罗沙替丁杂质44

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

实验步骤: 3-Chloropropylaminehydrochloride (6.5 g, 50 mmol) was used for reaction in the same manner as Production Example 310-1, purification was performed by silica gel column chromatography (hexane/ethyl acetate system), the obtained crystals were suspended in diethyl ether and diluted with hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (4.316 g, 20.20 mmol, 40.40%) as colorless crystals. the crystals were filtered out washed with hexane dried by aspiration

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

实验步骤: 2,3-Lutidine (321 g) was added with stirring to a solution of sodamide (351 g) in liquid ammonia (3 1). 1-Amino-3-chloropropane hydrochloride (429g) was added to this mixture over 8 minutes with stirring. Any liquid ammonia lost through evaporation was replaced. After 2 hours the reaction was quenched by the addition of ammonium chloride (120 g) and the reaction mixture was left to stand overnight to allow substantially complete escape of ammonia through evaporation. The residue so obtained was diluted with water (2 1) and extracted with dichloromethane. The extracts were dried (Na2SO4), the dichloromethane removed by evaporation and the residue distilled in vacuo to give 4-(3-methyl-2-pyridyl) butylamine (306.6 g). Any liquid ammonia lost through evaporation After 2 hours the reaction was quenched by the addition of ammonium chloride (120 g) the reaction mixture was left through evaporation The residue so obtained extracted with dichloromethane The extracts were dried (Na2SO4) the dichloromethane removed by evaporation the residue distilled in vacuo

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The pyrazole of Example 11 (200 mg, 0.71 mmol) was mixed with 3-chloropropylamine hydrochloride (138 mg, 1.06 mmol). The resulting mixture was heated neat at 150° C., for 24 hours under a nitrogen atmosphere. After cooling, the reaction mixture was partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (203 mg) as a brown oil. After cooling the reaction mixture was partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml) The organic phase was dried over anhydrous magnesium sulphate filtered concentrated under reduced pressure The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0, by volume)

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

实验步骤: To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6 Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR. The phases were separated the aq phase was extracted with additional CH2Cl2 (2×50 mL) dried (Na2SO4) concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (

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

实验步骤: 4-(7-Chloro-4-quinazolinylamino)benzenesulphonyl chloride hydrochloride (11.7 g, 0.03 mole) was added portionwise to a well stirred mixture of sodium carbonate (45 g) in water (350 ml) and 3-chloropropylamine hydrochloride (3.9 g, 0.03 mole) in chloroform (350 ml) was added at 10° C. After about 1 hour at room temperature, the mixture was filtered and the solid was washed with water and then dried to give 7.4 g of the title compound. A sample was recrystallised from a mixture of ethanol and water to give the title compound, m.p. 168°-171° C. was added at 10° C the mixture was filtered the solid was washed with water dried

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

实验步骤: To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR. The phases were separated the aq phase was extracted with additional CH2Cl2 (2×50 mL) dried (Na2SO4) concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (

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

实验步骤: To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2CL2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.63 (t, J=6 Hz, 2H), (t, J=6 Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR. The phases were separated the aq phase was extracted with additional CH2Cl2 (2×50 mL) dried (Na2SO4) concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Chloropropylamine hydrochloride (VI) (0.2 mol, 39 g) was dissolved into 3N sodium hydroxide solution (containing 10% sodium chloride) and extracted with 300 ml of benzene. The benzene layer was dried over anhydrous magnesium sulfate. Separately, 3-piperidinomethylphenol (V) (0.2 mol, 38.2 g), sodium hydroxide (0.25 mol, 10 g), 100 ml of dimethylsulfoxide, and 70 ml of benzene were charged to a flask equipped with a water quantitative measurement tube, and heated at 130° C. for 3 hours while stirring to remove water produced by the tube, followed by continued stirring for 2 hours at 140°-150° C. To the resulting reaction mixture was dropwise added said benzene solution of 3-chloropropylamine at 150° C. while stirring over 4 hours. The reaction mixture was allowed to stand still to cool to room temperature to separate deposited sodium chloride by filtration. The filtrate was concentrated under reduced pressure and vacuum distilled to obtain 42.7 g of N-[3-(3-aminopropoxy)benzyl] piperidine (VII) (yield: 86.0%). m.p. 148°-151° C./0.25 mmHg. extracted with 300 ml of benzene The benzene layer was dried over anhydrous magnesium sulfate equipped with a water quantitative measurement tube to remove water produced by the tube by continued stirring for 2 hours at 140°-150° C To the resulting reaction mixture was dropwise added at 150° C. while stirring over 4 hours to cool to room temperature to separate by filtration The filtrate was concentrated under reduced pressure and vacuum distilled

