4-(aminomethyl)cyclohexan-1-ol

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

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

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.02 g, 15.5 mmol), DMSO (6 ml) and 4-hydroxy cyclohexylmethylamine (2 g, 15.5 mmol) was heated at 110° C. overnight. The reaction mixture was partitioned between CH2Cl2 /water/NaHCO3, and the CH2Cl2 layer was separated, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford 1.8 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl) -1H-pyrazolo[3,4-b]quinolin-4-amine. The reaction mixture was partitioned between CH2Cl2 /water/NaHCO3 the CH2Cl2 layer was separated dried over MgSO4 evaporated The residue was purified by column chromatography on silica gel eluting with ethyl acetate

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

Procedure: A mixture of 4-hydroxycyclohexylmethylamine (2.2 g, 17.05 mmol), 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.0 g, 7.66 mmol) and DMSO was heated at 110°-120° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into ice-water and the mixture was extracted with CH2Cl2 (4×50 ml). The organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1), followed by a second silica gel column eluting with ethyl acetate to afford 1.3 g of crude product. The crude product was dissolved in warm methanol, cooled to room temperature and treated with an equivalent amount of methanesuflonic acid. Ether was added to the mixture and the solid which formed was collected by filtration, washed with ether and recrystallized from isopropanol to afford 0.85 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, as yellow crystals, m.p. 256°-258° C. (dec.). was heated at 110°-120° C. under a nitrogen atmosphere for 16 hours the mixture was extracted with CH2Cl2 (4×50 ml) dried over MgSO4 evaporated to dryness The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1) eluting with ethyl acetate to afford 1.3 g of crude product treated with an equivalent amount of methanesuflonic acid the solid which formed was collected by filtration washed with ether recrystallized from isopropanol

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

Procedure: To a stirred solution of N-benzyl-N-(4-hydroxycyclohexyl methyl)amine (8.5 g, 0.039 mol) in methanol (300 ml) under N2 was added ammonium formate (9.8 g, 0.0155 mol), followed by 10% palladium on carbon (1.0 g). The reaction mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was dissolved in CH2Cl2, filtered and the filtrate was evaporated to afford 1.3 g of 4-hydroxycyclohexylmethylamine. The reaction mixture was refluxed for 3 hours filtered The filtrate was evaporated to dryness the residue was dissolved in CH2Cl2 filtered the filtrate was evaporated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.02 g, 15.5 mmol), DMSO (6 ml) and 4-hydroxy cyclohexylmethylamine (2 g, 15.5 mmol) was heated at 110° C. overnight. The reaction mixture was partitioned between CH2Cl2 /water/NaHCO3, and the CH2Cl2 layer was separated, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford 1.8 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl) -1H-pyrazolo[3,4-b]quinolin-4-amine. The reaction mixture was partitioned between CH2Cl2 /water/NaHCO3 the CH2Cl2 layer was separated dried over MgSO4 evaporated The residue was purified by column chromatography on silica gel eluting with ethyl acetate

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

Procedure: A mixture of 4-hydroxycyclohexylmethylamine (2.2 g, 17.05 mmol), 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.0 g, 7.66 mmol) and DMSO was heated at 110°-120° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into ice-water and the mixture was extracted with CH2Cl2 (4×50 ml). The organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1), followed by a second silica gel column eluting with ethyl acetate to afford 1.3 g of crude product. The crude product was dissolved in warm methanol, cooled to room temperature and treated with an equivalent amount of methanesuflonic acid. Ether was added to the mixture and the solid which formed was collected by filtration, washed with ether and recrystallized from isopropanol to afford 0.85 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, as yellow crystals, m.p. 256°-258° C. (dec.). was heated at 110°-120° C. under a nitrogen atmosphere for 16 hours the mixture was extracted with CH2Cl2 (4×50 ml) dried over MgSO4 evaporated to dryness The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1) eluting with ethyl acetate to afford 1.3 g of crude product treated with an equivalent amount of methanesuflonic acid the solid which formed was collected by filtration washed with ether recrystallized from isopropanol

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

Procedure: To a stirred solution of N-benzyl-N-(4-hydroxycyclohexyl methyl)amine (8.5 g, 0.039 mol) in methanol (300 ml) under N2 was added ammonium formate (9.8 g, 0.0155 mol), followed by 10% palladium on carbon (1.0 g). The reaction mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was dissolved in CH2Cl2, filtered and the filtrate was evaporated to afford 1.3 g of 4-hydroxycyclohexylmethylamine. The reaction mixture was refluxed for 3 hours filtered The filtrate was evaporated to dryness the residue was dissolved in CH2Cl2 filtered the filtrate was evaporated

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

Procedure: To a stirred solution of N-benzyl-N-(4-hydroxycyclohexyl methyl)amine (8.5 g, 0.039 mol) in methanol (300 ml) under N2 was added ammonium formate (9.8 g, 0.0155 mol), followed by 10% palladium on carbon (1.0 g). The reaction mixture was refluxed for 3 hours, cooled to room temperature and filtered. The filtrate was evaporated to dryness and the residue was dissolved in CH2Cl2, filtered and the filtrate was evaporated to afford 1.3 g of 4-hydroxycyclohexylmethylamine. The reaction mixture was refluxed for 3 hours filtered The filtrate was evaporated to dryness the residue was dissolved in CH2Cl2 filtered the filtrate was evaporated

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: To a solution of 4-hydroxymethylcyclohexanol (2 mmol) in THF (10 mL) were added Ms-Cl (2.2 mmol) and triethylamine (3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 10 mL of DMF, and then NaN3(6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Then, the obtained compound was dissolved in methanol, and 10% Pd—C (0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide 4-aminomethyl-cyclohexanol. To a solution of 4-aminomethyl-cyclohexanel in dichloromethane (10 mL) were added 1-pyrrolidinecarbonyl chloride (2 mmol) and triethylamine (3 mmol). After overnight stirring at room temperature, the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:1) to provide a pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide. The pyrrolidine-1-carboxylic acid (4-hydroxy-cyclohexylmethyl)-amide compound was dissolved in acetonitrile (10 mL), and then CDI (2.2 mmol) was added. After 1 hours stirring at 80° C., methyl iodide (10 mmol) was added and stirred for additional 1 hour at 80° C. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (10 mL) and C-pyridine-2-yl-methylamine (3 mmol) was added. After 4 hours stirring at 80° C., the reaction mixture was diluted with water, followed by few times of extraction with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=1:3), thereby completing the preparation of a target compound (180 mg, 25% yield). The reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate washed with water The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The residue was dissolved in 10 mL of DMF After overnight stirring at 60° C. washed with water The organic layer was dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure Then, the obtained compound was dissolved in methanol After overnight stirring under hydrogen atmosphere the reaction mixture was filtered washed with methanol concentrated under reduced pressure