4-Bromo-2,2-diphenylbutyronitrile

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: 15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2. 2. 1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(4-azabicyclo[2. 2. 1]hept-7-yl)butyronitrile, melting at 79°-81° C. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 parts of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° C for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-[1,1-diphenyl-3-(7-azabicyclo[2. 2. 1]hept-7-yl)]propyl-1H-tetrazole, melting at 284°-286° C. The reaction mixture is cooled extracted with dilute hydrochloric acid The aqueous hydrochloric acid extract extracted with ether The ether extracts are dried over anhydrous sodium sulfate Filtration and removal of the ether by evaporation at reduced pressure

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 500 g (1.67 mol) of 4-bromo-2,2-diphenylbutyronitrile, 685 g (8.34 mol) of 2-methylimidazole and 250 mL of dimethylsulfoxide (DMSO) was stirred for 5 hours at 95 to 105° C., and then cooled with ice water. After 2 L of ethyl acetate and 2 L of water were added therein at an inner temperature of 39° C., and the mixture was stirred for 5 minutes, organic layer was separated. After washing the organic layer with 2 L of water and then 2 L of 2.5% acetic acid, the organic layer was concentrated under reduced pressure. The residual oil was dissolved in 2 L of ethanol and to this solution a solution of 192 g (1.67 mol) of 85% phosphoric acid and 1 L of ethanol was added dropwise at an inner temperature of 31° C. under stirring, and this dropwise addition was interrupted when the solution became milky white (about 500 mL were added dropwise). After confirming the precipitation of crystals by stirring for 30 minutes, remaining phosphoric acid solution was added dropwise, and successively the solution was stirred for 16 hours at an inner temperature of 30° C. The precipitated crystals were collected by filtration and, after washing them with 1 L of ethanol, the crystals were dried for 5 hours at 60° C. under reduced pressure (vacuum pump) to obtain 496 g (74.5%) of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutyronitrile phosphate. Out of these crystals, 100 g were completely dissolved with stirring into a mixture of 100 mL of purified water and 400 mL of 2-propanol and to this solution 500 mL of 2-propanol were added under stirring, followed by cooling with ice water. After stirring this solution for 1 hour at an inner temperature of below 15° C., the precipitated crystals were collected by filtration which were then washed with 100 mL of 2-propanol, then with 100 mL of ethyl acetate. The crystals were dried for 17 hours at 60° C. under reduced pressure (vacuum pump) to obtain 91.3 g (Total yield: 68%) of purified product of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutyronitrile phosphate as white crystalline powder with hygroscopicity. After a mixture of 80.0 g (200 mmol) of the purified product thus obtained, 132 g (2.02 mol) of 86% potassium hydroxide and 400 ml of 2-propanol was refluxed for 5 hours under an atmosphere of argon, the mixture was cooled with ice water. Under stirring, 800 mL of 2 mol/L hydrochloric acid were added into the mixture at an inner temperature of 30° C. (temperature was raised to 50° C.) to crystallize out of the mixture, and, after stirring for 1 hour at an inner temperature of below 15° C., the crystals were collected from the solution by filtration. These crystals were washed with a mixture of 30 mL of 2-propanol and 60 mL of purified water, then with each 250 mL of purified water five times (fifth washed solution: pH 8.80). The crystals were dried for 16 hours at 40° C. in blower to obtain 55.2 g (86.4%) of crude crystals. Into a mixed solution of 200 mL of 95% 2-propanol, 27.6 g out of these were dissolved completely by heating, which was then stirred for 1 hour at room temperature to crystallize out of the solution, followed by cooling with ice water. After stirring the solution for 1 hour at an inner temperature of below 15° C., the precipitated crystals were collected by filtration and washed with 10 mL of 2-propanol. The crystals were dried for 3 hours at 60° C. under reduced pressure (vacuum pump) to obtain 25.7 g (Total yield: 80%) of crude crystals of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutanamide as white crystalline powder. at an inner temperature of 39° C., and the mixture was stirred for 5 minutes organic layer was separated After washing the organic layer with 2 L of water 2 L of 2.5% acetic acid, the organic layer was concentrated under reduced pressure was added dropwise at an inner temperature