2-prop-2-ynylisoindole-1,3-dione

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:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Propargylphthalimide (2.35 g mg, 12.7 mmol) was added to 1,1,1-tributyl-N,N-dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL) and stirred in a sealed vial at 70° C. for 2 hours. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 609.3 (M+H)+. The mixture was cooled to ambient temperature the vial was stirred unsealed for 10 minutes heated to 130° C. overnight The mixture was purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Propargylphthalimide (2.35 g mg, 12.7 mmol) was added to 1,1,1-tributyl-N,N-dimethylstannanamine (4.23 mg, 12.7 mmol) in hexane (3.0 mL) and stirred in a sealed vial at 70° C. for 2 hours. The mixture was cooled to ambient temperature and the vial was stirred unsealed for 10 minutes. Benzyl azide (2.0 mL, 16.0 mmol) was added and the vial was resealed and heated to 130° C. overnight. The mixture was purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 609.3 (M+H)+. The mixture was cooled to ambient temperature the vial was stirred unsealed for 10 minutes heated to 130° C. overnight The mixture was purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes

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

Procedure: A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.21 mole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give the crude product mp 130°-133° C. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C. was obtained the resulting mixture stirred for 20 hr The volatiles were removed at reduced pressure the residue was triturated with 200 ml of isopropanol The resulting precipitate was collected by filtration

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

Procedure: A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.21 mole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give the crude product mp 130°-133° C. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C. was obtained the resulting mixture stirred for 20 hr The volatiles were removed at reduced pressure the residue was triturated with 200 ml of isopropanol The resulting precipitate was collected by filtration

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

Procedure: A mixture of 0.94 g (2 mmol) of 6-(2-fluorophenyl) 8-iodo-1-(trifluoromethyl)-4H-[1,2,4]triazolo [4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N-propargylphthalimide 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 0.6 ml of triethylamine and 50 ml of dimethylformamide was degassed with argon for 10 minutes. Palladium acetate, 25 mg. was then added and the mixture was stirred for 3 days at room temperature. The product was precipitated by dilution with sodium bicarbonate solution and was collected by filtration. It was dissolved in methylene chloride and the solution was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-ProPynyl}-1H-isoindole-1,3(2H)-dione with m.p. 204°-206° . was degassed with argon for 10 minutes was then added The product was precipitated by dilution with sodium bicarbonate solution was collected by filtration It was dissolved in methylene chloride the solution was washed with bicarbonate solution dried evaporated The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride The combined good fractions were evaporated the residue was crystallized from ethyl acetate

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

Procedure: A mixture of 0.94 g (2 mmol) of 6-(2-fluorophenyl) 8-iodo-1-(trifluoromethyl)-4H-[1,2,4]triazolo [4,3-a][1,4]-benzodiazepine, 0.55 g (3 mmol) of N-propargylphthalimide 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 0.6 ml of triethylamine and 50 ml of dimethylformamide was degassed with argon for 10 minutes. Palladium acetate, 25 mg. was then added and the mixture was stirred for 3 days at room temperature. The product was precipitated by dilution with sodium bicarbonate solution and was collected by filtration. It was dissolved in methylene chloride and the solution was washed with bicarbonate solution, dried and evaporated. The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 2-{3-[6-(2-fluorophenyl)-1-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-ProPynyl}-1H-isoindole-1,3(2H)-dione with m.p. 204°-206° . was degassed with argon for 10 minutes was then added The product was precipitated by dilution with sodium bicarbonate solution was collected by filtration It was dissolved in methylene chloride the solution was washed with bicarbonate solution dried evaporated The residue was chromatographed over 40 g of silica gel using 5% (v/v) of ethanol in methylene chloride The combined good fractions were evaporated the residue was crystallized from ethyl acetate

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

Procedure: A mixture of 10 g of N-propargylphthalimide and 2 g of sodium borohydride in 100 ml of ethanol was heated on the steam bath for 15 minutes with stirring. The resulting solution was concentrated under reduced pressure to one third of the volume and the product was crystallized by addition of ice and saturated sodium bicarbonate solution. The precipitated crystals of the title compound were collected by filtration, washed with water and sucked dry. After drying in vacuum they had m.p. 157°-159° C. was heated on the steam bath for 15 minutes The resulting solution was concentrated under reduced pressure to one third of the volume the product was crystallized by addition of ice and saturated sodium bicarbonate solution The precipitated crystals of the title compound were collected by filtration washed with water sucked dry After drying in vacuum they

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

Procedure: Coupling of 1-(3-bromophenethyl)cyclohexanol with 2-(prop-2-ynyl)isoindoline-1,3-dione following the method described in Example 12 gives 2-(3-(3-(2-(1-hydroxycyclohexyl)ethyl)phenyl)prop-2-ynyl)isoindoline-1,3-dione.