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In tetrahydrofuran at -78℃; for 1h; Schlenk technique; Inert atmosphere; |
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With hydrogenchloride In tetrahydrofuran |
77.1 3-chloro-5-((1-((5-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazin-3-yl)methyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyrimidin-5-yl)oxy)benzonitrile
Step 1 ethyl 2-(4-fluorophenyl)-2-oxoacetate Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl oxalate (360 g, 2.46 mol, 1.00 equiv) in tetrahydrofuran (3000 mL). This was followed by the addition of a solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran (1.9 L, 1 N 0.78 equiv) dropwise with stirring at -78° C. in 2.5 hr. The resulting solution was stirred for 30 min at -78° C., then slowly warmed to -20° C. The reaction was then quenched by the addition of 500 mL of 2 M HCl. The resulting solution was extracted with 2*500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2*200 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (5 mm Hg) and the fraction was collected at 106° C. This resulted in 290 g of ethyl 2-(4-fluorophenyl)-2-oxoacetate as a yellow oil. |
| 290 g |
In tetrahydrofuran at -78 - -20℃; Inert atmosphere; |
77.1 Step 1 ethyl 2-(4-fluorophenyl)-2-oxoacetate
Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl oxalate (360 g, 2.46 mol, 1.00 equiv) in tetrahydrofuran (3000 mL). This was followed by the addition of a solution of 4- fluorophenylmagnesium bromide in tetrahydrofuran (1.9 L, 1 N 0.78 equiv) dropwise with stirring at -78 C in 2.5 hr. The resulting solution was stirred for 30 min at -78 C , then slowly warmed to -20 C. The reaction was then quenched by the addition of 500 mL of 2 M HC1. The resulting solution was extracted with 2 x 500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 200 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (5 mm Hg) and the fraction was collected at 106 C. This resulted in 290 g of ethyl 2-(4-fluorophenyl)-2-oxoacetate as a yellow oil. |
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In tetrahydrofuran at -78℃; for 1h; |
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In tetrahydrofuran at -78 - 20℃; |
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In tetrahydrofuran at -78℃; for 3h; Inert atmosphere; |
Stepl: ethyl 2-(4-fluorophenyl)-2-oxoacetate
Into a 10-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of diethyl oxalate (360 g, 2.46 mol, 1.00 equiv) in tetrahydrofuran (3000 mL). This was followed by the addition of a solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran (1.9 L, 1 N 0.78 equiv) dropwise with stirring at -78 °C in 2.5 hr. The resulting solution was stirred for 30 min at -78 °C, then slowly warmed to -20 °C. The reaction was then quenched by the addition of 500 mL of 2 M HC1. The resulting solution was extracted with 2 x 500 mL of ethyl acetate and the organic layers combined.The resulting mixture was washed with 2 x 200 mL of brine. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (5 mm Hg) and the fraction was collected at 106 °C to provide ethyl 2-(4-fluorophenyl)-2- oxoacetate. |
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In tetrahydrofuran at -78 - 25℃; for 1.5h; |
A Step A- Ethyl 2-(4-fluorophenyl)-2-oxoacetate
Into a flask was placed a solution of diethyl oxalate (28.5 g, 195 mmol) in THF (300 mL) which was cooled at -78°C. 4- Fluorophenylmagnesium bromide (150 mL, 1.0 M in THF) was added dropwise, and the resulting solution was stirred for 1.5 h with warming to ambient temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride. The resulting solution was extracted with EtOAc (3X) and the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography with EtOAc:petroleum ether (1%) to afford the title compound |
| 0.74 g |
In tetrahydrofuran at -78 - 20℃; for 3h; Inert atmosphere; |
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In tetrahydrofuran at -78℃; for 1.5h; |
A Step A- Ethyl 2-(4-fluorophenyl)-2-oxoacetate:
Into a flask was placed a solution ofdiethyl oxalate (28.5 g, 195 mmol) in THF (300 mL) which was cooled at -78°C. 4- Fluorophenylmagnesium bromide (150 mL, 1 .0 M in THF) was added dropwise, and the resulting solution was stirred for 1 .5 h with warming to rt. The reaction was quenched by the addition of satd. aq. NH4CI. The resulting solution was extracted with EtOAc (3X)and the organic layers were combined, dried over anhyd. Na2504, and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography with EtOAc:PE (1%) to afford the title compound. |
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In tetrahydrofuran at -78 - 20℃; for 1.5h; |
A Step A- Ethyl 2-(4-fluorophenyl)-2-oxoacetate:
Into a flask was placed a solution of diethyl oxalate (28.5 g, 195 mmol) in THF (300 mL) which was cooled at -78°C. 4- Fluorophenylmagnesium bromide (150 mL, 1.0 M in THF) was added dropwise, and the resulting solution was stirred for 1 .5 h with warming to RT. The reaction was quenched by the addition of saturated aqueous NH4CI. The resulting solution was extracted with EtOAc (3X) and the organic layers were combined, dried over anhyd. Na2S04, and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by silica gel chromatography with EtOAc: PE (1 %) to afford the title compound. |
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In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; |
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In tetrahydrofuran at -78 - 25℃; for 1.5h; |
A Step A- Ethyl 2-(4-fluorophenyl)-2-oxoacetate:
Into a flask was placed a solution of diethyl oxalate (28.5 g, 195 mmol) in THF (300 mL) which was cooled at -78oC.4- fluorophenylmagnesium bromide (150 mL, 1.0 M in THF) was added dropwise, and the resulting solution was stirred for 1.5 h with warming to RT. The reaction was quenched by the addition of sat. aq. NH4Cl. The resulting solution was extracted with EtOAc (3X) and the organic layers were combined, dried over anhydr. Na2SO4, and filtered. The filtrate was conc. in vacuo to dryness. The residue was purified by silica gel chromatography with EtOAc:petroleum ether (1%) to afford the title compound. |
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In tetrahydrofuran at -78℃; for 2h; |
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