(2-aminophenyl)cyclohexylMethanone

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16 mmol) in methanol (5 ml) and concentrated hydrochloric add (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel, using petrol:ethyl acetate (2:1), to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360 MHz, CDCL3)-- 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J -7 and 1 Hz). add (15 ml) After this time the solution was cooled to ambient temperature the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

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

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the amine (0.40 g). Mp 73°-75° C. 1H NMR (360 MHz, CDCl3) δ 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J=7 and 1 Hz). the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

Conditions: temp:21.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of triphosgene (1.2 g, 4 mmol) in toluene (10 mL) was added slowly a solution of (2-amino-phenyl)-cyclohexyl-methanone (2.4 g) and triethylamine (3.3 ml) in toluene (16 mL). The mixture was then warmed up to 20-23° C. and aged for a period of about 1 hr under stirring. The resulting slurry was then added slowly to a warm (60° C.) mixture of ethyl hydrazine-acetate hydrochloride (1.8 g) and triethylamine (1.4 g) in toluene (20 mL). The reaction mixture was aged at 60° C. for about 20 m in and then heated to about 100° C. While at this temperature, trifluoroacetic acid (0.5 mL) was added and the reaction mixture was aged until the cyclization was completed (approximately 10 min). The reaction mixture was then cooled to about 20-23° C. and filtered. The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) and then evaporated to a residue. The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL), and then heptane (˜50 mL) was slowly added. The product which precipitated out of the solution, was collected by filtration and dried to yield (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester as an off-white solid. The resulting slurry was then added slowly to a warm was aged at 60° C. for about 20 m then heated to about 100° C (approximately 10 min) The reaction mixture was then cooled to about 20-23° C. filtered The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) evaporated to a residue The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL) heptane (˜50 mL) was slowly added The product which precipitated out of the solution was collected by filtration dried

Conditions: temp:21.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of triphosgene (1.2 g, 4 mmol) in toluene (10 mL) was added slowly a solution of (2-amino-phenyl)-cyclohexyl-methanone (2.4 g) and triethylamine (3.3 ml) in toluene (16 mL). The mixture was then warmed up to 20-23° C. and aged for a period of about 1 hr under stirring. The resulting slurry was then added slowly to a warm (60° C.) mixture of ethyl hydrazine-acetate hydrochloride (1.8 g) and triethylamine (1.4 g) in toluene (20 mL). The reaction mixture was aged at 60° C. for about 20 m in and then heated to about 100° C. While at this temperature, trifluoroacetic acid (0.5 mL) was added and the reaction mixture was aged until the cyclization was completed (approximately 10 min). The reaction mixture was then cooled to about 20-23° C. and filtered. The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) and then evaporated to a residue. The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL), and then heptane (˜50 mL) was slowly added. The product which precipitated out of the solution, was collected by filtration and dried to yield (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester as an off-white solid. The resulting slurry was then added slowly to a warm was aged at 60° C. for about 20 m then heated to about 100° C (approximately 10 min) The reaction mixture was then cooled to about 20-23° C. filtered The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) evaporated to a residue The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL) heptane (˜50 mL) was slowly added The product which precipitated out of the solution was collected by filtration dried

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

Procedure: 3.1 g of magnesium turnings, 10 ml of ethyl ether and several pieces of iodide were placed in a flask under a nitrogen gas, and the mixture was refluxed to fade out the color caused by iodide. 90 ml of an ethyl ether solution containing 20 g of cyclohexyl bromide was added dropwise over a 30-minute period under reflux with stirring. The temperature of the reaction solution was returned to room temperature, 40 ml of a tetrahydrofuran solution containing 4.8 g of 2-aminobenzonitrile was added dropwise over a 30-minute period, and the mixture was stirred for 30 minutes. 150 ml of an aqueous 1N hydrochloric acid solution was cautiously added, and the mixture was neutralized with a dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1) and recrystallized from ethyl acetate-n-hexane to give 6.2 g of 2-cyclohexylcarbonylaniline. the mixture was refluxed was added dropwise over a 30-minute period under reflux was returned to room temperature was added dropwise over a 30-minute period the mixture was stirred for 30 minutes extracted with ethyl acetate The ethyl acetate layer was washed, in turn, with water a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate The solvent was evaporated the resulting residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=20:1) recrystallized from ethyl acetate-n-hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16 mmol) in methanol (5 ml) and concentrated hydrochloric add (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel, using petrol:ethyl acetate (2:1), to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360 MHz, CDCL3)-- 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J -7 and 1 Hz). add (15 ml) After this time the solution was cooled to ambient temperature the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

