2-chloro-6-methoxybenzaldehyde

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:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.00 g, 3.08 mmol) and 2-chloro-6-methoxybenzaldehyde (526 mg, 3.08 mmol) in THF (10 mL) was added tetra-butylammonium fluoride (121 mg, 462 μmol) at 25° C., the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25° C. for 30 min and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded {4-[2-(2-chloro-6-methoxy-phenyl)-2-hydroxy-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (0.45 g, 35%) as an oil. after the addition The aqueous phase was extracted three times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate Filtration followed by concentration in vacuo gave a brown solid

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

実験手順: A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-chloro-6-methoxybenzaldehyde (9.4 mg) and a solution of (4R,8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (18.3 mg) in N,N-dimethylformamide (50 μl) at 25° C. and the whole was stirred at room temperature for 2 hours. The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90). The solution was concentrated in vacuo. To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution. The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) and eluted with ethyl acetate. The eluate was concentrated in vacuo to give (4R,8aS)-4-benzhydryl-2-(2-chloro-6-methoxybenzyl)octahydropyrrolo[1,2-a]pyrazine (11.0 mg) The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90) The solution was concentrated in vacuo To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) eluted with ethyl acetate The eluate was concentrated in vacuo

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

実験手順: A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-chloro-6-methoxybenzaldehyde (9.4 mg) and a solution of (4R,8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (18.3 mg) in N,N-dimethylformamide (50 μl) at 25° C. and the whole was stirred at room temperature for 2 hours. The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90). The solution was concentrated in vacuo. To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution. The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) and eluted with ethyl acetate. The eluate was concentrated in vacuo to give (4R,8aS)-4-benzhydryl-2-(2-chloro-6-methoxybenzyl)octahydropyrrolo[1,2-a]pyrazine (11.0 mg) The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90) The solution was concentrated in vacuo To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) eluted with ethyl acetate The eluate was concentrated in vacuo

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

実験手順: 2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours. The mixture was cooled to room temperature, and the volume reduced to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase extracted with two additional 100 ml. portions of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the methylene chloride removed by distillation at atomspheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45° C. The mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro-6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHCl3 )]. the stirred reaction mixture heated to reflux for 3 hours by distillation in vacuo Water (400 ml.) and methylene chloride (200 ml.) were added The organic phase was separated the aqueous phase extracted with two additional 100 ml The combined organic layers were dried over anhydrous sodium sulfate filtered the methylene chloride removed by distillation at atomspheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml to crystallize at 45° C The mixture was cooled to room temperature filtered

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

実験手順: 2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours. The mixture was cooled to room temperature, and the volume reduced to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase extracted with two additional 100 ml. portions of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45° C. The mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro-6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHCl3 )]. the stirred reaction mixture heated to reflux for 3 hours by distillation in vacuo Water (400 ml.) and methylene chloride (200 ml.) were added The organic phase was separated the aqueous phase extracted with two additional 100 ml The combined organic layers were dried over anhydrous sodium sulfate filtered the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml to crystallize at 45° C The mixture was cooled to room temperature filtered

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

実験手順: To a solution of furan (10.7 mL, 147 mmol) in anhydrous tetrahydrofuran (100 mL) under an N2 atmosphere at −10°C. was added n-butyl lithium (65 mL of a 2.5M solution in hexanes, 162 mmol) dropwise over 35 minutes (the internal temperature was maintained at less than −7°C.). The mixture was stirred at this temperature for 1 hour 35 minutes before adding a solution of 2-chloro-6-methoxy-benzaldehyde (27.6 g, 162 mmol) in anhydrous tetrahydrofuran (100 mL) dropwise over 1 h 30 (internal temperature approx −5°C.). On completion of addition, the reaction mixture was warmed to room temperature and stirred at this temperature for 18 hours. Water (100 mL) was added then the mixture was diluted with EtOAc (100 ml). The phases were separated and aqueous phase was extracted into EtOAc (2×100 ml). The combined organics extracts were washed with brine (50 ml), dried over MgSO4 and concentrated to a yellow oil. The crude product was adsorbed onto silica and purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product (33.9 g, 97%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 (d, 1H), 7.25-7.21 (m, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.34-6.29 (m, 2H), 6.06 (dt, 1H), 4.38 (d, 1H), 3.87 (s, 3H). was maintained at less than −7°C.) On completion of addition stirred at this temperature for 18 hours The phases were separated aqueous phase was extracted into EtOAc (2×100 ml) The combined organics extracts were washed with brine (50 ml) dried over MgSO4 concentrated to a yellow oil purified by flash chromatography over silica using an EtOAc/isohexane gradient

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

実験手順: 2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours. The mixture was cooled to room temperature, and the volume reduced to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase extracted with two additional 100 ml. portions of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45° C. The mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro-6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHCl 3)]. the stirred reaction mixture heated to reflux for 3 hours by distillation in vacuo Water (400 ml.) and methylene chloride (200 ml.) were added The organic phase was separated the aqueous phase extracted with two additional 100 ml The combined organic layers were dried over anhydrous sodium sulfate filtered the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml to crystallize at 45° C The mixture was cooled to room temperature filtered

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

実験手順: 2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours. The mixture was cooled to room temperature, and the volume reduced to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase extracted with two additional 100 ml. portions of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45° C. The mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro-6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHCl 3)]. the stirred reaction mixture heated to reflux for 3 hours by distillation in vacuo Water (400 ml.) and methylene chloride (200 ml.) were added The organic phase was separated the aqueous phase extracted with two additional 100 ml The combined organic layers were dried over anhydrous sodium sulfate filtered the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml to crystallize at 45° C The mixture was cooled to room temperature filtered

反応条件: temp:0.00; pressure:0.00; stir: