1-(4-hydroxypiperidin-1-yl)ethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 1-(4-hydroxy-piperidin-1-yl)-ethanone in analogy to Example 9c): MS (ISP): 521.2 and 523.2 (M+H)+; MS (ISN): 519.1 and 521.2 (M−H)−.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-acetyl-4-hydroxypiperidine (30.5 g.) in dimethylformamide (200 ml.) is added dropwise to a stirred suspension of sodium hydride (11.26 g., 50% dispersion in mineral oil) in dimethylformamide (300 ml.) under an atmosphere of nitrogen. The reaction temperature is kept below 30° C. by external cooling and, after the addition is complete, stirring is continued for a further 11/4 hours. A solution of 1-bromo-3-methoxypropane (35.2 g.) in dimethylformamide (100 ml.) is then added dropwise with external cooling, and the resulting clear solution is stirred at room temperature overnight. The reaction mixture is then evaporated in vacuo, the residue partitioned between water and chloroform, the organic extracts dried (Na2SO4) and evaporated to leave a crude residue. The above aqueous phase is saturated with sodium chloride, further extracted with chloroform, and the organic phase is dried (Na2SO4), and evaporated to leave a further residue. This residue is combined with the original residue and heated on a steam bath overnight with hydrochloric acid (243 ml., 2N). The reaction mixture is extracted with chloroform to remove the residual mineral oil, the aqueous phase concentrated, basified with sodium hydroxide (pH 12), then reextracted with chloroform. The organic extracts are washed with brine, dried (Na2SO4) and evaporated to afford the desired product. is kept below 30° C. by external cooling after the addition 4 hours the resulting clear solution is stirred at room temperature overnight The reaction mixture is then evaporated in vacuo the residue partitioned between water and chloroform the organic extracts dried (Na2SO4) evaporated to leave a crude residue further extracted with chloroform the organic phase is dried (Na2SO4) evaporated to leave a further residue The reaction mixture is extracted with chloroform to remove the residual mineral oil the aqueous phase concentrated The organic extracts are washed with brine dried (Na2SO4) evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-acetyl-4-hydroxypiperidine (100 g.) in dimethylformamide (250 ml.) was added dropwise to sodium hydride (38 g., 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours then allyl bromide (93 g.) was added slowly whilst maintaining the reaction temperature at 25° C. by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml.) and ether (500 ml.), filtered, and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypiperidine (108.8 g.), B.P. 128° C./2 mm, identified spectroscopically. The mixture was then stirred at room temperature overnight filtered evaporated in vacuo Distillation of the residue

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylazodicarboxylate (40% in toluene, 5.7 g, 11.3 mmol) was added to a solution of (2S)-2-(4-hydroxyphenyl)-4-benzylmorpholine (2.0 g, 7.43 mmol), triphenylphosphine (3.0 g, 11.4 mmol) and 1-acetyl-4-hydroxypiperidin (1.6 g, 11.2 mmol) in tetrahydrofuran (40 ml) at room temperature and the mixture stirred for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography eluting 10-50% ethyl acetate in hexane to furnish (2S)-2-(4-(1-acetylpiperidin-4-yloxy)phenyl)-4-benzylmorpholine (1.68 g, 57%) as colorless oil. The mixture was partitioned between ethyl acetate and water The organic layer was washed with brine dried over magnesium sulfate concentrated in vacuo The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography eluting 10-50% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Acetyl-4-hydroxypiperidine (9.2 g) was dissolved in dimethylformamide (20 ml) and to the solution was added sodium hydride (oily, 60%, 2.6 g). The mixture was stirred at room temperature for 30 minutes, followed by adding dropwise 2-fluoro-5-nitrotoluene (10 g). The mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added water (50 ml) which was extracted with methylene chloride (50 ml×3). The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=20/1 (v/v)) to obtain 1-acetyl-4-(4-nitro-2-methylphenyloxy)piperidine (12.6 g) as yellow crystals, m.p. 139°-141° C. The mixture was stirred at room temperature for 10 minutes was extracted with methylene chloride (50 ml×3) The extract was dried over anhydrous sodium sulfate the solvent was distilled off The residue was purified by silica gel chromatography (developing solvent: methylene chloride/methanol=20/1 (v/v))