(2S)-1-[(2-甲基丙烷-2-基)氧羰基]哌啶-2-羧酸

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

实验步骤: Triethylamine (14.46 ml) was added to a solution of (2S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (18.3 g) [see Preparation 1] in tetrahydrofuran (240 ml) at −20° C. under an atmosphere of nitrogen. Ethyl chloroformate (7.52 ml) was then added to the mixture and the resulting solution was stirred for 40 mins. at −10° C. and then 0.88 aqueous ammonia solution (32 ml) added. The reaction mixture was stirred for 10 mins. after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate and water. The organic layer was separated and dried over magnesium sulphate and the solvent was removed under reduced pressure to afford tert-butyl (2S)-2-(aminocarbonyl)-1-piperidinecarboxylate (18.65 g) as a white solid. 1H-NMR (CDCl3) δ: 6.0 (1H, bs), 5.40 (1H, bs), 4.80 (1H, s), 4.00 (1H, m), 2.85 (1H, t), 2.30 (1H, d), 1.80-1.40 (14H, m). The reaction mixture was stirred for 10 mins after which time the solvent was removed under reduced pressure the residue diluted with ethyl acetate and water The organic layer was separated dried over magnesium sulphate the solvent was removed under reduced pressure

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

实验步骤: 380 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (S)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.

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

实验步骤: 380 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using (S)-1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(3-fluoro-4-methoxybenzoyl)propionic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.

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

实验步骤: To a solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) in tetrahydrofuran (45 mL) was added 2-methylpropyl chlorocarbonate (2.84 mL) at 10° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 7 days. Ethyl acetate (50 mL) and aqueous sodium hydrogen carbonate (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl(2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (50 mL) was added 2M aqueous sodium hydroxide solution (24.8 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was neutralized with 6M hydrochloric acid (8.5 mL) under ice-cooling, and water (10 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (3.03 g) as a pale-yellow solid. The optical purity was 73.8% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm). the separated aqueous layer was extracted with ethyl acetate (20 mL) The combined organic layers were washed with brine (10 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was 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 solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 ml) was added 2-methylpropyl chlorocarbonate (0.309 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 15 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (240 mg) as a pale-yellow solid. the separated aqueous layer was extracted with ethyl acetate (5 mL) The combined organic layers were washed with brine (5 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was 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 solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 ml) was added 2-methylpropyl chlorocarbonate (0.309 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 15 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (240 mg) as a pale-yellow solid. the separated aqueous layer was extracted with ethyl acetate (5 mL) The combined organic layers were washed with brine (5 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was 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 solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) in tetrahydrofuran (45 mL) was added 2-methylpropyl chlorocarbonate (2.84 mL) at 10° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 7 days. Ethyl acetate (50 mL) and aqueous sodium hydrogen carbonate (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (50 mL) was added 2M aqueous sodium hydroxide solution (24.8 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was neutralized with 6M hydrochloric acid (8.5 mL) under ice-cooling, and water (10 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (3.03 g) as a pale-yellow solid. The optical purity was 73.8% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm). the separated aqueous layer was extracted with ethyl acetate (20 mL) The combined organic layers were washed with brine (10 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was 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 solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g) and triethylamine (3.16 mL) in tetrahydrofuran (45 mL) was added 2-methylpropyl chlorocarbonate (2.84 mL) at 10° C., and the mixture was stirred at room temperature for 1 hr. Thereafter, to the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (2.19 g) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 7 days. Ethyl acetate (50 mL) and aqueous sodium hydrogen carbonate (50 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl (2S)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (50 mL) was added 2M aqueous sodium hydroxide solution (24.8 mL), and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was neutralized with 6M hydrochloric acid (8.5 mL) under ice-cooling, and water (10 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (3.03 g) as a pale-yellow solid. The optical purity was 73.8% ee. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/2-propanol/diethylamine (700/300/1), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm). the separated aqueous layer was extracted with ethyl acetate (20 mL) The combined organic layers were washed with brine (10 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was 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 solution of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (518 mg) and triethylamine (0.392 mL) in tetrahydrofuran (5 mL) was added 2-methylpropyl chlorocarbonate (0.309 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, in tetrahydrofuran (5 mL), and the mixture was stirred at 60° C. for 15 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate as a pale-yellow oil. To a solution of tert-butyl 2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]piperidine-1-carboxylate produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (5 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (240 mg) as a pale-yellow solid. the separated aqueous layer was extracted with ethyl acetate (5 mL) The combined organic layers were washed with brine (5 mL) dried over anhydrous sodium sulfate Insoluble material was filtered off the filtrate was concentrated under reduced pressure

