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CAS No. : | 138-41-0 | MDL No. : | MFCD00007938 |
Formula : | C7H7NO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UCAGLBKTLXCODC-UHFFFAOYSA-N |
M.W : | 201.20 | Pubchem ID : | 8739 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 44.4 |
TPSA : | 105.84 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.17 cm/s |
Log Po/w (iLOGP) : | 0.13 |
Log Po/w (XLOGP3) : | 0.5 |
Log Po/w (WLOGP) : | 1.11 |
Log Po/w (MLOGP) : | -0.05 |
Log Po/w (SILICOS-IT) : | -0.62 |
Consensus Log Po/w : | 0.22 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.61 |
Solubility : | 4.92 mg/ml ; 0.0244 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.29 |
Solubility : | 1.03 mg/ml ; 0.0051 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.34 |
Solubility : | 9.13 mg/ml ; 0.0454 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.05% | at 100℃; for 10 h; | Example 11: Weigh 1 mmol of p-carboxybenzenesulfonamide,3,5-dinitro-N-hydroxy-N-methylbenzamide0.05 mmol, cobalt acetate 0.01 mmol,Add 25mL reaction bottle,Add acetic acid 5mL, into the oxygen,The reaction was continued for 10 hours while maintaining the oxygen pressure at 1 atm and raising the temperature to 100 ° C,After completion of the reaction, the reaction mixture was cooled to room temperature. The filtrate was decompressed to remove acetic acid,Acetic acid can be recycled. The residue was repeatedly washed with water to remove the residual acetic acid and the cobalt acetate co-catalyst,A small amount of acetone to remove 3,5-dinitro-N-hydroxy-N-methyl benzamide and a small amount of p-hydroxymethyl benzene sulfonimide, filter cake drying, can be carboxy benzenesulfonamide,The yield of p-toluenesulfonamide was 94.05percent, the conversion of p-toluenesulfonamide was 99.33percent, the selectivity to p-carboxybenzenesulfonamide was 94.68percent. The purity of the product was 95.14percent by Agilent1200 high performance liquid chromatograph. |
90% | With sodium hydroxide; potassium permanganate In water at 70 - 90℃; for 2 h; | Example 3 p-Aminosulfonyl-benzoic Acid To the solution of 17.1 g (0.1 mol) of p-toluenesulfonamide prepared in Example 1, 20 g (0.5 mol) of sodium hydroxide in 300 ml of water was added in portions 20 g (0.13 mol) of potassium permanganate. The temperature raised to 70° C. spontaneously, keep the reaction mixture in 90° C. for 2 h. The mixture was then cooled and filtered, and the filtrate was acidified with HCl. The resulting precipitate was filtered, and washed with water, dried in vacuo to give the title compound (18.1 g) as white powder, yield 90percent, m.p. 291-292° C. |
17.2 g | With hydrogenchloride; sodium bromate; sodium bromide In water at 25 - 100℃; for 13 h; | This example illustrates the Carboxylazo sulfonamide preparation method of the present invention provides.At room temperature (25 ), the will-methyl-benzenesulfonamide 17.1g (100mmol), sodium bromate 16.6g (110mmol), sodium bromide 0.1g (1mmol) sequentially into 500mL four-necked flask was added 150mL of water as a solvent starting mix means open condensate, temperature was raised to 95 deg.] C, after complete dissolution of the solid (dissolution time of 30min), the reaction solution was added dropwise (dropping of 0.6mL / min) at a concentration of 37percent by weight of concentrated hydrochloric acid 7g (71mmol), to become increasingly red color of the reaction solution, incubated at 100 solids after about 1h, and then reacted with stirring 12h, the reaction solution until the color faded completely off the heating, the reaction mixture was cooled to room temperature, followed suction filtration, washed with water and dried to give 17.2g of white solid with a purity of 97percent, a yield of 83percent by weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid; for 8h;Reflux; | Commercially available, 73 4-sulfamoylbenzoic acid 5 (10mmol) was refluxed in dried 74 methanol with a catalytic amount of 75 conc. H2SO4 acid for 8h. After completion of the reaction, the mixture was poured into ice cold water and obtained precipitate was filtered and dried to give 11 methyl 4-sulfamoylbenzoate 6. 4.3.2 11 Methyl 4-sulfamoylbenzoate (6) (0035) White crystalline solid; yield 95%; mp: 148-150C; 1H NMR (DMSO-d6,400MHz):delta 3.87 (s, 3H, OCH3), 7.55 (s, 2H, NH2), 7.94 (d, 2H, Ar, J=8.4Hz), 8.12 (d, 2H, Ar, J=8.4Hz); LC-MS: m/z; 216 (M+1). |
93% | With sulfuric acid;Reflux; | Concentrated sulfuric acid (1 ml) was added dropwise to a mixture of 4-aminosulfonylbenzoic acid (2.010 g, 10 mmol) in methanol (60 mL) and reacted under reflux until TLC showed the reaction was complete.Then, the solvent was removed under reduced pressure, and the residue was added to an aqueous sodium hydroxide solution to adjust the pH 6-7.The mixture was then stirred and filtered to obtain 2.000 g of white solid with a yield of 93.0%. |
92% | With sulfuric acid; at 20℃;Reflux; | 4-Sulfamoyl-benzoic acid methyl ester; To a mixture of 5.16 g 4-carboxylbenzenesulfonamide in 150 ml. methanol was added 6.84 ml_ sulfuric acid. The mixture was refluxed overnight and cooled to room temperature. The mixture was evaporated to dryness and the residue was triturated with Et2O. The formed precipitation was filtered off, washed with Et2O and dried to give 5.2 gram (92%) of a white solid. 1H NMR (400 MHz, CDCI3) delta 3.90 (s, 3H), 7.59 (s, 2H), 7.97 (d, J=5.84 Hz, 2H), 8.15 (d, J=5.84 Hz, 2H). |
75% | With thionyl chloride; at 0 - 20℃; | To a suspension of 4-(aminosulfonyl)benzoic acid (500 mg, 2.5 mmol) in MeOH (2 ml) at O0C is added thionylchloride (0.2 ml, 7.4 mmol). The reaction mixture is stirred at rt overnight. When TLC confirms the total consumption of the starting acid, the solvent and excess thionyl chloride are removed under reduced pressure to afford 400 mg (75 %) of the title compound, which was used in the next step without any further purification. LC/MS: (ES+):215.9, (ES-):214.1. |
Reflux; Acidic conditions; | Tolylsulfonamide 10 (1.00mM) was first converted to 4-aminosulfonyl benzoic acid by refluxing its aqueous suspension with KMnO4 (3.00mM) to generate the corresponding carboxylic acid followed by refluxing its methanolic solution firstly in acidic condition and then in excess of hydrazine hydrate.37 Yield 74%, lit. mp: 230-232C, Obs. mp: 228-230C. | |
With thionyl chloride; at 0 - 40℃; for 2h; | To the solution of 4-sulfamoylbenzoic acid (200 mg, 0.53 mmol) inMeOH (8 mL) added SOCl2 (1348 muL, 1.84 mmol) at 0 C. The mixturewas stirred at 40 C for 2 h, and then concentrated. Ester (214 mg,1.00 mmol) and (Boc)2O (238 mg, 1.09 mmol) were dissolved in DCM(8 mL). Et3N (138 muL, 1 mmol) and DMAP (12.2 mg, 0.1 mmol) wereadded and the mixture was stirred at rt. for 1.5 h. The solution wasconcentrated and purified to afford methyl 4-(N-(tert-butoxycarbonyl)sulfamoyl)benzoate. DIBAL-H (2 mL, 2 mmol) was added slowly tomethyl benzoate (300 mg, 1.00 mmol) in DCM (8 mL) at -78 C and themixture was stirred at -78 C for 2 h. The reaction was quenched by MeOH (2 mL), and then warmed to 0 C and added 10% citric acidunder stirring. The mixture was extracted with DCM, and the organicswere washed, dried, concentrated and purified to afford 4-formylbenzenesulfonamide.Using 4-formylbenzenesulfonamide, thecompound 44 was obtained from 5 by the general procedure as above.To the solution of 44 (95 mg, 0.20 mmol) in DCM (4 mL) added TFA(300 muL, 0.04 mmol). The mixture was stirred at rt. for 1 h. The solutionwas adjusted to pH 7-8 by NaHCO3. The mixture was extracted withEA, and the organics were washed, dried, concentrated and purified toafford 17, 54% yield for five steps, 94.0% HPLC purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; chlorine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonium hydroxide; | Step 1: Preparation of 4-(aminosulfonyl)benzoic acid To a solution of 4-(chlorosulfonyl)benzoic acid (25 g, 0.11 mol) in ether (1.2 L), ammonium hydroxide (36 ml) was added. After stirring at room temperature for 5 hours, the solvent was removed and the residue was stirred with 3N HCl (1 L) for 80 minutes and filtered. The solid obtained was washed with water (2*20 ml) and with ether (3*20 ml), and dried under reduced pressure at 80 C. After concentration, the white solid obtained (22 g, 97%) was used in the next step without further purification: mp 279-81 C. Anal Calc'd. for C7 H7 NSO4: C, 41.79; H, 3.51; N, 6.46; S, 15.99. Found: C, 41.90; H, 3.45; N, 6.98; S, 15.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.05% | With oxygen; cobalt(II) acetate; 3,5-dinitro-N-hydroxy-N-methylbenzamide; acetic acid; at 100℃; under 760.051 Torr; for 10h; | Example 11: Weigh 1 mmol of p-carboxybenzenesulfonamide,3,5-dinitro-N-hydroxy-N-methylbenzamide0.05 mmol, cobalt acetate 0.01 mmol,Add 25mL reaction bottle,Add acetic acid 5mL, into the oxygen,The reaction was continued for 10 hours while maintaining the oxygen pressure at 1 atm and raising the temperature to 100 C,After completion of the reaction, the reaction mixture was cooled to room temperature. The filtrate was decompressed to remove acetic acid,Acetic acid can be recycled. The residue was repeatedly washed with water to remove the residual acetic acid and the cobalt acetate co-catalyst,A small amount of acetone to remove 3,5-dinitro-N-hydroxy-N-methyl benzamide and a small amount of p-hydroxymethyl benzene sulfonimide, filter cake drying, can be carboxy benzenesulfonamide,The yield of p-toluenesulfonamide was 94.05%, the conversion of p-toluenesulfonamide was 99.33%, the selectivity to p-carboxybenzenesulfonamide was 94.68%. The purity of the product was 95.14% by Agilent1200 high performance liquid chromatograph. |
