甲基 1-[2-[(2-甲基丙-2-基)氧基]-2-氧乙基]哌啶-4-羧酸乙酯

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

实验步骤: To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (3.0 g, 12 mmol) in dichloromethane (9 mL) was added hydrochloric acid in 1,4-dioxane (4 M) and stirred at ambient temperature for 24 h. The final product was formed as a white solid, which was washed with ether and filtered (2.3 g). 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 2H), 3.64 (s, 3H), 3.46 (br. s., 2H), 3.11 (br. s., 2H), 2.67 (br. s., 1H), 1.82-2.12 (m, 4H)

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

实验步骤: To a mixture of methyl isonipecotate (10.0 g, 69.8 mmol) and triethylamine (19.5 mL, 140 mmol) in tetrahydrofuran (200 mL) was added tert-butyl bromoacetate (10.3 mL, 69.8 mmol). The solution was heated at reflux for 24 h, concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 5:95) to provide the title compound (18 g). 1H NMR (400 MHz, CDC3) δ 3.61 (s, 3H), 3.04 (s, 2H), 2.84 (d, J=11.5 Hz, 2H), 2.12-2.31 (m, 3H), 1.64-1.91 (m, 4H), 1.39 (s, 9H). The solution was heated at reflux for 24 h concentrated under reduced pressure purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 5:95)

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

实验步骤: To a solution of 1-tert-butoxycarbonylmethyl-piperidine-4-carboxylic acid methyl ester (0.65 g, 2.53 mmol, 1 eq.) in 2.5 mL of dichloromethane was added TFA (2.53 mL, 32.8 mmol, 13 eq.). The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and dried under high vacuum. To this oil (0.52 g, 2.22 mmol, 1 eq.) was added DIEA (1.16 mL, 6.66 mmol, 3 eq.) in 5 mL of DMF, followed by HATU (1.69 g, 4.44 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,4a,5,7,8,8a-hexahydro-pyrano[4,3-d]pyrimidin-4-one (0.7 g, 2.22 mmol, 1 eq.) in 5 mL of DMF was added and the resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was quenched with H2O (25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated and purified via preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.69 g). Exact mass calculated for C21H33N4O5 421.2. MS (ESI) m/z 421.6 (M+H)+. After 18 h the reaction mixture was concentrated dried under high vacuum The resulting mixture was stirred at room temperature for 30 min the resulting mixture was stirred at room temperature overnight After 18 h the reaction mixture was quenched with H2O (25 mL) extracted with dichloromethane (3×50 mL) The combined organic layer was concentrated purified via preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min)

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

实验步骤: To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+. The resulting mixture was heated at reflux overnight the resulting mixture was concentrated purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH)

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

实验步骤: To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+. The resulting mixture was heated at reflux overnight the resulting mixture was concentrated purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH)

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

实验步骤: To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (3.0 g, 12 mmol) in dichloromethane (9 mL) was added hydrochloric acid in 1,4-dioxane (4 M) and stirred at ambient temperature for 24 h. The final product was formed as a white solid, which was washed with ether and filtered (2.3 g). 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 2H), 3.64 (s, 3H), 3.46 (br. s., 2H), 3.11 (br. s., 2H), 2.67 (br. s., 1H), 1.82-2.12 (m, 4H)

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

实验步骤: To a mixture of methyl isonipecotate (10.0 g, 69.8 mmol) and triethylamine (19.5 mL, 140 mmol) in tetrahydrofuran (200 mL) was added tert-butyl bromoacetate (10.3 mL, 69.8 mmol). The solution was heated at reflux for 24 h, concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 5:95) to provide the title compound (18 g). 1H NMR (400 MHz, CDC3) δ 3.61 (s, 3H), 3.04 (s, 2H), 2.84 (d, J=11.5 Hz, 2H), 2.12-2.31 (m, 3H), 1.64-1.91 (m, 4H), 1.39 (s, 9H). The solution was heated at reflux for 24 h concentrated under reduced pressure purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 5:95)

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

实验步骤: To a solution of 1-tert-butoxycarbonylmethyl-piperidine-4-carboxylic acid methyl ester (0.65 g, 2.53 mmol, 1 eq.) in 2.5 mL of dichloromethane was added TFA (2.53 mL, 32.8 mmol, 13 eq.). The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and dried under high vacuum. To this oil (0.52 g, 2.22 mmol, 1 eq.) was added DIEA (1.16 mL, 6.66 mmol, 3 eq.) in 5 mL of DMF, followed by HATU (1.69 g, 4.44 mmol, 2 eq.). The resulting mixture was stirred at room temperature for 30 min. 2-[(Cyclopropylmethyl-amino)-methyl]-3,4a,5,7,8,8a-hexahydro-pyrano[4,3-d]pyrimidin-4-one (0.7 g, 2.22 mmol, 1 eq.) in 5 mL of DMF was added and the resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was quenched with H2O (25 mL) and extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated and purified via preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min) to give the title compound as a white solid (0.69 g). Exact mass calculated for C21H33N4O5 421.2. MS (ESI) m/z 421.6 (M+H)+. After 18 h the reaction mixture was concentrated dried under high vacuum The resulting mixture was stirred at room temperature for 30 min the resulting mixture was stirred at room temperature overnight After 18 h the reaction mixture was quenched with H2O (25 mL) extracted with dichloromethane (3×50 mL) The combined organic layer was concentrated purified via preparative HPLC (20-100% CH3CN/H2O over 10 min with 0.1% TFA, sun fire C18 OBD 50×50 mm column with flow rate of 60 mL/min)

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

实验步骤: To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+. The resulting mixture was heated at reflux overnight the resulting mixture was concentrated purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH)