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3(B) 3-Cyano-piperidine-1-carboxylic acid tert-butyl ester Phosphorus oxychloride (0.64 mL, 6.89 mmol) was added dropwise at 0 C. to a solution of <strong>[91419-49-7]3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester</strong> (1.58 g, 6.89 mmol) in pyridine (15 mL), under nitrogen atmosphere. After stirring overnight at room temperature, ethyl acetate was added and the solution was washed with 10% HCl (2 times). The phases were separated and the organics were dried over sodium sulphate and evaporated to dryness under reduced pressure. The title compound was used for the next step without further purification. Yield: quantitative; LCMS (RT): 4.48 min (Method A); MS (ES+) gave m/z: 211.1.
100%
With phosphorus pentoxide; In pyridine; at 0 - 20℃;
Phosphorus oxychloride (0.64 mL, 6.89 mmol) was added dropwise at 0C to a solution of S-carbamoyl-piperidine-l-carboxylic acid tert-butyl ester (1.58 g, 6.89 mmol) in pyridine (15 mL), under nitrogen atmosphere. After stirring overnight at room temperature, ethyl acetate was added and the solution was washed with 10% HCl (2 times). The phases were separated and the organics were dried over sodium sulphate and evaporated to dryness under reduced pressure. The title compound was used for the next step without further purification. Yield: quantitative; LCMS (RT): 4.48 min (Method A); MS (ES+) gave m/z: 211.1 (MH+).
87%
With triethylamine; trifluoroacetic anhydride; In dichloromethane; at 20℃; for 16h;
Tert-butyl 3-cyanopiperidine-l-carboxylate (3). To a solution of tert-butyl-3- carbamoyl piperidine-l-carboxylate 2 (1.0 g, 4 mmol) in anhydrous dichloromethane (20 mL), triethylamine (3.1 g, 31.0 mmol) was added followed by the dropwise addition of trifluoroaceticanhydride (4.1 g, 20.0 mmol). The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was washed with saturated bicarbonate solution (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3 (800 mg, 87%) as a thick liquid. 1H NMR (400 MHz, CDC13) delta 1.49 (s, 9H), 1.77 (m, 2H), 1.97 (brs, 1H), 2.66 (m, 1H), 3.35-3.84 (brs, 4H),
53%
Step 3. Tert-butyl 3-cyanopiperidine-1-carboxylate; A 250-mL 3-necked round-bottomed flask was charged with a solution of <strong>[91419-49-7]tert-butyl 3-carbamoylpiperidine-1-carboxylate</strong> (5 g, 21.49 mmol, 1.00 equiv, 98%) in pyridine (50 mL). To this solution, POCl3 (5 g, 32.24 mmol, 1.50 equiv, 98%) was added drop wise at 0 C. and allowed to stir at 0 C. for 1 hour. The progress was monitored by TLC (EA:PE=1:1). The pyridine was removed by distillation. The mixture was diluted with H2O (40 mL) and pH was adjusted to 8 by addition of aqueous NaHCO3. Then, the resulting mixture was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The crude was purified by distillation under reduced pressure (30 mm Hg) and the fractions collected at 40 C. to afford tert-butyl 3-cyanopiperidine-1-carboxylate as yellow oil (2.6 g, 53%).
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at -78 - 27℃; for 0.5h;
A solution of tert-butyl 3-cyanopiperidine-1-carboxylate 62 (5.0 g, 23.00 mmol) in Ether (40 mL) was cooled to -78°C followed by drop wise addition of LAH (2.40 M solution in THF, 19.80 ml, 47.0 mmol). The resulting solution was then stirred for 30 mm. at RT. Reaction was monitored by TLC, reaction mixture was quenched with saturated NaOH solution at 0°C & reaction mixture was filtered through sodium sulfate, combined organic extracts were dried over Na2SO4 and concentrated to obtain crude compound (3.50 g, quantitative yield), which was carried forward as such for the next step. MS: 215.17 (M+H).
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