part of target compounds.Deacetylation under acidic conditions gave the other part of our targeted sulfonamide derivatives [28].The reaction scheme is given in Figure 1.
N-(sulfathiazole)-3,4,5-triacetoxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In acetone; at 0 - 20℃; for 20h;
General procedure: Secondary sulfonamides were synthesized using naturally available 4-hydroxy and3,4,5-trihydroxy benzoic acids (gallic acid) in various plants and fruits, which were reacted with aceticanhydride to obtain 4-acetoxy and 3,4,5-triacetoxy benzoic acids for the protection of hydroxyl groups.Then, they were converted to their corresponding chloride derivatives by treating with thionyl chlorideto produce benzoyl chlorides, which underwent reactions with secondary sulfonamides having thiazole, pyrimidine, pyridine, isoxazole and thiadiazole groups to obtain secondary sulfonamidederivatives of acetoxybenzamides and triacetoxybenzamides as one part of target compounds.Deacetylation under acidic conditions gave the other part of our targeted sulfonamide derivatives [28].The reaction scheme is given in Figure 1.
General procedure: Aliquots of sulfonamide derivative solutions (sulfanilamide, sulfamethoxazole,sulfamethiazole, sulfathiazole, sulfacetamide,Ssulfamerazine, sulfadiazine, sulfadimethoxine) ranging from 0.1-1.0 mL (10 mug mL-1) were transferred into each of the series of10 mL flasks, 1 mL of sodium (1% w/v) and 1 mL of 1 M hydrochloricacid were added with swirling at room temperature. After 5 min,1 mL of sulfamic acid (2% w/v) and 1 mL of <strong>[1465-25-4]N-(1-naphthyl)ethylenediamine dihydrochloride</strong> (1% w/v) were added withswirling. The volumes were adjusted to the mark with distilledwater, and then the solutions were mixed thoroughly. The absorbanceof the light pink colored solutions was measured at 536 nmagainst the reagent blank. Fig. 2 shows a picture of a gradient of concentrationsof the pink colored solutions tested.
2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With pyridine; In N,N-dimethyl-formamide; for 4h;Reflux;
General procedure: A mixture of equimolar amounts (0.01 mol, 3.7 g) of2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl chloride (1) and appropriate sulpha drug (0.01 mol)in DMF (10 mL) containing few drops of pyridine wasrefluxed for 4 h. The reaction mixture was poured overcrushed ice, few drops of HCl was added and the separatedsolid product was filtered, dried and recrystallized fromethanol to give:
4-(1-(2-oxopyrrolidin-1-yl)ethylamino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With acetic acid; In hexane; at 20℃; for 14h;
General procedure: To a magnetically stirred solution of enamide (1.2 mmol) and aromatic amines (1 mmol) in n-hexane (3 mL), was added acetic acid (1 mmol, 0.06 mL). The reaction mixture was stirred at room temperature for 14 h. Completion of the reaction was monitored by TLC (ethyl acetate/petroleum ether, 1/3). The products were precipitated in the reaction mixture and collected by simple filtration. Otherwise, evaporation of the solvent gave the crude product which was purified by recrystallization in CH 2 Cl 2 .
4-(2-(methoxycarbonyl)benzoyl)benzoyl chloride[ No CAS ]
methyl 2-{4-[4-(thiazol-2-yl-sulfamoyl)phenylcarbamoyl]benzoyl}benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.5%
With pyridine; In tetrahydrofuran; at 20℃; for 12h;
<strong>[72-14-0]Sulfathiazole</strong> (0.255g, lmmol) was dissolved in 5mL pyridine, was added dropwise 4- (2- (methoxycarbonyl) benzoyl) benzoyl chloride (1.1mmol) THF solution 5mL, stirred at room temperature for 12 hours, TLC The reaction was monitored completely, THF was distilled off, cooled and poured into 1 OmL ice water. The oil was separated, extracted with ethyl acetate, washed with 5% HC1 solution, saturated NaHCO3 solution and H2O, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain white Powder 19g, yield 36.5%. mp: 203 ~ 206 C.
The metal sodium(0.6g, 26mmo 1) - disposable placed in 15mL of methanol was stirred at room temperature,After a large amount of bubbles were produced and sodium particles were completely reacted, sulfadiazine (1.53 g, 6 mmol) and paraformaldehyde (0.42 g, 14 mmol) were added and stirred at 50 C. for 8 hours. Then sodium borohydride g, 10.6 mmol) was added and the mixture was heated to reflux for 1 hour. A solution of 1 mol / L sodium hydroxide was added dropwise and heating was continued for 2 hours. After cooling, the solution was adjusted to pH 6 with 10% hydrochloric acid solution and extracted with ethyl acetate. Dried over anhydrous sodium sulfate, and recrystallized from ethanol to give 1.15 g white needles,Yield 71.4% 153~155 C.
