2,4-dibromobutanoyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

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: To a solution of 1.64 g of 3-chloro-6-(4-methoxyphenyl)methylamino-α-cyclopropylethynyl-α-(trifluoromethyl)benzyl alcohol and 2.0 mL of diisopropylethylamine in 30 mL of dry methylene chloride was added 1.6 g of 2,4-dibromobutyryl chloride. After stirring at room temperature overnight, the mixture was poured onto water and extracted with ether. The ether layer was washed with aqueous sodium bicarbonate, dried, and evaporated to an oil. This material was subjected to column chromatography over silica gel (elution with 5-10% ethyl acetate in hexanes) affording 1.13 g of the title compound as a mixture of diastereomers. the mixture was poured onto water extracted with ether The ether layer was washed with aqueous sodium bicarbonate dried evaporated to an oil

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred mixture of 5.3 g (47 mmol) of N-isopropylhydroxylamine hydrochloride in 100 ml of methylene chloride cooled to 5° C. was added 3.8 g (47 mmol) of 50% sodium hydroxide solution in 20 ml of water. To this mixture was added with stirring 12.4 g (47 mmol) of 2,4-dibromobutyrylchloride and twenty minutes later an additional 7.6 g (94 mmol) of 50% sodium hydroxide solution was added. After twenty hours the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated to an oil. This oil was chromatographed on silica gel with 40% ethyl acetate-hexane to afford 1.1 g of oily dihydro-4-bromo-2-isopropyl-2H-1,2-oxazin-3(4H)-one. To this mixture was added was added After twenty hours the organic phase was separated dried over anhydrous magnesium sulfate concentrated to an oil This oil was chromatographed on silica gel with 40% ethyl acetate-hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated at 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature, then a very excessive amount of ethyl acetate was added thereto. The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine, then the resulting solution was dried over magnesium sulfate and evaporated. The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to make the amount of the solution about 50 ml, then which was poured into ethyl acetate. The layer of ethyl acetate was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was washed well with n-hexane, whereby 15.7 g of the objective compound was obtained in 66% yield. The reaction mixture was cooled to room temperature The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine the resulting solution was dried over magnesium sulfate evaporated The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) cooled To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit the mixture was stirred at room temperature for 2 hours The reaction mixture was evaporated which was poured into ethyl acetate The layer of ethyl acetate was washed with water and saturated brine dried over magnesium sulfate evaporated The obtained residue was washed well with n-hexane

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 30 g of 2,4-dibromobutyryl chloride (J. Med. Chem., p1995, 30. 1987) and 13.63 g of urea dissolved into 150 ml of benzene was heated at 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature, then a very excessive amount of ethyl acetate was added thereto. The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine, then the resulting solution was dried over magnesium sulfate and evaporated. The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) and cooled. To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to make the amount of the solution about 50 ml, then which was poured into ethyl acetate. The layer of ethyl acetate was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The obtained residue was washed well with n-hexane, whereby 15.7 g of the objective compound was obtained in 66% yield. The reaction mixture was cooled to room temperature The layer of ethyl acetate was washed with an aqueous solution of sodium bicarbonate and saturated brine the resulting solution was dried over magnesium sulfate evaporated The obtained residue (28 g) was dissolved into 30 ml of tetrahydrofuran (THF) cooled To this mixture was added 4.7 g of NaH (55% in mineral oil) bit by bit the mixture was stirred at room temperature for 2 hours The reaction mixture was evaporated which was poured into ethyl acetate The layer of ethyl acetate was washed with water and saturated brine dried over magnesium sulfate evaporated The obtained residue was washed well with n-hexane

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

実験手順: To a stirred solution of 4-chloro-3-methoxybenzeneamine (4.7 g, 29.6 mmol) in methylene chloride (100 mL) at ˜0° C. was slowly added 2,4dibromobutyryl chloride (5.1 mL, 39 mmol). After the addition, the reaction mixture was stirred for ˜5 minutes and triethylamine (24.7 mL, 178 mmol) was then added. The resulting reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 5 days. Water (˜100 mL) was then added to the reaction mixture. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, ˜33% ethyl acetate/˜67% hexanes) to give the title compound as a yellow solid (3.9 g) melting at 113–115° C. at ˜0° C. After the addition The resulting reaction mixture stirred at room temperature for 5 days The organic layer was separated dried over MgSO4 concentrated The residue was purified by column chromatography (silica gel, ˜33% ethyl acetate/˜67% hexanes)

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

実験手順: To a solution of 4-bromoaniline (1.73 g) in dichloromethane (40 ml), triethylamine (2.8 ml) and a solution of 2,4-dibromobutyryl chloride (3.2 g) in dichloromethane (10 ml) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After addition of 1 N hydrochloric acid to the reaction solution, the mixture was separated into two layers. The aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified. the mixture was separated into two layers The aqueous layer was subjected to extraction with chloroform washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

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

実験手順: To a solution of 4-bromoaniline (1.73 g) in dichloromethane (40 ml), triethylamine (2.8 ml) and a solution of 2,4-dibromobutyryl chloride (3.2 g) in dichloromethane (10 ml) were added under ice cooling, and the mixture was stirred at room temperature for 5 hours. After addition of 1 N hydrochloric acid to the reaction solution, the mixture was separated into two layers. The aqueous layer was subjected to extraction with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified. the mixture was separated into two layers The aqueous layer was subjected to extraction with chloroform washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 500 mL round-bottom flask was charged with 6-bromo-2-methylpyridin-3-amine (8.15 g, 43.6 mmol), THF (180 mL) and triethylamine (9.72 mL, 69.7 mmol). The mixture was cooled to 0° C. and 2,4 dibromobutanoyl chloride (6.39 mL, 48.4 mmol) in THF (45 mL) was added dropwise into the reaction mixture over 30 min. A LC/MS analysis indicated the consumption of the starting material in 1 hour at room temperature. To the reaction mixture was added tetrabutylammonium bromide (0.702 g, 2.179 mmol), followed by 20 mL of 5 M aq KOH solution dropwise. The reaction mixture was stirred at room temperature under argon overnight. A LC/MS analysis confirmed the reaction was complete. Ethyl acetate (50 mL) was added to the reaction. The organic layer was separated and washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to a dark solid (18.5 g), which was used directly to next step. MS (ESI) 334 (M+H). the consumption of the starting material in 1 hour at room temperature The organic layer was separated washed with water (50 mL), brine (50 mL) dried over MgSO4 filtered concentrated to a dark solid (18.5 g), which

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15° C., then warmed to 30° C. and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to afford the product (16.3 g, 98%). 1H NMR δ (400 MHz, CDCl3) 2.35-2.45 (m, 1H), 2.57-2.67 (m, 1H), 2.81 (d, 3H), 3.44-3.54 (m, 2H), 4.46 (q, 1H), 6.34 (s, 1H). The organic layer was separated the aqueous layer re-extracted with DCM (2×10 mL) the combined organic layers were washed with brine (20 mL) dried (MgSO4) evaporated

反応条件: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15° C., then warmed to 30° C. and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to afford the product (16.3 g, 98%). 1H NMR δ (400 MHz, CDCl3) 2.35-2.45 (m, 1H), 2.57-2.67 (m, 1H), 2.81 (d, 3H), 3.44-3.54 (m, 2H), 4.46 (q, 1H), 6.34 (s, 1H). The organic layer was separated the aqueous layer re-extracted with DCM (2×10 mL) the combined organic layers were washed with brine (20 mL) dried (MgSO4) evaporated