阿维巴坦杂质79

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

实验步骤: A mixture of 4-chloro-N-(4-chloro[1,5]naphthyridin-3-yl)butanamide (3.1 g, 11 mmol) and O-benzylhydroxylamine hydrochloride (2.1 g, 13 mmol) in isopropanol (75 mL) was heated at reflux for 24 hours, then pyridinium p-toluenesulfonate (0.25 g, 1.0 mmol) was added and reflux continued for 48 more hours. The reaction mixture was then concentrated under reduced pressure and dichloromethane (50 mL) and saturated aqueous sodium carbonate (25 mL) were added and the mixture was stirred for 72 hours. The dichloromethane layer was then separated, concentrated under reduced pressure, and the residue purified by chromatography (silica gel eluted with 10% methanol in dichloromethane containing 5 mL of ammonium hydroxide solution per liter) to provide 0.13 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c][1,5]naphthyridine. was heated at reflux for 24 hours reflux The reaction mixture was then concentrated under reduced pressure and dichloromethane (50 mL) and saturated aqueous sodium carbonate (25 mL) were added The dichloromethane layer was then separated concentrated under reduced pressure the residue purified by chromatography (silica gel eluted with 10% methanol in dichloromethane containing 5 mL of ammonium hydroxide solution per liter)

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-chloro-N-(4-chloroquinolin-3-yl)propanamide (1.682 g, 6.243 mmol) and O-benzylhydroxylamine hydrochloride (1.10 g, 6.87 mmol) in 60 mL of isopropanol was heated to 40° C. under an atmosphere of N2. After 25 hours the mixture was cooled, solids were filtered off and rinsed with hexane. Chromatography (SiO2, 8-100% EtOAc/dichloromethane) gave 0.6308 g of 1-(benzyloxy)-2-(2-chloroethyl)-1H-imidazo[4,5-c]quinoline as a tan solid. After 25 hours the mixture was cooled solids were filtered off rinsed with hexane

反应条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 5-chloro-N-(4-chloroquinolin-3-yl)pentanamide (1.0 g, 3.365 mmol) and O-benzylhydroxylamine hydrochloride (0.59 g, 3.70 mmol) in 10 mL of isopropanol was heated to 82° C. under an atmosphere of N2. After 2 days the mixture was cooled, solids were filtered off and rinsed with hexane and then ether. The brown solid was dried to give 0.4105 g of 2-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-1-ol. After 2 days the mixture was cooled solids were filtered off rinsed with hexane The brown solid was dried

反应条件: temp:82.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-bromo-N-(4-chloroquinolin-3-yl)butanamide (2.090 g, 6.379 mmol) and O-benzylhydroxylamine hydrochloride (1.527 g, 9.569 mmol) in 20 mL of isopropanol was heated to 82° C. under an atmosphere of N2. After 18 hours the solution was cooled, solids were filtered off and rinsed with ether. The brown solid was dried to give 1.87 g of 2-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-1-ol. After 18 hours the solution was cooled solids were filtered off rinsed with ether The brown solid was dried

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

实验步骤: In step (2) of Reaction Scheme I, an N-(4-chloroquinolin-3-yl)amide or N-(4-chloro[1,5]naphthyridin-3-yl)amide of Formula XXI is reacted with O-benzylhydroxylamine hydrochloride to provide a benzyloxy substituted 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXII. The reaction can be carried out by combining a compound of Formula XXI and O-benzylhydroxylamine hydrochloride in an alcoholic solvent, such as isopropanol, and heating the resulting mixture. In step (2) of Reaction Scheme I

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

实验步骤: A mixture of 5 g of phenylacetaldehyde, 6.7 g of O-benzylhydroxylamine hydrochloride, and 3 g of potassium carbonate in 30 ml of aqueous methanol (1:1) was refluxed for 2 hours. The aqueous solution was extracted with ethyl acetate and the organic solution was dried and evaporated to give 8 g of crude product which was used without purification. was refluxed for 2 hours The aqueous solution was extracted with ethyl acetate the organic solution was dried evaporated

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

实验步骤: To a 0° C. solution of O-benzylhydroxylamine hydrochloride (1.6 g, 10 mmol) in THF (40 mL) was added bromoacetyl bromide (871 μL, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol). The reaction mixture was warmed to room temperature overnight and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography with ethyl acetate-hexane to give 1.27 g (52%) of the title compound. The aqueous layer was separated extracted with ethyl acetate dried over Na2SO4 filtered concentrated in vacuo The crude material was purified by silica gel flash column chromatography with ethyl acetate-hexane

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

实验步骤: To a solution of O-benzylhydroxylamine hydrochloride (1.6 g, 10 mmol) in THF (40 mL) at 0° C., was added bromoacetyl bromide (871 μL, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol). The reaction mixture was warmed to room temperature overnight and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography with ethyl acetate-hexane to give 1.27 g (52%) of the title compound. The aqueous layer was separated extracted with ethyl acetate dried over Na2SO4 filtered concentrated in vacuo The crude material was purified by silica gel flash column chromatography with ethyl acetate-hexane

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

实验步骤: A solution of 2-(4methoxybenzenesulfonylamino)-2-methylpropionic acid (1.08 grams, 3.95 mmole) in methylene chloride (120 mL) was cooled in an ice bath. Triethylamine (2.2 mL, 15.8 mmole), (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (2.6 grams, 5.88 mmole) and O-benzylhydroxylamine hydrochloride (0.95 grams, 5.95 mmole) were subsequently added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was taken up in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine. After drying over sodium sulfate, the solvent was evaporated to afford an oil from which the desired product, N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.41 grams, 95%), a white solid, was obtained by chromatography on silica gel eluting with 1:2 ethyl acetate/hexanes. The solvent was evaporated The solution was washed successively with aqueous 1 N hydrochloric acid solution, aqueous saturated sodium bicarbonate solution, water and brine After drying over sodium sulfate the solvent was evaporated

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

实验步骤: To a suspension of 5.0 g of isatin in 200 ml of ethanol was added a solution of 9.75 g of O-benzylhydroxylamine hydrochloride and 4.18 g of sodium acetate in 50 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gave 6.06 g (71%) of 3-(benzyloxyimino)indolin-2-one as yellow crystals. concentrated The concentrate was diluted with ethyl acetate washed with water The organic layer was dried over anhydrous sodium sulfate concentrated Recrystallization of the crude product from ethanol

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

实验步骤: To a suspension of 4.91 g of 7-methylisatin in 100 ml of ethanol was added a solution of 5.59 g of O-benzylhydroxylamine hydrochloride and 3.29 g of sodium acetate in 40 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from benzene yielded 5.40 g (68%) of the title compound. concentrated The concentrate was diluted with chloroform washed with water The organic layer was dried over anhydrous sodium sulfate concentrated Recrystallization of the crude product from benzene

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

实验步骤: A solution of 1.10 g of methyl ester from Example 10 and 568 mg of O-benzylhydroxylamine hydrochloride in 7 ml of THF was treated at -20° with 3.5 ml of a 2M i-PrMgCl solution in THF and, after 1 hr. at -20°, treated with a further 1.7 ml of the Grignard reagent. After a further 21/2 hrs. at -20° the mixture was treated with ammonium chloride solution and extracted with methylene chloride. The extracts were dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VII, m.p. 135-137°. 2 hrs extracted with methylene chloride The extracts were dried concentrated The residue was crystallized from t-butyl methyl ether/hexane the crystallizate was dried