2-methylcyclohexan-1-amine

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: Prepared in a similar manner to Example 162 using 2,6-dimethylbenzoic acid and 2-methylcyclohexylamine. Yield: 59%. 1H NMR (500 MHz, CDCl3): δ 0.88-0.94 (3H, dd), 1.14-1.89 (9H, m), 2.21-2.22 (6H, d), 3.39-3.45 (1H, m), 7.02-7.03 (2H, d), 7.12-7.15 (1H, t), 8.11-8.13 (1H, d). MS (M+H, 246.2).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3,5,6-tetrafluoro-p-toluic acid (4.00 g, 19.22 mmol), HOBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0° C. and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3.05 mL, 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with 1N HCl, water, aqueous NaHCO3, water and brine, drying over MgSO4, filtration and removal of solvent in vacuo, afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) and drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). 1H NMR (CDCl3) δ 0.95, 1.01 (d, J=7.0, 6.6 Hz, 3H) 1.1-2.1 (m, 9H), 2.29 (m, 3H), 3.70, 4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS (304.1, M+H). m. p. 202-204° C. to slowly warm to ambient temperature stirred overnight washed with 1N HCl, water, aqueous NaHCO3, water and brine drying over MgSO4, filtration and removal of solvent in vacuo afforded the crude product as a pale yellow solid Recrystallization (EtOH/H2O) drying in vacuo

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

Procedure: Prepared in a similar manner as described in example 4 from 3-(2-methoxy-phenyl)-acrylic acid and 2-methyl-cyclohexylamine. MS (M+H, 274.2). Prepared in a similar manner

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

Procedure: A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL ×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H]+. the solution was extracted with ethyl acetate (3 mL ×2) The organic phase was then washed with water (3 mL) dried over Na2SO4 evaporated The residue was purified by preparative TLC plate

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

Procedure: A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL ×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H]+. the solution was extracted with ethyl acetate (3 mL ×2) The organic phase was then washed with water (3 mL) dried over Na2SO4 evaporated The residue was purified by preparative TLC plate

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

Procedure: To a solution of 2-methylcyclohexylamine (98% cis and trans isomers, 10.0 g, 88.3 mmol) in tetrahydrofuran (60 mL) was slowly added a solution of 1,3-propane sultone (10.5 g, 84.1 mmol) in THF (20 mL). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×50 mL). The solid was dissolved in 50% EtOH/water (200 mL); and solution was treated with Dowex 50WX8 resin (15 g). The suspension stirred at room temperature for 15 min. The resin was removed by filtration. The filtrate was concentrated to half of the original volume on a rotary evaporator. The solid product slowly crystallized. The product was collected by filtration, washed with acetone (2×50 mL) and dried in a vacuum oven (50° C.), to afford compound DJ (10.4 g, 53%): 1H NMR (D2O, 500 MHz) δ ppm 3.15 (m, 1H), 3.03 (m, 1H), 2.88 (t, 2H, J=7.3 Hz), 2.76 (m, 1H), 1.98 (m, 3H), 1.68 (m, 2H), 1.51 (m, 2H), 1.18 (m, 3H), 1.01 (m, 1H), 0.92 (m, 3H). 13C NMR (D2O, 125 MHz) δ ppm 62.97, 48.16, 42.72, 34.77, 33.50, 27.57, 24.51, 24.23, 21.51, 17.80. ES-MS 234 (M−1). at reflux for 2 hours The solid material was collected by filtration washed with acetone (2×50 mL) The solid was dissolved in 50% EtOH/water (200 mL) and solution was treated with Dowex 50WX8 resin (15 g) The suspension stirred at room temperature for 15 min The resin was removed by filtration The filtrate was concentrated to half of the original volume on a rotary evaporator The solid product slowly crystallized The product was collected by filtration washed with acetone (2×50 mL) dried in a vacuum oven (50° C.) to afford compound DJ (10.4 g, 53%)