4-methylsulfonylpiperidine;hydrochloride

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μl, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid. The reaction mixture was partitioned with ethyl acetate and water the organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel chromatography (chloroform:methanol=20:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Purification on silica

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5 g) and ethyl acetate (10 mL) was added dropwise a 4N hydrochloric acid.ethyl acetate solution (2.5 mL) with stirring under ice-cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(methylsulfonyl)piperidine hydrochloride as crystals (1.08 g, yield 95%). Recrystallization from ethanol gave colorless prism crystals. melting point: 271–272° C. cooling the precipitated crystals were collected by filtration washed with ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Purification on silica

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Purification on silica

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonylpiperidine hydrochloride (385 mg, 1.93 mmol), diisopropylethylamine (672 μl, 3.9 mmol), and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (81 mg, 33%) as a pale yellow solid. The reaction mixture was partitioned with ethyl acetate and water the organic layer was dried over magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel chromatography (chloroform:methanol=20:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methanesulfonyl-piperidine hydrochloride salt was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 following General Procedure B-3. Purification on silica yielded 2-chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Purification on silica

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5 g) and ethyl acetate (10 mL) was added dropwise a 4N hydrochloric acid.ethyl acetate solution (2.5 mL) with stirring under ice-cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(methylsulfonyl)piperidine hydrochloride as crystals (1.08 g, yield 95%). Recrystallization from ethanol gave colorless prism crystals. melting point: 271–272° C. cooling the precipitated crystals were collected by filtration washed with ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of tert-butyl 4-(methylsulfonyl)piperidine-1-carboxylate (1.5 g) and ethyl acetate (10 mL) was added dropwise a 4N hydrochloric acid.ethyl acetate solution (2.5 mL) with stirring under ice-cooling. After stirring overnight at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate to give 4-(methylsulfonyl)piperidine hydrochloride as crystals (1.08 g, yield 95%). Recrystallization from ethanol gave colorless prism crystals. melting point: 271–272° C. cooling the precipitated crystals were collected by filtration washed with ethyl acetate

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 250 mL round bottom flask, 2,6-difluorobenzaldehyde (7.12 g, 5.4 mL, 50.1 mmol), 4-methanesulfonylpiperidine hydrochloride (10 g, 50.1 mmol) and DIPEA (7.77 g, 60.1 mmol) were combined with acetonitrile (75 mL). The mixture was stirred and heated at 80° C. overnight. The mixture was evaporated and extracted with dichloromethane and citric acid solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The crude solid was triturated with cold ethyl acetate to afford 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (12 g, 84% yield). LC-MS calcd for C13H16FNO3S (m/e) 285.08, obsd 286.0 (M+H). The mixture was evaporated extracted with dichloromethane and citric acid solution The organic layer was washed with brine dried over sodium sulfate evaporated The crude solid was triturated with cold ethyl acetate

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Methylsulfonyl-piperidine hydrochloride (6.89 g, 34.5 mmol) was grinded into fine powder and mixed with fine powder of sodium tert-butoxide (7.65 g, 79.6 mmol) in dry dioxane (180 mL). After 30 minutes of stirring, 4-bromo-1-(2-(methylthio)pyrimidin-4-yl)-1H-indole (8.5 g, 26.5 mmol) was added followed by dry dioxane (10 mL) and the mixture was bubbled with argon for 10 minutes. Bis(tri-tert-butylphosphine)palladium (1.02 g, 2.0 mmol) was added followed by dry dioxane (10 mL). The mixture was bubbled with argon for 5 minutes and then sealed. The sealed thick wall bottle was put into oil bath at 65° C. and heated to 120° C. The mixture was stirred at 120° C. for 1.5 hr. The resulting mixture was cooled to 50° C. and filtered through a thin layer of Celite, rinsed with dioxane (100 mL). The filtrate was concentrated and extracted with dichloromethane and saturated ammonium chloride solution. The organic layer was dried and concentrated to a volume about 25 mL. The mixture was treated with ethyl acetate (150 mL) and the yellow solid was filtered to give the desired compound (4.65 g). The filtrate was concentrated and dissolved in dichloromethane and purified through ISCO flash column chromatography (200 g silica gel, 20% to 100% ethyl acetate in hexanes) to give second batch of desired product as a yellow solid (1.67 g, combined total 6.32 g, yield 59.1%). LC-MS calcd for C19H22N4O2S2 (m/e) 402.12, obsd 402.9 (M+H). the mixture was bubbled with argon for 10 minutes The mixture was bubbled with argon for 5 minutes sealed The sealed thick wall bottle was put into oil bath at 65° C. The mixture was stirred at 120° C. for 1.5 hr The resulting mixture was cooled to 50° C. filtered through a thin layer of Celite rinsed with dioxane (100 mL) The filtrate was concentrated extracted with dichloromethane and saturated ammonium chloride solution The organic layer was dried concentrated to a volume about 25 mL The mixture was treated with ethyl acetate (150 mL) the yellow solid was filtered

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 250 mL round bottom flask, 2,6-difluorobenzaldehyde (7.12 g, 5.4 mL, 50.1 mmol), 4-methanesulfonylpiperidine hydrochloride (10 g, 50.1 mmol) and DIPEA (7.77 g, 60.1 mmol) were combined with acetonitrile (75 mL). The mixture was stirred and heated at 80° C. overnight. The mixture was evaporated and extracted with dichloromethane and citric acid solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The crude solid was triturated with cold ethyl acetate to afford 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (12 g, 84% yield). LC-MS calcd for C13H16FNO3S (m/e) 285.08, obsd 286.0 (M+H). The mixture was evaporated extracted with dichloromethane and citric acid solution The organic layer was washed with brine dried over sodium sulfate evaporated The crude solid was triturated with cold ethyl acetate