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INTERMEDIATE B6 tert-Butyl 4-(bromoacetyl)piperidine-l-carboxylate To a cooled (-78 0C) suspension of tert-butyi 4-acetylpiperidine-l-carboxylate (Intermediate B5; 2.87 g, 12.6 mmol) in THF (30 mL) was added 1 M lithium bis(trimethylsilyl)amide in THF (13.3 mL) over 20 min. The mixture was stirred for 1 h before the addition of trimethylsilyl chloride (1.74 mL, 13.7 mmol). After stirring at 0 0C for 30 min, the solution was cooled to -78 0C and bromine (0.645 mL, 12.6 mmol) was added. The mixture was allowed to reach r.t. and then poured into a solution of 10percent Na2S2O3 (20 mL) and saturated NH4Cl (20 mL). Extraction with EtOAc (2 x 80 mL) gave the title compound. Yield 3.69 g (96percent).
To a cooled (-78 °C) solution of 2.0 M LDA (in HEPTANE/THF/BENZENE, 13.7 mL, 27.3 mmol) in 100 mL THF was added dropwise over 40 min a solution of the methyl ketone prepared as described in Step B (5.17 g, 22.8 mmol) in 40 mL THF. After an additional 25 min, chlorotrimethylsilane (5.79 ML, 45.6 mmol) was added dropwise over 10 minutes. After stirring the for 1 h, the reaction mixture was poured into 300 mL of saturated NAHC03 solution and the resulting mixture was extracted twice with 200 mL of ether. The combined ethereal layers were washed with brine, dried over anhydrous MGS04, filtered, and concentrated to give 7.35 g of TMS-enol ether, which was then redissolved in 120 ML THF, cooled to 0 °C, and treated with sodium bicarbonate (2.87 g, 34.2 mmol), followed by N-BROMOSUCCINIMIDE (4.06 g, 22.8 mmol). The reaction mixture was warmed to rt and stirred for 1 h and 10 min, at which point, it was poured into 200 ML of saturated NAHC03 solution. The resulting mixture was extracted twice with 200 mL of ether and the combined ethereal layers were washed with saturated NAHC03 solution and brine, dried over anhydrous MGS04, filtered, and concentrated to give 7.62 g of crude product which was used without further purification.
Intermediate F: Preparation of tert-butyl 4- 2-bromoacetyl)piperidine-l-carboxylate To a solution of tert-butyl 4-acetylpiperidine-l-carboxylate (2.0 g, 8.8 mmol) in THF (50 mL) was added LHMDS (10.5 mL, 10.5 mmol) at -78 °C. The reaction was stirred at that temperature for 1 h. Then trimethyl chlorosilane (1.45 mL, 11.4 mmol) was added. The mixture was warmed to 0 °C and stirred at that room temperature for 30 min, then cooled to -78 °C again. Br2 (0.45 mL, 8.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred at that room temperature for 30 min. Saturated Na2S03 aqueous solution (30 mL) was added to the reaction vessel and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The resulting oil (3.2 g) was directly used for the next step without further purification. LCMS [M+H]+ =306.1.
With N-Bromosuccinimide; n-butyllithium; triethylamine; diisopropylamine; In tetrahydrofuran; hexane; methyloxirane;
Step A 4-Bromoacetyl-1-t-butoxycarbonyl-piperidine To a freshly prepared solution of LDA (from diisopropylamine (0.61 g, 6.0 mmol) and n-BuLi (2.2 ml, 2.5 M soln. in hexane) in 10 ml THF at -78° C. was added a solution of 4-acetyl-1-t-butoxycarbonyl-piperidine (1.0 g, 4.7 mmol) in 2.0 ml THF and the resultant mixture was stirred for 20 min. A mixture of TMSCl and triethylamine (1.37 ml, 10.8 mmol and 2.16 ml, 15.5 mmol) was added and the reaction mixture was gradually warmed to RT and stirred for an additional 1 hr. All the volatiles were removed and the crude silyl enolether was dissolved in 10 mL of THF and the mixture was cooled to 0° C. To this mixture was added in succession propylene oxide (1.0 ml) and NBS (1.0 g) and the mixture was stirred for 15 min, quenched with saturated NaHCO3 solution followed by extraction with CH2Cl2. The CH2Cl2 layer was washed with brine, dried, evaporated and purified by silica column chromatography. Elution with methylene chloride and ether (19:1) gave the title compound (1.11 g) as an yellow solid. 1H-NMR (500MHz, CDCl3): delta 4.16 (s, 2H), 4.12 (m, 2H), 2.79-2.84 (m, 3H), 1.5-2. (m, 4H), 1.47 (s, 9H).
With sodium tetrahydroborate; In ethanol; at 20℃; for 1h;
To a solution of 0.400 g (1.76 mmol) of 4-acetyl-piperidine-l-carboxylic acid ie/ -butyl ester in ethanol (3 mL) is added 0.134 g (3.52 mmol) of sodium borohydride. The mixture is stirred at room temperature for 1 hour then a saturated aqueous solution of ammonium chloride is added to consume excess reactants. The mixture is washed with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.390 g (96.6%) of 4-(l-hydroxy-ethyl)- piperidine-l-carboxylic acid ieri-butyl ester as a colorless oil.
Step 3: tert-butyl 4-(l-hydroxyethyl)piperidine-l-carboxylate <n="35"/>tert-Butyl 4-acetylpiperidine-l-carboxylate from the previous step was dissolved in 50 ml methanol. NaBH4 (2.01g, 53 mmol) was added in batches at 0 0C. The resulting reaction mixture was stirred at 0 0C for 30 minutes. The volatiles were removed under vacuum. The residue was partitioned between 150 ml 10% KOH solution and 200 ml ether. The organic layers were washed with 100 ml brine, dried over sodium sulfate and concentrated to give 22.5 g colorless oil, which was azotropically dried by addition of 50 ml toluene and reconcentration under vacuum. This material was used for next step without further purification.1H-NMR (CDCl3): 54.17 (b, 2H), 3.62 (m, IH), 2.69 (b, 2H), 1.85 (m, IH), 1.6 (m, IH), 1.48 (s, 9H), 1.46 (m, IH), 1.24 (m, HH), 1.22 (d, J = 6.2 Hz, 3H).
655 g
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 0.5h;
Compound 6 (652 g, 2.87 mol) was dissolved in methanol (1.5 L)Sodium borohydride (108.6 g, 2.87 mol) was added portionwise under ice-cooling and the reaction system temperature was maintained at 0-5 C,And the mixture was stirred at room temperature for 0.5 hour.After the reaction system was concentrated,Water (3 L)And methyl tert-butyl ether (3 L)The aqueous phase was treated with methyl t-butyl ether (1.5 L x 3)The organic phases were combined,Brine washing,Dried over sodium sulfate,And concentrated by filtration to obtain Compound 7 (655 g) as a colorless oil,Without further purification,Directly for the next reaction.
380 mg
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1.66667h;
To a stirred solution of tert-butyl 4-acetylpiperidine-l-carboxylate (390 mg, 1.715mmol, 1.0 equiv.) in MeOH (7 mL) was added NaBEL (97 mg, 2.57 mmol, 1.5 equiv.) portion wise at 0 C and stirred for 10 minutes. The reaction mixture was allowed to stir for 1 hour 30 min at RT. Product formation was confirmed by TLC and LCMS. After completion of reaction, reaction mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). Combined organic extracts were washed with water (2 x 50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to obtain tert-butyl 4-(l -hydroxy ethyl) piperidine-l-carboxylate as colorless liquid (380 mg).
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