N-(4-(N'-thiazol-2-ylsulfamoyl)phenyl)myrtenamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.3%
With triethylamine; In acetone; at 40℃;Cooling with ice;
General procedure: Synthesisof the target compound 5a was employed as an example. Under anhydrous atmosphere, a solution of myrtenyl chloride(4, 12.5 mmol) in acetone (10.0 mL) was added slowly to a rapidly stirred mixture of a finely ground p-aminobenzenesulfonamidepowder (12.8 mmol); Et3N (12.8 mmol) served as acid-binding agent in acetone (30 mL), with ice-water cooling. Afterwards,the ice-water bath was removed, and the reaction temperature was raised gradually to room temperature and heated to 40C.The reaction process was monitored using thin-layer chromatography (TLC). After completion of the reaction, a little H2Owas added to destroy the unreacted myrtenyl chloride. The resulting mixture was filtered, and the filter cake was washed withHCl (5%), distilled H2O, NaOH (5%), and distilled H2O. The crude product was purified further by recrystallization inEtOH/distilled H2O to afford the target compound 5a.
(2Z)-2-hydroxy-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}-4-(4-chlorophenyl)but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium acetate; In acetic acid; for 0.333333h;Reflux;
a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvate and 0.82 g (0.01 mol) of anhydrous sodium acetate in 10 mL of glacial acetic acid was added to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacial acetic acid. The reaction mixture was refluxed for 20 min. After cooling the precipitate was filtered off and recrystallized from acetic acid-dioxane (1 : 1).Yield 4.17 g (90%), mp 211-213C (AcOH-dioxane, 1 : 1). IR spectrum, nu, cm-1: 3360 (NH), 3130 (OH), 1696 (CONH), 1660 (C=O), 1360, 1148 (SO2). 1NMR spectrum, delta, ppm: 4.59 s (2H, COCH2CO), 6.77d (1H, C5Hthiazole, J = 4.6 Hz), 7.14 s (1H, CH=), 7.19 d (1H, C4Hthiazole, J = 4.6 Hz), 7.46-8.04 m (8H, CHAr), 10.81 s (1H, CONH), 12.71 br.s (1H, SO2NH). Mass spectrum, m/z: 463 [M]+. Found, %: 49.04; H 3.08; N 8.97; S 13.92. C19H14ClN3O5S2. Calculated, %: C 49.19; H 3.04; N 9.06; S 13.82.
methyl 4-(3,4-dimethoxyphenyl)-2,4-dioxobutanoate[ No CAS ]
(2Z)-2-hydroxy-4-(3,4-dimethoxyphenyl)-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With sodium acetate; In acetic acid; for 0.333333h;Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvate and 0.82 g (0.01 mol) of anhydrous sodium acetate in 10 mL of glacial acetic acid was added to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
(2Z)-2-hydroxy-4-(4-methylphenyl)-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium acetate; In acetic acid; for 0.333333h;Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvateand 0.82 g (0.01 mol) of anhydroussodium acetate in 10 mL of glacial acetic acid wasadded to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
(2Z)-2-hydroxy-4-(3-methoxyphenyl)-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium acetate; In acetic acid;Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvateand 0.82 g (0.01 mol) of anhydroussodium acetate in 10 mL of glacial acetic acid wasadded to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
(2Z)-2-hydroxy-4-(4-methoxyphenyl)-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium acetate; In acetic acid; for 0.333333h;Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvateand 0.82 g (0.01 mol) of anhydroussodium acetate in 10 mL of glacial acetic acid wasadded to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
(2Z)-2-hydroxy-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}-4-phenylbut-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With sodium acetate In acetic acid for 0.333333h; Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvateand 0.82 g (0.01 mol) of anhydroussodium acetate in 10 mL of glacial acetic acid wasadded to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
(2Z)-2-hydroxy-4-oxo-N-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenyl}-4-(4-fluorophenyl)but-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium acetate; In acetic acid; for 0.333333h;Reflux;
General procedure: a. A solution of 2.40 g (0.01 mol) of methyl 4-chlorobenzoylpyruvateand 0.82 g (0.01 mol) of anhydroussodium acetate in 10 mL of glacial acetic acid wasadded to a solution of 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfamido)thiazole in 15 mL of glacialacetic acid. The reaction mixture was refluxed for 20 min.
N-(2-((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)carbamoyl)phenyl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
General procedure: In slight modification to our previous reported method to obtain better yields of compounds 3a-e and 5a-c, [32] a mixture of the appropriate benzylamine and/or sulfonamide derivatives (1.5 mmol), potassium tert-butoxide (6.5 mmol) in acetonitrile (10 mL) was stirred under reflux for two hours, a solution of methyl 2-(picolinamido)benzoate (1) (1 mmol) in acetonitrile (10 mL) was added portion-wise. The reaction mixture was refluxed for overnight until the reaction was judged complete by TLC and then poured into ice water. The resulting solid thus formed was filtered and recrystallized from the appropriate solvent.