90% | With sodium hydroxide; potassium permanganate; In water; at 70 - 90℃; for 2h; | Example 3 p-Aminosulfonyl-benzoic Acid To the solution of 17.1 g (0.1 mol) of p-toluenesulfonamide prepared in Example 1, 20 g (0.5 mol) of sodium hydroxide in 300 ml of water was added in portions 20 g (0.13 mol) of potassium permanganate. The temperature raised to 70 C. spontaneously, keep the reaction mixture in 90 C. for 2 h. The mixture was then cooled and filtered, and the filtrate was acidified with HCl. The resulting precipitate was filtered, and washed with water, dried in vacuo to give the title compound (18.1 g) as white powder, yield 90%, m.p. 291-292 C. |
With potassium permanganate; In water;Reflux; | Tolylsulfonamide 10 (1.00mM) was first converted to 4-aminosulfonyl benzoic acid by refluxing its aqueous suspension with KMnO4 (3.00mM) to generate the corresponding carboxylic acid followed by refluxing its methanolic solution firstly in acidic condition and then in excess of hydrazine hydrate.37 Yield 74%, lit. mp: 230-232C, Obs. mp: 228-230C. |
17.2 g | With hydrogenchloride; sodium bromate; sodium bromide; In water; at 25 - 100℃; for 13h; | This example illustrates the Carboxylazo sulfonamide preparation method of the present invention provides.At room temperature (25 ), the will-methyl-benzenesulfonamide 17.1g (100mmol), sodium bromate 16.6g (110mmol), sodium bromide 0.1g (1mmol) sequentially into 500mL four-necked flask was added 150mL of water as a solvent starting mix means open condensate, temperature was raised to 95 deg.] C, after complete dissolution of the solid (dissolution time of 30min), the reaction solution was added dropwise (dropping of 0.6mL / min) at a concentration of 37% by weight of concentrated hydrochloric acid 7g (71mmol), to become increasingly red color of the reaction solution, incubated at 100 solids after about 1h, and then reacted with stirring 12h, the reaction solution until the color faded completely off the heating, the reaction mixture was cooled to room temperature, followed suction filtration, washed with water and dried to give 17.2g of white solid with a purity of 97%, a yield of 83% by weight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | To a 100-mL two-neck eggplant-shaped flask, 4- sulfamoylbenzoic acid (500 mg, 2.5 mmol, 1 eq) , WSCHC1 (720 mg, 3.8 mmol, 1.5 eq) , N, N-diisopropylethylamine (1.3 mL, 7.5 mmol, 3 eq) , and 20 mL of dry dimethylformamide were added. Then, N- hydroxysuccinimide (374 mg, 3.3 mmol, 1.3 eq) was added thereto. The mixture was stirred at room temperature for 4 hours in an argon atmosphere. The reaction was followed by TLC (SiO2/CHCl3 : MeOH = 10 : 1) and completed when the production of the compound of interest was confirmed. The solvents were distilled off under reduced pressure using a vacuum pump. After the addition of ethyl acetate (300 mL) , the organic phase was washed with an aqueous saturated sodium bicarbonate solution (100 mL, three times) , with distilled water (100 mL, three times) , and with a saturated saline (100 mL, three times) . The organic phase was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off. Then, the solvents were distilled off under reduced pressure. The residue was vacuum-dried to obtain a white solid. Identification was conducted by1H-NMR.Experimental Results>White SolidYield: 650 mg ( 87% ) c |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Erhitzen; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: 2-Amino-5-mercapto-1,3,4-thiadiazole With dmap In N,N-dimethyl-formamide at 45℃; for 24h; | 4.1.2 Synthesis of 2a-3f General procedure: 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25°C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45°C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a. |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In methanol; hexane; dichloromethane; at 20℃; for 2h; | . To a stirred suspension of 4- [SULFAMOYL-BENZOIC] acid (25.0 g, 0.124 mol) in 4: 1 CH2CI2/MeOH at rt was added 1.0 M TMSCHN2 in hexane (175 mL), and the reaction mixture was allowed to stir for 2 h. The mixture was diluted with 1 N [NAOH] (100 mL) and CH2CI2 (150 mL), and the layers were separated. The organic layer was dried over [NA2SO4,] then filtered, and the solvent was removed under reduced pressure to afford the desired ester (25.2 g, 95%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) : 8.14 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H). |
95% | To a stirred suspension of 4-sulfamoyl-benzoic acid (25.0 g, 0.124 mol) in 4:1 CH2CI2/MeOH at rt wasadded 1.0 M TMSCHN2 in hexane (175 ml), and the reaction mixture was20 allowed to stir for 2 h. The mixture was diluted with 1N NaOH (100 ml) andCH2CI2 (150 ml), and the layers were separated. The organic layer was driedover Na2SO4, then filtered, and the solvent was removed under reduced pressure to afford the desired ester (25.2 g, 95%), which was used withoutfurther purification. 1H NMR (400 MHz, DMSO-c/6): 8.14 (d, J = 8.1 Hz, 2H),7.96 (d, J= 8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H). | |
In methanol; hexane; dichloromethane; for 2h; | A. 4-Sulfamoyl-benzoic acid methyl ester. To a stirred suspension of 4-sulfamoyl-benzoic acid (25.0 g, 0.124 mol) in 4:1 CH2Cl2/MeOH at rt was added 1.0 M TMSCHN2 in hexane (175 mL), and the reaction mixture was allowed to stir for 2 h. The mixture was diluted with 1 N NaOH (100 mL) and CH2Cl2 (150 mL), and the layers were separated. The organic layer was dried over Na2SO4, then filtered, and the solvent was removed under reduced pressure to afford the desired ester (25.2 g, 95%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): 8.14 (d, J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H), 7.58 (s, 2H), 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | tert-butyl (2-(2-(2-(4-sulfamoylbenzamido)ethoxy)ethoxy)ethyl)carbamate - 31 To a solution of 4-carboxybenzenesulfonamide (46 mg, 0.23 mmol) in MeCN (2 mL) was added NHS (29 mg, 0.25 mmol) followed by EDCHC1 (48 mg, 0.25 mmol). After stirringfor 4 h at room temperature more EDCHC1 (24 mg, 0.13 mmol) was added and the reaction stirred for a further 1 h at room temperature. A solution of 19 (52 mg, 0.21 mmol) and DIPEA (140 jiL, 0.85 mmol) in DMF (1 mL) was added. After stirring for 10 h at room temperature, the reaction was filtered through a pad of silica eluting with EtOAc, the solvent removed under reduced pressure and the residue purified over silica (EtOAc to 10%MeOH in EtOAc) to give the product as a white solid (61 mg, 0.14 mmol, 67%).1H-NMR (400 MHz, DMSO-d6) [ppm] = 8.71 (br m, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.90(d, J = 8.1 Hz, 2H), 7.46 (br s, 2H), 6.76 (br m, 1H), 3.55-3.33 (m, 1OH), 3.06-3.05 (m,2H), 1.37 (s, 9H); 13C-NMR (125 MHz, DMSO-d6) [ppm] = 165.8, 156.1, 146.7, 137.7,128.3, 126.1, 78.1, 70.0, 69.9, 69.6, 69.2, 67.1, 39.1, 28.7; HRMS: (mlz) [M + H] calcd.for C18H29N3NaO7S, 454.1618; found 454.1623. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-sulfonamido benzoic acid (1 eq) in THF there is added under inert atmosphere Et3N (1.3 eq) and sulfonyl chloride (1.1 eq). The reaction mixture is then stirred at room temperature for 30 minutes. The temperature is decreased to O0C (ice / water bath) and hydrazine in solution in methanol (30 eq) is slowly added to the reaction mixture, the resulting mixture is stirred from O0C to room temperature for 2 hours. The reaction mixture is quenched with water and extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The desired product is isolated by precipitation using ethyl acetate / Hexanes mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91 - 95% | With thionyl chloride; In chlorobenzene; at 120℃; for 7 - 9h; | Example 1 4-[(2-Methoxy-5-chlorobenzoyl)amino]sulfonyl)benzoyl chloride A mixture of 4-aminosulfonylbenzoic acid (1 mol), 2-methoxy-5-chlorobenzoic acid (1 mol) and thionyl chloride (2.5 mol) in chlorobenzene (700 ml) was heated at 120C for 7-9 hours. After the reaction was complete 200 ml of the solvent was removed in vacuo. The mixture was cooled and the precipitate filtered off and washed with heptane to give the title compound, mp. 138-140C, yield 93 % of theory. 4-[(Benzoyl)amino]sulfonyl)benzoyl chloride was prepared in a similar manner from 4-aminosulfonylbenzoic acid and benzoic acid, mp. 180-182C, yield 96 % of theory. 4-[(2-Chlorobenzoyl)amino]sulfonyl)benzoyl chloride was prepared in a similar manner from 4-aminosulfonylbenzoic acid and 2-chlorobenzoic acid, mp. 198-200C, yield 95 % of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(aminosulfonyl)-benzoic acid; Estriol With pyridine; dicyclohexyl-carbodiimide at 20℃; for 1h; Stage #2: With hydrogenchloride In pyridine; water | ||
