2-(2-溴乙氧基)-1,3-二氟苯

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with 3 times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained filtered washed with 3 times 30 cm3 of petroleum ether (40-65° C.) The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm) eluting with petroleum ether (40-65° C.) collecting 100-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with three times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm) eluting with ethyl acetate collecting 50-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with 3 times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained filtered washed with 3 times 30 cm3 of petroleum ether (40-65° C.) The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm) eluting with petroleum ether (40-65° C.) collecting 100-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with three times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm) eluting with ethyl acetate collecting 50-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with 3 times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained filtered washed with 3 times 30 cm3 of petroleum ether (40-65° C.) The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm) eluting with petroleum ether (40-65° C.) collecting 100-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with three times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm) eluting with ethyl acetate collecting 50-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with three times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm) eluting with ethyl acetate collecting 50-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2,6-difluoro phenol (18 g, 0.385 mol), 1,2-dibromoethane (71.6 ml, 0.83 mol) and K2CO3 (47.86 g, 0.3463 mol) in dry acetonitrile (190 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 7% ethyl acetate in petroleum ether as eluent to give the title compound (20.8 g) as colorless oil. The reaction mixture was filtered solvent concentrated under reduced pressure The residue was purified by column chromatography over silica gel using 7% ethyl acetate in petroleum ether as eluent

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 10 g of 2,6-difluorophenol, 40.5 cm3 of 1,2-dibromoethane and 15.3 g of potassium carbonate in 300 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 200 cm3 of petroleum ether (40-65° C.), filtered and washed with 3 times 30 cm3 of petroleum ether (40-65° C.). The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm), eluting with petroleum ether (40-65° C.) and collecting 100-cm3 fractions. Fractions 22 to 58 were combined and then concentrated to dryness under the above conditions. 14.5 g of 1-(2-bromoethoxy)-2,6-difluorobenzene were obtained in the form of a thick colorless oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with 3 times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained filtered washed with 3 times 30 cm3 of petroleum ether (40-65° C.) The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 7 cm; height: 28 cm) eluting with petroleum ether (40-65° C.) collecting 100-cm3 fractions concentrated to dryness under the above conditions

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil. After cooling to a temperature in the region of 20° C. the reaction mixture was filtered washed with three times 30 cm3 of acetonitrile The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm) eluting with ethyl acetate collecting 50-cm3 fractions concentrated to dryness under the above conditions