N-羟基-2-甲氧基乙脒

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

实验步骤: A suspension of 2-methoxyacetamidoxime (260 mg, 2.5 mmol) and 4 Å molecular sieves (1 g) in anhydrous tetrahydrofuran (15 mL) was stirred at room temperature for 0.5 hours, then treated with sodium hydride (2.75 mmol, 110 mg of 60% mineral oil suspension). The mixture was heated at reflux for 1 hour. After cooling to room temperature, a suspension of methyl 9-(3,5-dinitrobenzyl)-9H-β-carboline-3-carboxylate (205 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added. The resulting mixture was heated at reflux for 15 hours, cooled, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent to afford the desired product (86 mg, 38% yield) as a white solid. 1H NMR (DMSO-d6) δ9.41 (s, 1H), 9.24 (s, 1H), 8.72 (t, J=1.9 Hz, 1H), 8.59 (d, J=7.8, 1H), 8.49 (d, J=1.9 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 6.20 (s, 2H), 4.67 (s, 2H), 3.42 (s, 3H); MS (APCI; (M+H)+) m/z 461. The mixture was heated at reflux for 1 hour After cooling to room temperature was added The resulting mixture was heated at reflux for 15 hours cooled filtered the filtrate concentrated in vacuo The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent

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

实验步骤: A suspension of 2-methoxyacetamidoxime (260 mg, 2.5 mmol) and 4 Å molecular sieves (1 g) in anhydrous tetrahydrofuran (15 mL) was stirred at room temperature for 0.5 hours, then treated with sodium hydride (2.75 mmol, 110 mg of 60% mineral oil suspension). The mixture was heated at reflux for 1 hour. After cooling to room temperature, a suspension of methyl 9-(3,5-dinitrobenzyl)-9H-β-carboline-3-carboxylate (205 mg, 0.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added. The resulting mixture was heated at reflux for 15 hours, cooled, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent to afford the desired product (86 mg, 38% yield) as a white solid. 1H NMR (DMSO-d6) δ9.41 (s, 1H), 9.24 (s, 1H), 8.72 (t, J=1.9 Hz, 1H), 8.59 (d, J=7.8, 1H), 8.49 (d, J=1.9 Hz, 2H), 7.94 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.8Hz, 1H), 7.45 (t, J=7.5 Hz, 1H), 6.20 (s, 2H), 4.67 (s, 2H), 3.42 (s, 3H); MS (APCI; (M+H)+) m/z 461. The mixture was heated at reflux for 1 hour After cooling to room temperature was added The resulting mixture was heated at reflux for 15 hours cooled filtered the filtrate concentrated in vacuo The residue was purified by preparative thin layer chromatography with 4% 2M NH3—CH3OH in CH2Cl2 as eluent

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

实验步骤: A mixture of 6.80 g (20 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. The solution is then evaporated and the residue is partitioned between methylene chloride and water. The organic phase is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 7-chloro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 213°-215°. The solution is then evaporated the residue is partitioned between methylene chloride and water The organic phase is dried over magnesium sulphate evaporated By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate

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

实验步骤: A mixture of 6.80 g (20 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. The solution is then evaporated and the residue is partitioned between methylene chloride and water. The organic phase is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 7-chloro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 213°-215°. The solution is then evaporated the residue is partitioned between methylene chloride and water The organic phase is dried over magnesium sulphate evaporated By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate

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

实验步骤: A mixture of 6.50 g (20 mmol) of 1-[[8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole, 50 ml of N,N-dimethylformamide and 2.10 g (20 mmol) of methoxyacetamidoxime is stirred at 100° overnight. After evaporation of the solvent the residue is dissolved in methylene chloride and washed with water. The organic solution is dried over magnesium sulphate and evaporated. By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate there is obtained 8-fluoro-4,5-dihydro-3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 192°-194°. After evaporation of the solvent the residue is dissolved in methylene chloride washed with water The organic solution is dried over magnesium sulphate evaporated By chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from methylene chloride and ethyl acetate

