替罗非班杂质83 盐酸盐

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

实验步骤: To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g). The reaction mixture was concentrated in vacuo the residue partitioned between water (20 ml) and ethyl acetate (30 ml) The aqueous was re-extracted with ethyl acetate (1×30 ml) dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), concentrated in vacuo

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

实验步骤: To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g). The reaction mixture was concentrated in vacuo the residue partitioned between water (20 ml) and ethyl acetate (30 ml) The aqueous was re-extracted with ethyl acetate (1×30 ml) dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), concentrated in vacuo

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

实验步骤: To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g). The reaction mixture was concentrated in vacuo the residue partitioned between water (20 ml) and ethyl acetate (30 ml) The aqueous was re-extracted with ethyl acetate (1×30 ml) dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), concentrated in vacuo

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

实验步骤: 120 g (620 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 400 ml 3,4-dihydro-2H-pyran and added to 1.5 g pyridinium tosylate and 5 ml 8 M methanolic hydrochloric acid. This is stirred for three hours and left to stand at RT overnight. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl]-piperidine is dissolved in 500 ml acetonitrile without further purification and added to 193 g (742 mmol) diphenylmethylbromide (95%) and 160 g (1157 mmol) potassium carbonate and stirred for three days at RT. The mixture is filtered and the filtrate is stirred for one day at RT with a further 20 g (76.8 mmol) diphenylmethylbromide (95%) and 16 g (115.8 mmol) potassium carbonate. The mixture is filtered and the solvent is removed under vacuum The resulting 1-diphenylmethyl-4-[4-(tetrahydropyran-2-yloxy)-butly]-piperldine is dissolved in 700 ml methanol without further purification, added to 120 ml conc. hydrochloric acid, and the mixture is left to stand for two days at RT. Subsequently, the solvent is removed under vacuum and the residue is taken up with 1500 ml water and extracted with 1500 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is adjusted to alkaline with sodium hydroxide and extracted with 700 ml acetic acid ethyl ester. After washing the organic phase with 200 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum. The brown oil is dried under high-vacuum and processed further without purification. Yield: 145 g (72%). left to stand at RT overnight this is concentrated under vacuum to dryness The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl]-piperidine is dissolved in 500 ml acetonitrile without further purification stirred for three days at RT The mixture is filtered The mixture is filtered the solvent is removed under vacuum The resulting 1-diphenylmethyl-4-[4-(tetrahydropyran-2-yloxy)-butly]-piperldine is dissolved in 700 ml methanol without further purification added to 120 ml conc. hydrochloric acid the mixture is left to stand for two days at RT Subsequently, the solvent is removed under vacuum extracted with 1500 ml acetic acid ethyl ester extracted with 700 ml acetic acid ethyl ester After washing the organic phase with 200 ml water this is dried over sodium sulfate the solvent is removed under vacuum The brown oil is dried under high-vacuum processed further without purification

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

实验步骤: 20 g (103 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 1.0 g pyridinium tosylate. The mixture is stirred for two days at RT. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl)-piperidine is dissolved without further purification in 100 ml acetonitrile and added to 25.1 g (105 mmol) bis-(4-fluorophenyl)-chloromethane, 30 g (217 mmol) potassium carbonate and 5.0 g (30 mmol) potassium iodide and stirred for four days at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-yloxy)-butyl]-piperldine is dissolved without further purification in 150 ml methanol, added to enough 6 M methanolic hydrochloric acid until the pH of the mixture is acidic and left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum and the residue is dispersed between sodium hydroxide solution and acetic acid ethyl ester. The aqueous solution is extracted three times with acetic acid. The combined organic phases are dried over sodium sulfate and the residue is chromatographically purified over silica gel with CH2Cl2/CH3OH(99/1 to 94/4). Yield: 23.8 g (63%). this is concentrated under vacuum to dryness The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl)-piperidine is dissolved without further purification in 100 ml acetonitrile stirred for four days at RT The mixture is filtered the solvent is removed under vacuum The resulting 1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-yloxy)-butyl]-piperldine is dissolved without further purification in 150 ml methanol added to enough 6 M methanolic hydrochloric acid until the pH of the mixture left to stand for two days at RT the residue is dispersed between sodium hydroxide solution and acetic acid ethyl ester The aqueous solution is extracted three times with acetic acid The combined organic phases are dried over sodium sulfate the residue is chromatographically purified over silica gel with CH2Cl2/CH3OH(99/1 to 94/4)

