1-piperidin-1-ylethanone

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-acetylpiperidine (0.61 ml) under argon, was added phosphorus oxychloride (0.45 ml) at ambient temperature. After stirring for 0.5 h 1,2-dichloroethane (10 ml) was added and the mixture cooled to 0° C. A solution of 2-(2-methoxy-3-phenylsulphonylphenyl)-1H-pyrrole (D25) (1.0 g) in 1,2-dichloroethane (10 ml) was added dropwise over 0.3 h. Stirring was continued at 0° C. for 3 h and at ambient temperature for 18 h. The mixture was cooled to 0° C. and sodium borohydride (1 g) added portionwise over 0.16 h. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C. Water (5 ml) followed by MeOH (5 ml) was added dropwise followed by dilution with more water (50 ml). The mixture was extracted with dichloromethane (3×200 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo. Methanol (10 ml) and concentrated HCl (4.8 ml) were added and the mixture stirred for 4 h. Water (100ml) was added and the solution basified with NaOH (10%) and extracted with dichloromethane (3×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. This material was dissolved in EtOAc and added to a hot solution of oxalic acid (1 equivalent) in EtOAc. Sufficient MeOH was added to dissolve the precipitated solid and the resultant solution cooled to give the title compound (E38) (0.27 g). was added The mixture was cooled to 0° C. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C was added dropwise The mixture was extracted with dichloromethane (3×200 ml) the combined extracts dried (Na2SO4) evaporated in vacuo Methanol (10 ml) and concentrated HCl (4.8 ml) were added the mixture stirred for 4 h Water (100ml) was added extracted with dichloromethane (3×200 ml) Combined extracts were dried (Na2SO4) evaporated in vacuo This material was dissolved in EtOAc to dissolve the precipitated solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-acetylpiperidine (0.61 ml) under argon, was added phosphorus oxychloride (0.45 ml) at ambient temperature. After stirring for 0.5 h 1,2-dichloroethane (10 ml) was added and the mixture cooled to 0° C. A solution of 2-(2-methoxy-3-phenylsulphonylphenyl)-1H-pyrrole (D25) (1.0 g) in 1,2-dichloroethane (10 ml) was added dropwise over 0.3 h. Stirring was continued at 0° C. for 3 h and at ambient temperature for 18 h. The mixture was cooled to 0° C. and sodium borohydride (1 g) added portionwise over 0.16 h. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C. Water (5 ml) followed by MeOH (5 ml) was added dropwise followed by dilution with more water (50 ml). The mixture was extracted with dichloromethane (3×200 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo. Methanol (10 ml) and concentrated HCl (4.8 ml) were added and the mixture stirred for 4 h. Water (100ml) was added and the solution basified with NaOH (10%) and extracted with dichloromethane (3×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. This material was dissolved in EtOAc and added to a hot solution of oxalic acid (1 equivalent) in EtOAc. Sufficient MeOH was added to dissolve the precipitated solid and the resultant solution cooled to give the title compound (E38) (0.27 g). was added The mixture was cooled to 0° C. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C was added dropwise The mixture was extracted with dichloromethane (3×200 ml) the combined extracts dried (Na2SO4) evaporated in vacuo Methanol (10 ml) and concentrated HCl (4.8 ml) were added the mixture stirred for 4 h Water (100ml) was added extracted with dichloromethane (3×200 ml) Combined extracts were dried (Na2SO4) evaporated in vacuo This material was dissolved in EtOAc to dissolve the precipitated solid