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

Procedure: A solution of (2acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16 mmol) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate, (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360 MHz, CDCl3) δ 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J=7 and 1 Hz). An alternative procedure could be used for preparation of (2-aminophenyl) cyclohexyl methanone: To a cooled (0° C.) and stirred solution of 2-aminobenzonitrile (59.5 g, 0.5 mol) in anhydrous diethyl ether (210 ml) was added dropwise cyclohexylmagnesium chloride (2M in diethyl ether, 700 ml) at such a rate as to maintain the temperature below 25° C. After a further 18 h stirring at room temperature, the mixture was cooled to -60° C. and treated dropwise (CAUTION! highly exothermic reaction) with 5N hydrochloric acid (600 ml). The mixture was then allowed to warm to room temperature, diluted. with additional 5N hydrochloric acid (500 ml) and the ethereal layer was separated. The acidic aqueous solution was basified to pH 4-5 with solid potassium hydroxide and then extracted with ethyl acetate (3×700 ml). The ethereal and ethyl acetate. solutions were combined, washed with brine (1000 ml), dried (MgSO4) and concentrated under vacuum to give the title compound (97 g, 94%) as a pale yellow solid. the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate, (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

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

Procedure: [1-(3,3-Dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid was prepared using steps a-d of the method employed in the preparation of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d), except that (2-amino-phenyl)-pyridin-2-yl-methanone (G. Semple, et. al. Synth. Commun., (1996), 26, 721) was used in step a instead of (2-amino-phenyl)-cyclohexyl-methanone. 1H NMR (DMSO-d6) 12.50 (1H, br s), 8.57 (1H, m), 7.94 (2H, m), 7.50 (2H, m), 7.16 (3H, m), 4.78 (2H, s), 4.25 (2H, br s), 1.15 (9H, s).

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

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g, 2.16mmol) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 hour. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica in 2:1 petrol:ethyl acetate, to afford the amine (0.40 g, 91%) as a white solid. mp 73°-75° C. 1H NMR (360MHz, CDCl3) δ1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1Hz), 7.76 (1H, dd, J=7 and 1Hz). the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica in 2:1 petrol

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

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 hour. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the title compound (0.40 g) as a solid. The spectroscopic properties of this material were identical to those described in Method A. the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

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

Procedure: A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 h. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the amine (0.40 g). Mp 73°-75° C. 1H NMR (360 MHz, CDCl3) δ 1.23-2.09 (10H, m), 3.27 (1H, m), 6.29 (2H, brs), 6.64 (2H, m), 7.25 (1H, dt, J=6 and 1 Hz), 7.76 (1H, dd, J=7 and 1 Hz). the solvents removed in vacuo The residue was dissolved in water (10 ml) The mixture was then extracted into ethyl acetate (4×20 ml) dried (MgSO4) The solvent was evaporated the residue chromatographed on silica gel

Conditions: temp:21.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of triphosgene (1.2 g, 4 mmol) in toluene (10 mL) was added slowly a solution of (2-amino-phenyl)-cyclohexyl-methanone (2.4 g) and triethylamine (3.3 ml) in toluene (16 mL). The mixture was then warmed up to 20-23° C. and aged for a period of about 1 hr under stirring. The resulting slurry was then added slowly to a warm (60° C.) mixture of ethyl hydrazine-acetate hydrochloride (1.8 g) and triethylamine (1.4 g) in toluene (20 mL). The reaction mixture was aged at 60° C. for about 20 m in and then heated to about 100° C. While at this temperature, trifluoroacetic acid (0.5 mL) was added and the reaction mixture was aged until the cyclization was completed (approximately 10 min). The reaction mixture was then cooled to about 20-23° C. and filtered. The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) and then evaporated to a residue. The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL), and then heptane (˜50 mL) was slowly added. The product which precipitated out of the solution, was collected by filtration and dried to yield (5-cyclohexyl-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl)-acetic acid ethyl ester as an off-white solid. The resulting slurry was then added slowly to a warm was aged at 60° C. for about 20 m then heated to about 100° C (approximately 10 min) The reaction mixture was then cooled to about 20-23° C. filtered The filtrate was washed with 1N HCl (10 mL), water (10 mL), brine (10 mL) evaporated to a residue The residue (5.2 g) was dissolved in methyl t-butyl ether (10 mL) heptane (˜50 mL) was slowly added The product which precipitated out of the solution was collected by filtration dried