三水合乙酸钠

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

实验步骤: To cold dimethylformamide (9 g) was slowly added phosphorous oxychloride (18 g). After the reagent complex was formed, a solution of N-(4-pyridinyl)-N-(1H-pyrrol-1-yl)carbamic acid ethyl ester (11 g) in 100 ml of dichloroethane was added. After stirring eight hours at 90°, the reaction mixture was cooled, hydrolyzed with a solution of sodium acetate trihydrate (20 g) in 100 ml of water, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated at 14 g of an oil. This oil was purified by HPLC (silica, 20% ethyl acetate in dihcloromethane) to give 4 g of pure product which was converted to the maleate salt and recrystallized twice from isopropanol to give 3.4 g of needles, d 139°-140°. After the reagent complex was formed the reaction mixture was cooled extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered evaporated at 14 g of an oil This oil was purified by HPLC (silica, 20% ethyl acetate in dihcloromethane)

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

实验步骤: To cold dimethylformamide (11.1 g) was slowly added phosphorous oxychloride (23.2 g). The resultant clear complex was stirred one hour at ambient temperature and thereafter a solution of N-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (20.5 g) in 135 ml of dichloroethane was added. After stirring twelve hours at 95° the reaction mixture was cooled and hydrolyzed for one hour at 95° with a solution of sodium acetate trihydrate (40 g) in 150 ml of water. The reaction mixture was cooled, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 24 g of an oil. This oil was purified first by flash chromatography (silica, dichloromethane, than 10% ethyl acetate in dichloromethane), then by high-pressure liquid chromatography (silica, ethyl acetate) to give 8 g of the pyrrole-2-aldehyde as an oil and 8 g of the pyrrole-3-aldehyde as an oil. 2.5 g of the pyrrole-3-aldehyde was converted to the maleate salt in 2-propanol to give 3.4 g of crystals, d 135°-136° C. After stirring twelve hours at 95° the reaction mixture The reaction mixture was cooled extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered evaporated to 24 g of an oil This oil was purified first by flash chromatography (silica, dichloromethane, than 10% ethyl acetate in dichloromethane)

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

实验步骤: To cold dimethylformamide (11.1 g) was slowly added phosphorous oxychloride (23.2 g). The resultant clear complex was stirred one hour at ambient temperature and thereafter a solution of N-ethyl-N-(1H-pyrrol-1-yl)-4-pyridinamine (20.5 g) in 135 ml of dichloroethane was added. After stirring twelve hours at 95° the reaction mixture was cooled and hydrolyzed for one hour at 95° with a solution of sodium acetate trihydrate (40 g) in 150 ml of water. The reaction mixture was cooled, basified with sodium carbonate and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride solution and thereafter dried over anhydrous magnesium sulfate, filtered and evaporated to 24 g of an oil. This oil was purified first by flash chromatography (silica, dichloromethane, then 10% ethyl acetate in dichloromethane), then by high-pressure liquid chromatography (silica, ethyl acetate) to give 8 g of the pyrrole-2-aldehyde as an oil and 8 g of the pyrrole-3-aldehyde as an oil. 2.5 g of the pyrrole-2-aldehyde was converted to the hydrochloride salt in 2-propanol to give 2.2 g of crystals, mp 214°-215° C. After stirring twelve hours at 95° the reaction mixture The reaction mixture was cooled extracted with dichloromethane The organic extract was washed with water and saturated sodium chloride solution dried over anhydrous magnesium sulfate filtered evaporated to 24 g of an oil This oil was purified first by flash chromatography (silica, dichloromethane

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 160a (140 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (410 mg, 1.0 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (136 mg, 1.0 mmol), acetonitrile (15 mL), and water (0.5 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 25:1) to afford 160b (150 mg, 52%) as a yellow solid. MS-ESI: [M+H]+ 570.2. A 50-mL round-bottomed flask equipped with a reflux condenser The system was evacuated refilled with N2 It was then cooled to room temperature filtered The filtrate was concentrated under reduced pressure the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (100:1 to 25:1)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A round-bottomed flask equipped with a reflux condenser was charged with 117c (200 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-yl-boronic acid 116c (300 mg, 0.75 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (150 mg, 1.0 mmol), and acetonitrile/water (20/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 117d as a yellow solid (110 mg, 42%). MS-ESI: [M+H]+ 724.4 A round-bottomed flask equipped with a reflux condenser After three cycles of vacuum/argon flush It was then cooled to room temperature filtered The filtrate was evaporated under reduced pressure the residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 116d (175 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (300 mg, 0.75 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (150 mg, 1.0 mmol), and acetonitrile/water (20/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 116e as a yellow solid (150 mg, 45%). MS-ESI: [M+H]+ 683.3 A 50-mL round-bottomed flask equipped with a reflux condenser After three cycles of vacuum/argon flush It was then filtered the filtrate was evaporated under reduced pressure The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (144 mg, 0.40 mmol), 115c (240 mg, 0.60 mmol), PdCl2(dppf) (20 mg, 0.020 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate trihydrate (120 mg, 0.80 mmol), and acetonitrile/water (15 mL/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 115d as a yellow solid (100 mg, 42%). MS-ESI: [M+H]+ 600.3 A round-bottomed flask equipped with a reflux condenser After three cycles of vacuum/argon flush It was then cooled to room temperature filtered The filtrate was evaporated under reduced pressure The residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol

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

实验步骤: A mixture of commercially available 2-chloro-5,6,7,8-tetrahydroquinoline-3-carbonitrile [CAS no 65242-27-5] (1 g, 5.19 mmol), zinc dust (activated) (602 mg, 9.2 mmol) and sodium acetate trihydrate (694 mg, 479 μl, 5.1 mmol) in acetic acid (5.19 g, 4.95 ml, 86.4 mmol) was stirred at 60° C. for 2 hours. Water (2.5 ml) was added and the mixture stirred at 60° C. for another 5 hours. After cooling to 23° C., the mixture was basified with aqueous 1 M NaOH solution, filtered through Celite®, the filtrate extracted with THF, the organic layers dried over Na2SO4 and the solvent evaporated leaving a yellow liquid. The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the 5,6,7,8-tetrahydroquinoline-3-carbonitrile as a white solid (433 mg, 53% yield). MS (ISP): m/z=159.1 [(M+H)+]. the mixture stirred at 60° C. for another 5 hours After cooling to 23° C. filtered through Celite® the filtrate extracted with THF the organic layers dried over Na2SO4 the solvent evaporated leaving a yellow liquid The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate

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

实验步骤: A solution of 3,3-dichloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine (6.2 g, 22 mmol) in glacial acetic acid (200 ml) was placed under an atmosphere of nitrogen. Sodium acetate trihydrate (3.8 g, 28 mmol) was added. After 5 minutes palladium on carbon (10%, 0.6 g) was added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature using 450 ml of hydrogen gas. The reaction mixture was filtered through Celite and the solvent was evaporated in vacuo. After reevaporation with toluene (250 ml), the residue was suspended in water (100 ml), stirred for 5 minutes and the solid was isolated by filtration and dried in vacuo to afford 1.7 g of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine. was hydrogenated at atmospheric pressure and room temperature The reaction mixture was filtered through Celite the solvent was evaporated in vacuo After reevaporation with toluene (250 ml) the solid was isolated by filtration dried in vacuo

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

实验步骤: To a solution of sodium acetate trihydrate (7.07 g, 52 mmol) in water (30 ml) was added hydroxylamine hydrochloride (3.61 g, 52 mmol). Ethanol (75 ml) and 3,4-dihydro-2H-phenantren-1-one (5.0 g, 26 mmol) were added and the suspension was heated at reflux for 2h. The reaction mixture was cooled on an ice-bath and the precipitated solid was isolated by filtration, washed with cold water and dried in vacuo to afford 4.8 g of 3,4-dihydro-2H-phenanthren-1-one-oxime. the suspension was heated at reflux for 2h The reaction mixture was cooled on an ice-bath the precipitated solid was isolated by filtration washed with cold water dried in vacuo

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

实验步骤: 19.7 g (87.4 mmole) of stannous chloride dihydrate was added to a solution of 6.62 g (17.5 mmole) of (2R)-(8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methyl 4-methylbenzenesulfonate in 400 mL of 1:1 tetrahydrofuran/methanol followed by the addition of 23.8 g (0.17 mole) of sodium acetate trihydrate. The mixture was stirred under nitrogen for a period of 48 hours. The solvent was removed in vacuo and replaced with an equal amount of methylene chloride and the solution was washed with 400 mL portions of saturated aqueous sodium bicarbonate and saturated brine and dried over magnesium sulfate. After the solution was filtered and concentrated in vacuum, the crude oil obtained was column chromatographed on silica gel with methylene chloride as eluant and the product fractions were combined and evaporated in vacuum to give 4.47 g (71%) of the (R)-enantiomer of the title compound as a light yellow solid, m.p.109-110° C. The solvent was removed in vacuo the solution was washed with 400 mL portions of saturated aqueous sodium bicarbonate and saturated brine dried over magnesium sulfate After the solution was filtered concentrated in vacuum the crude oil obtained chromatographed on silica gel with methylene chloride as eluant evaporated in vacuum

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

实验步骤: 3,6-Difluorophthalic anhydride (10 g, 54 mmol) was added to a mixture of sodium acetate trihydrate (10 g, 73 mmol) and hydrazine hydrate (5 ml, 156 mmol) in 40% aqueous acetic acid. The reaction was heated under reflux conditions for 16 h and the reaction was filtered to give the title-compound as a white solid (10.5 g, 98%), 1H NMR (250 MHz, d6-DMSO) δ 8.01 (2H, t, J=9 Hz), 11.50-11.80 (2H, br s). The reaction was heated under reflux conditions for 16 h the reaction was filtered