of 31° C. under stirring this dropwise addition were added dropwise) the precipitation of crystals by stirring for 30 minutes was added dropwise successively the solution was stirred for 16 hours at an inner temperature of 30° C The precipitated crystals were collected by filtration after washing them with 1 L of ethanol the crystals were dried for 5 hours at 60° C. under reduced pressure (vacuum pump)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 500 g (1.67 mol) of 4-bromo-2,2-diphenylbutyronitrile, 685 g (8.34 mol) of 2-methylimidazole and 250 mL of dimethylsulfoxide (DMSO) was stirred for 5 hours at 95 to 105° C., and then cooled with ice water. After 2 L of ethyl acetate and 2 L of water were added therein at an inner temperature of 39° C., and the mixture was stirred for 5 minutes, organic layer was separated. After washing the organic layer with 2 L of water and then 2 L of 2.5% acetic acid, the organic layer was concentrated under reduced pressure. The residual oil was dissolved in 2 L of ethanol and to this solution a solution of 192 g (1.67 mol) of 85% phosphoric acid and 1 L of ethanol was added dropwise at an inner temperature of 31° C. under stirring, and this dropwise addition was interrupted when the solution became milky white (about 500 mL were added dropwise). After confirming the precipitation of crystals by stirring for 30 minutes, remaining phosphoric acid solution was added dropwise, and successively the solution was stirred for 16 hours at an inner temperature of 30° C. The precipitated crystals were collected by filtration and, after washing them with 1 L of ethanol, the crystals were dried for 5 hours at 60° C. under reduced pressure (vacuum pump) to obtain 496 g (74.5%) of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutyronitrile phosphate. Out of these crystals, 100 g were completely dissolved with stirring into a mixture of 100 mL of purified water and 400 mL of 2-propanol and to this solution 500 mL of 2-propanol were added under stirring, followed by cooling with ice water. After stirring this solution for 1 hour at an inner temperature of below 15° C., the precipitated crystals were collected by filtration which were then washed with 100 mL of 2-propanol, then with 100 mL of ethyl acetate. The crystals were dried for 17 hours at 60° C. under reduced pressure (vacuum pump) to obtain 91.3 g (Total yield: 68%) of purified product of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutyronitrile phosphate as white crystalline powder with hygroscopicity. After a mixture of 80.0 g (200 mmol) of the purified product thus obtained, 132 g (2.02 mol) of 86% potassium hydroxide and 400 ml of 2-propanol was refluxed for 5 hours under an atmosphere of argon, the mixture was cooled with ice water. Under stirring, 800 mL of 2 mol/L hydrochloric acid were added into the mixture at an inner temperature of 30° C. (temperature was raised to 50° C.) to crystallize out of the mixture, and, after stirring for 1 hour at an inner temperature of below 15° C., the crystals were collected from the solution by filtration. These crystals were washed with a mixture of 30 mL of 2-propanol and 60 mL of purified water, then with each 250 mL of purified water five times (fifth washed solution: pH 8.80). The crystals were dried for 16 hours at 40° C. in blower to obtain 55.2 g (86.4%) of crude crystals. Into a mixed solution of 200 mL of 95% 2-propanol, 27.6 g out of these were dissolved completely by heating, which was then stirred for 1 hour at room temperature to crystallize out of the solution, followed by cooling with ice water. After stirring the solution for 1 hour at an inner temperature of below 15° C., the precipitated crystals were collected by filtration and washed with 10 mL of 2-propanol. The crystals were dried for 3 hours at 60° C. under reduced pressure (vacuum pump) to obtain 25.7 g (Total yield: 80%) of crude crystals of 4-(2-methylimidazole-1-yl)-2,2-diphenylbutanamide as white crystalline powder. at an inner temperature of 39° C., and the mixture was stirred for 5 minutes organic layer was separated After washing the organic layer with 2 L of water 2 L of 2.5% acetic acid, the organic layer was concentrated under reduced pressure was added dropwise at an inner temperature of 31° C. under stirring this dropwise addition were added dropwise) the precipitation of crystals by stirring for 30 minutes was added dropwise successively the solution was stirred for 16 hours at an inner temperature of 30° C The precipitated crystals were collected by filtration after washing them with 1 L of ethanol the crystals were dried for 5 hours at 60° C. under reduced pressure (vacuum pump)

