1-(aminomethyl)cyclohexan-1-ol

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: 1-Aminomethyl-1-cyclohexanol hydrochloride (1 g, 6.04 mmol) was dissolved in cold water and then K2CO3 and ether were added. The mixture was stirred and then the ether layer was separated and the aqueous layer was again extracted with ether. The ether layers were combined, dried over MgSO4 and concentrated to afford 1-aminomethyl-1-cyclohexanol which was mixed with DMSO (3 mL) and 1-ethyl-6-methoxy-1H-pyrazolo[3,4-b]quinoline (0.8 g, 3 mmol). The reaction mixture was stirred at 110° C. overnight and then was partitioned between water and CH2Cl2. The CH2Cl2 layer was separated, dried, filtered and evaporated. The residue was crystallized from CH2Cl2 and recrystallized from acetonitrile to afford 0.65 g of 1-ethyl-6-methoxy-N-[(1-hydroxycyclohexyl)methyl]-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 201-°203° C. the ether layer was separated the aqueous layer was again extracted with ether dried over MgSO4 concentrated

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

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

Procedure: A mixture of 3,3-dimethylbutanal (3.0 mL, 24 mmol), 1-(aminomethyl)cyclohexanol, hydrochloric acid (3.6 g, 22 mmol), triethylamine (3.0 mL, 22 mmol), and 3 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (25 mL) was stirred at ambient temperature for 20 h. The material was filtered through Celite® with acetonitrile (additional 20 mL) then potassium thiocyanate (2.8 g, 29 mmol) was added and the mixture was warmed to 50° C. Iodine (5.5 g, 22 mmol) was added and the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was then stirred with 50 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3×10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound which was carried on without further purification. MS (DCI/NH3) m/z 269 (M+H)+. The material was filtered through Celite® with acetonitrile (additional 20 mL) the mixture was warmed to 50° C the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with 3×10 mL CH2Cl2 The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: A mixture of 3,3-dimethylbutanal (3.0 mL, 24 mmol), 1-(aminomethyl)cyclohexanol, hydrochloric acid (3.6 g, 22 mmol), triethylamine (3.0 mL, 22 mmol), and 3 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (25 mL) was stirred at ambient temperature for 20 h. The material was filtered through Celite® with acetonitrile (additional 20 mL) then potassium thiocyanate (2.8 g, 29 mmol) was added and the mixture was warmed to 50° C. Iodine (5.5 g, 22 mmol) was added and the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature. The mixture was then stirred with 50 mL of 20% aqueous sodium metabisulfite for 1 h then the layers were separated and the aqueous layer was extracted with 3×10 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound which was carried on without further purification. MS (DCI/NH3) m/z 269 (M+H)+. The material was filtered through Celite® with acetonitrile (additional 20 mL) the mixture was warmed to 50° C the mixture was stirred at 50° C. for 16 h then was cooled to ambient temperature the layers were separated the aqueous layer was extracted with 3×10 mL CH2Cl2 The combined organics were dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: 2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of 1-aminomethyl-cyclohexanol (93 mg, 0.56 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-(1-hydroxy-cyclohexylmethyl)-nicotinamide (86 mg) as an off-white solid. were then added The mixture was concentrated under reduced pressure partitioned between ethyl acetate (20 ml) and water (20 ml) the organic phase was removed dried over MgSO4 concentrated under reduced pressure The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume)

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

Procedure: 2-(3-Ethylsulfanyl-phenoxy)-5-fluoro-nicotinic acid (150 mg, 0.51 mmol) was added to a solution of 1-aminomethyl-cyclohexanol (93 mg, 0.56 mmol) and triethylamine (0.21 ml, 1.5 mmol) in dimethylformamide (3 ml) under nitrogen at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (108 mg, 0.56 mmol) followed by 1-hydroxybenzotriazole (76 mg, 0.56 mmol) were then added and the reaction was stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate (20 ml) and water (20 ml) and the organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-(1-hydroxy-cyclohexylmethyl)-nicotinamide (86 mg) as an off-white solid. were then added The mixture was concentrated under reduced pressure partitioned between ethyl acetate (20 ml) and water (20 ml) the organic phase was removed dried over MgSO4 concentrated under reduced pressure The residue was purified by flash column chromatography on a silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:2, by volume)