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

Procedure: To 1-acetylpiperidine (0.36 ml) under argon was added phosphorous oxychloride (0.26 ml) at room temperature. The mixture was stirred at room temperature for 50 minutes and 1,2-dichloroethane (5 ml) was added. The solution was cooled to 5° C. and 2-(3,5-dibromo-2-isopropoxyphenyl)-1H-pyrrole (D7) (0.52 g) in 1,2-dichloroethane (5 ml) was added in one portion. The mixture was stirred at 5°-10° C. for 20 minutes and was then stirred at room temperature for 22 hrs. The mixture was cooled in an ice bath and sodium borohydride (0.50 g) was added in one portion. After stirring for a further 2 hrs, water (7.2 ml) was added dropwise over 6 minutes. After a further 4 minutes, MeOH (6 ml) was added over 6 minutes. After stirring for a further 10 minutes, the mixture was partitioned between water (100 ml) and dichloromethane (50 ml). The aqueous layer was re-extracted with dichloromethane (2×40 ml) and the combined organic layers were dried over sodium sulphate. The residue was dissolved in MeOH (7 ml), dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs. The mixture was partitioned between dichloromethane (100 ml) and water (60 ml). The aqueous layer was brought to pH 12 with 10% NaOH and was extracted with dichloromethane (2×40 ml). The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was chromatographed on neutral alumina to give the free base of the title compound. This material was dissolved in diethyl ether (100 ml) and was washed with water and was extracted with 0.4M HCl (4×25ml). The combined HCl layers were extracted with dichloromethane (4×50 ml). The ether layer was then diluted with pentane and re-extracted with the HCl layer. The acid layer was extracted with dichloromethane and the combined dichloromethane extracts were dried over sodium sulphate and evaporated in vacuo to give the title compound (E20). The solution was cooled to 5° C. The mixture was stirred at 5°-10° C. for 20 minutes was then stirred at room temperature for 22 hrs The mixture was cooled in an ice bath After stirring for a further 2 hrs After a further 4 minutes After stirring for a further 10 minutes the mixture was partitioned between water (100 ml) and dichloromethane (50 ml) The aqueous layer was re-extracted with dichloromethane (2×40 ml) the combined organic layers were dried over sodium sulphate The residue was dissolved in MeOH (7 ml) dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs The mixture was partitioned between dichloromethane (100 ml) and water (60 ml) was extracted with dichloromethane (2×40 ml) The combined organic layers were dried over sodium sulphate the solvent was removed in vacuo The residue was chromatographed on neutral alumina

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

Procedure: To 1-acetylpiperidine (0.36 ml) under argon was added phosphorous oxychloride (0.26 ml) at room temperature. The mixture was stirred at room temperature for 50 minutes and 1,2-dichloroethane (5 ml) was added. The solution was cooled to 5° C. and 2-(3,5-dibromo-2-isopropoxyphenyl)-1H-pyrrole (D7) (0.52 g) in 1,2-dichloroethane (5 ml) was added in one portion. The mixture was stirred at 5°-10° C. for 20 minutes and was then stirred at room temperature for 22 hrs. The mixture was cooled in an ice bath and sodium borohydride (0.50 g) was added in one portion. After stirring for a further 2 hrs, water (7.2 ml) was added dropwise over 6 minutes. After a further 4 minutes, MeOH (6 ml) was added over 6 minutes. After stirring for a further 10 minutes, the mixture was partitioned between water (100 ml) and dichloromethane (50 ml). The aqueous layer was re-extracted with dichloromethane (2×40 ml) and the combined organic layers were dried over sodium sulphate. The residue was dissolved in MeOH (7 ml), dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs. The mixture was partitioned between dichloromethane (100 ml) and water (60 ml). The aqueous layer was brought to pH 12 with 10% NaOH and was extracted with dichloromethane (2×40 ml). The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was chromatographed on neutral alumina to give the free base of the title compound. This material was dissolved in diethyl ether (100 ml) and was washed with water and was extracted with 0.4M HCl (4×25ml). The combined HCl layers were extracted with dichloromethane (4×50 ml). The ether layer was then diluted with pentane and re-extracted with the HCl layer. The acid layer was extracted with dichloromethane and the combined dichloromethane extracts were dried over sodium sulphate and evaporated in vacuo to give the title compound (E20). The solution was cooled to 5° C. The mixture was stirred at 5°-10° C. for 20 minutes was then stirred at room temperature for 22 hrs The mixture was cooled in an ice bath After stirring for a further 2 hrs After a further 4 minutes After stirring for a further 10 minutes the mixture was partitioned between water (100 ml) and dichloromethane (50 ml) The aqueous layer was re-extracted with dichloromethane (2×40 ml) the combined organic layers were dried over sodium sulphate The residue was dissolved in MeOH (7 ml) dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs The mixture was partitioned between dichloromethane (100 ml) and water (60 ml) was extracted with dichloromethane (2×40 ml) The combined organic layers were dried over sodium sulphate the solvent was removed in vacuo The residue was chromatographed on neutral alumina