With pyridine; dicyclohexyl-carbodiimide at 20℃; for 1h; | 5 0.4 g of estriol is dissolved in 7 ml of pyridine. After 0.8 g of 4-sulfamoylbenzoic acid and 0.8 g of dicyclohexylcarbodiimide (DCC) are added, it is stirred for 1 hour at room temperature. Then, it is acidified with 10% HCl (pH=2), and 8 ml of water is added. The precipitate is filtered off and washed with 10% NaHCO3 solution and water. The product that is obtained is chromatographed on silica gel. 16α,17β-Dihydroxyestra-1,3,5(10)-3-yl 4'-sulfamoylbenzoate is obtained. 1H-NMR (DMSO-d6): 0.69 (s, 3H, H-18), 3.32 (m, 1H, H-17), 3.85 (m, 1H, H-16), 7.62 (s, 2H, NH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; | Step 2 Preparation of methyl [4-(aminosulfonyl)]benzoate To a solution of 4-(aminosulfonyl)benzoic acid (16 g, 79.6 mmol) (Step 1) in methanol (600 ml), conc. H2 SO4 (1.2 ml) was added and the mixture was heated at reflux for 4 days. The solvent was removed and washed with ether. The white solid (16.5 g, 96%) was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In methanol; | EXAMPLE 74 4-(Aminosulfonyl)benzoic acid methyl ester A slurry of 30.2 g (0.15 mole) of p-carboxybenzenesulfonamide in 500 ml of methanol was treated with 30 g of anhydrous hydrogen chloride and the mixture was heated at reflux temperature for 3 hr. The solution was concentrated under vacuum to give 32.3 g of white, crystalline residue. A 5.0 g portion of this residue was recrystallized from 25 ml of methanol to give 3.3 g of title compound as a white powder, mp 174-178 C. Analysis: Calculated for C8 H9 NO4 S: C, 44.65; H, 4.22; N, 6.51. Found: C 44.80; H, 4.30; N, 6.47. | |
With potassium hydroxide; In diethyl ether; water; | 8(a) 4-Sulfamoyl-benzoic acid methyl ester. To a solution of KOH (108 mg, 2.0 mmol) in water (1 mL) was added Et2O and cooled to 0 C. MNNG (292 mg, 1.99 mmol) was added and the resulting yellow solution was added to a suspension of 4-Sulfamoyl-benzoic acid in Et2O at room temperature and stirred overnight. The reaction was quenched with acetic acid and the resulting mixture was diluted with water. The mixture was then extracted with ethyl acetate and the combined organic extracts was washed with bine and dried over Na2SO4. Removal of solvent gave the crude product which was used in the next reaction without further purification. 1H NMR (400 MHz, MeOD) delta 8.17 (d, 2H), 8.00 (d, 2H), 3.92 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 - 90% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dicyclohexyl-carbodiimide; In ethanol; at 20℃; for 2h; | c) 0.01 mol of the N-substituted 5,6-diaminouracil (16b) was suspended in EtOH (100 ml), then subsequently added 0.011 mol of the appropriate acid (p-sulfamoylbenzoic acid) and 0.012 mol of the condensing agent (dicyclohexylcarbodiimide), N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride). The mixture stirred at room temp. for 2 hours, the precipitate filtered off and purified by recrystallization from EtOH to give colorless crystals (16a). Yield: 80-90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | To a solution of 4-carboxybcnzenesulfbnamide (2 g; 9.9 mmol; 1 cq) in THF (30 mL) at 00C is added l ,l'-carbonyldiimidazole (1.9 g; 11,9 mmok 1.2 eq) in one portion and the mixture is stirred for 3 h at room temperature. 4-Fluoropipcridine (3.1 g; 29.8 mmol; 3 eq) in THF (3 mL) and DMF (10 ml.) is added dropwisc and the mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and a saturated solution of NaHCCh is added to the colourless oil which precipitates. The solid is filtered off. washed with water arid dried under vacuum to afford 2.6 g (91 %) of the title compound as a white solid. 'H NMR (DMSOd6) delta 7.87 (d, J= 8.3, 2H), 7.58 (d, J= 8.3. 2H), 7.37 (br s, 2H), 4.92 (d, J = 48.2, IH), 3.67 (br s, 2H), 3.25 (br s, 2H), 1.87 (m, 4H). HPLC1 (max plot) 99%; fit 1.77 min. IXVMS: (ES l ) 2X7.0; (ES-) 285.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In water; at 45℃; for 0.5h; | Example 2Preparation of sodium 4-sulfamoylbenzoate (VIII); [Gubert, S., Farmaco 45, 59 (1990); Rodionov,V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].In the 500 ml Erlenmeyer flask the solution of 20.1 g (0.2 mol) <strong>[298-14-6]potassium bicarbonate</strong> in 180 ml of the distilled water was prepared. To this solution, 40.2 g (0.2 mol) of 4-sulfamoylbenzoic acid VII was added portionwise for 30 minutes under stirring at 45 0C, each time until dissolution. The mixture was fizzing by leaking CO2. Then the water was distilled off to the dryness from the solution on the vacuum rotatory evaporator (the temperature of the bath did not exceed 60 0C). Remaining humidity was removed by severalfold azeotropic distillation with toluene on the vacuum evaporator. The solid residue was shaken with dichloromethane, this was decanted and the solid product was dried under the infralamp. Colourless solid. Yield 43 g (98 %) of potassium 4-sulfamoylbenzoate VIII. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | To a solution of 4-sulfamoylbenzoic acid (1.69 g, 8.4 mmol) in CH2Cl2 (60 mL) was added sequentially DMAP (1.2 g, 9.8 mmol) and EDC hydrochloride (1.7 g, 9.1 mmol). To the resulting mixture was added 1-(p-trifluoromethylphenyl)-3-(4-aminopiperidine)-urea 7 (2.0 g, 6.9 mmol) as a solid at rt. After stirring for 18 h at rt the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Chromatography on silica gel eluting with 6% MeOH/CH2Cl2 gave pure product 4-1 (2.6 g, 80%) as a white solid with m.p. 220-228 and an HPLC purity 99%. The product identity was confirmed with LCMS: 471 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 12h; | Into a 100-mL round-bottom flask, was placed 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol) in THF (15 mL). This was followed by the addition of BFL-THF (14.3 mL, 149 mmol) dropwise with stirring at 0C in an ice/ethanol bath. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of HCl (50 mL, 2 M) dropwise in an ice bath and stirred for lh at RT. The mixture was extracted with 8x50 mL of ethyl acetate. The organic layers were combined and concentrated. This resulted in 800 mg (86%) of the title compound as a yellow solid. MS-ESI: 188 (M+l). |
64.47% | With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 10℃; for 12h; | To a solution of 63 (5.0 g, 25 mmol) in THF (100 mL) was added BH3-Me2S (7.55 g, 100 mmol) dropwise at 0 C over 10 mm. After addition, the mixture was stirred at 10 C for 12 h. The mixture was quenched by MeOH (100 mL) dropwise at 0 C and then concentrated under reduced pressure to give 64(3 g, yield 64.47%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.78 (d, J = 8.0 Hz, 2H), 7.49 (d, J =8.4 Hz, 2H), 7.29 (s, 2H), 5.37 (s, 1H), 4.57 (s, 2H). To a mixture of 64 (1.5 g, 8.0 mmol) and NaH (705 mg, 32 mmol) in DMF (7 mL) was degassed and purged with N2 for 3 times and stirred for 12 mm, and then SEM-CI (2.54 g, 15 mmol) was added to the mixture and stirred at 20 C for 1 h under N2 atmosphere. After quenched by addition NH4CI 50 mL at 10 C, the mixture was extracted with MTBE(5OmL x 2), the combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2:1) to give 65 (2.2 g, 61%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.80 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 5.43 (t, J = 5.2 Hz, 1 H), 4.71 (s, 4H), 4.57 (d, J= 4.8 Hz, 2H), 3.34 (t, J= 8.4 Hz ,4H), 0.74 (t, J= 8.0 Hz, 4H), -0.07 (s, 18 H). |
Step 1: 4-hydroxymethyl-benzene-sulphonamide. LiAlH4 (235 mg, 6.2 mmoles) was suspended in dry THF (10 mL) under nitrogen atmosphere. The suspension was cooled to 0 C. and 4-sulphamoyl-benzoic acid (500 mg, 2.48 mmoles, as a suspension in 10 mL of dry THF) was added. The resulting mixture was then refluxed for 18 hours. The reaction was quenched by addition of 3N HCl at 0 C. The quenched mixture was extracted with AcOEt, the organic layer was dried over Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt from 9/1 to 1/1) to yield the title compound in amount of 105 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | To a mixture of 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol), Et3N (1.5 ml, 10.78 mmol), DMF (5 ml) and THF (5 ml) isobutyl choroformate (0.70 ml, 5.36 mmol) was added dropwise at -10C. After stirring for 1 h, a solution of <strong>[61296-22-8]2-amino-5-bromothiazole hydrobromide</strong> (1,55 g, 5.96 mmol) and Et3N (0.83 ml, 5.96 mmol) in DMF (6 ml) and THF (4 ml) was added dropwise to the mixture at the same temperature. The resulting mixture was gradually warmed to room temperature over a period of 3 h and then concentrated by evaporation of the solvent in vacuo. To the resultant residue AcOEt and 5% aqueous NaHCO3 were added. The separated organic phase was washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residual solid was purified by flash cromatography (dichloromethane/methanol/30% aqueous ammonia=95:5:0.5) to afford the title compound as a yellow solid (0.77 g, 43%) m.p. 268-270C1H-NMR (DMSO-d6) delta ppm: 7.54 (s, 2H, SO2NH2); 7.67 (s, 1H, thiazole CH); 7.94 (d, J=8.8 Hz, 2H, H3 and H5 Ph); 8.21 (d, J=8.8 Hz, 2H, H2 and H6 Ph); 13.10 (bs, 1H, CONH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 52 To a solution of carboxylic acid IV-1 (0.2 g, 1.0 mmol) in DMF (6 mL) was added 1-Dodecanol (0.392 g, 0.47 mL, 2.0 mmol), DMAP (66 mg, 0.54 mmol) and EDCl (0.192 g, 1.0 mmol) respectively. The reaction mixture was stirred at room temperature for 16 h before being partitioned between EtOAc (20 mL) and aq. HCl (10 mL, 1 N). The organic layer was washed with half-saturated brine (2×15 mL). The dried (Na2SO4) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-30% EtOAc/CH2Cl2, to give ester IV-2 (0.195 g, 0.528 mmol, 53%) as a white solid. Mp: 105-106 C.; IR (neat) 3330, 2916, 2845, 1713, 1467, 1282, 1157, 1124, 1092, 906, 765, 738, 694 cm-1; 1H NMR (400 MHz, CDCl3) 8.20 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 4.99 (s, 2H), 4.38 (t, J=6.4 Hz, 2H), 1.79-1.83 (m, 2H), 1.29-1.46 (m, 19H), 0.90 (t, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) delta 165.2, 145.6, 134.4, 130.4, 126.5, 66.0, 31.9, 29.64, 29.58, 29.53, 29.4, 29.3, 28.6, 26.0, 22.7, 14.