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Chloropropylamine hydrochloride (VI) (0.2 mol, 39 g) was dissolved into 3N sodium hydroxide solution (containing 10% sodium chloride) and extracted with 300 ml of benzene. The benzene layer was dried over anhydrous magnesium sulfate. Separately, 3-piperidinomethylphenol (V) (0.2 mol, 38.2 g), sodium hydroxide (0.25 mol, 10 g), 100 ml of dimethylsulfoxide, and 70 ml of benzene were charged to a flask equipped with a water quantitative measurement tube, and heated at 130° C. for 3 hours while stirring to remove water produced by the tube, followed by continued stirring for 2 hours at 140°-150° C. To the resulting reaction mixture was dropwise added said benzene solution of 3-chloropropylamine at 150° C. while stirring over 4 hours. The reaction mixture was allowed to stand still to cool to room temperature to separate deposited sodium chloride by filtration. The filtrate was concentrated under reduced pressure and vacuum distilled to obtain 42.7 g of N-[3-(3-aminopropoxy)benzyl] piperidine (VII) (yield: 86.0%). m.p. 148°-151° C./0.25 mmHg. extracted with 300 ml of benzene The benzene layer was dried over anhydrous magnesium sulfate equipped with a water quantitative measurement tube to remove water produced by the tube by continued stirring for 2 hours at 140°-150° C To the resulting reaction mixture was dropwise added at 150° C. while stirring over 4 hours to cool to room temperature to separate by filtration The filtrate was concentrated under reduced pressure and vacuum distilled

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

实验步骤: 100 g (0.55 mol) of 6-chloro-3,4-dihydro-2(1H)-naphthalenone were dissolved in 2 l of toluene under argon, treated with 64.0 g of powdered potassium hydroxide, heated to boiling temperature, 165 g of 3-chloropropylamine hydrochloride were added portionwise thereto during 30 minutes and the mixture was boiled on a water separator until educt can no longer be detected in a thin-layer chromatogram. After cooling to room temperature the mixture was treated with 155 ml of triethylamine. The mixture was treated dropwise with 60 ml of acetyl chloride dissolved in 450 ml of toluene while cooling with ice so that an internal temperature of 25° was not exceeded. The mixture was stirred at room temperature for 1 hour, extracted with water/methylene chloride, dried with magnesium sulphate, the solvent was distilled off in vacuo and there was obtained 4-acetyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline in the form of brown crystals which can be employed as the crude product for the reaction described hereinafter. heated were added portionwise while cooling with ice so that an internal temperature of 25° extracted with water/methylene chloride dried with magnesium sulphate the solvent was distilled off in vacuo

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

实验步骤: 3-chloropropylamine hydrochloride (6.0 g), diaza(1,3)bicyclo[5.4.0]-undecane (DBU, 4.1 g) and 1,2-dimethoxyethane (21.5 g) solvent were placed in the round bottom flask equipped with mechanical stirring under nitrogen. Solution of 2-(perfluorohexyl)ethanesulfonyl chloride CF3(CF2)5(CH2)2SO2Cl (10.1 g), in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 30 minutes at 20-25° C. while stirring at 250 rpm. Then additional DBU (2.6 g) was added. Reaction mixture was stirred for 2 h after the DBU addition was completed. The reaction was monitored by GC to ensure the complete conversion of 2-(perfluorohexyl)ethanesulfonyl chloride. The final reaction mixture was filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane and combined filtrate was evaporated in vacuum to obtain 11.3 g of crude CF3(CF2)5(CH2)2SO2NH(CH2)3Cl as yellow solid. 9.5 g of the crude product was additionally dissolved in hot toluene (7 g) and washed with 14 mL of 2.5 wt % HCl aqueous solution, followed with 12 mL water wash. Toluene solution was evaporated in vacuum to obtain 8.35 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl (GC purity 93%, yield 88%). equipped while stirring at 250 rpm Reaction mixture was stirred for 2 h The final reaction mixture was filtered from solids through 2 mm layer of CELITE 545 The solids were washed with 1,2-dimethoxyethane was evaporated in vacuum

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

实验步骤: 3-chloropropyl amine hydrochloride (4.7 g), K2CO3 (6.9 g) and 1,2-dimethoxyethane (19.3 g) solvent were placed in the round bottom flask equipped with mechanical stirring under nitrogen. Solution of 2-(perfluorohexyl)ethanesulfonyl chloride CF3(CF2)5(CH2)2SO2Cl (10.1 g), in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 1 hour at room temperature while stirring at 250 rpm. After the addition was completed, the reaction was gradually heated to 75° C. and reacted for 12 h. The reaction was monitored by GC to ensure the complete conversion of CF3(CF2)5(CH2)2SO2Cl. The final reaction mixture with pH=3.5 was cooled down and filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane (10 mL) and combined filtrate was evaporated in vacuum to obtain 8.2 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl. The product was additionally dissolved in hot toluene (8 g) and washed with 15.5 mL of 1 wt % HCl aqueous solution. equipped while stirring at 250 rpm After the addition reacted for 12 h The final reaction mixture with pH=3.5 was cooled down filtered from solids through 2 mm layer of CELITE 545 The solids were washed with 1,2-dimethoxyethane (10 mL) was evaporated in vacuum