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

Procedure: To a stirred -10° C. solution of 1-acetylpiperidine (127 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -40° C. to -50° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and extracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford (R)-ε-hydroxy-α,γ-dioxo-1-piperidineheptanenitrile as an oil. while maintaining the temperature between -40° C. to -50° C. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C. The aqueous layer is extracted with 500 mL of ethyl acetate the aqueous layer is separated extracted with 100 mL of ethyl acetate concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-acetylpiperidine (0.61 ml) under argon, was added phosphorus oxychloride (0.45 ml) at ambient temperature. After stirring for 0.5 h 1,2-dichloroethane (10 ml) was added and the mixture cooled to 0° C. A solution of 2-(2-methoxy-3-phenylsulphonylphenyl)-1H-pyrrole (D25) (1.0 g) in 1,2-dichloroethane (10 ml) was added dropwise over 0.3 h. Stirring was continued at 0° C. for 3 h and at ambient temperature for 18 h. The mixture was cooled to 0° C. and sodium borohydride (1 g) added portionwise over 0.16 h. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C. Water (5 ml) followed by MeOH (5 ml) was added dropwise followed by dilution with more water (50 ml). The mixture was extracted with dichloromethane (3×200 ml) and the combined extracts dried (Na2SO4) and evaporated in vacuo. Methanol (10 ml) and concentrated HCl (4.8 ml) were added and the mixture stirred for 4 h. Water (100ml) was added and the solution basified with NaOH (10%) and extracted with dichloromethane (3×200 ml). Combined extracts were dried (Na2SO4) and evaporated in vacuo. This material was dissolved in EtOAc and added to a hot solution of oxalic acid (1 equivalent) in EtOAc. Sufficient MeOH was added to dissolve the precipitated solid and the resultant solution cooled to give the title compound (E38) (0.27 g). was added The mixture was cooled to 0° C. Stirring was continued at ambient temperature for 2.5 h before the mixture was cooled to 0° C was added dropwise The mixture was extracted with dichloromethane (3×200 ml) the combined extracts dried (Na2SO4) evaporated in vacuo Methanol (10 ml) and concentrated HCl (4.8 ml) were added the mixture stirred for 4 h Water (100ml) was added extracted with dichloromethane (3×200 ml) Combined extracts were dried (Na2SO4) evaporated in vacuo This material was dissolved in EtOAc to dissolve the precipitated solid