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With DIPEA; sodium hydrogencarbonate; trifluoroacetic acid; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; | Synthesis of N-(2-amino-5-(thiophen-2-yl)phenyl)-4-sulfamoylbenzamide (BRD-7726) A solution of <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (0.30 g, 1.03 mmol, 1 eq), 4-sulfamoylbenzoic acid (0.42 g, 2.06 mmol, 2 eq), HATU (780 mg, 2.06 mmol, 2.0 eq.), and DIPEA (0.45 mL, 2.58 mmol, 2.5 eq) in DMF (5 mL) was stirred for 15 h at room temperature. The reaction was quenched with a saturated solution of sodium bicarbonate. The solid obtained was filtered and dried under reduced pressure. The product was purified by column chromatography (silica gel, 3% MeOH/CH2Cl2) to afford the desired product (0.25 g, 51% yield). To a stirred solution of tert-butyl 2-(4-sulfamoylbenzamido)-4-(thiophen-2-yl)phenylcarbamate (0.15 g, 0.32 mmol, 1 eq) in CH2Cl2 (2 mL) was added TFA (1 mL) at 0 C. The reaction was stirred at room temperature for 2 h. The reaction was then concentrated. The residue was dissolved in EtOAc. The solution was washed with a saturated solution of sodium bicarbonate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography (silica gel, 3% MeOH/CH2Cl2) to afford the desired product (0.03 g, 24.9% yield). ESI+ MS: m/z (rel intensity) 374 (98.32, M+H), 1H NMR (500 MHz, d6-DMSO): delta 8.15 (d, J=8.5 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.49 (s, 1H), 7.36 (d, J=4.5 Hz, 1H), 7.31 (dd, J=8.5, 2 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.05 (t, J=3.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 5.21 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.7% | With sodium azide; trichloroacetonitrile; triphenylphosphine; In acetone; at 20℃; for 18h; | Step 14-sulfamoylbenzoyl azide (JS129)4-sulfamoylbenzoic acid (1 .00 g, 4.97 mmol), triphenylphosphine (2.61 g, 9.94 mmol) and sodium azide (0.388 g, 5.96 mmol) were suspended in anhydrous acetone (10 ml). To this milky white suspension was added trichloroacetonitrile (0.997 ml, 9.94 mmol) drop wise and the reaction was left to stir at RT for 18 h. The solvent was removed in vacuo and the resulting dark yellow slurry was diluted with CH2CI2 and washed with H20 and brine, dried (MgS04), filtered and concentrated in vacuo. Flash chromatography (Pet Ether; 3:1 to 2:1 to 1 :1 Pet Ether/EtOAc) afforded the title compound as a white solid (906.9 mg, 4.01 mmol, 80.7%). Mpt: 1 18 C; Rf = 0.23 (1 :1 Pet Ether/EtOAc); IR (vmax/cm"1, thin film): 3362 (aromatic C-H stretch), 3258 (N-H stretch), 2137 (N=N=N stretch), 1687 (CO stretch), 1339 (S=0 stretch, asymmetrical), 1238, 1 155 (S=0 Symmetrical stretch); 1H NMR (600 MHz, CD3OD): deltaEta = 8.02 (ap.d, J = 6.9 Hz, 2H, 4-H), 8.18 (ap.d, J = 6.8 Hz, 2H, 3-H); 13C NMR (150 MHz, CD3OD): 5C = 127.6 (C-4), 131.0 (C-3), 134.9 (C-2), 150.2 (C-5), 172.8 (C-1 ); LRMS/HRMS m/z (ES+): no product mass present; Anal. Calcd. for C7H6N403S: C, 37.17; H, 2.67; N, 24.77. Found C, 37.27; H, 2.49; N, 24.40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 375.038 Torr; for 24h; | General procedure: Aryl iodide (1.0 mol equiv), nucleophile (1.1 mol equiv), Pd2dba3 (0.025 mol equiv), tri-2- furylphosphine (0.05 mol equiv), K2C03 (2.0 mol equiv) and DMF (10-20 ml / mmol) were combined in a Schlenk tube with a stirrer bar, subjected to two freeze -pum -thaw cycles and charged with allene (0.5 bar). The Schlenk tube was thawed and stirred vigourously at 80 C for 24 h, cooled to room temperature, diluted with H20 (60 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with H20 (20 ml), dried (MgS04), filtered and concentrated in vacuo. Column chromatography of the residue afforded the product. Prepared by the general procedure from 2-iodocinnamonitrile (0.255 g, 1.0 mmol), 4- (aminosulfonyl)benzoic acid (0.201 g, 1.0 mmol), Pd2dba3 (0.022 g, 0.025 mmol), TFP (0.023 g, 0.1 mmol), K2CO3 (0.276 g, 2.0 mmol) and allene (0.5 bar) in DMF (10 mL), heated at 80 C for 24 h. Column chromatography (40 g silica, 2: 1 v/v Et20 : hexanes) afforded the product as an amorphous pale yellow solid (0.195 g, 53 %). Found: 391.0717; Ci9H16N204SNa requires 391.0723. deltaEta (DMSO-?/beta, 500 MHz): 7.79 (d, J 8.4, 2H, H-3), 7.73 (d, J 8.4, 2H, H-2), 7.43 (d, J 7.8, IH, H-7), 7.34 (d, J 7.7, IH, H-10), 7.22 (dd, J 7.5, 7.4, IH, H-9), 7.12 (dd, J 7.8, 7.4, IH, H-8), 5.51 (s, IH, H-6), 5.48 (dd, J 10.1, 4.4, IH, H-l l), 5.13 (s, IH, H-5), 4.53 (d, J 16.9, IH, H-4), 4.41 (d, J 16.9, IH, H-4), 3.34 (dd, J 17.1, 10.1, IH, H-12), 3.08 (dd, J 17.1, 4.4, IH, H-12). 8C (DMSO- , 75 MHz): 166.3, 142.5, 134.6, 134.0, 132.2, 130.8, 129.7, 128.6, 128.1, 127.9, 127.7, 124.0, 118.3, 111.3, 53.5, 45.0, 24.7. v/max (film): 3386, 1697, 1342, 1160. m/z (%) 391 (MNa+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In tetrahydrofuran; at 20.0℃; for 1.0h; | Example 68 1-Cyclopropyl-4-{4-[(5-methyl-3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}-1H-pyrazol-1-yl)methyl]pyridin-2-yl}piperazine 4-sulfamoylbenzoate 206 mg (0.994 mmol) of 4-sulfamoylbenzoic acid were added to a solution of 522 mg (0.994 mmol) of the compound from Example 65 in 20 ml of THF at RT and the mixture was stirred at RT for 1 h. The mixture was then concentrated completely to dryness on a rotary evaporator. After the residue had been dried under a high vacuum, 632 mg (88% of th.) of the title compound were obtained. 1H-NMR (400 MHz, DMSO-d6, delta/ppm): 13.37 (broad, 1H), 8.20 (d, 2H), 8.11 (d, 2H), 8.04 (d, 1H), 7.93 (d, 2H), 7.59 (d, 2H), 7.53 (s, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 6.27 (d, 1H), 5.43 (s, 2H), 3.44-3.40 (m, 4H), 2.62-2.58 (m, 4H), 2.33 (s, 3H), 1.67-1.61 (m, 1H), 0.47-0.41 (m, 2H), 0.37-0.33 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; under 375.038 Torr; for 24h;Schlenk technique; | General procedure: Aryl iodide (1.0 mol equiv), nucleophile (1.1 mol equiv), Pd2dba3 (0.025 mol equiv), tri-2-furylphosphine (0.05 mol equiv), K2CO3 (2.0 mol equiv) and DMF (10-20 ml/mmol) were combined in a Schlenk tube with a stirrer bar, subjected to two freeze-pump-thaw cycles and charged with allene (0.5 bar). The Schlenk tube was thawed and stirred vigorously at 80 C. for 24 h, cooled to room temperature, diluted with H2O (60 ml) and extracted with EtOAc (2×20 ml). The combined organic extracts were washed with H2O (20 ml), dried (MgSO4), filtered and concentrated in vacuo. Column chromatography of the residue afforded the product.; Intermediate 12: 4-[1-(Cyanomethyl)-4-methylene-3,4-dihydroisoquinolin-2(1H)-yl]sulfonyl}benzoic acid Prepared by the general procedure from 2-iodocinnamonitrile (0.255 g, 1.0 mmol), 4-(aminosulfanyl)benzoic acid (0.201 g, 1.0 mmol), Pd2dba3 (0.022 g, 0.025 mmol), TFP (0.023 g, 0.1 mmol), K2CO3 (0.276 g, 2.0 mmol) and allene (0.5 bar) in DMF (10 mL), heated at 80 C. for 24 h. Column chromatography (40 g silica, 2:1 v/v Et2O:hexanes) afforded the product as an amorphous pale yellow solid (0.195 g, 53%). Found: 391.0717; C19H16N2O4SNa requires 391.0723. deltaH (DMSO-d6, 500 MHz): 7.79 (d, J 8.4, 2H, H-3), 7.73 (d, J 8.4, 2H, H-2), 7.43 (d, J 7.8, 1H, H-7), 7.34 (d, J 7.7, 1H, H-10), 7.22 (dd, J 7.5, 7.4, 1H, H-9), 7.12 (dd, J 7.8, 7.4, 1H, H-8), 5.51 (s, 1H, H-6), 5.48 (dd, J 10.1, 4.4, 1H, H-11), 5.13 (s, 1H, H-5), 4.53 (d, J 16.9, 1H, H-4), 4.41 (d, J 16.9, 1H, H-4), 3.34 (dd, J 17.1, 10.1, 1H, H-12), 3.08 (dd, J 17.1, 4.4, 1H, H-12). deltaC (DMSO-d6, 75 MHz): 166.3, 142.5, 134.6, 134.0, 132.2, 130.8, 129.7, 128.6, 128.1, 127.9, 127.7, 124.0, 118.3, 111.3, 53.5, 45.0, 24.7. v/max (film): 3386, 1697, 1342, 1160. m/z (%) 391 (MNa+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 6.0h; | General procedure: A solution of <strong>[883535-89-5]2-(2-methyl-1H-indol-1-yl)ethanamine</strong> (4a) (65 mg, 0.373 mmol) and 4-(piperidin-1-yl)benzoic acid (5) (76 mg, 1 eq.), and dimethylaminopyridine (catalytic, ?5 mg) in dichloromethane (6 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.hydrochloride (EDCI) (92 mg, 1.3 eq.) at room temperature. The resulting reaction mixture was stirred for 6h. At the conclusion of the reaction (TLC), water (15 mL) was added to quench the reaction. The product was extracted with ethyl acetate (20mL×3). Organics were washed with dilute HCl (10 mL), saturated NaHCO3 solution (10 mL), water (10 mL) and brine solution (10 mL) and dried over Na2SO4 and concentrated. The resulting crude product was subjected to silica gel chromatography eluting with 0-40% ethyl acetate in hexane to furnish 7k (TG7-152) (100mg, 74% yield). 1H NMR (CDCl3): delta 7.52 (d, J=5.6Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.30 (d, J=8Hz, 1H), 7.07 (m, 2H), 6.80 (d, J=8.2Hz, 2H), 6.23 (s, 1H), 5.98 (t, J=5.4Hz, 1H), 4.33 (t, J=6Hz, 2H), 3.76 (q, J=6Hz, 2H), 3.25 (t, J=4.8Hz, 4H), 2.37 (s, 3H), 1.6 (m, 6H). LCMS (ESI): >97% purity at lambda 254, MS; m/z, 362 [M+H]+. Anal. Calcd. for C23H27N3O: C, 76.42; H, 7.53; N, 11.62; found; C, 76.48; H, 7.55; N, 11.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 0℃; | To a solution of (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (intermediate 3; 206 mg, 970 muiotaetaomicron), N-methylmorpholine (294 mg, 2.91 mmol) and 4- sulfamoylbenzoic acid (203 mg, 970 muiotaetaomicron) in N,N-dimethylformamide (10 ml) was added 0-(7- azabenzotriazol-l-yl)-N,N,N',N' -tetramethyluronium hexafluoro-phosphate (369 mg, 970 muiotaetaomicron) at 0C, then after 10 min the ice-bath was removed. After 16 h the reaction mixture was partitioned between dichloromethane and sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with sat. aq. ammonium chloride solution and brine, dried over magnesium sulfate, filtered and evaporated. After trituration in tert-butyl methyl ether the precipitate was collected by filtration to afford the title compound (348 mg, 91 ). Light yellow solid, MS: 396.6 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; diisopropyl-carbodiimide; In dichloromethane; ethyl acetate; at 20℃; for 72h; | The amide formation of the amine 15 was carried out using p-sulfamoylbenzoic acid(2.22 g, 2.4 eq.) and DIC (1.7 mL, 2.4 eq.) in DCM (75 mL) followed by the addition of theamine 15 (2.2 g, 1 eq.) and DMAP (56 mg, 0.1 eq.) . The reaction was not soluble initially so15 ethyl acetate (35 mL) was added and the reaction mixture was stirred at rt for 3 days. Thereaction was filtered and the filtrate was concentrated. The residue was purified by silica gelchromatography using 10 % ethyl acetate in hexanes as eluent to afford the white solid product16 (1.90 g, 63% yield). |
63% | With dmap; N,N'-dicyclopropylcarbodiimide; In dichloromethane; ethyl acetate; at 20℃; for 72h; | General procedure: N-Cbz-methylalanine 3f (2.45 g, 2 eq.) was treated with DIC(1.6 mL, 2 eq.) in DCM (33 mL) for 30 min under nitrogen at rt.TBS-Estradiol 2 (2.0 g, 1 eq.) and DMAP (0.063 g, 0.1 eq.) were thenadded and the resulting white mixture was stirred for 16 h rt. Afterfiltration, the filtrate was concentrated and the residue was purifiedby silica gel chromatography using 5-40% ethyl acetate in hexanesas eluent to afford the white solid product 4f (2.85 g, 91%yield). The Cbz group of ester 4f (2.85 g) was then removed usingPd/C (10% Pd, 0.51 g) and hydrogen (30 psi) on a Parr shaker inethyl acetate (35 mL) as solvent for 16 h. After filtration throughCelite and concentration of the solvent, the white solid product5f (2.2 g, quantitative) was obtained. The amide formation of theamine 5 was carried out using p-sulfamoylbenzoic acid (2.22 g,2.4 eq.) and DIC (1.7 mL, 2.4 eq.) in DCM (75 mL) followed by theaddition of the amine 5f (2.2 g, 1 eq.) and DMAP (56 mg, 0.1 eq.).The reaction was not soluble initially so ethyl acetate (35 mL)was added and the reaction mixture was stirred at rt for 3 days.The reaction was filtered and the filtrate was concentrated. Theresidue was purified by silica gel chromatography using 10% ethylacetate in hexanes as eluent to afford the white solid product 6f(1.90 g, 63% yield). The silyl ether 6f (1.90 g) was then removedusing p-toluenesulphonic acid (1.16 g, 2 eq.) in DCM (14 mL), acetone(14 mL), methanol (0.4 mL) and water (0.3 mL) at rt for 16 h.The reaction was quenched with aq. sodium bicarbonate andextracted with ethyl acetate (2 60 mL). The combined organiclayer was dried with sodium sulfate, filtered and concentrated.The residue was purified by silica gel chromatography using10-30% acetone in DCM as eluent to afford [(13S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,-17-decahydrocyclopenta[a]phenanthren-17-yl](2S)-2-[methyl-(4-sulfamoylbenzoyl)amino]propanoateas white solid 7f (1.47 g, 94% yield): 1H NMR (d, CDCl3 300 MHz):7.96 (d, 2H, J = 8.1 Hz), 7.99 (d, 2H, J = 8.1 Hz), 7.13 (d, 1H, ArH,J = 8.1 Hz), 6.62 (dd, 1H, ArH, J = 2.7, 8.4 Hz), 6.54 (d, 1H, ArH,J = 2.7 Hz), 5.30 (s, 1H), 4.95 (s, 2H, NH2), 4.80 (m, 1H), 3.00 (s,1H, CH3, rotamer), 2.90 (s, 2H, CH3, rotamer), 0.85 (s, 2H, CH3, rotamer),0.83 (s, 1H, CH3, rotamer). IR (cm1): 3353, 3257, 2924, 2862,1731, 1617. [a]D24 = 10 (c = 0.5, 1,4-dioxane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With pyridine; toluene-4-sulfonic acid; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 72h; | To a solution of 3 (0.22 g, 0.5 mmol) and 4-sulfamoyl benzoic acid (0.24 g, 1.15 mmol) inpyridine (10 mL) was added p-TsOH (0.08 g, 0.5 mmol) followed by a 1M solution DCC in15 dichloromethane (0.24 g, 1.15 mmol). After stirring at rt for 72 h, water was added and the pH ofthe reaction was brought to 7 by the addition of 4N hydrochloric acid. The reaction mixture wasextracted three times with ethyl acetate and the combined organic layers were washed withwater, brine and dried over anhydrous Na2S04. The solvent was removed under vacuum and thecrude was purified by column chromatography (Si02, hexane-EtOAc) to give the 3-TBS ether of20 3A (0.27 g, 86%). 1H NMR (8, CDCh, 300 MHz): 8.23 (d, J = 8.5 Hz, 2H, ArH), 8.02 (d, J = 8.5Hz, 2H, ArH), 7.10 (d, J= 8.4 Hz, IH, ArH), 6.61 (dd, J1 = 8.4 Hz, Jz = 2.5 Hz, IH, ArH), 6.53(d, J = 2.4 Hz, IH, ArH), 4.89 (s, 2H, -OCH2), 4.80 (t, J = 8.9 Hz, IH, -CH), 2.80 (m, 2H, -CH2),0.97 (s, 9H, Si-CH3), 0.78 (s, 3H, -CH3), 0.18 (s, 6H, Si-CH3), 0.18 (s, 6H, Si-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 17h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With thionyl chloride; In Isopropyl acetate; at 80 - 90℃; | Into the initial charge of 1.02 eq. of ortho-methoxybenzoic acid compounds of theformula (III) (MBA) and 1 eq. of 4-sulphamoylbenzoic acid compounds of the formula(IV) (SBA) in isopropyl acetate are metered 2.5 eq. of thionyl chloride at 80-90C within1-1.5 hours. After about 1-2 hours with stirring at 90C, a clear solution is obtained.After a further hour of continued stirring time, no free acids are present any longer, butonly the corresponding acid chlorides and the product. A clear solution is present atthis time. The excess thionyl chloride and a portion of the solvent (about 50%) are distilled off at about 800 mbar. The concentrated suspension is stirred at 90C for a further 3 hours.The concentrating of the reaction mixture accelerates the conversion of the acidchlorides of the ortho-methoxybenzoic acid compounds of the formula (III) (MBCI) and of the chlorides of the 4-sulphamoylbenzoic acid compounds of the formula (IV) (SBCI) to the amide chloride (4-[[(2-methoxybenzoyl)amino]sulphonyl]benzoyl chloride). Forthe purpose of better stirrability and conversion, the thick suspension is diluted againwith isopropyl acetate. This is followed by cooling to 0C and filtration. To displace the mother liquor, the filtercake is washed with isopropyl acetate (displacement wash) and dried at 60C under reduced pressure. The isolated yield is 95-96% of theory at a purity of> 98%. |
A mixture of 2235 g of p-carboxyphenylsulfonamide (11 mol, 99%), 1506 g of o-methoxybenzoic acid (99%, 10 mol), 335 g of p-nitrobenzenesulfonic acid was stirred in a four-necked flask with 4,500g toluene solvent for 1 hour , heated to reflux reaction for 3 hours to clear; Cooled to 50 C, 1562 g of thionyl chloride was added dropwise to the bottle, and the mixture was added dropwise for 5 hours. The solvent was removed and 3000 g of methylene chloride was added to give a solution of 4 - [[(2-methoxybenzoyl) amino] sulfonyl] benzoyl chloride. Dichloromethane (400 g), 806 g of cyclopropylamine (1.05 eq) were added to the other four vials at a temperature of -6 C. While stirring, a solution of 4 - [[(2-methoxybenzoyl) amino] sulfonyl] benzoyl chloride in dichloromethane was added dropwise to the system with 1860 g of aqueous sodium hydroxide solution (30% by mass). After the dropwise addition, the mixture was incubated at a temperature of -5 C for 5 hours and at -3 C to obtain white crystals, the content was 98.9% and the total yield was 93.