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Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 1 h;
A solution of n-butyl lithium (2.5 M in hexanes, 12 mL, 30.1 mmol) was added dropwise to a pre- cooled solution at 0 °C of diisopropylamine (3.05 g, 30.1 mmol) in tetrahydrofuran (25 mL) under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature then cooled to -78 °C. To the reaction mixture was added dropwise a solution of acetonitrile (1.24 g, 30.2 mmol) in tetrahydrofuran at -78 °C. The mixture was stirred for 1 h at -78 °C then a solution of tert-butyl 4-oxopiperidine-l-carboxylate (3.0 g, 15.1 mmol) in tetrahydrofuran (12 mL) was added. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched by ammonium chloride (aq . 100 mL), extracted with ethyl acetate, and the organic wash was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-20percent ethyl acetate in petroleum ether) to afford the title compound (1.5 g, 41 percent) as a white solid. LCMS (ESI): [M+H]+ = 241.
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1.16667 h; Stage #2: at 20℃; for 2 h;
To an oven-dried flask equipped with a stirring bar and rubber septum was added anhydrous THF (250 mL). Diisopropylamine (7.0 mL, 50.2 mmole) was added and the solution cooled to-78 °C. To the cooled solution was added n-butyllithium (1.6 M in hexanes, 31 mL, 50.2 MMOLE) over 10 minutes. The reaction mixture was stirred for 60 min and N-BOC-4-PIPERIDONE (10.0 g, 50.2 mmole, in 10 mL of anhydrous THF) BROMOACETONITRILE (4.2 mL, 60.2 mmole) and HMPA (20 mL) was added and the mixture stirred for an additional 2 h at RT. The reaction mixture was quenched with brine and concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with sat. NAHCO3 (2 x 200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to obtain the title compound (7.0 g, 58percent) as a yellow oil : H NMR (400 MHz, CDCl3) 8 3.90 Hz (bs, 2H), 3.16 Hz (m, 2H), 2.55 Hz (s, 2H), 1.74 Hz (m, 2H), 1.50 (m, 2H), and 1.47 (s, 9H). LC-MS (ES) M/E 241.2 (M + H).
To an oven-dried flask equipped with a stirring bar and rubber septum was added anhydrous THF (250 mL). Diisopropylamine (7.0 mL, 50.2 mmole) was added and the solution cooled to-78 C. To the cooled solution was added n-butyllithium (1.6 M in hexanes, 31 mL, 50.2 MMOLE) over 10 minutes. The reaction mixture was stirred for 60 min and N-BOC-4-PIPERIDONE (10.0 g, 50.2 mmole, in 10 mL of anhydrous THF) BROMOACETONITRILE (4.2 mL, 60.2 mmole) and HMPA (20 mL) was added and the mixture stirred for an additional 2 h at RT. The reaction mixture was quenched with brine and concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with sat. NAHCO3 (2 x 200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to obtain the title compound (7.0 g, 58%) as a yellow oil : H NMR (400 MHz, CDCl3) 8 3.90 Hz (bs, 2H), 3.16 Hz (m, 2H), 2.55 Hz (s, 2H), 1.74 Hz (m, 2H), 1.50 (m, 2H), and 1.47 (s, 9H). LC-MS (ES) M/E 241.2 (M + H).
Lithium diisopropylamide (2M, 50 mL, 100.0 mmol) was added to 150 mL of tetrahydrofuran, and acetonitrile (4.10 g, 100.0 mmol) was added under nitrogen protection at -78 C, and stirred at -78 C for 1 hour.Subsequently, N-Boc-4-piperidone (10.0 g, 50.0 mmol) was dissolved in 50 mL of tetrahydrofuran and added dropwise to the reaction system.After the dropwise addition was completed, the temperature was slowly raised to room temperature and the reaction was maintained for 1 hour.After the reaction was completed, it was quenched with an appropriate amount of a saturated ammonium chloride aqueous solution, 150 mL of water was added, and extraction was performed with 600 mL of ethyl acetate three times.The organic phases were combined, washed with 300 mL of saturated brine, and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated under reduced pressure,Silica gel column chromatography gave the compound N-Boc-4-cyanomethyl-4-hydroxypiperidine (6.2 g, yield 52%).
41%
A solution of n-butyl lithium (2.5 M in hexanes, 12 mL, 30.1 mmol) was added dropwise to a pre- cooled solution at 0 C of diisopropylamine (3.05 g, 30.1 mmol) in tetrahydrofuran (25 mL) under nitrogen atmosphere. The resulting mixture was stirred for 0.5 h at room temperature then cooled to -78 C. To the reaction mixture was added dropwise a solution of acetonitrile (1.24 g, 30.2 mmol) in tetrahydrofuran at -78 C. The mixture was stirred for 1 h at -78 C then a solution of tert-butyl 4-oxopiperidine-l-carboxylate (3.0 g, 15.1 mmol) in tetrahydrofuran (12 mL) was added. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched by ammonium chloride (aq . 100 mL), extracted with ethyl acetate, and the organic wash was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-20% ethyl acetate in petroleum ether) to afford the title compound (1.5 g, 41 %) as a white solid. LCMS (ESI): [M+H]+ = 241.
