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9). Synthesis of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-piperidine-1- carboxylic acid tert-butyl ester; A solution of 2-ethyl-4-oxo-piperidine-1 -carboxylic acid tert-butyl ester (1 g, 4.4 mmol), 3,5-bis(trifluoromethyl)benzylamine (1.4g, 4.84 mmol), titanium isopropoxide (catalytic, 3 drops) in 7.5 mL of methanol and 7.5 mL of dichloroethane are stirred with NaBH4 (183 mg, 4.84 mmol) at room temperature for 6 hours under nitrogen atmosphere. The reaction is quenched by addition of saturated aqueous ammonium chloride and filtered, and the cake is washed with ethyl acetate. The mixture is extracted with ethyl acetate (2 X 5OmL). The organic layer is washed with brine, dried over anhydrous sodium sulfate, and then concentration give 1.7 g (76%) of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl- piperidine-1 -carboxylic acid tert-butyl ester; ESI-MS m/z: 455 [M+1]+, Retention time 1.75 min (condition A).
4-(4-bromo-phenylamino)-2-ethyl-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12). Synthesis of 4-(4-bromo-phenylamino)-2-ethyl-piperidine-1-carboxylic acid tert- butyl ester; A mixture of <strong>[324769-07-5]2-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester</strong> (114 mg, 0.5 mmol), p-bromoaniline (95 mg, 0.55 mmol), sodium triacetoxyborohydride (111 mg, 0.525 mmol) and acetic acid (34 mu L, 0.6 mmol) in 1 ,2-dichloroethane (0.8 mL) is stirred at room temperature for 5 hours. To the mixture is added sodium triacetoxyborohydride (111 mg, 0.525 mmol). Then, the mixture is stirred at room temperature for 20 hours. The mixture is basified with aq. 1N sodium hydroxide solution until pH 10, then extracted with 1 ,2- dichloroethane. The organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/4) to give 93 rng of 4-(4-brornupsilon-muiieiiotayiamino)-2-ethyi-piperidine-1-carboxylic acid tert-butyl ester; ESI- MS m/z: 383 [M+1]+, Retention time 2.18 min (condition A).
4-cyclohexylamino-2-ethyl-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13). Synthesis of 4-cyclohexylamino-2-ethyl-piperidine-1-carboxylic acid tert-butyl ester; A mixture of <strong>[324769-07-5]2-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester</strong> (114 mg, 0.5 mmol), cyclohexylamine (63 mu L, 0.55 mmol), sodium triacetoxyborohydride (111 mg, 0.525 mmol) and acetic acid (34 mu L, 0.6 mmol) in 1 ,2-dichloroethane (0.8 ml.) is stirred at room temperature for 5 hours. To the mixture is added sodium triacetoxyborohydride (111 mg, 0.525 mmol). Then, the mixture is stirred at room temperature for 20 hours. The mixture is basified with aq. 1N sodium hydroxide solution until pH 10, then extracted with 1 ,2- dichloroethane. The organic layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1/10) to give 124 mg of 4-cyclohexylamino-2-ethyl-piperidine-1-carboxylic acid tert-butyl ester; ESI- MS m/z: 311 [M+1] Retention time 1.63 min (condition A).
Method 2 2-Methylpropan-2-yl 4-[4-amino-3-(propan-2-yloxy)phenyl]-2-ethylpiperidine-1-carboxylate 0.89 ml of diisopropylamine is introduced into 5 ml of THF. After cooling to -78 C., 2.45 ml of 2.5 M n-BuLi in hexane are added and the mixture is stirred for 15 minutes at -78 C. A solution of 1 g of <strong>[324769-07-5]1-boc-2-ethylpiperidin-4-one</strong> in solution in 10 ml of THF is added dropwise. The reaction medium is stirred for 15 minutes at -78 C. and then N-phenylbis(trifluoromethanesulfonimide) in solution in 15 ml of THF is added. The reaction medium is brought back to ambient temperature and stirred for 16 hours at this temperature. The mixture is poured into 15 ml of a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 mum), elution being carried out with a dichloromethane/methanol (98/2) mixture. 870 mg of 2-methylpropan-2-yl 6-ethyl-4-[(trifluoromethyl)sulfonyl]oxy}-3.6-dihydropyridine-1(2H)-carboxylate are obtained in the form of a pale yellow oil.
870 mg
0.89 ml of diisopropylamine is introduced into 5 ml of THF. After cooling to -78C, 2.45 ml of 2.5 M n-BuLi in hexane are added and the mixture is stirred for 15 minutes at -78 C. A solution of 1 g of 1 -boc-2-ethylpiperidin-4-one in solution in 10 ml of THF is added dropwise. The reaction medium is stirred for 15 minutes at -78C and then N-phenylbis(trifluoromethanesulfonimide) in solution in 15 ml of THF is added. The reaction medium is brought back to ambient temperature and stirred for 16 hours at this temperature. The mixture is poured into 15 ml of a saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 muetaiota), elution being carried out with a dichloromethane/methanol (98/2) mixture. 870 mg of 2-methylpropan-2-yl 6-ethyl-4-[(trifluoromethyl)sulfonyl]oxy}-3.6- dihydropyridine-1 (2H)-carboxylate are obtained in the form of a pale yellow oil.
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