N-methylhydroxylamine;hydrochloride

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

实验步骤: 0.62 g of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid ethyl ester (XVIIa) was mixed with 0.21 g of N-methylhydroxylamine hydrochloride and 0.42 ml of triethylamine in 10 ml of dry ethanol. The mixture was refluxed for 20 hours, evaporated to dryness and purified on silica gel giving 0.275 g (42%) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) as a colorless oil 1H-NMR (CDCl3, δ in ppm): 7.93 (d, 1H), 7.30-7.45 (m, 5H), 5.43 (s, 1H), 4.37 (q, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.40 (t, 3H). The mixture was refluxed for 20 hours evaporated to dryness purified on silica gel giving 0.275 g (42%) of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) as a colorless oil 1H-NMR (CDCl3, δ in ppm): 7.93 (d, 1H), 7.30-7.45 (m, 5H), 5.43 (s, 1H), 4.37 (q, 2H), 2.99 (s, 3H), 2.61 (s, 3H), 1.40 (t, 3H)

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

实验步骤: 300 mg 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa), 80 mg MeNHOH.HCl and 100 mg triethylamine were refluxed in 2 ml of ethanol for 18 hours. After evaporation of the solvent the residue was purified on silica gel giving 210 mg (65%) of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) as a colorless resin. After evaporation of the solvent the residue was purified on silica gel giving 210 mg (65%) of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) as a colorless resin

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

实验步骤: To a suspension of N-methyl hydroxylamine hydrochloride (9.82 g, 117.6 mmol) in THF (150 mL) at room temperature there was added triethylamine (16.3 mL, 117.6 mmol) and the mixture stirred for 10 minutes. There was added, over 15 minutes, a solution of the isocyanate from Step 1 in THF (100 mL). After 2 hours of stirring at room temperature, the THF was evaporated and the residue, on trituration with water, afforded a yellow solid which was filtered. This solid was stirred in ether (150 mL) and filtered again. This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride. The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours and filtered and the solid crystallized from ethyl acetate to afford the pure title product as yellow crystals, mp 190-192° C. dec. There was added, over 15 minutes After 2 hours of stirring at room temperature the THF was evaporated the residue, on trituration with water, afforded a yellow solid which was filtered This solid was stirred in ether (150 mL) filtered again This crude material was chromatographed on silica gel eluting with 5% ethanol in methylene chloride The more polar component of the mixture was stirred with methylene chloride (50 mL) for 2 hours filtered the solid crystallized from ethyl acetate

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

实验步骤: To a suspension of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene) inden-3-ylacetic acid (U.S. Pat. No. 3,647,858; U.S. Pat. No. 3,654,349; J.O.C. Vol. 42, 1914-1919 (1977) (130 mg, 0.38 mmol) in methylene chloride (3 mL) at room temperature there was added oxalyl chloride (96.5 mg, 0.76 mmol) and one drop of N, N-dimethylformamide (DMF). When gassing had subsided another drop of DMF was added and stirring was continued for 30 minutes. This solution was added, at 0° C., to a mixture of N-methyl hydroxylamine hydrochloride (125 mg, 1.5 mmol) and triethylamine (253 mg, 2.5 mmol) in tetrahydrofuran (THF) (5 mL). After 30 minutes at 0° C., the mixture was diluted with water and ethyl acetate and acidified with iN aqueous HCl. The crude product from the organic extract was crystallized from a mixture of ethyl acetate and hexane to afford the title product as yellow-orange crystals, mp: slow decomp. from 118° C. was added After 30 minutes at 0° C. The crude product from the organic extract was crystallized from a mixture of ethyl acetate and hexane

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

实验步骤: N-methylhydroxylamine hydrochloride (14.6 g.) in 20 ml. of water was cooled in an ice-bath and treated with 20 g. of t-butyl azidoformate. A solution of 22.4 g. of sodium hydroxide in 80 ml. of water was added dropwise with stirring over 45 minutes while controlling the temperature below 10° C. The mixture was allowed to warm to room temperature with stirring over a 60 minute period after the addition during which time a little more sodium hydroxide solution and N-methyl hydroxylamine were added. The solution was extracted with 2 × 50 ml. of ether, and the extracts were discarded. The aqueous phase, with cooling, was adjusted to pH 3.5 with 6 N hydrochloric acid, and extracted with 5 × 60 ml. of ether. The combined ether extracts were dried over magnesium sulfate and evaporated to 16 g. of oily N-t-butoxycarbonyl-N-methyl hydroxylamine. treated with 20 g the temperature below 10° C with stirring over a 60 minute period were added The solution was extracted with 2 × 50 ml The aqueous phase, with cooling extracted with 5 × 60 ml The combined ether extracts were dried over magnesium sulfate evaporated to 16 g

