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5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgS04 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1 -Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91 percent; ESI-MS: 279 [M+H]+
89%
With triethylamine In dichloromethane at 20℃; for 1 h;
EXAMPLE 4; Preparation of 4-(2-chloro-6-fluoro-benzoylamino)- 1 H-pyrazole-3 -carboxylic acid ( 1 -methanesulphonyl-piperidin-4-yl)-amide4A. 4-Amino-1H-pyrazole-3-carboxylic acid (l-methanesulphonyl-piperidin-4-yl) amideTo a stirred solution of 4-(N-BOC amino)piperidine (2.5 g, 12.5 mmoles) in dichloromethane (30 ml) was added triethylamine (2.1 ml, 15.0 mmoles), and then EPO <DP n="165"/>dropwise methanesulphonyl chloride (1.06 ml, 13.8 mmoles). The solution formed was stirred at room temperature for one hour. The reaction mixture was partitioned between EtOAc and water. The organic portion was washed with water, 2N HCl, brine, dried (MgSO4) filtered and evaporated in vacuo to give 4-(N-BOC-amino)-l- methanesulphonylpiperidine as a white solid (3.1g, 89percent).
55%
With triethylamine In dichloromethane at 20℃; for 4 h;
General procedure: To a stirred solution of 2 (0.20 g, 1.00 mmol) in anhydrous DCM(5 mL) was added Et3N (0.42 mL, 3.00 mmol) at room temperature.Then 3a–i (3.96 mmol) was added in small portions at room temperature.The reaction was stirred for 4 h at this temperature and then quenched the reaction with saturated aqueous solution ofNaHCO3. The aqueous layer was extracted with ethyl acetate(3 10 mL). The combined organic layers were dried over anhydrousNa2SO4, filtered, and concentrated. Silica gel flash columnchromatography (EtOAc/hexanes = 1:2) of the residue gave 4a–ias the product. Dissolved 4a–i (0.34 g, 0.97 mmol) in 25 mL TFAat room temperature, the reaction was stirred at room temperature for 10 h. Distilled the TFA under vacuum and then diluted with saturated aqueous solution of NaHCO3. The aqueous layer wasextracted with ethyl acetate (3 10 mL). The combined organiclayers were dried over anhydrous Na2SO4, filtered, and concentrated.Silica gel flash column chromatography (EtOAc/hexanes =1:1) of the residue gave 5a–i as the product.
With pyridine In pyridine at 20℃; for 16 h; Cooling with ice
5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgSO4 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1-Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91percent; ESI-MS: 279 [M+H]+
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