ethyl 2-[tert-butyl(dimethyl)silyl]oxyacetate

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

実験手順: 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyl-oxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (20 g) in tetrahydrofuran (200 mL) was added a THF solution (49.9 mL) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (800 mL), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) and carbon tetrabromide (15.4 g) in methylene chloride (340 mL) was added triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice-cooling and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (3.84 g) as a pale-yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1-(naphthalen-1-yl)piperazine (334 mg) and the mixture was stirred under ice-cooling for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (500 mg) under ice-cooling and the mixture was stirred under ice-cooling for 6 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (1:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals. the resulting mixture was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was crystallized from ethyl acetate

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

実験手順: 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals. the resulting mixture was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was crystallized from ethyl acetate

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

実験手順: 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals. the resulting mixture was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was crystallized from ethyl acetate

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O -dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to 1/3 volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated to 1/3 volume The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O -dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to 1/3 volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated to 1/3 volume The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

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

実験手順: To a solution of ethyl 2-(tert-butyldimethylsilyloxy)acetate (59, 20.0 g, 91.59 mmol), N,O-dimethylhydroxylamine hydrochloride (18.76 g, 192.3 mmol) and THF (800 mL) cooled to 0° C. was added dropwise via addition funnel isopropylmagnesium chloride (183.2 mL, 366.4 mmol) and the reaction was stirred for 3 h. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane to afford 15.12 g (70.7%) of 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (60). The reaction was quenched with saturated NH4Cl extracted with EtOAc The organic layer was dried filtered concentrated The crude product was purified by passage through a SiO2 plug eluting with 20% EtOAc/hexane

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

実験手順: 2M Isopropylmagnesium chloride in THF (91.6 mL, 183 mmol) was added dropwise to ethyl 2-(tert-butyldimethylsilyloxy)acetate (10.0 g, 45.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (9.38 g, 96.2 mmol) in THF (500 mL) cooled in ice. The mixture was stirred for 4.5 hours allowing to slowly warm to ambient temperature. The reaction mixture was quenched with aqueous NH4Cl and concentrated to ⅓ volume. The residue was diluted with water and extracted with EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (8.51 g, 36.5 mmol, 79.6% yield) as an oil. cooled in ice The reaction mixture was quenched with aqueous NH4Cl concentrated The residue was diluted with water extracted with EtOAc The EtOAc was washed with brine dried over MgSO4 filtered evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 32.7g (0.15 mole) of ethyl t-butyldimethylsilyloxyacetate in 924 ml of methylene chloride a solution of 1M diisopropylaluminum hydride in methylene chloride is added dropwise with stirring at -78° C. over a period of 1/2 h. The mixture is stirred for 45 min and 100 ml of methanol is added dropwise. The mixture is diluted with 3 l of ether, 100 ml of brine and 70 g of sodium sulfate are added and the mixture is stirred at room temperature for 15 h. The solids are filtered, the filtrates are evaporated and the residue is distilled to give t-butyldimethylsilyloxyacetaldehyde, b.p. 65°-75° C. (14 mm/Hg). The mixture is stirred for 45 min are added the mixture is stirred at room temperature for 15 h The solids are filtered the filtrates are evaporated the residue is distilled

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

実験手順: A solution of 33.93 g of ethyl glycolate, 62.7 g of t-butyldimethylchlorosilane and 58.5 g of imidazole in 150 ml of dimethylformamide is stirred at room temperature for 15 h. The mixture is diluted with ether and washed with water (2×100 ml), brine, dried (MgSO4) and evaporated. The residue is distilled to give ethyl t-butyldimethylsilyloxyacetate, b.p. 100°-105° C. (14 mm/Hg). washed with water (2×100 ml), brine dried (MgSO4) evaporated The residue is distilled

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

実験手順: 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyl-oxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 1001. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (20 g) in tetrahydrofuran (200 mL) was added a THF solution (49.9 mL) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (800 mL), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (12.7 g) and carbon tetrabromide (15.4 g) in methylene chloride (340 mL) was added triphenylphosphine (12.2 g) in methylene chloride (100 mL) under ice-cooling and the mixture was stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (3.84 g) as a pale-yellow solid. To a suspension of sodium hydride (60 mg) in DMF (10 mL) was added 1-(naphthalen-1-yl)piperazine (334 mg) and the mixture was stirred under ice-cooling for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (500 mg) under ice-cooling and the mixture was stirred under ice-cooling for 6 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (1:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (370 mg) as white crystals. the resulting mixture was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was crystallized from ethyl acetate

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

実験手順: 4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals. the resulting mixture was washed with a saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was crystallized from ethyl acetate