N-(2-苯乙基)-4-哌啶甲酸乙酯

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

实验步骤: To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5 M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H). was cooled once again to -78° to warm to -40° to stir at room temperature for 3 hours The mixture was evaporated to dryness the residue was dissolved in water The aqueous solution was extracted with methylene chloride the extracts were dried evaporated

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

实验步骤: A mixture of 5.90 g (17.5 mmol) of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of platinum (IV) oxide and 100 mL of methanol was hydrogenated at 50 p.s.i. and room temperature for 1.5 hours. The reaction mixture was filtered, concentrated and the residue dissolved in water. The aqueous solution was made alkaline to pH 9-10 with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to afford 4.11 g of 1-(2-phenylethyl)-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.16-7.32 (m, 5H); 4.08-4.19 (q, 2H); 2.91-3.02 (m, 2H); 2.77-2.88 (m, 2H); 2.53-2.65 (m, 2H); 2.23-2.35 (m, 1H); 2.03-2.15 (m, 2H); 1.87-1.98 (m, 2H); 1.72-1.88 (m, 4H); 1.20-1.30 (t,3H). The reaction mixture was filtered concentrated the residue dissolved in water extracted with ethyl acetate The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution dried evaporated

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

实验步骤: 1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 ml) and CH2Cl2 (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield) (procedure E). 1H NMR (CD3Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh2CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)2), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)2), 1.96-1.81 (4H, m).

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

实验步骤: 1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 ml) and CH2Cl2 (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield) (procedure E). 1H NMR (CD3Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh2CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)2), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)2), 1.96-1.81 (4H, m).

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

实验步骤: 1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 ml) and CH2Cl2 (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield)(procedure E). 1H NMR (CD3Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh2CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)2), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)2), 1.96-1.81 (4H, m).

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

实验步骤: 1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 ml) and CH2Cl2 (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield)(procedure E). 1H NMR (CD3Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh2CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)2), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)2), 1.96-1.81 (4H, m).

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

实验步骤: To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5 M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H). was cooled once again to -78° to warm to -40° to stir at room temperature for 3 hours The mixture was evaporated to dryness the residue was dissolved in water The aqueous solution was extracted with methylene chloride the extracts were dried evaporated

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

实验步骤: A mixture of 5.90 g (17.5 mmol) of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of platinum (IV) oxide and 100 mL of methanol was hydrogenated at 50 p.s.i. and room temperature for 1.5 hours. The reaction mixture was filtered, concentrated and the residue dissolved in water. The aqueous solution was made alkaline to pH 9-10 with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to afford 4.11 g of 1-(2-phenylethyl)-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.16-7.32 (m, 5H); 4.08-4.19 (q, 2H); 2.91-3.02 (m, 2H); 2.77-2.88 (m, 2H); 2.53-2.65 (m, 2H); 2.23-2.35 (m, 1H); 2.03-2.15 (m, 2H); 1.87-1.98 (m, 2H); 1.72-1.88 (m, 4H); 1.20-1.30 (t,3H). The reaction mixture was filtered concentrated the residue dissolved in water extracted with ethyl acetate The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution dried evaporated

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

实验步骤: A suspension of 1-(2-phenylethyl)-4-carbetoxypiperidine (12.2 g, 0.047 mol) obtained as described in J. Med. Chem. 1996 (39), 749-756, in 1N NaOH (100 ml) was heated under reflux for 4 h. After cooling to room temperature, the solution was made acid with 6N HCl to pH 2, concentrated by evaporation at reduced pressure, and the solid thus obtained was filtered and dried in a stove under vacuum to give the desired product (12.1 g), obtained under reflux for 4 h concentrated by evaporation at reduced pressure the solid thus obtained was filtered dried in a stove under vacuum

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

实验步骤: To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H). was cooled once again to -78° to warm to -40° to stir at room temperature for 3 hours The mixture was evaporated to dryness the residue was dissolved in water The aqueous solution was extracted with methylene chloride the extracts were dried evaporated

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

实验步骤: A mixture of 5.90 g (17.5 mmol) of 1-(2-phenylethyl)-4-carboethoxypyridinium bromide, 0.60 g of platinum (IV) oxide and 100 mL of methanol was hydrogenated at 50 p.s.i. and room temperature for 1.5 hours. The reaction mixture was filtered, concentrated and the residue dissolved in water. The aqueous solution was made alkaline to pH 9-10 with aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried and evaporated to afford 4.11 g of 1-(2-phenylethyl)-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.16-7.32 (m, 5H); 4.08-4.19 (q, 2H); 2.91-3.02 (m, 2H); 2.77-2.88 (m, 2H); 2.53-2.65 (m, 2H); 2.23-2.35 (m, 1H); 2.03-2.15 (m, 2H); 1.87-1.98 (m, 2H); 1.72-1.88 (m, 4H); 1.20-1.30 (t, 3H). The reaction mixture was filtered concentrated the residue dissolved in water extracted with ethyl acetate The organic extracts were washed with saturated sodium bicarbonate solution, saturated sodium chloride solution dried evaporated

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

实验步骤: 1-(phenylethyl)-4-(ethoxycarbonyl)piperidine (0.25 g, 0.95 mmol) was converted into its carboxylic acid, which was then reacted with bis(4-fluorophenyl)methyl amine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.27 mmol), HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 ml) and CH2Cl2 (20 ml) to produce 4-[(bis(4-fluorophenyl)ethylamino)carbonyl-1-(phenylethyl)piperidine, 0.32 g (74% yield)(procedure E). 1H NMR (CD3Cl) δ 7.29-7.03 (10H, m, Ar—H), 7.05-6.99 (3H, m, Ar—H), 6.22-6.20 (1H, d, J=7.8 Hz), p-FPh2CH), 6.00-5.97 (1H, d, J=7.5 Hz, NH), 3.08-3.04 (2H, bd, J=11.4 Hz, N(CH)2), 2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m, NCOCH), 2.10-2.03 (2H, t, J=11.4 Hz, N(CH)2), 1.96-1.81 (4H, m).