2,6-difluorobenzaldehyde

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:

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:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of (diazomethyl)trimethylsilane (2.0 M in hexanes, 25 mL, 50 mmol) in tetrahydrofuran (100 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 20 mL, 50 mmol) over 5 minutes. After the addition was complete, the reaction mixture temperature was maintained at about −78° C. for 30 minutes and then 2,6-difluorobenzaldehyde (7.1 g, 50 mmol) was added portionwise. The reaction mixture was maintained at −78° C. for an additional 30 minutes and then allowed to warm to room temperature, during which time gas evolution occurred. The reaction mixture was again cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 28 mL, 70 mmol) was added over 5 minutes. After 15 minutes at −78° C., methyl chloroformate (7.8 mL, 100 mmol) was added to the reaction mixture. After 30 minutes, the reaction mixture was allowed to warm to 0° C., and then partitioned between diethyl ether and saturated ammonium chloride solution. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (8.0 g). After the addition The reaction mixture was maintained at −78° C. for an additional 30 minutes to warm to room temperature, during which time gas evolution The reaction mixture was again cooled to −78° C. After 30 minutes to warm to 0° C. partitioned between diethyl ether and saturated ammonium chloride solution The organic phase was separated dried over magnesium sulfate filtered concentrated under reduced pressure The resulting material was purified by silica gel chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant)

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

実験手順: To a mixture of 2,6-difluorobenzaldehyde (10.0 g, 70 mmol) in acetone (85 mL) was added sodium hydroxide (1 N solution, 106 mL). After stirring at room temperature for 1.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with chloroform (2×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (0 to 20% gradient of ethyl acetate in hexanes as eluant) to afford the title product as a solid (8.1 g). extracted with chloroform (2×150 mL) The combined organic layers were dried over magnesium sulfate filtered concentrated under reduced pressure The resulting material was purified by MPLC (0 to 20% gradient of ethyl acetate in hexanes as eluant)

反応条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.300 g, 1.4 mmol), ammonium acetate (0.104 g, 1.4 mmol) and 2,6-difluorobenzaldehyde (0.145 mL, 1.3 mmol) in acetic acid (6 mL) was heated in the microwave at 160° C. for 2 minutes. The reaction mixture was diluted with MeOH and purified by SPE using a MP-TsOH resin cartridge (2500 mg). The crude mixture obtained was purified by preparative HPLC to afford ethyl 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxylate (0.029 g, 0.09 mmol, 7%) as a pale solid. LCMS (2) Rt: 2.46 min; m/z (ES+) 330. purified by SPE The crude mixture obtained was purified by preparative HPLC

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

実験手順: To a 100ml reaction bottle equipped with magnetic stir bar was charged 5.0 g (35.2 mmole) of 2,6-difluorobenzaldehyde in 20 ml acetone and to this was added 3.4 g of 50% aqueous NaOH (42 mmole) in 60 ml water (exothermic) and stirred at room temperature. The reaction was monitored by GLC and after 2 hours the reaction was worked up. The reaction mixture was extracted with 50 ml CHCl3, washed with 50 ml H2O, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuuo on a rotary evaporator to afford 5.7 g of trans-4-(2,6-difluorophenyl)-3-buten-2-one as a yellow oil in 81% purity by GC. and 89.5% isolated yield. To a 100ml reaction bottle equipped with magnetic stir bar The reaction mixture was extracted with 50 ml CHCl3 washed with 50 ml H2O dried over anhydrous MgSO4 filtered the solvent removed in vacuuo on a rotary evaporator

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 332 g of 2,6-difluorobenzaldehyde were placed under nitrogen in a 0.7 1 autoclave and admixed with 6.4 g of 5% strength by weight palladium-on-carbon (catalyst from Heraeus type K-0227, containing 50% by weight of water). The autoclave was closed and purged with nitrogen. 50 bar of hydrogen were then injected and the contents of the autoclave were heated to 80° C. Hydrogenation was carried out for a total of 4 hours while stirring. After cooling and venting, the reaction mixture was filtered through Celite® filter aid, the autoclave was rinsed with 50 g of isopropanol and the filter cake was washed with 150 g of isopropanol. The solvent was distilled from the combined filtrates and washings and the crude product mixture was subsequently distilled off. 288 g of 2,6-difluorobenzyl alcohol were obtained (90% of theory). The autoclave was closed purged with nitrogen was carried out for a total of 4 hours After cooling the reaction mixture was filtered through Celite® filter aid the autoclave was rinsed with 50 g of isopropanol the filter cake was washed with 150 g of isopropanol The solvent was distilled from the combined filtrates and washings the crude product mixture was subsequently distilled off

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

実験手順: Particularly preferably, 2,6-dichlorobenzaldehyde is used in the process of the invention and 2-fluoro-6-chlorobenzaldehyde, 2-fluoro-6-chlorobenzyl alcohol, 2,6-difluorobenzaldehyde or 2,6-difluorobenzyl alcohol is obtained or 2,4-dichlorobenzaldehyde is used and 2,4-difluoro-benzaldehyde or 2,4-difluorobenzyl alcohol is obtained or 3,4-dichloro-benzaldehyde is used and 3-chloro-4-fluorobenzaldehyde or 3-chloro-4-fluorobenzyl alcohol is obtained.