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: A mixture of 4-(aminosulfonyl)benzoic acid (7) (2 mmol,402 mg), N,N,N0,N0-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexafluorophosphate (HBTU) (2 mmol, 758 mg) in dimethylformamide(2 mL) was stirred at room temperature for 1 h. Then, a solution of the appropriate 1,2,3,4-tetrahydroisoquinoline(6a,c,e) or 1,2,3,4-tetrahydroquinoline (8c,e) (2 mmol) in TEA(2 mmol, 278 mL) was added dropwise. The reaction mixture wasleft overnight and then quenched with water (10 mL) and extractedwith EtOAc (3 5 mL). The organic phase was dried with Na2SO4and the solvent was removed in vacuo. The residue was purified byflash chromatography (DCM/MeOH 96:4), crystallized by treatmentwith diethyl ether and ethanol giving the desired final compounds4a,c,e and 5cee as white crystals. As starting reagent the benzamide3a was re-synthesized following a previously reported procedureand the spectral datawas in accordance with literature [37].The methoxy derivatives 3a, 4a,c and 5c (1 mmol) were dissolved inmethylene chloride (DCM) (5 mL), treated with BBr3 (1 M in DCM)(6 mmol, 6 mL) under nitrogen atmosphere and stirred overnight.After completion of the reaction, MeOH (7 mL) was carefully addedat 0 C and the solvents removed under reduced pressure. Theresidue was dissolved in EtOAc (10 mL) and washed with H2O(10mL 3). The organic layerwas dried (Na2SO4) and concentratedin vacuo. The crude products were crystallized from diethyl ether togive the desired corresponding hydroxy-derivatives 3b, 4b,d and5d. 4.1.1.3 4-[(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]benzenesulfonamide (4c) Yield 74%; mp 181-182 C; Rf = 0.46; 1H NMR (DMSO-d6): the compound exists as a pair of rotamers at room temperature. delta 2.79 (mc, 2H, major rotamer, CH2), 2.85 (mc, 2H, minor rotamer, CH2), 3.46 (mc, 2H, major rotamer, CH2), 3.70 (s, 3H, OCH3), 3.81 (mc, 2H, minor rotamer, CH2), 4.42 (mc, 2H, minor rotamer, CH2), 4.69 (mc, 2H, major rotamer, CH2), 6.74-7.18 (m, 3H, ArH), 7.47 (bs, 2H, NH2), 7.63 (d, J = 7.7, 2H, ArH), 7.87 (d, J = 8.2, 2H, ArH); GC-MS (EI) m/z (%): 346 (M+, 0), 222 (4.3), 194 (0.5), 177 (35), 176 (18), 164 (0.5), 150 (15), 149 (100), 121 (6.2), 105 (7.8); Anal. C17H18N2O4S. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | Step 1: (3aR,6aS)-tert-Butyl 5-(4-sulfamoylbenzoyl)hexahydropyrrolor3,4-clpyrrole-2(lH)- carboxylate To a colourless solution of (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate (CAS-RN 250275-15-1; 1.00 g, 4.48 mmol), 4-methylmorpholine (1.36 g, 13.4 mmol) and 4-sulfamoylbenzoic acid (900 mg, 4.48 mmol) in N,N-dimethylformamide (75 mL) was added 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluoro-phosphate (1.70 g, 4.48 mmol) at room temperature, then after 16 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate / 2-methyltetrahydrofuran. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in ethyl acetate/heptane 1: 1 to produce the title compound (1.46 g, 82%). White solid, MS: 394.5 (Mu-EtaGamma. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: a) To a mixture of the carboxylic acid (5 mmol) in acetone (20 mL) was added EDC (5.5 mmol). The reaction mixture was stirred at room temperature for 30 min, then the amidoxime (5 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. Acetone was evaporated at reduced pressure and to the residue was added water (100 mL). The resulting precipitate was filtered off, washed with water (50 ml) and dried under vacuum at rt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | General procedure: Potassium 4-(aminosulfonyl)benzoate (1.55 g, 6.49 mmol), prepared through the neutralization of the 4-(aminosulfonyl)benzoic acid (1b) with K2CO3 in distilled water at 40 C, was mixed with (4.67 g, 2.83 mL, 38.9 mmol) of thionyl chloride in anhydrous THF (7 mL) under argon in a 48 mL HW pressure vessel. After sonication in water bath at 65 C for 75-90min. the solvent was reduced under vacuum, anhydrous ether was added under argon, followed by removing the solvent again under vacuum. Anhydrous THF (7 mL) was added to the resulted adduct under argon followed by slow addition under argon to a mixture, in ice bath, of triethylamine (1.97 g, 1.40 mL, 19.5 mmol) and 4-substituted aniline 2a (0.779 g, 7.14 mmol), 2b (0.880 g, 7.14 mmol), 2c (0.980 g, 7.14 mmol). After stirring for 36 h at r. t., solvent was removed under vacuum and the crude solid was sonicated with a mixture of diethyl ether and THF (9:1) (50 mL) followed by suction filtration and additional wash with Et2O (2x50 mL) to offer the desired amide in a pure form 3d? (1.42 g, 4.87 mmol, 75%), 3e (1.39 g, 4.54 mmol, 70%), and 3f (1.52 g, 4.74 mmol, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In chlorobenzene; at 120℃; | A solution of 4-aminosulfonylbenzoic acid (20 g, 0.1 mol), 3-methyl-1-methyl-1H-pyrazole-0.1 mol) and thionyl chloride (30 g, 0.25 mol) in chlorobenzene (70 ml) was heated at 120 C for 7-9 hours. After completion of the reaction, 20 ml of solvent was removed in vacuo. The mixture was cooled and the precipitate was filtered off and washed with petroleum ether to give the title compound , Without further purification for the next-step reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | C5-Boc - 4-carboxybenzenesulfonamide (120.8 mg, 0.6 mmol, 1.25 equiv.), EDC.HC1 (143.8 mg, 0.75 mmol, 1.6 equiv.) and HOBT.H20 (114.5 mg, 0.75 mmol, 1.6 equiv.)were dissolved in dry DMF (2.5 mL) under argon. After 5-10 minutes stuffing, N-Boc1,5-diaminopentane (0.1 mL, 0.48 mmol, 1 equiv.) and DIEA (260 tL, 1.5 mmol,3.1 equiv.) were added. Reaction mixture was stirred overnight at room temperature. Solvent was removed by rotary evaporation and the resulting sticky solid was taken up ina 1:1 mixture of EtOAc and saturated aqueous solution of NaHCO3. After decantation, the organic layer was washed with brine, dried over Na2504, filtered and concentrated. The crude was purified by automated silica gel flash column chromatography (5% MeOH in DCM) to give the desired compound as a white solid (173.8 mg, 0.45 mmol, 94%). ?HNMR (400MHz, MeOD) oe (ppm): 7.98-7.93 (m, 4H), 3.39 (t, I = 7.1 Hz, 2H), 3.05 (t, I= 6.9 Hz, 2H), 1.65 (quintet, I = 7.3 Hz, 2H), 1.56-1.49 (m, 2H), 1.42-1.38 (m, 9H + 2H).?3C-NMR (101 MHz, MeOD) oe (ppm): 168.71, 158.53, 147.53, 139.16, 128.90, 127.26, 79.80, 41.02, 30.03, 28.77, 25.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Pathway i: To a solution of 4-(aminosulfonyl)benzoic acid (4)(6 mmol) in THF (15 mL) the carbonylimidazole (6 mmol) (CDI) at 0 C was added. The obtained mixture was stirred at room temperature for 3h and then the appropriate amine derivative(15 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2h. The solvent was removed in vacuo; by adding of aqueous solution of NaHCO3 (5 mL)we obtained compounds 5a and 5d as crude products, which were purified through crystallization by a mixture of Et2O and EtOH(1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In a 250 ml three-necked flask, 50 ml of deionized water, 0.01 mol of p-carboxybenzenesulfonamide, 0.02 mol of potassium hydroxide, and 0.01 mol of potassium carbonate were added and mixed uniformly; after the temperature was returned to room temperature, 0.0005 mol of octadecyl ether was added, and the mixture was stirred and dissolved. ,Dropped into 50ml dissolved 0.01molA toluene solution of 5-iodo-3-oxa-octafluoropentylsulfonyl fluoride monomer was reacted at 1000 rpm for 0.5 hmin. The reaction product was separated into an aqueous phase, the pH was adjusted to 4 with 5% hydrochloric acid, and ethyl acetate was evaporated.The yield is about 86%. The nuclear magnetic fluorine spectrum of this final product is shown in Fig. 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Take compound 6-7 (350 mg, 1.46 mmol),For sulfonamide benzoic acid (352 mg, 1.75 mmol, 1.2 eq.),HOBt (591 mg, 4.38 mmol, 3 equivalents) and EDCI (840 mg, 4.38 mmol, 3 equivalents) in a 25 mL single-mouth bottle, DMF andTEA (1 mL, 7.3 mmol, 5 eq.). Stir at room temperature.TLC tracking monitoring. Rotate DMF, add EA and water extraction,Wash with saturated brine, dry, spin dry, and pass through a column (DCM:acetone = 2.5:1).White solid product 400mg |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Take compound 4-7 (250 mg, 0.51 mmol),For sulfonamide benzoic acid (203 mg, 1.01 mmol, 2 equivalents),HOBt (409 mg, 3.03 mmol, 6 equivalents) and EDCI (581 mg, 3.03 mmol, 6 equivalents) in a 50 mL single-mouth bottle, DMF andTEA (1.95 mL, 12.84 mmol, 12 eq.). Stir at room temperature.TLC tracking monitoring. Rotate DMF, add EA and water extraction,Wash with saturated brine, dry, spin dry, and pass through a column (DCM:acetone = 3:1). The product was obtained as a white solid 323 mg (yield: 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | 2,7-diazaspiro[3.5]decane-7-carboxylic acid tert-butyl ester hydrochloride (300 mg, 1.14 mmol),For sulfonamide benzoic acid (230 mg, 1.14 mmol, 1 eq.), HOBt (462 mg, 3.42 mmol, 3 eq.) and EDCI (656 mg, 3.42 mmol, 3 eq.DMF and TEA (1.3 mL, 8.56 mmol, 8 eq.) were added.Stir at room temperature. TLC tracking monitoring. Rotate DMF, add EA and water extraction,Wash with saturated brine, dry, spin dry, and pass through a column (DCM:acetone = 3:1).The product was obtained as a white solid, 410 mg, yield 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; | Compound 3-7 (300 mg, 1.33 mmol), p-sulfonamide benzoic acid (294 mg, 1.46 mmol, 1.1 eq.), HOBt (539 mg, 3.99 mmol, 3 eq.) and EDCI (765 mg, 3.99 mmol, 3 eq.) in 50 mL Single mouth bottle,DMF and TEA (0.74 mL, 5.32 mmol, 4 eq.) were added.Stir at room temperature overnight. TLC