A flame-dried round bottom flask was cooled down to RT under argon. A solution of 1 M LiHMDS in THF (1.51 mL, 3.02 mmol, 2.0 equiv) was introduced into the flask and cooled down to -78 C (acetone/dry ice bath). Dry MeCN (157 muL, 3.02 mmol, 2.0 equiv) in anhydrous THF (5 mL) was then added dropwise under argon, and the reaction mixture was stirred for 45 minutes at -78 C. At this point, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (300 mg, 1.51 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise, and the reaction mixture was stirred at -78 C for 1 h. The reaction mixture was quenched with an aqueous saturated solution of ammonium chloride and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford tert-butyl 4-(cyanomethyl)- 4-hydroxypiperidine-1-carboxylate which was used as such in the next step.
A flame-dried round bottom flask was cooled down to RT under argon. A solution of 1 M LiHMDS in THF (1.51 mL, 3.02 mmol, 2.0 equiv) was introduced into the flask and cooled down to -78 C. (acetone/dry ice bath). Dry MeCN (157 muL, 3.02 mmol, 2.0 equiv) in anhydrous THF (5 mL) was then added dropwise under argon, and the reaction mixture was stirred for 45 minutes at -78 C. At this point, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (300 mg, 1.51 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise, and the reaction mixture was stirred at -78 C. for 1 h. The reaction mixture was quenched with an aqueous saturated solution of ammonium chloride and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate which was used as such in the next step.
Acetonitrile (2.06 g, 50.18 mmol) was added to tetrahydrofuran (30.00 mL); added dropwise with n-butyl lithium (2.5 M, 20.07 mL) at -78 C and under nitrogen protection,and stirred at -78 C for 1 hour. 4-oxoperidine-1-formic acid tert-butyl ester (5.00g, 25.09 mmol) was added to the reaction solution under nitrogen protection at -78-25 C, and the reaction mixture was stirred at -78-25 C for 9 hours. TLC showed that new products appeared but the raw materials were not completely consumed. The reaction solution was concentrated, added with ethyl acetate (10 mL) and water (20 mL), and then extracted with ethyl acetate (20 mL) three times. The combined organic phases were dried over anhydrous sodium sulfate (5 g), concentrated, separated and purified by column chromatography (PE: EA = 5:1 to 2:1) to give compound 11A. 1H NMR (400MHz, deuterated chloroform) delta = 3.91 (br s, 2H), 3.15 (br t, J=11.6 Hz, 2H), 2.54 (s, 2H), 1.77 - 1.70 (m, 2H), 1.67 - 1.60 (m, 2H), 1.46 (s, 9H).
tert-butyl 4-(cyanomethyl)-4-methoxypiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With sodium hydride; at 0 - 20℃; for 2h;
Sodium hydride (100 mg, 2.5 mmol) was added to a precooled solution at 0 C of tert-butyl 4- (cyanomethyl)-4-hydroxypiperidine-l -carboxylate (400 mg, 1.66 mmol), iodomethane (470 mg, 3.33 mmol) in NN-dimethylformamide (5 mL). The resulting mixture was stirred for 2 h at room temperature, and quenched by water (30 mL), extracted with ethyl acetate (3x), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (solvent gradient: 0-25% ethyl acetate in petroleum ether) to afford the title compound (350 mg, 83 %) as a colorless oil. LCMS (ESI): [M+H]+ = 255.
2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 120h;
tert-Butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (226 mg, 0.94 mmol, 1 equiv) was dissolved in dioxane (2.5 mL). 4 M HCl in dioxane (1.41 mL, 1.88 mmol, 6 equiv) was added, and the solution was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure. The titled compound was used as such without any further purification.
2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane; at 20℃; for 120h;
tert-Butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (226 mg, 0.94 mmol, 1 equiv) was dissolved in dioxane (2.5 mL). 4 M HCl in dioxane (1.41 mL, 1.88 mmol, 6 equiv) was added, and the solution was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure. The titled compound was used as such without any further purification.
2-oxo-1-oxa-3,9-diazaspiro[5.5]undecane-9-formic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogen; In methanol; at 40℃; under 2585.81 Torr; for 10h;
4-(Cyanomethyl)-4-hydroxy-piperidine-1- formic acid tert-butyl ester (800.00 mg, 3.33 mmol) was dissolved in methanol (20 mL), added with Boc2O (2.91 g, 13.32 mmol)and then added with Raney nickel (0.1 g). The reaction system was vacuumed, displaced with nitrogen gas three times and with hydrogen gas three times. The reaction mixture was stirred under hydrogen atmosphere (50 psi) at 40 C for 10 hours. TLC showed that new products appeared and the raw materials were completely consumed. The reaction solution was filtered with methanol (20 mL), concentrated, separated and purified by column chromatography (PE: EA = 5:1 to 2:1) to give compound 11B. 1H NMR (400MHz, deuterated chloroform) delta = 4.92 (br s, 1H), 3.79 (br s, 2H), 3.30 (q, J=6.4 Hz, 2H), 3.18 (br t, J=11.4 Hz, 2H), 1.65 - 1.57 (m, 4H), 1.52 (br dd, J=4.4, 11.4 Hz, 2H), 1.44 (s, 9H).
4-(cyanomethyl)-4-hydroxypiperidine trifluoroacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
In dichloromethane; at 0 - 20℃; for 5h;
The compound <strong>[774609-73-3]N-Boc-4-cyanomethyl-4-hydroxypiperidine</strong> (6.2 g, 25.8 mmol) was dissolved in 60 mL of dichloromethane, and 15 mL of trifluoroacetic acid was added at 0 C. After completion of the dropwise addition, the reaction was stirred at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 4- (cyanomethyl) -4-hydroxypiperidine trifluoroacetate (5.12 g, yield 97%).