1-[(3-chloro-4-fluorophenyl)methyl]-2,3-dihydropyridin-6-one

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

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (248 g, 1.16 mol; Example 1, step 5), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (199.2 g, 0.83 mol; Example 1, step 2), and deionized water (22.5 mL, 1.25 mol) in a glass lined stainless steel high pressure reactor (with the interstitial space between the liner and the pressure vessel was filled with water) was heated at 135° C. with stirring for 72 hours. The product mixture was cooled in an ice-water bath and the gaseous by-product was carefully vented. The orange solid product was triturated with methyl tert-butyl ether (300 mL) and collected by filtration. The product recrystallized from boiling ethanol-water (˜500 mL, 9:1 v/v), collected by filtration, washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried to afford the title compound. The product mixture was cooled in an ice-water bath The orange solid product was triturated with methyl tert-butyl ether (300 mL) collected by filtration The product recrystallized collected by filtration washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mmol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3 mmol), and water (2.82 mL, 156.7 mmol) was heated in a sealed heavy walled vessel at 130° C. with stirring for 72 hours. Upon cooling, the product mixture solidified. The solid was triturated with diethyl ether and collected by filtration. The product was further purified by crystallization from boiling ethyl acetate. Upon cooling The solid was triturated with diethyl ether collected by filtration The product was further purified by crystallization

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a cold (−20° C.) solution of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M in TIE) was added over a period of 40 minutes with the temperature of the reaction maintained at −20° C. After the addition was complete, the reaction mixture was stirred at −20° C. for one hour. Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100° C. for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane. Collection and concentration of appropriate fractions provide the title compound as oil. After the addition The reaction mixture was stirred at −20° C. for 30 minutes washed with water (four times; 2 L each time) The organic extract was concentrated under vacuum The residue was dissolved in toluene (4 L) treated with solid sodium carbonate (500 g) heated at 100° C. for one hour The product mixture was diluted with ethyl acetate (4 L) washed with water (4 times; 2 L each) The organic extract was concentrated under vacuum Collection and concentration of appropriate fractions

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (248 g, 1.16 mol; Example 1, step 5), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (199.2 g, 0.83 mol; Example 1, step 2), and deionized water (22.5 mL, 1.25 mol) in a glass lined stainless steel high pressure reactor (with the interstitial space between the liner and the pressure vessel was filled with water) was heated at 135° C. with stirring for 72 hours. The product mixture was cooled in an ice-water bath and the gaseous by-product was carefully vented. The orange solid product was triturated with methyl tert-butyl ether (300 mL) and collected by filtration. The product recrystallized from boiling ethanol-water (˜500 mL, 9:1 v/v), collected by filtration, washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried to afford the title compound. The product mixture was cooled in an ice-water bath The orange solid product was triturated with methyl tert-butyl ether (300 mL) collected by filtration The product recrystallized collected by filtration washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mmol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3 mmol), and water (2.82 mL, 156.7 mmol) was heated in a sealed heavy walled vessel at 130° C. with stirring for 72 hours. Upon cooling, the product mixture solidified. The solid was triturated with diethyl ether and collected by filtration. The product was further purified by crystallization from boiling ethyl acetate. Upon cooling The solid was triturated with diethyl ether collected by filtration The product was further purified by crystallization

反応条件: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a cold (−20° C.) solution of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M in TIE) was added over a period of 40 minutes with the temperature of the reaction maintained at −20° C. After the addition was complete, the reaction mixture was stirred at −20° C. for one hour. Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100° C. for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane. Collection and concentration of appropriate fractions provide the title compound as oil. After the addition The reaction mixture was stirred at −20° C. for 30 minutes washed with water (four times; 2 L each time) The organic extract was concentrated under vacuum The residue was dissolved in toluene (4 L) treated with solid sodium carbonate (500 g) heated at 100° C. for one hour The product mixture was diluted with ethyl acetate (4 L) washed with water (4 times; 2 L each) The organic extract was concentrated under vacuum Collection and concentration of appropriate fractions

反応条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (248 g, 1.16 mol; Example 1, step 5), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (199.2 g, 0.83 mol; Example 1, step 2), and deionized water (22.5 mL, 1.25 mol) in a glass lined stainless steel high pressure reactor (with the interstitial space between the liner and the pressure vessel was filled with water) was heated at 135° C. with stirring for 72 hours. The product mixture was cooled in an ice-water bath and the gaseous by-product was carefully vented. The orange solid product was triturated with methyl tert-butyl ether (300 mL) and collected by filtration. The product recrystallized from boiling ethanol-water (˜500 mL, 9:1 v/v), collected by filtration, washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried to afford the title compound. The product mixture was cooled in an ice-water bath The orange solid product was triturated with methyl tert-butyl ether (300 mL) collected by filtration The product recrystallized collected by filtration washed successively with a small quantity of ethanol, methyl tert-butyl ether (300 mL), and heptane (200 mL), and air dried

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6 mol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g, 104.3 mol), and water (2.82 mL, 156.7 mol) was heated in a sealed heavy walled vessel at 130° C. with stirring for 72 hours. Upon cooling, the product mixture solidified. The solid was triturated with diethyl ether and collected by filtration. The product was further purified by crystallization from boiling ethyl acetate. Upon cooling The solid was triturated with diethyl ether collected by filtration The product was further purified by crystallization