氟哌利多杂质6

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride (83.95 mmol, 25 g) in ethyl acetate (400 mL) was added saturated sodium bicarbonate solution (100 mL), and stirring was continued for 30 min. The organic layer was separated, dried, and concentrated to provide 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester. The ethyl ester was dissolved in ethyl acetate (100 mL) and di-tert-butyl dicarbonate (126 mmol, 27.48 g) was added followed by 10% palladium on carbon (5 g, wet). The resultant reaction mixture was subjected to catalytic hydrogenation at 55-60 psi of hydrogen for 24 h with stirring. The catalyst was filtered through a pad of celite, and the pad was washed with ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography by eluting with ethyl acetate in hexanes (1:9) to provide 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. The organic layer was separated dried concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel was placed ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride, (199.3 g, 0.67 mol) in dichloromethane (1.5 L). To this suspension was added saturated sodium bicarbonate (1.5 L) over one hour. After the solid dissolved, the organic layer was separated, washed with brine (250 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give 160.5 g (92%) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate as an oil. NMR 60 MHz, (CDCl3), δ 7.3 (s, 5H), 4.2 (q, 2H), 3.6 (s, 2H), 2.3-3.6 (m, 6H), 1.3 (t, 3H). In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel After the solid dissolved the organic layer was separated washed with brine (250 mL) filtered through 1 PS filter paper concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel was placed ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride, (199.3 g, 0.67 mol) in dichloromethane (1.5 L). To this suspension was added saturated sodium bicarbonate (1.5 L) over one hour. After the solid dissolved, the organic layer was separated, washed with brine (250 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give 160.5 g (92%) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate as an oil. NMR 60 MHz, (CDCl3), δ 7.3 (s, 5H), 4.2 (q, 2H), 3.6 (s, 2H), 2.3-3.6 (m, 6H), 1.3 (t, 3H). In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel After the solid dissolved the organic layer was separated washed with brine (250 mL) filtered through 1PS filter paper concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred suspension of 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride (83.95 mmol, 25 g) in ethyl acetate (400 mL) was added saturated sodium bicarbonate solution (100 mL), and stirring was continued for 30 min. The organic layer was separated, dried, and concentrated to provide 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester. The ethyl ester was dissolved in ethyl acetate (100 mL) and di-tert-butyl dicarbonate (126 mmol, 27.48 g) was added followed by 10% palladium on carbon (5 g, wet). The resultant reaction mixture was subjected to catalytic hydrogenation at 55-60 psi of hydrogen for 24 h with stirring. The catalyst was filtered through a pad of celite, and the pad was washed with ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography by eluting with ethyl acetate in hexanes (1:9) to provide 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. The organic layer was separated dried concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel was placed ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride, (199.3 g, 0.67 mol) in dichloromethane (1.5 L). To this suspension was added saturated sodium bicarbonate (1.5 L) over one hour. After the solid dissolved, the organic layer was separated, washed with brine (250 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give 160.5 g (92%) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate as an oil. NMR 60 MHz, (CDCl3), δ 7.3 (s, 5H), 4.2 (q, 2H), 3.6 (s, 2H), 2.3-3.6 (m, 6H), 1.3 (t, 3H). In a 5 L 3-necked flask equipped with a mechanical stirrer and a dropping funnel After the solid dissolved the organic layer was separated washed with brine (250 mL) filtered through 1 PS filter paper concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.76 (s, 4H), 3.28 (s, 2H), 3.71 (s, 2H), 7.25-7.40 (m, 6H), 7.81 (t, J=8.0 Hz, 1H), 8.35-8.40 (m, 1H), 8.52 (d, J=8.0 Hz, 2H), 8.93 (s, 1H); MS: m/z (ESI) 363 (M+H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.70-2.90 (m, 4H), 3.20-3.50 (m, 4H), 3.70-3.90 (m, 2H), 7.10-7.50 (m, 6H), 7.83 (s, 1H), 8.12 (s, 2H), 12.70 (br s, 1H); MS: m/z (ESI) 386 (M+H).

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3-nitro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.76 (s, 4H), 3.28 (s, 2H), 3.71 (s, 2H), 7.25-7.40 (m, 6H), 7.81 (t, J=8.0 Hz, 1H), 8.35-8.40 (m, 1H), 8.52 (d, J=8.0 Hz, 2H), 8.93 (s, 1H); MS: m/z (ESI) 363 (M+H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.70-2.90 (m, 4H), 3.20-3.50 (m, 4H), 3.70-3.90 (m, 2H), 7.10-7.50 (m, 6H), 7.83 (s, 1H), 8.12 (s, 2H), 12.70 (br s, 1H); MS: m/z (ESI) 386 (M+H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of anhydrous potassium carbonate (22.8 g) and 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester (10 g) in acetone (125 ml) was added a solution of butyl iodide (13.4 g, 8.3 ml) in acetone (50 ml) under argon over a period of 30 minutes. The resulting suspension was stirred at RT for 30 min and then refluxed for 12 hours. The suspension was cooled, filtered and concentrated in vacuo. The residue was dissolved in DCM and the solution was washed with water and brine, dried over Na2SO4 and evaporated. To the residue was added aqueous HCl (20%, 100 ml) and the solution was refluxed for 24 hours. The solution was evaporated and the residue was dissolved in DCM, washed with 10% aq. Na2CO3 solution and brine, dried and evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:2) to give the product as a slightly yellow oil (6.4 g). MS (ESI): 246.4 (MH+). refluxed for 12 hours The suspension was cooled filtered concentrated in vacuo The residue was dissolved in DCM the solution was washed with water and brine dried over Na2SO4 evaporated To the residue was added aqueous HCl (20%, 100 ml) the solution was refluxed for 24 hours The solution was evaporated the residue was dissolved in DCM washed with 10% aq. Na2CO3 solution and brine dried evaporated The crude product was purified by flash chromatography (ethyl acetate/hexanes 1:2)