decane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2R)-2-t-butoxycarbonylamino-2-methyl-4-[1-methyl-5-(5-phenylpentanoyl)pyrrol-2-yl]butan-1-ol (1.6928 g, 3.83 mmol) obtained in Example (43a) in dichloromethane (19 ml) were added successively 1H-tetrazole (1.7933 g, 25.60 mmol) and diallyl diisopropylphosphoramidite (2.02 ml, 7.64 mmol) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 2 hours. After stirring, to the reaction mixture was added a solution of t-butyl hydroperoxide in n-decane (5-6 mol/l) (2.3 ml, 11.5 mmol) with stirring under ice cooling, and the resulting mixture was stirred at the same temperature for 15 minutes. After stirring, to the reaction mixture was added an aqueous sodium sulfite solution to quench the reaction, and the resulting mixture was extracted with dichloromethane. The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (3:2) as the eluent to afford the title compound (1.5690 g, yield: 68%). cooling the resulting mixture was stirred at room temperature for 2 hours After stirring, to the reaction mixture with stirring under ice cooling the resulting mixture was stirred at the same temperature for 15 minutes After stirring, to the reaction mixture to quench the reaction the resulting mixture was extracted with dichloromethane The extract was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate After filtration the solvent was removed in vacuo the residue was purified by chromatography on a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, a mixture of 169.8 g of crude N-(2′-chloro-6′-fluorophenyl)-4-methylaniline, 172 ml (2.15 mol) of chloroacetyl chloride in 580 ml of toluene is heated under a nitrogen atmosphere for 2 hours at 70°. The reaction is cooled to room temperature, 450 ml of decane is added, and the volatiles are distilled off under 200 mbar pressure at 62-72°. To the mixture is added 150 ml of toluene and 385 g of aluminum chloride (2.87 mol) slowly at 20-40°. The mixture is heated at 120° for 5 hours, cooled to 20°, and added over 30 minutes to 800 ml of ethyl acetate. The mixture is quenched by addition to a pre-cooled solution of 67 ml of 37% hydrochloric acid in 800 ml of water at 20±10°, and the resultant mixture is filtered through a pad of Celite. The organic layer is separated and the volatiles are distilled off. To the residue is added 100 ml of heptane and the mixture is cooled to 0° over a 30 minute period and stirred for one hour. The mixture is filtered and the filter cake is washed three times with 45 ml of heptane. To the crude product is added 90 g of charcoal (DARCO G-60) and 4500 ml of methanol. The mixture is heated to reflux for two hours, cooled to room temperature, and filtered through a pad of Celite. After distilling off 4390 ml of methanol, the mixture is cooled to 15°. The product is collected by filtration, washed three times with 30 ml of methanol, and dried to give N-(2′-chloro-6′-fluorophenyl)-5-methyloxindole. is heated under a nitrogen atmosphere for 2 hours at 70° the volatiles are distilled off under 200 mbar pressure at 62-72° The mixture is heated at 120° for 5 hours cooled to 20° The mixture is quenched by addition to a pre-cooled solution of 67 ml of 37% hydrochloric acid in 800 ml of water at 20±10° the resultant mixture is filtered through a pad of Celite The organic layer is separated the volatiles are distilled off To the residue is added 100 ml of heptane the mixture is cooled to 0° over a 30 minute period The mixture is filtered the filter cake is washed three times with 45 ml of heptane To the crude product is added 90 g of charcoal (DARCO G-60) and 4500 ml of methanol The mixture is heated to reflux for two hours cooled to room temperature filtered through a pad of Celite After distilling off 4390 ml of methanol the mixture is cooled to 15° The product is collected by filtration washed three times with 30 ml of methanol dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol (1.5 g., 0.005 mole), 2-oxotricyclo(3.3.1.1.3,7)-decane (0.75 g., 0.005 mole) and p-toluenesulfonic acid (50 mg.) in benzene (25 ml.) is refluxed under a Dean-Stark trap for 2 hr. The solution is cooled, filtered, and evaporated to dryness. The residue is crystallized from ethanol to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-iodospiro[2H-1,3-benzoxazine-2,2'-tricyclo(3.3.1.13,7)decane] (1.4 g.), m.p. 165°-166° C. The solution is cooled filtered evaporated to dryness The residue is crystallized from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-aminomethyl-4-(2,2-dimethylethyl)-6-trifluoromethylphenol (1.24 g., 0.005 mole), 2-oxotricyclo(3.3.1.1.3,7)decane (0.75 g., 0.005 mole) and acetic acid (0.25 ml.) in dry benzene (50 ml.) is refluxed under a constant water separator for 3 hr. The solution is cooled, washed with 2% sodium hydroxide solution, water and salt brine and then dried (MgSO4) and evaporated under reduced pressure. The solid residue (1.2 g.) is crystallized from hexane to obtain 3,4-dihydro-6-(1,1-dimethylethyl)-8-trifluoromethylspiro[2H-1,3-benzoxazine-2,2'-tricyclo(3.3.1.1.3,7)decane] (0.65 g.), m.p. 125°-126.5° C. The solution is cooled washed with 2% sodium hydroxide solution, water and salt brine dried (MgSO4) evaporated under reduced pressure The solid residue (1.2 g.) is crystallized from hexane