2,2-dicyanomethyl-3-cyano-4,5,5-trimethyl dihydrofuran[ No CAS ]
4-(2-(4-cyano-5-(dicyanomethylene)-2,5-dihydro-2,2-dimethylfuran-3-yl)methylenehydrazinyl)−N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
General procedure: Sulfonamide derivative 4 (0.01mol) was dissolved in a mixture of concentrated hydrochloric acid (4mL) and water (5mL) and cooled to 0-5C in an ice bath. To this mixture a cold aqueous solution of sodium nitrite (0.01mol) was then added. The diazonium salt thus obtained was filtered into a cold mixture of sodium acetate (5g) and tricyanofuran 1 (0.01mol) in acetonitrile (5mL). After stirring the resulting mixture for one more hour, the crude solid product was filtered off with a Buchner funnel, washed with distilled water (3×5mL), crystallized and air dried to afford the solid product.
4-(3-pyridin-4-ylmethylureido)-N-thiazol-2-yl-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Triphosgen (70 mg, 0.23 5 mmol) was dissolved in DCM (10 mL) and cooled to -10C under N2 atmosphere. To this cooled solution was added dropwise a mixture of 4-amino-N-thiazol-2- yl-benzenesulfonamide (200 mg, 0.783 mmol) and TEA (238 mg, 2.35 mmol) in DCM (10 mL). The mixture was stirred at -10C for 5 mm and allowed to warm up to room temperature for 1 hour. Then a solution of c-pyridin-4-yl-methylamine (85 mg, 0.861 mmol) and TEA (238 mg, 2.35 mmol) in DCM (10 mL) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS. Then the mixture was diluted with DCM (20 mL) and washed with brine (20 mL). The organic layer was concentrated in vacuum to give a residue which was purified by prep-HPLC with NH4Ac as additive to afford 4-(3-pyridin-4-ylmethyl-ureido)-N-thiazol- 2-yl-benzenesulfonamide (151.6 mg, yield: 50%) as a yellow solid. ?H NIVIR (400 IVIHz, DMSO-d6):(5 = 9.17 (brs, 1H), 8.49 (dd, J 4.8, 1.6 Hz, 2H), 7.61 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.8 Hz, 2H), 7.28 (d, J 5.6 Hz, 2H), 7.09 (d, J 4.0 Hz, 1H), 7.05 (t, J= 6.0 Hz, 1H), 6.62 (d, J= 4.4 Hz, 1H),4.33 (d, J = 5.6 Hz, 2H). MS: m/z 389.9 (M+H).
4-(9-(2,3-dichlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With toluene-4-sulfonic acid; In ethanol; acetonitrile; at 80℃; for 6h;
General procedure: One pot three component mixture of 2 mmol 5,5-dimethyl-1,3-cyclohexanedione, 1 mmol 2,3-dichlorobenzaldehyde, 1 mmol sulfacompound (sulfadiazine or sulfathiazole) and a catalytic amount of p-toluenesulfonic acid (p-TSA) were heated with stirring at 80 C in20 mL ethanol: acetonitrile (1:1) mixture for 6 h. After the reaction was completed, monitored by TLC, the solid product formed uponcooling was filtered and purified by recrystallization from ethanol.
methyl (2E)-4-oxo-4-phenyl-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate[ No CAS ]
methyl (2Z)-4-oxo-4-phenyl-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
In ethanol; acetic acid for 0.166667h; Reflux;
Methyl (2Z)-4-(4-chlorophenyl)-4-oxo-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate(1a)
General procedure: A solution of 2.40 g (0.01 mol) of methyl (4-chlorobenzoyl)pyruvate in 15 mL of ethanol was added to a 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfonamido)thiazole dissolved under heating in 15 mLof glacial acetic acid. The reaction mixture was refluxed for 10 min. After cooling, a precipiate formed and was filtered off and recrystallized from ethanol. Yield 3.97 g (83%)
methyl (2Z)-4-(2,4-dichlorophenyl)-4-oxo-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate[ No CAS ]
methyl (2E)-4-(2,4-dichlorophenyl)-4-oxo-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
In ethanol; acetic acid for 0.166667h; Reflux;
Methyl (2Z)-4-(4-chlorophenyl)-4-oxo-2-{4-[(1,3-thiazol-2-yl)sulfamoyl]phenylamino}but-2-enoate(1a)
General procedure: A solution of 2.40 g (0.01 mol) of methyl (4-chlorobenzoyl)pyruvate in 15 mL of ethanol was added to a 2.55 g (0.01 mol) of 2-(4-aminobenzenesulfonamido)thiazole dissolved under heating in 15 mLof glacial acetic acid. The reaction mixture was refluxed for 10 min. After cooling, a precipiate formed and was filtered off and recrystallized from ethanol. Yield 3.97 g (83%)
With tris(pentafluorophenyl)borate; In N,N-dimethyl-formamide; at 20℃; for 24h;Green chemistry;
Under the air atmosphere,1b (42.3 mg, 0.3 mmol) was sequentially added to the reaction tube.<strong>[72-14-0]Sulfathiazole</strong> (51.1 mg, 0.2 mmol),B(C6F5)3 (2.6mg, 0.005mmol),N,N-dimethylformamide (0.5 mL),The reaction system was stirred at room temperature for 24 hours.After the reaction is completed,Dilute with dichloromethane,Remove the solvent,Column chromatography gave the white solid compound 3r (59.8 mg, 65%).