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 0° C. solution of N-methylhydroxylamine hydrochloride (701 mg, 2 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (1.75 ml, 3.0 eq.) was added 4-n-heptyl benzoic acid chloride (1.0 g, 4.2 mmol). The solution was stirred for 1/2 hour at 0° C. then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer washed with H2O, 1N HCl (2×), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave an oil which was flash chromatographed on LPS-1 silica gel eluting with (1:1) hexane:EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 448 mg (43%) as a light yellow oil which solidified upon standing. TLC (1:1) Hexane:EtOAc Rf =0.18, UV+PMA. Product streaks to baseline. to warm to room temperature stir overnight the organic layer washed with H2O, 1N HCl (2×), and brine dried over anhydrous MgSO4 Concentration in vacuo gave an oil which chromatographed on LPS-1 silica gel eluting with (1:1) hexane Product containing fractions were concentrated in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a 0° C. solution of N-methylhydroxylamine hydrochloride (793 mg, 2 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (198 ml, 3.0 eq.) was added 4-(n-pentyl) benzoic acid chloride (1.0 ml, 4.75 mmol). The solution was stirred for 0.5 hour at 0° C. then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O, 1N HCl (2×), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave a yellow oil which was flash chromatographed in LPS-1 silica gel eluting with (1:1) hexane/EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 380 mg (37%) as a light yellow oil. to warm to room temperature stir overnight the organic layer was washed with H2O, 1N HCl (2×), and brine dried over anhydrous MgSO4 Concentration in vacuo gave a yellow oil which chromatographed in LPS-1 silica gel eluting with (1:1) hexane/EtOAc Product containing fractions were concentrated in vacuo

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

实验步骤: To a stirred suspension of 9.97 g (50.9 mmol) of 2,3,4-trimethoxybenzaldehyde and 4.43 g (53.1 mmol) of N-methylhydroxylamine hydrochloride in 100 mL of ethanol was added a solution of 2.05 g (51.3 mmol) of sodium hydroxide in 15 mL of water. The mixture was stirred at room temperature for 22 h and evaporated in vacuo to remove the bulk of the solvent. The residual solid was taken up in 150 mL of dichloromethane, washed with 50 mL of water and dried over MgSO4. Removal of the solvent afforded 11.31 g of N-methyl-C-(2,3,4-trimethoxyphenyl)nitrone as a white solid. 1H-NMR (CDCl3) d 3.85-3.95 (9H), 6.75 (d, 1H), 7.65 (s, 1H), 9.1 (d, 1H). evaporated in vacuo to remove the bulk of the solvent washed with 50 mL of water dried over MgSO4 Removal of the solvent

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 (60 mmole) of methylhydroxylamine hydrochloride and 8 g (61 mmole) of cinnamaldehyde were combined in 25 mL of anhydrous methanol and stirred for 15 minutes at room temperature. The solvent was then removed at reduced pressure and replaced with 50 mL of methylene chloride. The solution was washed with 75 mL of saturated aqueous sodium bicarbonate followed by washing with a brine solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The solid residue was titurated with ether, filtered and dried. There was obtained 7.2 g (45 mmole or 74% yield) of α-cinnamyl-N-methylnitrone having a melting point of 85-6° C. The solvent was then removed at reduced pressure The solution was washed with 75 mL of saturated aqueous sodium bicarbonate by washing with a brine solution After drying over anhydrous magnesium sulfate the solvent was removed under reduced pressure filtered dried

