2-methyl-1-piperidin-4-ylpropan-2-ol

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

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

Procedure: Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-1-(piperidin-4-yl)propan-2-ol were reacted to give 266. LCMS: M+H+=519.4 were reacted

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

Procedure: Following General Procedure E of amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 2-methyl-1-(piperidin-4-yl)propan-2-ol were reacted to give 266. LCMS: M+H+=519.4 were reacted

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

Procedure: To a solution of 478 mg of 5-methoxyindole-2-carboxylic acid and 432 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 575 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 169 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.2M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-24:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 683 mg of 1-{1-[(5-methoxy-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal. followed by extraction with ethyl acetate The organic layer was washed with 0.2M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-24:1] crystallized from a mixture of ethyl acetate/diisopropyl ether

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

Procedure: To a solution of 1800 mg of 5-methylindole-2-carboxylic acid and 1500 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 25 mL of DMF were added 2100 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 1500 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from a mixture of ethyl acetate/diisopropyl ether to obtain 2140 mg of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol as a white crystal. followed by extraction with ethyl acetate The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1] crystallized from a mixture of ethyl acetate/diisopropyl ether

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

Procedure: To a solution of 370 mg of 5-chloroindole-2-carboxylic acid and 300 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 360 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 250 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from diisopropyl ether to obtain 268 mg of 1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal. followed by extraction with ethyl acetate The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1] crystallized from diisopropyl ether

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

Procedure: To a solution of 8.5 g of benzyl 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate in 120 mL of methanol was added 500 mg of 10% palladium-carbon, followed by stirring under a hydrogen atmosphere at room temperature for 1 day. Insoluble material was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 5.6 g of 2-methyl-1-(piperidin-4-yl)-2-propanol as a white solid. Insoluble material was removed by filtration through Celite the filtrate was concentrated under reduced pressure

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

Procedure: To a solution of 0.69 g (2.7 mmol) of 1-t-butoxycarbonyl-4-(methoxycarbonylethyl)piperidine (Example 22, Step 2) in 26 mL of ether at 0° C. was added dropwise 2.8 mL (8.4 mmol) of CH3MgBr (3 M in ether) and the reaction mixture was warmed slowly to rt. After stirring at rt for 6 h, the reaction was quenched by addition of 20 mL of sat'd NH4Cl solution and the mixture was stirred overnight. The mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes-:ethyl acetate, 3:1) to give 0.5 g of the title compound. the reaction was quenched by addition of 20 mL of sat'd NH4Cl solution the mixture was stirred overnight The mixture was extracted with ethyl acetate The combined organic fractions were washed with sat'd NaCl solution dried over MgSO4 filtered the filtrate was concentrated The residue was purified by chromatography (silica, hexanes-:ethyl acetate, 3:1)