ethyl 4-benzylpiperidine-4-carboxylate

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: To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity. the mixture was stirred extracted with chloroform The extract was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) dried in vacuo

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

Procedure: To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity. the mixture was stirred extracted with chloroform The extract was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) dried in vacuo

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

Procedure: To a solution of ethyl 4-benzylpiperidine-4-carboxylate (0.46 g, 1.86 mmol) in EtOH (10.0 mL) was added DIPEA (0.80 mL, 4.65 mmol) at rt which was stirred at rt for 10 minutes followed by addition of 5-bromo-2-chloropyrimidine (0.30 g, 1.55 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 4% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.16 (t, J=7.20 Hz, 3H), 1.47 (m, 2H), 2.00 (m, 2H), 2.80 (s, 2H), 2.97 (m, 2H), 4.08 (q, J=7.20 Hz, 2H), 4.40 (m, 2H), 7.02 to 7.27 (m, 5H) and 8.43 (s, 2H). The reaction was heated up to 70° C. for 1 h After completion of reaction (by TLC), solvent was evaporated the crude residue purified over 100-200 M silica-gel

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

Procedure: To a solution of ethyl 4-benzylpiperidine-4-carboxylate (0.46 g, 1.86 mmol) in EtOH (10.0 mL) was added DIPEA (0.80 mL, 4.65 mmol) at rt which was stirred at rt for 10 minutes followed by addition of 5-bromo-2-chloropyrimidine (0.30 g, 1.55 mmol). The reaction was heated up to 70° C. for 1 h. After completion of reaction (by TLC), solvent was evaporated and the crude residue purified over 100-200 M silica-gel using 4% EtOAc:hexane to obtain the desired product as a yellow solid (0.108 g, 45% yield). 1H NMR (DMSO-d6): δ 1.16 (t, J=7.20 Hz, 3H), 1.47 (m, 2H), 2.00 (m, 2H), 2.80 (s, 2H), 2.97 (m, 2H), 4.08 (q, J=7.20 Hz, 2H), 4.40 (m, 2H), 7.02 to 7.27 (m, 5H) and 8.43 (s, 2H). The reaction was heated up to 70° C. for 1 h After completion of reaction (by TLC), solvent was evaporated the crude residue purified over 100-200 M silica-gel

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

Procedure: To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity. the mixture was stirred extracted with chloroform The extract was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) dried in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil. After cooling extracted with ethyl acetate (3×200 ml) The combined organic phases were washed with saturated NaCl solution (3×100 ml) dried over sodium sulfate evaporated under reduced pressure A crude product was obtained which was purified on a column of alumina (eluting with chloroform)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil. After cooling extracted with ethyl acetate (3×200 ml) The combined organic phases were washed with saturated NaCl solution (3×100 ml) dried over sodium sulfate evaporated under reduced pressure A crude product was obtained which was purified on a column of alumina (eluting with chloroform)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Benzyl-piperidine-4-carboxylic acid ethyl ester (2.5 g, 10 mmol), (2-bromo-ethyl)-carbamic acid benzyl ester (2.58 g, 10 mmol) and DIPEA (1.7 mL, 10 mmol) are dissolved in THF (50 mL) and heated at 80° C. for 15 h. The mixture is poured into Et2O (200 mL) and washed with sat. Na2CO3 (50 mL). The ether phase is extracted with 1M aqueous HCl (3×50 mL), the aqueous extracts washed with ether (50 mL) and adjusted to pH 14 with cooled 33% aqueous NaOH. The aqueous phase is extracted with CH2Cl2 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound. washed with sat. Na2CO3 (50 mL) The ether phase is extracted with 1M aqueous HCl (3×50 mL) the aqueous extracts washed with ether (50 mL) with cooled 33% aqueous NaOH The aqueous phase is extracted with CH2Cl2 (4×50 mL) The organic extracts are dried (Na2SO4) filtered evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Benzyl-piperidine-4-carboxylic acid ethyl ester (2.5 g, 10 mmol), (2-bromo-ethyl)-carbamic acid benzyl ester (2.58 g, 10 mmol) and DIPEA (1.7 mL, 10 mmol) are dissolved in THF (50 mL) and heated at 80° C. for 15 h. The mixture is poured into Et2O (200 mL) and washed with sat. Na2CO3 (50 mL). The ether phase is extracted with 1M aqueous HCl (3×50 mL), the aqueous extracts washed with ether (50 mL) and adjusted to pH 14 with cooled 33% aqueous NaOH. The aqueous phase is extracted with CH2Cl2 (4×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide the title compound. washed with sat. Na2CO3 (50 mL) The ether phase is extracted with 1M aqueous HCl (3×50 mL) the aqueous extracts washed with ether (50 mL) with cooled 33% aqueous NaOH The aqueous phase is extracted with CH2Cl2 (4×50 mL) The organic extracts are dried (Na2SO4) filtered evaporated