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

实验步骤: A stirred solution of sodium methoxide, prepared from 290 mg (0.012 mole) of sodium in methanol (20 ml), under nitrogen was treated with methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 300 mg, 0.0019 mole), methoxyacetamide oxime (D10, 1.0 g, 0.0097 mole) and powdered 3A molecular sieves (2.5 g). The mixture was heated under reflux for 3.5 h, then cooled in an ice bath and adjusted to pH 6 by the addition of glacial acetic acid. The mixture was concentrated in vacuo and the residue basified with concentrated potassium carbonate solution, then shaken with ethyl acetate (100 ml). The mixture was filtered and the organic layer separated, dried (Na2SO4) and concentrated in vacuo to leave a yellow oil. This material was chromatographed twice on basic alumina, each time eluting initially with ether then with 20% ethyl acetate/ether to eventually give a colourless oil (80 mg). This was converted to its oxalate salt and crystallised from acetone to give the title compound (E9 ) as a white solid (12%) m.p. 102°-104° C. The mixture was heated under reflux for 3.5 h cooled in an ice bath The mixture was concentrated in vacuo The mixture was filtered the organic layer separated dried (Na2SO4) concentrated in vacuo to leave a yellow oil This material was chromatographed twice on basic alumina each time eluting initially with ether

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

实验步骤: A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methoxyethanimidamide (J.Med.Chem,; 40; 8; 1997; 1230-1246) (177 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as an oil (350 mg). the mixture was stirred for 17 hours The solvent was removed under reduced pressure the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of sodium ethoxide (prepared from sodium (180 mg;7.8 mmol)), distilled ethanol (20 ml), molecular sieves (5 g), and methoxymethylcarboxamide oxime (832 mg; 8 mmol) were added. The mixture was stirred at room temperature for 10 min. whereafter arecoline, HBr (1.0 g; 4.23 mmol) was added. The mixture was heated at 80° C. for 12 hours, filtered, and evaporated in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ether (3×25 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. Upon disolving the residue in ethanol (99.9%)(5 ml) a solution of oxalic acid (350 mg;3.9 mmol) in ethanol (99.9%)(10 ml) was added. Addition of ether gave an analytically pure product in a yield of 500 mg (40%). M.P. 153°-154° C. were added was added filtered evaporated in vacuo To the residue was added water (10 ml) the mixture was extracted with ether (3×25 ml) The combined extracts were dried (MgSO4) evaporated in vacuo was added gave an analytically pure product in a yield of 500 mg (40%)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of sodium ethoxide (prepared from sodium (180 mg;7.8 mmol)), distilled ethanol (20 ml), molecular sieves (5 g), and methoxymethylcarboxamide oxime (832 mg;8 mmol) were added. The mixture was stirred at room temperature for 10 min. whereafter arecoline, HBr (1.0 g;4.23 mmol) was added. The mixture was heated at 80° C. for 12 hours, filtered, and evaporated in vacuo. To the residue was added water (10 ml) and the mixture was extracted with ether (3×25 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. Upon disolving the residue in ethanol (99.9%)(5 ml) a solution of oxalic acid (350 mg;3.9 mmol) in ethanol (99.9%)(10 ml) was added. Addition of ether gave an analytically pure product in a yield of 500 mg (40%). M.P. 153°-154° C. were added was added filtered evaporated in vacuo To the residue was added water (10 ml) the mixture was extracted with ether (3×25 ml) The combined extracts were dried (MgSO4) evaporated in vacuo was added gave an analytically pure product in a yield of 500 mg (40%)

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

实验步骤: 200 mg (0.497 mmol) of the compound from Example 112A and 77 mg (0.746 mmol) of N′-hydroxy-2-methoxyethanimidamide were reacted according to the General Method 2. Yield: 55 mg (24% of theory).

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

实验步骤: 100 mg (0.25 mmol) of the compound from Example 44A and 31 mg (0.30 mmol) of N′-hydroxy-2-methoxyethanimidamide (J. Med. Chem., 1997, 40, 8, 1230-1246) were reacted according to the General Method 1. Yield: 19 mg (16% of theory).

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

实验步骤: A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mol) and the solution was stirred at room temperature for 1 hour. The N′-hydroxy-2-methoxyethanimidamide (J.Med.Chem,; 40; 8; 1997; 1230-1246) (177 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as an oil (350 mg). the mixture was stirred for 17 hours The solvent was removed under reduced pressure the residue was heated neat at 120° C. under a nitrogen atmosphere for 2 hours The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1)