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

Procedure: A mixture of 18.6 parts of 2,2-diphenyl-4-bromobutyronitrile, 10.0 parts of 4-phenylpiperidine, 8.0 parts of N,N-diisopropylethylamine and 200 parts by volume of 2-methoxyethanol is heated at reflux for 16 hours. The solution is then cooled and stripped in vacuum. The resulting residue is partitioned between dilute sodium hydroxide and ether. Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil. This oil and the aqueous phase of the partitioning are combined, treated with aqueous sodium hydroxide and extracted with 1:1 ether-benzene mixture. The ether-benzene extract is dried over sodium sulfate and stripped in vacuum to give a solid. Crystallization of the solid from a mixture of skelly B and ether provided 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile, melting at 88° - 89.5° C. and having the following formula ##STR7## is heated at reflux for 16 hours The solution is then cooled The resulting residue is partitioned between dilute sodium hydroxide and ether Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil extracted with 1:1 ether-benzene mixture The ether-benzene extract is dried over sodium sulfate to give a solid Crystallization of the solid from a mixture of skelly B and ether

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

Procedure: A mixture of 18.6 parts of 2,2-diphenyl-4-bromobutyronitrile, 10.0 parts of 4-phenylpiperidine, 8.0 parts of N,N-diisopropylethylamine and 200 parts by volume of 2-methoxyethanol is heated at reflux for 16 hours. The solution is then cooled and stripped in vacuum. The resulting residue is partitioned between dilute sodium hydroxide and ether. Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil. This oil and the aqueous phase of the partitioning are combined, treated with aqueous sodium hydroxide and extracted with 1:1 ether-benzene mixture. The ether-benzene extract is dried over sodium sulfate and stripped in vacuum to give a solid. Crystallization of the solid from a mixture of skelly B and ether provided 2,2-diphenyl-4-(4-phenylpiperidino)butyronitrile, melting at 88° - 89.5° C. and having the following formula ##STR7## is heated at reflux for 16 hours The solution is then cooled The resulting residue is partitioned between dilute sodium hydroxide and ether Extraction of the ether phase with dilute hydrochloric acid results in the precipitation of an oil extracted with 1:1 ether-benzene mixture The ether-benzene extract is dried over sodium sulfate to give a solid Crystallization of the solid from a mixture of skelly B and ether

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

Procedure: 15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2.2.1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(7-azabicyclo[2.2.1]hept-7-yl)butyronitrile, melting at 79°-81°. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 part of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-{[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7 -yl)]propyl}-1H-tetrazole, melting at 284°-286°. The reaction mixture is cooled extracted with dilute hydrochloric acid The aqueous hydrochloric acid extract extracted with ether The ether extracts are dried over anhydrous sodium sulfate Filtration and removal of the ether by evaporation at reduced pressure

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

Procedure: 15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2. 2. 1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(4-azabicyclo[2. 2. 1]hept-7-yl)butyronitrile, melting at 79°-81° C. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 parts of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° C for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-[1,1-diphenyl-3-(7-azabicyclo[2. 2. 1]hept-7-yl)]propyl-1H-tetrazole, melting at 284°-286° C. The reaction mixture is cooled extracted with dilute hydrochloric acid The aqueous hydrochloric acid extract extracted with ether The ether extracts are dried over anhydrous sodium sulfate Filtration and removal of the ether by evaporation at reduced pressure