tracking monitoring. Rotate the DMF,Add EA and water for extraction, wash with saturated brine, dry, spin dry, and pass through column (DCM:acetone = 3:1). A white solid of 450 mg was obtained in a yield of 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | at 50℃; for 8h; | General procedure: Complex 24 4 was prepared through an ordinary condensation reaction. A mixture of 25 di-methyltin oxide (0.234g, 2.0mmol) and 13 4-carboxybenzenesulfonamide (0.201g, 1.0mmol) in 15 methanol (50mL) further stirred for 8h at 50C. The resulting clear solution was then filtered and concentrated to 20mL. Slow evaporation of this concentrate afforded colourless block crystals of complex 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Pathway ii: A mixture of 4-(aminosulfonyl)benzoic acid (4)(2 mmol) and N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexafluorophosphate (HBTU) (2 mmol) in DMF(2 mL) was stirred at room temperature for 1 h. Then, a solution of the appropriate amine derivative (2 mmol) in TEA (2 mmol) was added dropwise. The reaction mixture was left overnight and then quenched with water (10 mL) and extracted with EtOAc (3 5 mL).The organic phase was dried with Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography(DCM/MeOH 96:4), crystallized by treatment with a mixtureof Et2O and EtOH (1:1) to give the desired final compounds 5b, 5c,6a, 7a-f and 8a-d as white crystals. For compounds 5 a-d, 6a, 8a and 8d registered CAS numbers have been already assigned. However,their synthetic procedures, chemical properties and structural characterization are not available in literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Pathway ii: A mixture of 4-(aminosulfonyl)benzoic acid (4)(2 mmol) and N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexafluorophosphate (HBTU) (2 mmol) in DMF(2 mL) was stirred at room temperature for 1 h. Then, a solution of the appropriate amine derivative (2 mmol) in TEA (2 mmol) was added dropwise. The reaction mixture was left overnight and then quenched with water (10 mL) and extracted with EtOAc (3 5 mL).The organic phase was dried with Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography(DCM/MeOH 96:4), crystallized by treatment with a mixtureof Et2O and EtOH (1:1) to give the desired final compounds 5b, 5c,6a, 7a-f and 8a-d as white crystals. For compounds 5 a-d, 6a, 8a and 8d registered CAS numbers have been already assigned. However,their synthetic procedures, chemical properties and structural characterization are not available in literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Pathway ii: A mixture of 4-(aminosulfonyl)benzoic acid (4)(2 mmol) and N,N,N,N-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexafluorophosphate (HBTU) (2 mmol) in DMF(2 mL) was stirred at room temperature for 1 h. Then, a solution of the appropriate amine derivative (2 mmol) in TEA (2 mmol) was added dropwise. The reaction mixture was left overnight and then quenched with water (10 mL) and extracted with EtOAc (3 5 mL).The organic phase was dried with Na2SO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography(DCM/MeOH 96:4), crystallized by treatment with a mixtureof Et2O and EtOH (1:1) to give the desired final compounds 5b, 5c,6a, 7a-f and 8a-d as white crystals. For compounds 5 a-d, 6a, 8a and 8d registered CAS numbers have been already assigned. However,their synthetic procedures, chemical properties and structural characterization are not available in literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium metabisulfite; sodium azide; tetrabutylammomium bromide; triphenylphosphine; In water; acetonitrile; at 80℃; for 4h;Inert atmosphere; Schlenk technique; | Under nitrogen protection,The diazonium salt 1y (294.9 mg, 1.25 mmol), NaN3 (32.5 mg, 0.5 mmol), PPh3 (157.4 mg, 0.6 mmol), Na2S2O5 (190.1 mg, 1.0 mmol),TBAB (241.7 mg, 0.75 mmol) and MeCN/H2O=2/1 (1 mL) was added to the Schlenk reaction tube. After the reaction was stirred at 80 C for 4 h,Reduce to room temperature, add 10mL water to the system to dilute,Extracted with ethyl acetate (10 mL*3), dried over anhydrous sodiumColumn chromatography gave a white solid 2y (60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h; | General procedure: N-(3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC·HCl; 3.2 mmol) was added into a solution of 4-carboxybenzenesulfonamide (6; 604 mg, 3 mmol) and ArCONHNH2 7 (3 mmol) in 5 mL anhydrous N,N-dimethylformamide (DMF). The solution was stirred at room temperature for 12 h, and then diluted with 15 ml cold water. The solid material was collected by filtration, washed with water and dried at 50 C. The crude product was purified by silica gel chromatography with CHCl3/MeOH (9:1-5:1, v/v) to afford 8a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; | 1.2. General procedure 1 (GP1): Synthesis of compounds 8a-e General procedure: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl; 3.2 mmol) was added into a solution of 4-carboxybenzenesulfonamide (6; 604 mg, 3 mmol) and ArCONHNH2 7 (3 mmol) in 5 mL anhydrous N,N-dimethylformamide (DMF). The solution was stirred at room temperature for 12 h, and then diluted with 15 ml cold water. The solid material was collected by filtration, washed with water and dried at 50 °C. The crude product was purified by silica gel chromatography with CHCl3/MeOH (9:1-5:1, v/v) to afford 8a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | General procedure: To a stirred solution of the carboxylic acid (1.0 mmol) in anhydrous CH2Cl2 (5 mL), the appropriate amine or its hydrochloric acid(1 mmol), Et3N (1 eq, 0.14 mL, 1 mmol or 2 eq, 0.28 mL, 2 mmol in caseof hydrochloric acid), HOBt (1 eq, 140 mg, 1 mmol) and EDCI (1.1 eq,211 mg, 1.1 mmol) were added at 0 C. The reaction mixture was stirred overnight at room temperature and then the solvent was removedunder reduced pressure. The residue was dissolved in AcOEt and washedwith H2O, 5% H2SO4, H2O, 5% NaHCO3, brine and H2O. In thecase of proline washing with 5% H2SO4, was omitted. The product was obtained after drying the organic phase over anhydrous Na2SO4, evaporation of the solvent under reduced pressure, and purification by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 4-(aminosulfonyl)-benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: (3‑nitrophenyl)(piperazin‑1‑yl)methanone In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-(aminosulfonyl)-benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: (4-nitro-phenyl)-piperazin-1-yl-methanone In N,N-dimethyl-formamide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | General procedure: To a solution of the carboxylic acids 33-36 (0.45 mmol) indimethylformamide (3 mL), an excess of EDCI (0.54 mmol) andhydroxybenzotriazole monohydrate (0.54 mmol), and a catalytic amount ofdimethylaminopyridine (0.02 mmol) were added. The mixture was stirred at roomtemperature for 2 h, then 5-(4-(aminomethyl)piperidin-1-yl)-2-(furan-2-yl)thiazolo[5,4-d]pyrimidin-7-amine(32) (0.49 mmol) was added. After stirring at room temperature for 3 h,20 mL of H2O were added to precipitate a solid which was filtered,washed with water and purified by column chromatography. N-((1-(7-Amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidin-5-yl)piperidin-4-yl)methyl)-4-sulfamoylbenzamide(8) Yield 85%. Mp: 166-168 C (column chromatography, eluting system ethylacetate/cyclohexane/methanol 7/2/1). 1H NMR (DMSO-d6): delta 8.71(t, 1H, NHCO, J=5.3 Hz), 8.00(d, 2H, J=8.4 Hz), 7.93-7.83(m, 3H), 7.48 (s, 2H, NH2), 7.24 (s, 2H, NH2), 7.05 (d,1H, J=3.2 Hz), 6.73-6.72 (m,1H), 4.68 (d, 2H, J=12.7 Hz),3.21-3.18 (m, 2H), 2.83 (t, 2H, J=12.0Hz), 1.86 (br s, 1H), 1.75 (d, 2H, J=11.8Hz), 1.14-1.11 (m, 2H). 13C NMR (DMSO-d6): delta 165.82,165.14, 159.21, 157.23, 148.62, 146.61, 145.80, 138.01, 128.34, 126.06, 124.69,113.20, 110.08, 45.35, 44.18, 36.55, 30.08. Anal. calcd. for (C22H23N7O4S2):C, 51.45%; H, 4.51%; N, 19.09%. Anal. found: C, 51.76%; H, 4.85%; N, 19.33%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | 4-(Aminosulfonyl)benzoic acid (1) (4.2 g, 20 mmol), EDCI (3.9 g,22 mmol) and HOBt (2.7 g, 20 mmol) were dissolved in anhydrousCH3CN (100 mL). The resulting mixture was stirred at rt for 30 min,then ethyl isonipecotate (2) (3.1 g, 20 mmol) was added. The mixturewas stirred at rt for 12 h. The solvent was removed in vacuo and theresidue was dissolved in ethyl acetate (30 mL) and washed sequentiallywith water (2 × 10 mL), saturated NaHCO3 aqueous solution(2 × 10 mL), 10% aqueous citric acid (2 × 10 mL) and brine(2 × 10 mL). The organic layer was dried over anhydrous sodiumsulfate (Na2SO4), filtered and evaporated under reduced pressure. Theresidue was tritured with isopropyl ether (iPr2O) and the formed solidwas filtered off, dried and used in the next step without further purification.Yield 77% M.p. 155-156 C. ESIMS (m/z): 341 (M+H)+.1HNMR (DMSO-d6): delta 1.17 (t, J = 7.5 Hz, 3H, CH3), 1.52 (m, 2H, CH2),1.78-1.92 (m, 2H, CH2), 2.63-2.95 (m, 2H, CH2), 3.09-3.43 (m, 2H,CH2), 4.07 (q, J = 7.5 Hz, 2H, CH2), 4.32 (m, 1H, CH), 7.42 (s, 2H,NH2), 7.55 (d, J = 8.0 Hz, 2H, Ar), 7.85 (d, J = 8.0 Hz, 2H, Ar). IR(Nujol) 3328, 3225, 1732, 1596 cm-1. Anal. Calcd for C15H20N2O5S(340.39) %C 52.93, %H 5.92, %N 8.23, found %C 52.99, %H 5.90, %N8.26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: 2-aminothiazole-4-carboxylate With dmap In N,N-dimethyl-formamide at 20 - 25℃; for 24h; | 2.1.2. General procedure for the synthesis of 2a-e General procedure: To a solution of N,N-dimethylformamide (DMF, 5 mL), 4-carboxy-benzenesul- phonamide (5.