4-amino-N-(thiazol-2-yl)-N-(2-((3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2.5h;
General procedure: Add the raw material sulfonamide or its sodium salt (SA),K2CO3 and N, N-dimethylformamide (DMF), stirred in a water bath at 60 C,Sulfonamide or its sodium salt quickly dissolved, and after 30 min the intermediate IM1 was added.TLC monitors the progress of the reaction. After completion of the reaction, water was added and stirred, and a solid precipitated.Extracted twice with dichloromethane (DCM), combined the organic layers, washed with 5 mL of 0.5 N HCl, and washed with a little water.The organic layer was dried over anhydrous MgSO4. Suction filtration and rotary evaporation under reduced pressure to dry yellow slime.Purify by column chromatography (PE / EA = 2/1, v / v). Collect the eluate and evaporate to dryness under reduced pressure. Most of the solution is colorless and transparent mucus. Add DMF to dissolve the mucous quickly. Add water to precipitate a large amount of solid immediately.Suction filtration, the filter cake was washed with a large amount of water, and dried under vacuum to obtain the target molecule TM2.
4-amino-N-(thiazol-2-yl)-N-(3-((3,6,9-trimethyldeca-hydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
General procedure: Add the raw material sulfonamide or its sodium salt (SA),K2CO3 and N, N-dimethylformamide (DMF), stirred in a water bath at 60 C,Sulfonamide or its sodium salt quickly dissolved, and after 30 min the intermediate IM1 was added.TLC monitors the progress of the reaction. After completion of the reaction, water was added and stirred, and a solid precipitated.Extracted twice with dichloromethane (DCM), combined the organic layers, washed with 5 mL of 0.5 N HCl, and washed with a little water.The organic layer was dried over anhydrous MgSO4. Suction filtration and rotary evaporation under reduced pressure to dry yellow slime.Purify by column chromatography (PE / EA = 2/1, v / v). Collect the eluate and evaporate to dryness under reduced pressure. Most of the solution is colorless and transparent mucus. Add DMF to dissolve the mucous quickly. Add water to precipitate a large amount of solid immediately.Suction filtration, the filter cake was washed with a large amount of water, and dried under vacuum to obtain the target molecule TM2.
4-((5-(morpholinosulfonyl)-2-oxoindolin-3-ylidene)amino)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.58%
With acetic acid; In methanol;Reflux;
General procedure: To a solution of isatin derivatives 1 (0.01 mol) in absolute methanol (20mL), acetic acid (0.5mL) was added. To this mixture, each of, 5-(2-(6-methoxynaphthalen-2-yl)propyl)-1,3,4-thiadiazol-2-amine 2a (0.01 mol), 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 2b (0.01 mol), pyridin-3-amine 2c (0.01 mol), adamantan-1-amine 2d (0.01 mol), sulfa-thiazole 4a (0.01 mol), sulfa guanidine 4b (0.01 mol), and aromatic amine (4a-c) (0.01 mol) was added and the reaction mixture was heated under reux conditions for 2-8 h. The progress of the reaction was monitored by TLC. The reaction mixture was allowed to cool, ltered, washed with methanol air-dried and then recrystallized from the proper solvent.
(E)-3-oxo-N-(4-(N-pyrimidin-2-ylsulfamoyl)phenyl)-2-(2-(4-(N-thiazol-2-ylsulfamoyl)phenyl)hydrazono)butanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: A well stirred solution of aromatic amines (20 mmol)in concentrated HCl (6 mL) and water (4 mL) was cooledin an ice bath and diazotized with a solution of sodiumnitrite (1.39 g, 20 mL) in water (5 mL).The above cooled diazonium salt solution was addeddrop wise to a well stirred cooled solution of 1 in pyridine(10 mL). The reaction mixture was stirred for 1-2 h untilgiving a complete coupling reaction. The crude insolubleprecipitate was purified, dehydrated well and recrystallizedfrom ethanol to offer compounds 19a-h, respectively
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