N-tert-butylcyclohexanamine

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert.-butyl-cyclohexyl-amine and 17.9 g of sodium nitrite is heated at 90° C. for 3 hours. On cooling, a solid precipitates and is filtered off with suction. Yield: 16.3 g melting point: 87° C. On cooling a solid precipitates is filtered off with suction

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert.-butyl-cyclohexyl-amine and 17.9 g of sodium nitrite is heated at 90° C. for 3 hours. On cooling, a solid precipitates and is filtered off with suction. Yield: 16.3 g melting point: 87° C. On cooling a solid precipitates is filtered off with suction

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

Procedure: Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32 mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine (5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was heated under reflux for 16 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The crude residue was dissolved in tetrahydrofuran (30 ml) and a solution of lithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) was slowly added. The reaction mixture was heated under reflux for 2 hours. An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefully added. The suspension was filtered and the liquid was concentrated under reduced pressure to give the title compound (3 g) as an oil. The reaction mixture was heated under reflux for 16 hours the solvent was removed under reduced pressure The residue was partitioned between dichloromethane (50 ml) and water (50 ml) The organic layer was dried over anhydrous magnesium sulphate the solvent was removed under reduced pressure The crude residue was dissolved in tetrahydrofuran (30 ml) The reaction mixture was heated under reflux for 2 hours The suspension was filtered the liquid was concentrated under reduced pressure

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

Procedure: Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32 mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine (5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was heated under reflux for 16 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The crude residue was dissolved in tetrahydrofuran (30 ml) and a solution of lithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) was slowly added. The reaction mixture was heated under reflux for 2 hours. An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefully added. The suspension was filtered and the liquid was concentrated under reduced pressure to give the title compound (3 g) as an oil. The reaction mixture was heated under reflux for 16 hours the solvent was removed under reduced pressure The residue was partitioned between dichloromethane (50 ml) and water (50 ml) The organic layer was dried over anhydrous magnesium sulphate the solvent was removed under reduced pressure The crude residue was dissolved in tetrahydrofuran (30 ml) The reaction mixture was heated under reflux for 2 hours The suspension was filtered the liquid was concentrated under reduced pressure

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

Procedure: To a solution of the intermediate from step F (464 mg, 0.90 mmol) in DMF (10 mL) was added HOAt (244 mg, 1.79 mmol), tert-butyl-cyclohexylamine (426 μL, 2.39 mmol), DIEA (623 μL, 3.57 mmol) and EDC (343 mg, 1.79 mmol). The resulting slurry was left stirring at room temperature overnight. The reaction was stirred to 50° C. for 3 hours. It was cooled to room temperature, diluted with ethyl acetate, washed with 1N HCl, saturated NaHCO3 solution, and dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes. The trans and cis isomers were obtained in a 2:1 ratio. Isomer A (trans isomer): 1H NMR (CDCl3, 500 MHz): 9.16 (d, J=1.8 Hz, 1H), 8.31 (dd, J=2.1, 8.3 Hz, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.61 (dd, J=2.1, 8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 6.92 (s, 1H), 5.89 (s, 2H), 3.97 (s, 3H), 3.9 (m, 1H), 2.14 (bd, J=11.3 Hz, 2H), 1.87 (bd, J=12.6 Hz, 2H), 1.0-1.4 (m, 5H), 0.88 (s, 9H). LC-MS: 2.81 min; (M+H)=529.2. Isomer B (cis isomer): 1H NMR (CDCl3, 500 MHz): 9.18 (d, J=2.1 Hz, 1H), 8.33 (dd, J=2.0, 8.2 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.64 (dd, J=2.1, 8.3 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.9 (s, 1H), 5.88 (s, 2H), 4.3 (m, 1H), 3.97 (s, 3H), 2.01 (d, J=13.8 Hz, 2H), 1.73 (m, 2H), 1.65 (m, 2H), 1.29 (m, 2H), 0.89 (s, 9H). LC-MS: 2.81 min; (M+H)=529.2. The resulting slurry was left The reaction was stirred to 50° C. for 3 hours It was cooled to room temperature washed with 1N HCl, saturated NaHCO3 solution dried over anhydrous Na2SO4 The solution was filtered concentrated in vacuo The residue was purified by flash chromatography The trans and cis isomers were obtained in a 2:1 ratio 2.81 min 2.81 min

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

Procedure: To a cold (0° C. to 5° C.) stirred solution of N-tertbutyl-N-cyclohexyl amine (3.73 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in dry THF (50 mL) is added dropwise a solution of acid chloride (5.0 g, 23 mmol) in THF (20 mL). The reaction is stirred at room temperature overnight and worked up in the same manner as for 4-bromo-3-methylbenzoic acid N-cyclopentyl-N-cyclohexyl amide. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents

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

Procedure: Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32 mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine (5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was heated under reflux for 16 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The crude residue was dissolved in tetrahydrofuran (30 ml) and a solution of lithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) was slowly added. The reaction mixture was heated under reflux for 2 hours. An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefully added. The suspension was filtered and the liquid was concentrated under reduced pressure to give the title compound (3 g) as an oil. The reaction mixture was heated under reflux for 16 hours the solvent was removed under reduced pressure The residue was partitioned between dichloromethane (50 ml) and water (50 ml) The organic layer was dried over anhydrous magnesium sulphate the solvent was removed under reduced pressure The crude residue was dissolved in tetrahydrofuran (30 ml) The reaction mixture was heated under reflux for 2 hours The suspension was filtered the liquid was concentrated under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert.-butyl-cyclohexyl-amine and 17.9 g of sodium nitrite is heated at 90° C. for 3 hours. On cooling, a solid precipitates and is filtered off with suction. Yield: 16.3 g melting point: 87° C. On cooling a solid precipitates is filtered off with suction

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

Procedure: Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32 mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine (5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reaction mixture was heated under reflux for 16 hours. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between dichloromethane (50 ml) and water (50 ml). The organic layer was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The crude residue was dissolved in tetrahydrofuran (30 ml) and a solution of lithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) was slowly added. The reaction mixture was heated under reflux for 2 hours. An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefully added. The suspension was filtered and the liquid was concentrated under reduced pressure to give the title compound (3 g) as an oil. The reaction mixture was heated under reflux for 16 hours the solvent was removed under reduced pressure The residue was partitioned between dichloromethane (50 ml) and water (50 ml) The organic layer was dried over anhydrous magnesium sulphate the solvent was removed under reduced pressure The crude residue was dissolved in tetrahydrofuran (30 ml) The reaction mixture was heated under reflux for 2 hours The suspension was filtered the liquid was concentrated under reduced pressure