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 6.0 mmol), and 1-hydroxybenzotriazole (HOBT, 6.0 mmol) were added. The mixture was stirred at room temperature (20-25 °C) for 30 min. Then, ethyl 2-aminothiazole-4-carboxylate (6.0 mmol) and 4-dimethylaminopyridine (DMAP, 1.5 mmol) were added to the solution. The reaction was carried out at room temperature (20-25 °C) for 24 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The solvent was dried and removed. The obtained solid was purified using column chro- matography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a . The method for synthesizing 2b -2f was the same as that for 2a.Ethyl 2-(4-sulfamoylbenzamido)thiazole-5-carboxylate ( 2a ) . white powder (yield 83.5%), m. p . > 300.0 °C; 1 H NMR (400 MHz, DMSO- d 6) δ ppm: 13.35 ( s , 1H, NH), 8.26 (m, 3H, Ar-H, S-CH), 7.99 (d, J = 8.0 Hz, 2H, Ar-H), 7.60 ( s , 2H, SO 2 NH 2 ), 4.31 ( q , 2H, OCH 2 ), 1.32 ( t , 3H, CH 3 ); ESI-MS m/z calcd. for C 13 H 13 N 3 O 5 S 2 [M + H] + : 356.0330, found: 356.0369. |
69% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: 2-aminothiazole-4-carboxylate With dmap In N,N-dimethyl-formamide at 45℃; for 24h; | 4.1.2 Synthesis of 2a-3f 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25°C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45°C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a. Ethyl 2-(4-sulfamoylbenzamido) thiazole-4-carboxylate (2a). White powder (yield 69%), m. p. 278.2-279.6°C, 1H NMR (DMSO-d6) δ ppm: 13.30 (s, 1H, CONH), 8.27 (d, J=8.0Hz, 2H, Ar-H), 8.18 (s, 1H, S-CH),7.98 (d, J=8.0Hz, 2H, Ar-H), 7.60 (s, 2H, SO2NH2), 4.32 (q, 2H, OCH2), 1.32 (t, 3H, CH3); 13C NMR (DMSO-d6) δ ppm: 165.18, 161.56, 159.06, 147.99, 141.72, 135.03, 129.55, 126.36, 123.96, 61.24, 14.75; ESI-MS m/z: calcd. for C13H13N3O5S2 [M+H]+: 356.03, found: 356.03. |
69% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-aminothiazole-4-carboxylate With dmap In N,N-dimethyl-formamide at 45℃; | 1 Example 1: ethyl 2-[(4-sulfamoylphenyl)formyl]aminothiazole-4-carboxylate 4-Carboxybenzenesulfonamide (10.0 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol)And 1-hydroxybenzotriazole (HOBT, 12.0 mmol) was added to DMF (10 ml) and stirred at room temperature for 30 minutes.Then 2-amino-4-ethoxycarbonylthiazole (12.0 mmol) and DMAP (3.0 mmol) were added.The reaction was performed at 45°C until the reaction was completed by TLC.The mixture was cooled to room temperature and extracted with ethyl acetate.The organic layer was washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The raw material product was purified by column chromatography (DCM/MT60:1-30:1) to obtain a white solid compound in 69% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: 1H-benzimidazol-2-amine With dmap In N,N-dimethyl-formamide at 45℃; for 24h; | 4.1.2 Synthesis of 2a-3f General procedure: 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25°C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45°C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: 4-Carboxybenzenesulphonamide (10.0mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.0mmol), and 1-hydroxybenzotriazole (HOBt, 12.0mmol) were added to 10mLN,N-dimethylformamide (DMF) and stirred at room temperature (20-25C) for 30min. Then, 2-amino-4-ethoxycarbonyl thiazole (12.0mmol) and 4-dimethylaminopyridine (DMAP, 3.0mmol) were added to the solution. The reaction was carried out at 45C for 24h. The mixture was cooled to room temperature and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a. The method for synthesising 2b-3f was the same as for 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; | 4.1.15. General procedure for the synthesis of sulfamoyl-substitutedN-(3-((4-(8-amino-3-oxo-2-phenyl-2,3-dihydro-1,2,4-triazolo [4,3-a]pyrazin-6-yl)phenyl)amino)-3-oxopropyl)-benzamides 20 and 21 A mixture of the 6-(4-(3-aminopropanamido)-phenyl)- derivative32 [24] (1.0 mmol), the suitable sulfamoylbenzoic acid(1.1 mmol), 1-(3-(dimethylamino)-propyl))-3-ethylcarbodiimidehydrochloride (1.1 mmol), triethylamine (1.1 mmol) and 1-hydroxybenzotriazole (1.1 mmol), in anhydrous DMF (3 mL), wasstirred for about 2 h, at rt and under nitrogen atmosphere. Themixturewas diluted with water (20 mL) and the obtained solid wascollected by filtration, rinsed with water (10 mL), Et2O (10 mL),dried and purified by recrystallization (20) or by column chromatography (21). 4.1.15.1. N-(3-((4-(8-Amino-3-oxo-2-phenyl-2,3-dihydro-1,2,4-triazolo[4,3-a]pyrazin-6-yl)phenyl)amino)-3-oxopropyl)-4-sulfamoylbenzamide (20). Yield 75%; mp 298-300 °C (nitromethane);1H NMR (DMSO-d6) 10.09 (br s, 1H, NH), 8.81 (br s, 1H,NH), 8.08 (d, 2H, ar, J = 8.1 Hz), 8.00 (d, 2H, ar, J = 8.4 Hz), 7.93-7.89(m, 4H, ar), 7.70-7.66 (m, 3H, ar), 7.58-7.56 (m, 4H, 2ar NH2), 7.47(br s, 2H, NH2), 7.36 (t, 1H, ar, J = 7.1 Hz), 3.59 (t, 2H, CH2, J = 6.9 Hz),2.67 (t, 2H, CH2, J = 6.8 Hz). 13C NMR (DMSO-d6) 169.91, 165.82,147.80, 147.62, 146.68, 139.55, 137.97, 137.83, 135.72, 131.56, 129.65,128.30, 126.75, 126.32, 126.08, 119.85, 119.88, 119.40, 101.01, 36.74,36.53. IR 3365.78, 3282.84, 1683.86, 1647.21, 1558.48, 1521.84. Anal.C27H24N8O5S (C, H, N). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 4-(aminosulfonyl)-benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Microwave irradiation; Stage #2: N-(furan-2-carbonyl)piperazine With triethylamine In N,N-dimethyl-formamide at 20℃; Microwave irradiation; | 4.3.2 General procedures for the synthesis of 4-(4-(hetero)aroylpiperazine-1-carbonyl)benzenesulfonamide derivatives (7a-m) General procedure: The activation of the 4-(aminosulfonyl)benzoic acid (1M equivalent) was conducted by addition of HBTU (1M equivalent) in dimethylformamide (DMF) (2mL); the mixture reaction was stirred for 1h at room temperature. Then, a mixture of TEA (2M equivalents) and appropriate 4-aroylpiperazine derivatives 9a-m (1M equivalent) was added dropwise. The reaction mixture was left overnight at room temperature and then quenched with H2O (10mL) and extracted with EtOAc (3×10mL). The organic phase was washed with saturated NaCl solution, dried with Na2SO4 and concentrated until dryness under reduced pressure. The residue was purified by crystallization from Et2O and EtOH to give the desired final compounds 7a-m as white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.1% | General procedure: To a solution of N,N-dimethylformamide (DMF, 5 mL), 4-carboxy-benzenesul- phonamide (5.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 6.0 mmol), and 1-hydroxybenzotriazole (HOBT, 6.0 mmol) were added. The mixture was stirred at room temperature (20-25 C) for 30 min. Then, ethyl 2-aminothiazole-4-carboxylate (6.0 mmol) and 4-dimethylaminopyridine (DMAP, 1.5 mmol) were added to the solution. The reaction was carried out at room temperature (20-25 C) for 24 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The solvent was dried and removed. The obtained solid was purified using column chro- matography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a . The method for synthesizing 2b -2f was the same as that for 2a.Ethyl 2-(4-sulfamoylbenzamido)thiazole-5-carboxylate ( 2a ) . white powder (yield 83.5%), m. p . > 300.0 C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | Stage #1: 4-(aminosulfonyl)-benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20 - 25℃; for 0.5h; Stage #2: ethyl 4-phenyl-2-aminothiazole-5-carboxylate With dmap In N,N-dimethyl-formamide at 20 - 25℃; for 24h; | 2.1.2. General procedure for the synthesis of 2a-e General procedure: To a solution of N,N-dimethylformamide (DMF, 5 mL), 4-carboxy-benzenesul- phonamide (5.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl, 6.0 mmol), and 1-hydroxybenzotriazole (HOBT, 6.0 mmol) were added. The mixture was stirred at room temperature (20-25 °C) for 30 min. Then, ethyl 2-aminothiazole-4-carboxylate (6.0 mmol) and 4-dimethylaminopyridine (DMAP, 1.5 mmol) were added to the solution. The reaction was carried out at room temperature (20-25 °C) for 24 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The solvent was dried and removed. The obtained solid was purified using column chro- matography (dichloromethane/methanol, 60:1-30:1) to recover compound 2a . The method for synthesizing 2b -2f was the same as that for 2a.Ethyl 2-(4-sulfamoylbenzamido)thiazole-5-carboxylate ( 2a ) . white powder (yield 83.5%), m. p . > 300.0 °C; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N,N-dimethyl acetamide In dichloromethane at 20℃; for 6h; |
Tags: 138-41-0 synthesis path| 138-41-0 SDS| 138-41-0 COA| 138-41-0 purity| 138-41-0 application| 138-41-0 NMR| 138-41-0 COA| 138-41-0 structure
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H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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