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Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3 h; Stage #2: at -78℃; for 2 h;
The synthesis of the intermediate I-11.1 is described in EP2072519 A1, p. 36. At −78° C., a hexane solution (94 mL, 150.81 mmol) of 1.6 M n-butyllithium is added dropwise to a THF solution (110 mL) of 2,2,6,6-tetramethylpiperidine (16.14 g, 113.10 mmol) and obtained solution is stirred for 1 hour. Afterwards a THF solution (50 mL) of 6-chloronicotinic acid (6.0 g, 37.70 mmol) is added dropwise over 1 hour and the reaction mixture is stirred for 2 hours. A THF solution (50 mL) of 1-benzyl-4-piperidone (21.6 g, 113.10 mmol) is added dropwise at −78° C. After stirred for 2 hours, water (70 mL) is added, and the reaction mixture is warmed to room temperature. The aqueous layer is separated, and the organic layer is extracted with aqueous 1 N sodium hydroxide solution (2×75 mL). The obtained aqueous layer is extracted with diethyl ether (100 mL), and the aqueous layer is acidified (pH-1) by adding concentrated hydrochloric acid. After stirring for 1 hour, the precipitate is filtered off, washed with water, and dissolved in ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The residue is washed with diethyl ether. Yield 66percent, m/z 329 [M+H]+, rt 0.72 min, LC-MS Method Z012_S04.
Stage #1: 6-Chloro-3-pyridinecarboxylic acid With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3h;
Stage #2: 1-phenylmethyl-4-piperidone In tetrahydrofuran; hexane at -78℃; for 2h;
1 Step 1: Synthesis of Intermediate I-11.1
The synthesis of the intermediate I-11.1 is described in EP2072519 A1, p. 36. At -78° C., a hexane solution (94 mL, 150.81 mmol) of 1.6 M n-butyllithium is added dropwise to a THF solution (110 mL) of 2,2,6,6-tetramethylpiperidine (16.14 g, 113.10 mmol) and obtained solution is stirred for 1 hour. Afterwards a THF solution (50 mL) of 6-chloronicotinic acid (6.0 g, 37.70 mmol) is added dropwise over 1 hour and the reaction mixture is stirred for 2 hours. A THF solution (50 mL) of 1-benzyl-4-piperidone (21.6 g, 113.10 mmol) is added dropwise at -78° C. After stirred for 2 hours, water (70 mL) is added, and the reaction mixture is warmed to room temperature. The aqueous layer is separated, and the organic layer is extracted with aqueous 1 N sodium hydroxide solution (2×75 mL). The obtained aqueous layer is extracted with diethyl ether (100 mL), and the aqueous layer is acidified (pH-1) by adding concentrated hydrochloric acid. After stirring for 1 hour, the precipitate is filtered off, washed with water, and dissolved in ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The residue is washed with diethyl ether. Yield 66%, m/z 329 [M+H]+, rt 0.72 min, LC-MS Method Z012_S04.
Stage #1: 6-Chloro-3-pyridinecarboxylic acid With n-butyllithium; 2,2,6,6-tetramethylpiperidine In tetrahydrofuran; hexane at -78℃; for 3h;
Stage #2: 1-phenylmethyl-4-piperidone In tetrahydrofuran; hexane at -78℃; for 2h;
4-1 Production of 1'-benzyl-6-chloro-3H-spiro[furo[3,4-c]pyridine-1,4'-piperidin]-3-one
Reference Example 4-1 Production of 1'-benzyl-6-chloro-3H-spiro[furo[3,4-c]pyridine-1,4'-piperidin]-3-one At -78°C, a hexane solution (500 mL) of 2.55 M n-butyllithium was dropwise added to a THF solution (900 mL) of 2,2,6,6-tetramethylpiperazine (162 mL). After stirred for 1 hour, a THF solution (450 mL) of 6-chloronicotinic acid (50.2 g) was dropwise added to it at -78°C over 1 hour. After further stirred for 2 hours, a THF solution (150 mL) of 1-benzyl-4-piperidone (177 mL) was dropwise added to it at -78°C. After stirred for 2 hours, water (500 mL) was added to it, and heated up to room temperature. The aqueous layer was separated, and the organic layer was extracted with aqueous 1 N sodium hydroxide solution. The obtained aqueous layer was extracted with diethyl ether, and the aqueous layer was made acidic (pH~1) by adding concentrated hydrochloric acid. After stirred for 1 hour, the precipitated red brown solid was collected through filtration, washed with water, and dissolved in ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and dried with anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the residue was washed with diethyl ether to obtain the entitled compound (60.1 g) as a pale yellow solid. ESI-MS Found: m/z 329[M+H]+
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