(2R)-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: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

实验步骤: O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 4.96 g, 13.1 mmol) was added to a stirred solution of (R)—N-Boc-2-piperidinecarboxylic acid (3.00 g, 13.1 mmol) and DIPEA (9.0 mL, 51.2 mmol) in anhydrous DMF (50 mL). The mixture was stirred at room temperature for 5 min and then 2-nitro-1,4-phenylenediamine (3.00 g, 13.1 mmol) was added. The mixture was stirred for a further 18 hr, then the DMF was removed by evaporation. The residue was partitioned between water (200 mL) and EA (100 mL) and the phases separated. The aqueous phase was extracted with two further portions of EA (100 mL each) and the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each). The solution was dried over magnesium sulfate and concentrated to give (R)-tert-butyl 2-[(4-amino-3-nitrophenyl)aminocarbonyl]-piperidine-1-carboxylate as a brown solid (4.80 g). The mixture was stirred for a further 18 hr the DMF was removed by evaporation The residue was partitioned between water (200 mL) and EA (100 mL) the phases separated The aqueous phase was extracted with two further portions of EA (100 mL each) the combined organic extracts washed with water, 1M sodium carbonate solution, water, and brine (100 mL each) The solution was dried over magnesium sulfate concentrated

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

实验步骤: 93 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 (R)-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: The title compound was prepared from (2R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (52 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Reverse phase HPLC [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.16 (s, 1 H), 7.90 (br s, 1 H), 7.59 (s, 1 H), 7.41 (d, J=8.4 Hz, 1 H), 7.24 (d, J =8.4 Hz, 1 H), 4.56 (br s, 1 H), 4.38 (br s, 1 H), 4.18–4.15 (m, 2 H), 3.80 (br s, 1 H), 3.58–3.52 (m, 3 H), 2.15–2.11 (m, 2 H), 2.05–1.98 (m, 2 H), 1.95–1.84 (m, 2 H), 1.70–1.68 (m, 2 H), 1.55 (br s, 2 H), 1.33 (s, 9 H). LCMS (M+H): 518.3.

反应条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (R)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.65 g., 99%). at rt for 2 h extracted with EtOAc (300 mL) The aqueous layer was re-extracted with EtOAc (2×150 mL) dried over anhydrous Na2SO4 concentrated

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

实验步骤: The title compound (D53) (650 mg) was prepared according to the general procedure for amides preparation (Method A) starting from (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (500 mg, available from Sigma Aldrich #516341), and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (470 mg). Reaction time: 18 hrs. Reaction time 18 hrs

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

实验步骤: 93 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 (R)-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: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

实验步骤: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g, 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3.Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS 116 (MH+-boc) was cooled to 0° C After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)

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

实验步骤: To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (1.2 g, 3.1 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.71 g, 3.1 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. under nitrogen was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 1.4 g, 3.7 mmol) and diisoproylethylamine (iPr2NEt, 0.80 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 1 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes) to afford the desired product (1.5 g, 2.6 mmol, 85%). The mixture was washed with saturated aqueous sodium bicarbonate and brine The organic layer was dried (Na2SO4) filtered concentrated in vacuo The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes)

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

实验步骤: To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (1.2 g, 3.1 mmol) and (R)-1-(t-butoxycarbonyl)piperidine-2-carboxylic acid (0.71 g, 3.1 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. under nitrogen was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 1.4 g, 3.7 mmol) and diisoproylethylamine (iPr2NEt, 0.80 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 1 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes) to afford the desired product (1.5 g, 2.6 mmol, 85%). The mixture was washed with saturated aqueous sodium bicarbonate and brine The organic layer was dried (Na2SO4) filtered concentrated in vacuo The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes)

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

实验步骤: A solution of (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 15 g. 18.5 g, 80.7 mmol) in anhydrous THF (44.4 mL) was cooled to 0° C. BH3Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes. After complete addition, the mixture was allowed to warm to room temperature, and stirring was continued for 18 hours. The mixture was quenched with water, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was flash chromatographed on silica gel (35% ethyl acetate in hexanes) to provide (R)-tert-butyl-2-(hydroxymethyl)piperidine-1-carboxylate as a white solid (14.2 g, 82%). MS116 (MH+-boc) was cooled to 0° C BH3Me2S (44.4 mL, 88.8 mmol) was added drop wise over 15 minutes After complete addition The mixture was quenched with water extracted with ethyl acetate The organic extract was dried over anhydrous Na2SO4 filtered concentrated chromatographed on silica gel (35% ethyl acetate in hexanes)