| 90% |
With triethylamine In dichloromethane at 0℃; for 0.5h; |
|
| 83% |
With triethylamine In dichloromethane at 0℃; for 2h; |
|
| 73% |
In N,N-dimethyl-formamide Inert atmosphere; |
|
|
With 1,4-dioxane |
|
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With acetone |
|
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With triethylamine In chloroform at 1 - 20℃; for 3h; |
13 1-Tosylpiperazine:
According to scheme 1, step 1: Commercially available anhydrous piperazine (13.4 mmol) was dissolved in chloroform. To this solution, Triethylamine (13.4 mmol) was added, keeping the temperature 1 °C. Tosyl chloride (6.7 mmol) dissolved in chloroform (10 mL)was added slowly within two hours with stirring at 1 °C keeping the reaction condition dry. The reaction mixture was further stirred for one hour at room temperature. The reaction was over and solvent was evaporated under reduced pressure to get crude. The desired product 1-acetylpiperazine was obtained by column chromatography using chloroform- methanol as eluent. The compound 1 -tosylpiperazine was obtained as colourless oil. |
| 2.1 g |
With triethylamine In dichloromethane at 0 - 20℃; for 2.16667h; Inert atmosphere; |
59.d Step d) Synthesis of 4-tolylsulfonylpiperazine (31, R2 =Me)
[0142] To a stinedsolution of p-tolylsulfonyl chloride 31 (1.90g,10.0mmol)in methylene chloride (50 mL) at 0 °C was added piperazine (0.95 g, 11.0 mmol) and triethyl amine (1.1 g, 11.0mmol),.Themixturewasstined at 0 °C for 10 min and at room temperatureunder argon atmosphere for 2 h. After the completion of reaction, as monitored by TLC, mixture was diluted with water. The aqueouslayer was extractedwith methylene chloride, and the combined organiclayer was dried over MgS04. The solvent removedunder reduced pressureto give 2.1 g of 4-tolylsulfonylpiperazine as a white solid,used in next step without further purification.1H NMR (400 MHz, CDCh) 8 7.65 (d, 2H,J = 8.0 Hz); 7.43 (d, 2H,J = 8.0 Hz); 3.07 (m, 4H); 2.60-2.51 (m, 4H); 2.45 (s, 3H) |
|
With triethylamine In dichloromethane at 0℃; |
|
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With triethylamine In dichloromethane at 0℃; for 0.5h; |
|
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In dichloromethane at 0 - 10℃; for 0.5h; |
General procedure for the synthesis of 1-((4-substituted-phenyl)sulfonyl)piperazine (2a-j)
4-substituted aryl sulfonyl chloride (10 mmol, 1 equiv) was added in one portion to a solution of piperazine (60 mmol, 6 equiv) in CH2Cl2 (10 mL) at 0 °C. The reaction mixture was stirred at 0-10 °C for 30 min. Dilute with more amount of CH2Cl2 (20 mL), and removed the excess piperazine by the addition of saturated NaHCO3 (aq) (50 mL). Separate the organic layer washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude product was used directly or purified by crystal-lization using methanol to yield pure 1-((4-substituted-phenyl)sulfonyl)piperazine. |
|
In dichloromethane at 0℃; for 0.5h; |
|
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With triethylamine In dichloromethane at 0 - 20℃; for 4h; |
General procedure for preparation of sulfonamide EA derivatives
General procedure: The synthesis of the key intermediates compounds 2(a-i), 3(a-i) as well as 4(a-i) were achieved following the previously reported procedures. Ethylene diamine sulfonyl 2(a-i) and piperaziene sulfonyl 3(a-i) were prepared according to references 48-53, while, the 4-aminopiperidine-1-sulfonyl 4(a-i) were prepared according to reference 55. To a solution of 1,2-diaminoethane or piperazine (5.00 mmol) in dichloromethane (10 mL), triethylamine (1.51 g, 2 mL, 15.00 mmol) were added with stirring. The mixture was cooled to 0°C and a solution of the appropriate sulfonyl chloride (2.50 mmol) in dichloromethane (2 mL) was added dropwise. The mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with 20 mL saturated aqueous solution of NaHCO3 and the organic layer was extracted with ethyl acetate (3x 20mL), dried over magnesium sulfate and concentrated under reduced pressure to give the desired intermediates 2(a-i) and 3(a-i). For the synthesis of intermediates 4(a-i), a solution of 4-(N-Boc) aminopiperidine (0.10 g, 0.50 mmol) in dichloromethane (10 mL) and triethylamine (0.15 g, 0.2 mL, 1.50 mmol) was added at 0°C. Then, a solution of sulfonyl chloride (0.50 mmol) in dichloromethane (2 mL) was added in small portions. The reaction was stirred for 4 hours, then, the reaction mixture was quenched with 20 mL of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (3x 20mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was dissolved in solution (5 mL) of HCl in dioxane at room temperature for 1h. All solvents were removed under reduced pressure, which gave the corresponding crude salt. The intermediates 2(a-i), 3(a-i) and 4(a-i) were used in the next step directly without further purification. To a solution of EDC (0.62 g, 0.39 mmol), HOBt (0.60 g, 0.39 mmol) and ethacrynic acid (0.10 g, 0.33 mmol) in dry DMF (5 mL) at 0°C, crude amine (2(a-i) or 3(a-i)) was added. In the case of the intermediates 4(a-i), 0.30 mmol of triethylamine was used and the solution was stirred at room temperature. The reaction was monitored by TLC until all the amine was consumed. The mixture was diluted with ethyl acetate (100 mL) and extracted (3x 20mL). The organic phase was washed with water (2 × 50 mL) and brine (3 × 50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography. |
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In acetonitrile Schlenk technique; Inert atmosphere; |
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