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

Procedure: To 1-acetylpiperidine (0.36 ml) under argon was added phosphorous oxychloride (0.26 ml) at room temperature. The mixture was stirred at room temperature for 50 minutes and 1,2-dichloroethane (5 ml) was added. The solution was cooled to 5° C. and 2-(3,5-dibromo-2-isopropoxyphenyl)-1H-pyrrole (D7) (0.52 g) in 1,2-dichloroethane (5 ml) was added in one portion. The mixture was stirred at 5°-10° C. for 20 minutes and was then stirred at room temperature for 22 hrs. The mixture was cooled in an ice bath and sodium borohydride (0.50 g) was added in one portion. After stirring for a further 2 hrs, water (7.2 ml) was added dropwise over 6 minutes. After a further 4 minutes, MeOH (6 ml) was added over 6 minutes. After stirring for a further 10 minutes, the mixture was partitioned between water (100 ml) and dichloromethane (50 ml). The aqueous layer was re-extracted with dichloromethane (2×40 ml) and the combined organic layers were dried over sodium sulphate. The residue was dissolved in MeOH (7 ml), dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs. The mixture was partitioned between dichloromethane (100 ml) and water (60 ml). The aqueous layer was brought to pH 12 with 10% NaOH and was extracted with dichloromethane (2×40 ml). The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was chromatographed on neutral alumina to give the free base of the title compound. This material was dissolved in diethyl ether (100 ml) and was washed with water and was extracted with 0.4M HCl (4×25ml). The combined HCl layers were extracted with dichloromethane (4×50 ml). The ether layer was then diluted with pentane and re-extracted with the HCl layer. The acid layer was extracted with dichloromethane and the combined dichloromethane extracts were dried over sodium sulphate and evaporated in vacuo to give the title compound (E20). The solution was cooled to 5° C. The mixture was stirred at 5°-10° C. for 20 minutes was then stirred at room temperature for 22 hrs The mixture was cooled in an ice bath After stirring for a further 2 hrs After a further 4 minutes After stirring for a further 10 minutes the mixture was partitioned between water (100 ml) and dichloromethane (50 ml) The aqueous layer was re-extracted with dichloromethane (2×40 ml) the combined organic layers were dried over sodium sulphate The residue was dissolved in MeOH (7 ml) dichloromethane (8 ml) and hydrochloric acid (35%; 2 ml) and was stirred at room temperature for 3 hrs The mixture was partitioned between dichloromethane (100 ml) and water (60 ml) was extracted with dichloromethane (2×40 ml) The combined organic layers were dried over sodium sulphate the solvent was removed in vacuo The residue was chromatographed on neutral alumina

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

Procedure: To a stirred -10° C. solution of 1-acetylpiperidine (127 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -40° C. to -50° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and extracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford (R)-ε-hydroxy-α,γ-dioxo-1-piperidineheptanenitrile as an oil. while maintaining the temperature between -40° C. to -50° C. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C. The aqueous layer is extracted with 500 mL of ethyl acetate the aqueous layer is separated extracted with 100 mL of ethyl acetate concentrated in vacuo

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

Procedure: In the same manner as indicated in Example 6 there are electrolyzed 21.6 g of N-acetylpiperidine and 54.4 g of methanol in the presence of 0.56 g of tetra-n-propylammonium hexafluorophosphate as conducting salt. After throughput of 2.0 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 28.7 volts. Work-up of the electrolysis solution by molecular distillation gives 21.5 g of 1-acetyl-2-methoxypiperidine, which corresponds to a product yield of 80.5% and a current efficiency of 80.5%. Work-up of the electrolysis solution by molecular distillation

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

Procedure: In the same manner as indicated in Example 6 there are electrolyzed 8.5 g of N-acetylpiperidine and 49.7 g of n-butanol in the presence of 0.3 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 91 volts. Work-up of the electrolysis solution gives 7.6 g of 1-acetyl-2-n-butoxypiperidine (boiling point 70° C./0.1 mbar; nD25 =1.4656), which corresponds to a product yield of 56.8% and a current efficiency of 45.5%.

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

Procedure: To a stirred -10° C. solution of 1-acetylpiperidine (127 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -40° C. to -50° C., and the mixture is stirred at -20° C. to -30° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is then added to the previous mixture. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and extracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford (R)-ε-hydroxy-α,γ-dioxo-1-piperidineheptanenitrile as an oil. while maintaining the temperature between -40° C. to -50° C. The reaction mixture is stirred for 30 minutes at -25° C. to -20° C. The aqueous layer is extracted with 500 mL of ethyl acetate the aqueous layer is separated extracted with 100 mL of ethyl acetate concentrated in vacuo