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

实验步骤: 10.0 g of N-methylhydroxylamine hydrochloride was added to 100 ml of tetrahydrofuran. 19.8 g of pyridine was added to the mixture. A solution of 16.8 g of benzoyl chloride in 100 ml of tetrahydrofuran was dropwise added to the mixture under stirring at room temperature over 1 hr. The stirring was continued at room temperature for additional 8 hr. to conduct the reaction. 50 ml of dilute hydrochloric acid was added thereto and then tetrahydrofuran was removed under reduced pressure. After extraction with ethyl acetate, the extract was dehydrated over anhydrous magnesium sulfate. Ethyl acetate was removed under reduced pressure. The resultant crude product was purified according to column chromatography (packing: silica gel, developer: ethyl acetate/hexane) to obtain 8.5 g of N-benzoyl-N-methylhydroxylamine as an oil having a melting point of 20° C. or below. 130 ml of tetrahydrofuran was added to 7.6 g of N-benzoyl-N-methylhydroxylamine and 12.6 g of 4-vinyl-1-naphthalenesulfonyl chloride. A solution of 5.1 g of triethylamine in 20 ml of tetrahydrofuran was dropwise added thereto under stirring over 2 hr. while the mixture was cooled so that the temperature of the solution was below 25° C. After conducting the reaction at 15° to 25° C. for additional 2 hr., the reaction solution was poured into 700 ml of water and the precipitate thus formed was collected by filtration. After recrystallization from acetonitrile, 12.8 g of o-(4-vinyl-1-naphthalenesulfonyl)-N-benzoyl-N-methylhydroxylamine was obtained. The stirring was continued at room temperature for additional 8 hr the reaction tetrahydrofuran was removed under reduced pressure After extraction with ethyl acetate Ethyl acetate was removed under reduced pressure The resultant crude product was purified

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

实验步骤: To a stirring solution of 4.77 g of N-methylhydroxylamine hydrochloride in 100 ml of absolute ethanol was added 6.38 g of potassium tert-butoxide. To the resulting suspension was added 6.98 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, and an additional 150 ml of absolute ethanol. The suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride and the filter cake was washed with absolute ethanol. The resulting solution was concentrated in vacuo to a waxy solid. The solid was dissolved in 300 ml of methylene chloride and partitioned against 200 ml of water. The organic phase was dried with 200 ml of saturated aqueous sodium chloride, collected, dried again (Na2SO4), filtered, and concentrated in vacuo to an oil. The oil solidified upon standing, and was recrystallized from isopropanol to give 3.09 g of 4-(4,10-dihydro-10 -oxothieno[3,2-c][1]benzoxepin-8-yl)-N-hydroxy-N-methyl-1-butylamine, m.p. 107°-108° C. to reflux for 24 hours The suspension was filtered to remove potassium chloride the filter cake was washed with absolute ethanol The resulting solution was concentrated in vacuo to a waxy solid The solid was dissolved in 300 ml of methylene chloride partitioned against 200 ml of water The organic phase was dried with 200 ml of saturated aqueous sodium chloride collected dried again (Na2SO4) filtered concentrated in vacuo to an oil was recrystallized from isopropanol

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

实验步骤: To a stirring solution of 13.06 g of N-methylhydroxylamine hydrochloride in 250 ml of absolute ethanol was added 17.48 g of potassium tert-butoxide. To the resulting suspension was added 9.0 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propanol methanesulfonate. The resulting product suspension was allowed to reflux for 24 hours and was then cooled to room temperature. The suspension was filtered to remove potassium chloride, and the mother liquor was then treated with 200 ml of water and concentrated in vacuo to remove ethanol. The resulting mixture was partitioned against a total of 450 ml of methylene chloride and 250 ml of water. The organic phase was washed with 250 ml of saturated sodium chloride solution, dried (Na2SO4), filtered, and concentrated in vacuo to a viscous oil which solidified upon triturating the oil, with 10 ml of ethyl acetate and 3 drops of hexane and refrigerating. Thin layer analysis of the solids indicated a mixture, which was separated via HPLC (silica gel). The purified oil solidified upon standing to give 4.03 g of 3-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-hydroxy-N-methyl-1-propylamine m.p. 113°-114.5° C. to reflux for 24 hours The suspension was filtered to remove potassium chloride the mother liquor was then treated with 200 ml of water concentrated in vacuo to remove ethanol The resulting mixture was partitioned against a total of 450 ml of methylene chloride and 250 ml of water The organic phase was washed with 250 ml of saturated sodium chloride solution dried (Na2SO4) filtered concentrated in vacuo to a viscous oil which upon triturating the oil was separated via HPLC (silica gel)