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

实验步骤: 6.2 g of HOBT and then 9.45 g of DCC are added at RT to a solution of 10 g of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (commercial) in 130 ml of DCM, and the mixture is left stirring for 1 hour. The reaction mixture is cooled on an ice bath, dimethylamine gas is added by bubbling for two times 10 minutes and the mixture is then left stirring overnight at RT. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a gradient of a DCM/MeOH mixture of from (98/2; v/v) to (96/4; v/v). The product obtained is taken up in ether and the precipitate is spin-filtered off. 8.5 g of the expected product are obtained. the mixture is left The reaction mixture is cooled on an ice bath by bubbling for two times 10 minutes the mixture is then left stirring overnight at RT An insoluble material is filtered off the filtrate is concentrated under vacuum The residue is chromatographed on silica gel eluting with a gradient of a DCM/MeOH mixture of from (98/2; v/v) to (96/4; v/v) The product obtained the precipitate is spin-filtered off

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

实验步骤: 6.2 g of HOBT and then 9.45 g of DCC are added at RT to a solution of 10 g of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (commercial) in 130 ml of DCM, and the mixture is left stirring for 1 hour. The reaction mixture is cooled on an ice bath, dimethylamine gas is added by bubbling for two times 10 minutes and the mixture is then left stirring overnight at RT. An insoluble material is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a gradient of a DCM/MeOH mixture of from (98/2; v/v) to (96/4; v/v). The product obtained is taken up in ether and the precipitate is spin-filtered off. 8.5 g of the expected product are obtained. the mixture is left The reaction mixture is cooled on an ice bath by bubbling for two times 10 minutes the mixture is then left stirring overnight at RT An insoluble material is filtered off the filtrate is concentrated under vacuum The residue is chromatographed on silica gel eluting with a gradient of a DCM/MeOH mixture of from (98/2; v/v) to (96/4; v/v) The product obtained the precipitate is spin-filtered off

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

实验步骤: A mixture of (2S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (299 mg, 1.30 mmol), 1-[5-chloro-2-(1H-tetraazol-1-yl)phenyl]methanamine (293 mg, 1.40 mmol), EDC (376 mg, 1.96 mmol) and HOAt (89 mg, 0.65 mmol) in DMF (7 mL) was stirred at room temperature for 16 h. Water and saturated aqueous K2CO3 were added and the mixture was extracted with EtOAc. The organic layer was washed with brine and the combined aqueous layers were extracted once with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to a yellow oil. Silica gel chromatography (65% EtOAc-hexanes) afforded the title compound as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1 H), 7.60 (d, J=1.8 Hz, 1 H), 7.46 (dd, J=1.8, 8.4 Hz, 1 H), 7.29–7.26 (m, 1 H), 6.84 (br m, 1 H), 4.74 (br m, 1 H), 4.29–4.16 (m, 2 H), 4.04 (br m, 1 H), 2.76–2.70 (m, 1 H), 2.24–2.04 (m, 1 H), 1.64–1.32 (br m, 5 H), 1.48 (s, 9 H). the mixture was extracted with EtOAc The organic layer was washed with brine the combined aqueous layers were extracted once with CH2Cl2 The combined organic extracts were dried (Na2SO4) concentrated to a yellow oil