(S)-6-氟-1-异丙基-3,4-二氢-1H-萘-2-酮

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired. The solution was warmed to 25° C. volatiles were removed in vacuo Tetrahydrofuran, 20 mL, was added via syringe to the residue the resulting yellow solution cooled to 0° C The yellow solution was stirred at 0° C. for fifteen minutes After stirring at -78° C. for two hours The suspension that formed was extracted with 50 mL diethyl ether and the combined ether extracts were dried over anhydrous magnesium sulfate filtered concentrated in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired. The solution was warmed to 25° C. volatiles were removed in vacuo Tetrahydrofuran, 20 mL, was added via syringe to the residue the resulting yellow solution cooled to 0° C The yellow solution was stirred at 0° C. for fifteen minutes After stirring at -78° C. for two hours The suspension that formed was extracted with 50 mL diethyl ether and the combined ether extracts were dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

实验步骤: The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffmnann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.

反应条件: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Lithium diisopropylamide, 1.3 mL of 0.84 molar solution in tetrahydrofuran, was added to a solution of 0.11 mL N,N-dimethylacetamide in 1 mL tetrahydrofuran at -78° C. The mixture was stirred for fifteen minutes, then allowed to warm to -55° C. A solution of 220 mg (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 1 mL tetrahydrofuran was added at that temperature, then allowed to warm to 0-5° C. with stirring, and stirred for 2.5 hours. The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride, and extracted three times with 3 mL portions of diethyl ether. The ether extracts were combined, dried with magnesium sulfate, and stripped to give 290 mg (1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetamide as a pale yellow oil. to warm to 0-5° C. with stirring stirred for 2.5 hours The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride extracted three times with 3 mL portions of diethyl ether dried with magnesium sulfate

反应条件: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Lithium diisopropylamide, 1.3 mL of 0.84 molar solution in tetrahydrofuran, was added to a solution of 0.11 mL N,N-dimethylacetamide in 1 mL tetrahydrofuran at -78° C. The mixture was stirred for fifteen minutes, then allowed to warm to -55° C. A solution of 220 mg (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 1 mL tetrahydrofuran was added at that temperature, then allowed to warm to 0-5° C. with stirring, and stirred for 2.5 hours. The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride, and extracted three times with 3 mL portions of diethyl ether. The ether extracts were combined, dried with magnesium sulfate, and stripped to give 290 mg (1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetamide as a pale yellow oil. to warm to 0-5° C. with stirring stirred for 2.5 hours The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride extracted three times with 3 mL portions of diethyl ether dried with magnesium sulfate

反应条件: temp:-55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Lithium diisopropylamide, 1.3 mL of 0.84 molar solution in tetrahydrofuran, was added to a solution of 0.11 mL N,N-dimethylacetamide in 1 mL tetrahydrofuran at -78° C. The mixture was stirred for fifteen minutes, then allowed to warm to -55° C. A solution of 220 mg (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 1 mL tetrahydrofuran was added at that temperature, then allowed to warm to 0-5° C. with stirring, and stirred for 2.5 hours. The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride, and extracted three times with 3 mL portions of diethyl ether. The ether extracts were combined, dried with magnesium sulfate, and stripped to give 290 mg (1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetamide as a pale yellow oil. to warm to 0-5° C. with stirring stirred for 2.5 hours The reaction mixture was quenched with 3 mL saturated aqueous ammonium chloride extracted three times with 3 mL portions of diethyl ether dried with magnesium sulfate

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

实验步骤: The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy) ethyl]-1,2,3,4-tetrahydro-naphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffmann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S, 2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy) ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol. 4,680,310 (also to Hoffmann-La Roche), is prepared

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired. The solution was warmed to 25° C. volatiles were removed in vacuo Tetrahydrofuran, 20 mL, was added via syringe to the residue the resulting yellow solution cooled to 0° C The yellow solution was stirred at 0° C. for fifteen minutes After stirring at -78° C. for two hours The suspension that formed was extracted with 50 mL diethyl ether and the combined ether extracts were dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

实验步骤: The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffinann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.

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

实验步骤: The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffinann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under a dry nitrogen atmosphere, a 2.5 molar solution of butyllithium in hexane, 8.4 mL (21 mmol) was added by syringe to 20 mL pentane. The solution was cooled to 0° C. and 2.75 mL (2.13 g, 21 mmol) diisopropylamine was added by syringe over six minutes. The solution was warmed to 25° C. and stirred for three hours, then volatiles were removed in vacuo. Tetrahydrofuran, 20 mL, was added via syringe to the residue, and the resulting yellow solution cooled to 0° C. A solution of 2.42 g (10.5 mmol) N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide in 10 mL tetrahydrofuran was added by syringe over nine minutes. The yellow solution was stirred at 0° C. for fifteen minutes, then cooled to -78° C. (S)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, 2.166 g, 87.2% pure, 97.6:2.4 S:R, in 2 mL toluene was added by syringe over twelve minutes, and a further 2 mL toluene was used to complete the transfer. After stirring at -78° C. for two hours, the viscous yellow mixture was added to 50 mL water at less than 10° C. The suspension that formed was extracted with 50 mL diethyl ether, then with a further 25 mL diethyl ether; and the combined ether extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3.74 g of impure (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a yellow foam. The foam was recrystallized from 6-8 mL toluene, and washed on the filter with 5 mL of toluene at -30° C. to afford 2.69 g of (1S,2S)-N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide as a colorless solid, m.p. 132°-138° C. This material may be recrystallized a second time from toluene to remove residual (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one if necessary and desired. The solution was warmed to 25° C. volatiles were removed in vacuo Tetrahydrofuran, 20 mL, was added via syringe to the residue the resulting yellow solution cooled to 0° C The yellow solution was stirred at 0° C. for fifteen minutes After stirring at -78° C. for two hours The suspension that formed was extracted with 50 mL diethyl ether and the combined ether extracts were dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

实验步骤: The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffmnann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.