N-hydroxyethanimidoyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane 45 described above and 6.3 ml of triethylamine are added with stirring at 0° C. to a solution of 8.0 g of 2,2-dimethyl-5-(ethynyl)-4H-(1,3)benzodioxin-4-one in 400 ml of methyl tert-butyl ether, and the mixture is allowed to come to room temperature and is subsequently stirred overnight. A further 53 ml of the solution of 1-chloro-1-(N-hydroxyimino)ethane described above and 6.3 ml of triethylamine are added and the reaction solution is stirred at room-temperature for 24 h. It is then poured into water containing phosphoric acid (pH 4) at 0° C. and extracted with methyl tert-butyl ether, and the combined organic phases are carefully washed with water, dried over sodium sulfate and concentrated. 8.8 g of crude product remain, which is chromatographed on silica gel using n-hexane/ethyl acetate. 4.1 g of colorless crystals are obtained, m.p. 74° C. (cf. Table 1, No. 1.020). to come to room temperature are added extracted with methyl tert-butyl ether the combined organic phases are carefully washed with water dried over sodium sulfate concentrated which is chromatographed on silica gel

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the presence of triethylamine (5.2 mL, 10.7 mmol) in a solution of THF (50 mL), 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 3.50 g, 10.7 mmol) was reacted with N-hydroxyethanimidoyl chloride that was generated from acetaldehyde oxime (1.90 g, 32.1 mmol) and N-chlorosuccinimide (4.30 g, 32.1 mmol) using the method described in Part B of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate). The appropriate fractions were combined and concentrated to provide a solid that was triturated with diethylether. The solid was isolated by filtration and dried to yield 4-chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g) as a white solid. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate) concentrated to provide a solid that was triturated with diethylether The solid was isolated by filtration dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the presence of triethylamine (5.2 mL, 10.7 mmol) in a solution of THF (50 mL), 4-chloro-2-(ethoxymethyl)-1-pent-4-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part F of Example 6, 3.50 g, 10.7 mmol) was reacted with N-hydroxyethanimidoyl chloride that was generated from acetaldehyde oxime (1.90 g, 32.1 mmol) and N-chlorosuccinimide (4.30 g, 32.1 mmol) using the method described in Part B of Example 5. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate). The appropriate fractions were combined and concentrated to provide a solid that was triturated with diethylether. The solid was isolated by filtration and dried to yield 4-chloro-2-(ethoxymethyl)-1-[3-(3-methylisoxazol-5-yl)propyl]-1H-imidazo[4,5-c]quinoline (1.87 g) as a white solid. The crude product was purified by flash chromatography (silica gel, gradient elution with 4:1 to 2:3 hexanes/ethyl acetate) concentrated to provide a solid that was triturated with diethylether The solid was isolated by filtration dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Hydroxyethanimidoyl chloride (prepared as described in Part D of Example 1, 2.10 g, 22.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline prepared as described in Part D of Example 3, 5.39 g, 18.0 mmol) and triethylamine (3.70 mL, 27.0 mmol) in dichloromethane (60 mL). The solution was heated at reflux for 16 hours and then was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate) to provide 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g) as a white solid. prepared The solution was heated at reflux for 16 hours was concentrated under reduced pressure The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-Hydroxyethanimidoyl chloride (prepared as described in Part D of Example 1, 2.10 g, 22.5 mmol) was added to a solution of 4-chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline prepared as described in Part D of Example 3, 5.39 g, 18.0 mmol) and triethylamine (3.70 mL, 27.0 mmol) in dichloromethane (60 mL). The solution was heated at reflux for 16 hours and then was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate) to provide 4-chloro-2-(ethoxymethyl)-1-[(3-methylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (4.21 g) as a white solid. prepared The solution was heated at reflux for 16 hours was concentrated under reduced pressure The crude product was purified by flash chromatography (silica gel, gradient elution from 7:3 to 2:3 hexanes/ethyl acetate)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid. After 20 hours the solution was washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate filtered concentrated The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid. After 20 hours the solution was washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate filtered concentrated The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Triethylamine (123.4 mg, 170 μL, 1.21 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)prop-2-yn-1-yl]-4-methyl-1,3-oxazolidin-2-one (21.9 mg, 0.0423 mmol) and N-hydroxyethanimidoyl chloride (124.4 mg, 1.33 mmol) in dry toluene (2 mL) at room temperature under N2. The reaction was heated at reflux for 2 days. The reaction mixture was cooled to room temperature, diluted with 1N HCl and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-methylisoxazol-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.38 (20% EtOAc/hexanes). LCMS calc.=575.2; found=575.3 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.84 (s, 1H); 7.64 (s, 2H); 7.31 (d, J=8.3 Hz, 1H); 6.68 (d, J=11.8 Hz, 1H); 5.27 (d, J=8.0 Hz, 1H); 4.78 (d, J=15.6 Hz, 1H); 4.00 (d, J=15.6 Hz, 1H); 3.82 (s, 3H); 3.72-3.68 (m, 1H); 3.22-3.16 (m, 1H); 2.38 (s, 3H); 1.24 (d, J=7.0 Hz, 3H); 1.22 (d, J=7.0 Hz, 3H); 0.42 (d, J=6.6 Hz, 3H). The reaction was heated at reflux for 2 days extracted with EtOAc (3×20 mL) The combined extracts were dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved in EtOAc (15 ml) under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) and KHCO3 (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the subtitle compound (0.031 g, 53%) as a white powder. the mixture was partitioned between EtOAc (25 ml) and water (25 ml) The organic phase was washed (water, brine) dried Filtration and evaporation gave a crude mixture which was purified by chromatography on silica Freeze-drying the pure fractions

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound obtained in step (a) (0.050 g, 0.15 mmol) was dissolved in EtOAc (15 ml) under magnetic stirring. To this solution was added N-hydroxyacetimidoyl chloride (0.15 g, 1.6 mmol), water (0.3 ml) and KHCO3 (0.16 g, 1.6 mmol). The mixture was stirred for 2 days at which time LC-MS showed 90% conversion. The reaction was stopped and the mixture was partitioned between EtOAc (25 ml) and water (25 ml). The organic phase was washed (water, brine) and dried. Filtration and evaporation gave a crude mixture which was purified by chromatography on silica. Freeze-drying the pure fractions afforded the subtitle compound (0.031 g, 53%) as a white powder. the mixture was partitioned between EtOAc (25 ml) and water (25 ml) The organic phase was washed (water, brine) dried Filtration and evaporation gave a crude mixture which was purified by chromatography on silica Freeze-drying the pure fractions

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution (40 mL) of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (2.7 g) and triethylamine (7.5 mL) in methylene chloride was added N-hydroxyethanimidoyl chloride (5 g) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 28%). washed with 1 N hydrochloric acid with saturated brine, and dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography