N-[(2-chlorophenyl)methylidene]hydroxylamine

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: 2-Chlorobenzaldoxime (46.7 g, 0.3 mol) in chloroform (350 ml) was cooled and stirred in an ice/salt bath. Chlorine gas was bubbled into the reaction until an excess was present. Excess chlorine and solvent were removed and the remaining 2-chloro-N-hydroxybenzenecarboximidoyl chloride dissolved in ether (250 ml). Solutions of triethylamine (30.3 g, 0.3 mol) in ether (50 ml) and 2-chloroethanethiol (29 g, 0.3 mol) in ether (50 ml) were added simultaneously with stirring and cooling. After the addition, the reaction was allowed to warm to room temperature and left overnight. Water was added, and the ether layer was washed with additional water, then dried with anhydrous magnesium sulphate. Evaporation left a white solid, 2-chloroethyl 2-chloro-N-hydroxybenzenecarboximidothioate, m.p. 115°-117° C., (Found: C, 43.29; H, 3.58; N, 5.59. C9H9Cl2NOS requires C, 43.21; H, 3.62; N, 5.60). Chlorine gas was bubbled into the reaction until Excess chlorine and solvent were removed the remaining 2-chloro-N-hydroxybenzenecarboximidoyl chloride dissolved in ether (250 ml) with stirring cooling After the addition the ether layer was washed with additional water dried with anhydrous magnesium sulphate Evaporation left a white solid, 2-chloroethyl 2-chloro-N-hydroxybenzenecarboximidothioate, m.p. 115°-117° C., (Found: C, 43.29; H, 3.58; N, 5.59. C9H9Cl2NOS requires C, 43.21; H, 3.62; N, 5.60)

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

実験手順: 224 mg of 2-chlorobenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane and then washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 400 mg of 3-(2-chlorophenyl)-5-((2,6-difluorobenzyloxy)methyl)-5-methyl-4,5-dihydroisoxazole. at a temperature of 0° C the reaction mixture was cooled to a temperature 0° C. slowly added The reaction mixture was stirred at room temperature overnight washed with water the obtained organic layer was dried concentrated the concentrate was separated by silicagel column chromatography

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: 224 mg of 2-chlorobenzaldehyde oxime was dissolved in 4 mL of 1,2-dichloroethane, and then, 230 mg of N-chlorosuccinimide and 0.4 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by TLC. When the oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature 0° C., and then, 182 mg of NaHCO3, 27 mg of tetrabutylammonium iodide, and 342 mg of 1,3-difluoro-2-((2-methylallyloxy)methyl)benzene were sequentially, slowly added thereto. The reaction mixture was stirred at room temperature overnight, and then, diluted with dichloromethane and then washed with water, and the obtained organic layer was dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 400 mg of 3-(2-chlorophenyl)-5-((2,6-difluorobenzyloxy)methyl)-5-methyl-4,5-dihydroisoxazole. at a temperature of 0° C the reaction mixture was cooled to a temperature 0° C. slowly added The reaction mixture was stirred at room temperature overnight washed with water the obtained organic layer was dried concentrated the concentrate was separated by silicagel column chromatography

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

実験手順: N-Chlorosuccinimide (56.1 g) was added slowly to a 0° C. solution of the compound prepared in Example 4 (65.4 g) in N,N-dimethylformamide (1.2 L). The reaction was stirred at room temperature overnight and then diluted with ice water and methyl tert-butyl ether. The layers were separated and the aqueous phase was extracted once more with methyl tert-butyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (79.5 g) having the following physical data. The layers were separated the aqueous phase was extracted once more with methyl tert-butyl ether washed with brine dried over anhydrous magnesium sulfate concentrated

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

実験手順: Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data. concentrated to half volume The mixture was extracted twice with ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated

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

実験手順: Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data. concentrated to half volume The mixture was extracted twice with ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated

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

実験手順: Hydroxylamine hydrochloride (35.6 g) was added to a 0° C. mixture of 2-chlorobenzaldehyde (60.0 g) and sodium carbonate (22.6 g) in methanol (1.0 L)-water (1.0 L). The reaction was stirred overnight and then concentrated to half volume. The mixture was extracted twice with ethyl acetate. The organics were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (65.4 g) having the following physical data. concentrated to half volume The mixture was extracted twice with ethyl acetate washed with brine dried over anhydrous magnesium sulfate concentrated

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

実験手順: 2-Chlorobenzaldoxime (46.7 g, 0.3 mol) in chloroform (350 ml) was cooled and stirred in an ice/salt bath. Chlorine gas was bubbled into the reaction until an excess was present. Excess chlorine and solvent were removed and the remaining 2-chloro-N-hydroxybenzenecarboximidoyl chloride dissolved in ether (250 ml). Solutions of triethylamine (30.3 g, 0.3 mol) in ether (50 ml) and 2-chloroethanethiol (29 g, 0.3 mol) in ether (50 ml) were added simultaneously with stirring and cooling. After the addition, the reaction was allowed to warm to room temperature and left overnight. Water was added, and the ether layer was washed with additional water, then dried with anhydrous magnesium sulphate. Evaporation left a white solid, 2-chloroethyl 2-chloro-N-hydroxybenzenecarboximidothioate, m.p. 115°-117° C., (Found: C, 43.29; H, 3.58; N, 5.59. C9H9Cl2NOS requires C, 43.21; H, 3.62; N, 5.60). Chlorine gas was bubbled into the reaction until Excess chlorine and solvent were removed the remaining 2-chloro-N-hydroxybenzenecarboximidoyl chloride dissolved in ether (250 ml) with stirring cooling After the addition the ether layer was washed with additional water dried with anhydrous magnesium sulphate Evaporation left a white solid, 2-chloroethyl 2-chloro-N-hydroxybenzenecarboximidothioate, m.p. 115°-117° C., (Found: C, 43.29; H, 3.58; N, 5.59. C9H9Cl2NOS requires C, 43.21; H, 3.62; N, 5.60)

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

実験手順: To a suspension of 60% NaH (0.063 g, 1.57 mmol) in anhydrous tetrahydrofuran (THF; 5 mL) was added in portions a solution of 2-chlorobenzaldehyde oxime (0.254 g, 1.64 mmol in 1 mL of THF) at room temperature, and the resulting frothy mixture was stirred for 1 h. To the resulting tan mixture was added 5-fluoro-2-methanesulfonylpyrimidin-4-ylamine (0.25 g, 1.31 mmol), at which point the reaction mixture turned orange and most of the solids dissolved. Within minutes of the addition a new solid had precipitated, and the resulting orange mixture was stirred at room temperature for 16 h. The entire reaction mixture was adsorbed to Celite (2.5 g) and the adsorbed material was purified by flash chromatography (24 g SiO2; 0→100% EtOAc/hexanes) to give 2-chlorobenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.173 g, 50%) as a white solid: mp 220-230° C. dec; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.05 (d, J=3.1 Hz, 1H), 7.92 (dd, J=7.8, 1.5 Hz, 1H), 7.54 (m, 5H); ESIMS m/z 267 ([M+H]+), 265 ([M−H]−). dissolved Within minutes of the addition a new solid had precipitated the resulting orange mixture was stirred at room temperature for 16 h The entire reaction mixture the adsorbed material was purified by flash chromatography (24 g SiO2; 0→100% EtOAc/hexanes)

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

実験手順: A solution of 26.0 grams (0.7 mole) of 2-chlorobenzaldoxime and a trace of methyl orange indicator in 200 ml of methanol was stirred in a flask equipped with a drying tube and two dropping funnels. A solution of 13.2 grams (0.21 mole) of sodium cyanoborohydride in 70 ml of methanol and a solution of 190 ml of methanolic 2 N hydrochloric acid were both added dropwise with the rates of addition adjusted to keep the pH of the reaction mixture at about 3.0 as shown by the pink color of the indicator. The borohydride solution was added over a period of about thirty minutes: addition of the acid solution was complete after about four and one half hours. The reaction mixture was stirred at room temperature for about 16 hours and then concentrated under reduced pressure to a solid residue. The solid was slurried with 200 ml of water. The mixture was adjusted to pH 9 with aqueous 6 N potassium hydroxide and then extracted with one portion of 300 ml of chloroform. The organic layer was washed with an aqueous solution saturated with sodium chloride and then dried with sodium sulfate. The solution was filtered from the sodium sulfate, and the filtrate was concentrated under reduced pressure to give a residual solid. The solid was twice recrystallized from 15% ethyl acetate in hexane to give 13.7 grams of N-(2-chlorophenylmethyl)hydroxylamine; mp 73°-75.5° C. The nmr and the ir spectra were consistent with the assigned structure. equipped with a drying tube both added dropwise with the rates of addition addition of the acid solution was complete after about four and one half hours concentrated under reduced pressure to a solid residue extracted with one portion of 300 ml of chloroform The organic layer was washed with an aqueous solution saturated with sodium chloride dried with sodium sulfate The solution was filtered from the sodium sulfate the filtrate was concentrated under reduced pressure to give a residual solid The solid was twice recrystallized from 15% ethyl acetate in hexane