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

实验步骤: 120 g (620 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 400 ml 3,4-dihydro-2H-pyran and added to 1.5 g pyridinium tosylate and 5 ml 8 M methaneolic hydrochloric acid. This is stirred for three hours and left to stand at RT overnight. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-Tetrahydro-pyran-2-yloxy)-butyl]-piperidine is. dissolved in 500 ml acetonitrile without further purification and added to 193 g (742 mmol) diphenylmethyl bromide (95%) and 160 g (1157 mmol) potassium carbonate and stirred for three days at RT. The mixture is filtered and the filtrate is stirred with a further 20 g (76.8 mmol) diphenylmethyl bromide (95%) and 16 g (115.8 mmol) potassium carbonate for one day at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-diphenylmethyl-4-[4-(tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 700 ml methanol without further purification, added to 120 ml conc. hydrochloric acid and the mixture is left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum, the residue is taken up with 1500 ml water and extracted with 1500 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is made alkaline with 95 g sodium hydroxide and extracted with 700 ml acetic acid ethyl ester. After washing the organic phase with 200 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum. The brown oil is dried under high-vacuum and further processed without additional purification. Yield 145 g (72%). left to stand at RT overnight this is concentrated under vacuum to dryness dissolved in 500 ml acetonitrile without further purification stirred for three days at RT The mixture is filtered The mixture is filtered the solvent is removed under vacuum The resulting 1-diphenylmethyl-4-[4-(tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 700 ml methanol without further purification added to 120 ml conc. hydrochloric acid the mixture is left to stand for two days at RT extracted with 1500 ml acetic acid ethyl ester extracted with 700 ml acetic acid ethyl ester After washing the organic phase with 200 ml water this is dried over sodium sulfate the solvent is removed under vacuum The brown oil is dried under high-vacuum further processed without additional purification

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

实验步骤: 120 g (620 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 400 ml 3,4-dihydro-2H-pyran and added to 1.5 g pyridinium tosylate and 5 ml 8 M methaneolic hydrochloric acid. This is stirred for three hours and left to stand at RT overnight. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-Tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 500 ml acetonitrile without further purification and added to 193 g (742 mmol) diphenylmethyl bromide (95%) and 160 g (1157 mmol) potassium carbonate and stirred for three days at RT. The mixture is filtered and the filtrate is stirred with a further 20 g (76.8 mmol) diphenylmethyl bromide (95%) and 16 g (115.8 mmol) potassium carbonate for one day at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-diphenylmethyl-4-[4-(tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 700 ml methanol without further purification, added to 120 ml conc. hydrochloric acid and the mixture is left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum, the residue is taken up with 1500 ml water and extracted with 1500 ml acetic acid ethyl ester. The organic phase is discarded and the aqueous phase is made alkaline with 95 g sodium hydroxide and extracted with 700 ml acetic acid ethyl ester. After washing the organic phase with 200 ml water, this is dried over sodium sulfate and the solvent is removed under vacuum The brown oil is dried under high-vacuum and further processed without additional purification. Yield 145 g (72%). left to stand at RT overnight this is concentrated under vacuum to dryness The resulting 4-[4-Tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 500 ml acetonitrile without further purification stirred for three days at RT The mixture is filtered The mixture is filtered the solvent is removed under vacuum The resulting 1-diphenylmethyl-4-[4-(tetrahydro-pyran-2-yloxy)-butyl]-piperidine is dissolved in 700 ml methanol without further purification added to 120 ml conc. hydrochloric acid the mixture is left to stand for two days at RT extracted with 1500 ml acetic acid ethyl ester extracted with 700 ml acetic acid ethyl ester After washing the organic phase with 200 ml water this is dried over sodium sulfate the solvent is removed under vacuum The brown oil is dried under high-vacuum further processed without additional purification

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

实验步骤: To stirring solution of 4-(4-piperidinyl)-1-butanol hydrochloride (4.51 g, 23.28 mmol) and potassium carbonate (8.04 g, 58.2 mmol) in dry acetonitrile (60 ml) was added iodoethane (2.070 ml, 25.6 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous was re-extracted with ethyl acetate (1×30 ml) then dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), combined and concentrated in vacuo to give the title compound as a yellow gum (2.41 g). The reaction mixture was concentrated in vacuo the residue partitioned between water (20 ml) and ethyl acetate (30 ml) The aqueous was re-extracted with ethyl acetate (1×30 ml) dichloromethane (1×30 ml), the organic layers dried by passage through a hydrophobic frit), concentrated in vacuo