(R)-3-叔丁氧羰基氨基吡咯烷

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

实验步骤: Prepare the title compound by essentially following the procedure as described for Preparation 49, using 5-bromo-2-fluoro-pyridine (6.26 g, 35.61 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (6.632 g, 35.61 mmol) to give 3.77 g (30%) of the title compound. LC-MS/ES m/z (81Br) 344.3 [M+H]+. as described for Preparation 49

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

实验步骤: [(R)-1-((R)-2-Hydroxy-propionyl)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (500 mg) was prepared by following General Procedure F starting from (R)-2-hydroxy-propionic acid (200 mg), (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (372 mg), HBTU (800 mg), and DIEA (400 uL) in DMF (4 mL).

反应条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DMA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield). The reaction was cooled to room temperature concentrated purified by silica gel chromatography (500:15 DCM:MeOH)

反应条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol) were placed in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.55 g, 60% yield). The reaction was cooled to room temperature concentrated purified by silica gel chromatography (500:15 DCM:MeOH)

反应条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide (0.040 g, 0.13 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.074 g, 0.40 mmol) and DIEA (0.069 mL, 0.40 mmol, d 0.742) were placed in n-BuOH (1 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-60% CH3CN/water) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.040 g, 65% yield). The reaction was then cooled to room temperature concentrated to dryness The resulting residue was purified by reverse phase chromatography (Biotage SP4

反应条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide (0.200 g, 0.694 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.388 g, 2.08 mmol), and DIEA (0.121 mL, 0.694 mmol, d 0.742) were placed in n-BuOH and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-75% CH3CN/water) to give the product (R)-tert-butyl 1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.150 g, 48% yield). The reaction was then cooled to room temperature concentrated to dryness The resulting residue was purified by reverse phase chromatography (Biotage SP4

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (R)-tert-Butyl pyrrolidin-3-ylcarbamate (333 mg, 1.79 mmol) was added to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg, 0.597 mmol) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for 24 hours. The reaction was concentrated to dryness, and then the residue was purified by chromatography (SP4, C-18 25M+ column, gradient of 10-90% CH3CN/water, 30CV) to yield (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (105 mg, 35.1% yield) as a solid. The reaction was concentrated to dryness the residue was purified by chromatography (SP4

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

实验步骤: When the above reaction was run using 15.6 g (50 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester, 10.2 g (55 mmol) of (R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]pyrrolidine, 10.1 g (0.1 mol) triethylamine and 100 ml of acetonitrile, the yield of the title compound was 23.8 g. When the above reaction

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (100 mg, 0.20 mmole) and (3R)-3-(N-tert-butoxycarbonylamino)pyrrolidine; (380 mg, 10 equiv) in a sealed tube was heated at 130° C. for 35 hr. The reaction mixture was taken up in DCM, washed water and dried (Na2SO4). After removal of the solvent the residue was taken up in DCM (1.5 mL) and TFA (1 mL) was added. The solvents were removed and the residue was dissolved in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 1 to 5% MeOH) to afforded the title compound as an oil (13 mg, 14%). 1H NMR (CDCl3) δ 1.49 (br s, 2H), 1.66 (m, 1H), 2.29 (m, 1H), 2.43 (m, 1H), 3.69 (m, 1H), 3.87 (d, 1H, J=13.5 Hz), 3.96 (d, 1H, J=13.5 Hz), 5.58 (s, 2H), 6.49 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.92 (s, 1H), 8.04 (s, 1H), 8.26 (d, 1H, J=2 Hz); MS: 457 (M+H)+; HPLC Ret Time: 1.15 min (YMC Xterra ODS S7 C18, 3.0×50 mm column, 2 min gradient, 5 mL/min). washed water dried (Na2SO4) After removal of the solvent the residue TFA (1 mL) was added The solvents were removed the residue was dissolved in DCM washed with water dried (Na2SO4) Removal of the solvent followed by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 1 to 5% MeOH)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 867 mg (3.49 mmol) of 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexanol was dissolved in 20 ml of acetonitrile. 0.58 ml (1.20 eq).of triethylamine and 0.30 ml (1.10 eq) of mesyl chloride were added thereto. After 10 minutes, brine was added, and the objective product was extracted with ethylacetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The product was dissolved in 30 ml of acetonitrile, 1.57 g (3.00 eq) of sodium iodine, 0.54 ml (1.10 eq) of triethylamine and 845 mg (4.54 mmol) of (3R)-3-tert-butoxycarbonylaminopyrrolidine were added, and the mixture was heated at 60° C. After completion of the reaction, brine was added, and the objective product was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to 100 g of Cromatorex NH silica gel (ethyl acetate:hexane=25 to 35% of ethyl acetate), to give 1.34 g (3.21 mmol, 92.0%) of the title compound as a yellow oil. The physico-chemical data of the compound was as below. the objective product was extracted with ethylacetate The organic layer was washed with brine dried over anhydrous magnesium sulfate The solvent was evaporated to give a crude product was added the objective product was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous magnesium sulfate The solvent was evaporated to give a crude product

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

实验步骤: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound. the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL) The mixture was extracted with dichloromethane (25 mL) the organic layer was dried over anhydrous magnesium sulfate filtered concentrated The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) stirred for one hour The mixture was concentrated

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

实验步骤: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound. the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL) The mixture was extracted with dichloromethane (25 mL) the organic layer was dried over anhydrous magnesium sulfate filtered concentrated The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) stirred for one hour The mixture was concentrated