4-fluoro-N-hydroxybenzenecarboximidoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flame dried flask containing 4-fluorobenzaldoxime (1.00 g) in DMF (100 mL) is added N-chlorosuccinimide (1.70 g) slowly at 0° C. The reaction is warmed to 50° C. for 3 hours, poured over ice, diluted with H2O(100 mL), and extracted with EtOAc (150 mL). The organic phase is washed with H2O (5×100 mL), saline (100 mL), dried over sodium sulfate, concentrated in vacuo to give a quantitative yield of 4-fluoro-N-hydroxy-benzenecarboximidoyl chloride. To a flask containing 4-fluoro-N-hydroxy-benzenecarboximidoyl chloride (1.25 g) and allyl acetamide (780 mg) in methylene chloride (75 mL) at 0° C. under an inert atmosphere is added triethylamine (3.05 mL, 21.60 mmol). The reaction is slowly warmed to ambient temperature, stirred 20 hours, quenched with water (100 mL), and extracted with methylene chloride (3×100 mL). The organic extracts are combined, washed with saline (50 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (99/1). The appropriate fractions are combined (Rf =0.26, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give (±)-N-[[4,5-dihydro-3-(4-fluorophenyl)-5-isoxazolyl]methyl]acetamide, mp 167-168° C. quenched with water (100 mL) extracted with methylene chloride (3×100 mL) washed with saline (50 mL) dried over sodium sulfate concentrated in vacuo chromatographed on silica gel (230-400 mesh, 200 mL) eluting with chloroform/methanol (99/1) concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-fluorobenzaldehyde oxime (222 mg, 1.60 mmol) dissolved in 3 mL of DMF was treated with N-chlorosuccinimide (212 mg, 1.60 mmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and then washed with H2O (4×20 mL). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as a white solid. The material was dissolved in 10 mL of CH2Cl2 and the solution was cooled to 0° C. A solution of (11S)-11-ethynyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (190 mg, 0.76 mmol) dissolved in 3 mL of CH2Cl2 was then added followed by triethylamine (318 μL, 2.29 mmol). The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and chromatography (0-2% methanol/CHCl3) gave (11R)-11-[3-(4-fluorophenyl)isoxazol-5-yl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light-brown solid. washed with H2O (4×20 mL) The organic portion was washed with brine dried over Na2SO4 filtered concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-fluorobenzaldehyde oxime (222 mg, 1.60 mmol) dissolved in 3 mL of DMF was treated with N-chlorosuccinimide (212 mg, 1.60 mmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and then washed with H2O (4×20 mL). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as a white solid. The material was dissolved in 10 mL of CH2Cl2 and the solution was cooled to 0° C. A solution of (11S)-11-ethynyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (190 mg, 0.76 mmol) dissolved in 3 mL of CH2Cl2 was then added followed by triethylamine (318 μL, 2.29 mmol). The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and chromatography (0-2% methanol/CHCl3) gave (11R)-11-[3-(4-fluorophenyl)isoxazol-5-yl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light-brown solid. washed with H2O (4×20 mL) The organic portion was washed with brine dried over Na2SO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-fluoro-benzaldehyde oxime (1.39 g, 10.0 mmol) in DMF (10 mL) was added portionwise within 5 minutes at 15 to 20° C. N-chlorosuccinimide (1.36 g, 10.0 mmol) and the resulting mixture was stirred at room temperature for 90 minutes. The yellow solution (containing N-Hydroxy-4-fluoro-benzenecarboximidoyl chloride) was then treated within 2 minutes at room temperature with a solution of ethyl-3-(1-pyrrolidino)crotonate (1.89 g, 10.0 mmol) in 5 mL of DMF and the resulting solution was stirred at room temperature for 28 hours. The mixture was diluted with water (25 mL) and subsequently extracted with ethyl acetate (4×25 mL). The combined organic layers were washed with 1 M HCl (2×25 mL) and water (2×25 mL), dried over Na2SO4 and subsequently concentrated to dryness (45° C./25 mbar) to afford 2.37 g (95%) of the title ester as a brownish solid with a purity of 100% (by GC) and 97% (by HPLC). was added portionwise within 5 minutes at 15 to 20° C subsequently extracted with ethyl acetate (4×25 mL) The combined organic layers were washed with 1 M HCl (2×25 mL) and water (2×25 mL) dried over Na2SO4 subsequently concentrated to dryness (45° C./25 mbar)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and N-(3-butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was stirred at room temperature for 24 hours and then diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over potassium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 29.87 g of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione. A portion of the product was recrystallized from isopropyl alcohol and dried to provide an analytically pure sample as white crystals, mp 155.0-156.0° C. washed sequentially with aqueous potassium carbonate, water, and brine dried over potassium sulfate filtered and concentrated under reduced pressure The resulting solid was triturated with ethanol isolated by filtration washed with diethyl ether

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (54 g, 230 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-3-nitro-N-prop-2-ynylquinolin-4-amine (30.2 g, 115 mmol), prepared as described in Part A of Example 3, in dichloromethane (1 L) at room temperature. Triethylamine (26 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16.5 hours and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, and the work-up and isolation procedures described in Part B of Example 18 were followed to provide 36.12 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitroquinolin-4-amine as a yellow solid. prepared at room temperature a precipitate formed concentrated under reduced pressure The resulting solid was dissolved in ethyl acetate

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (52.0 g, 225 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine (26.92 g, 112.3 mmol) in anhydrous dichloromethane (1 L) at room temperature. Triethylamine (25 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16 hours, diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to a suspension. The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether and dried under vacuum to provide 32.45 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine. a precipitate formed washed sequentially with aqueous potassium carbonate, water, and brine dried over sodium sulfate filtered and concentrated under reduced pressure to a suspension The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether dried under vacuum

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (52.0 g, 225 mmol), prepared as described in Parts A through C of Example 11, was added to a solution of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine (26.92 g, 112.3 mmol) in anhydrous dichloromethane (1 L) at room temperature. Triethylamine (25 g, 250 mmol) was added; a precipitate formed. The resulting mixture was heated at 40° C. under nitrogen for 16 hours, diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure to a suspension. The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether and dried under vacuum to provide 32.45 g of 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine. a precipitate formed washed sequentially with aqueous potassium carbonate, water, and brine dried over sodium sulfate filtered and concentrated under reduced pressure to a suspension The suspension was filtered to isolate a yellow solid, which was washed with diethyl ether dried under vacuum

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (44.6 g, 257 mmol) was added to a mixture of 3-nitro-N-prop-2-ynyl[1,5]naphthyridin-4-amine (29.34 g, 129 mmol) and anhydrous triethylamine (39.5 mL, 283 mmol) in anhydrous dichloromethane (1 L). The reaction was stirred at 40° C. for 18 hours and then concentrated under reduced pressure. The residue was triturated with water; the resulting solid was isolated by filtration, washed sequentially with isopropanol and a small amount of diethyl ether, and then dried under vacuum to provide 15.02 g of N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine as a brownish-green solid. concentrated under reduced pressure The residue was triturated with water the resulting solid was isolated by filtration washed sequentially with isopropanol a small amount of diethyl ether, and then dried under vacuum