methyl 3,3-dicyano-2,2-dimethylpropanoate

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 liter 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen bubbler, was charged with malononitrile (251 g, 3.802 moles) and THF (2 liters). Potassium t-butoxide (1M THF, 3.802 L, 3.802 moles) was then added. The mixture was stirred at 50° C. for 30 min. Methyl 2-bromoisobutyrate (688 g, 3.80 moles) was added and the reaction mixture was stirred overnight at 50° C. The reaction was partitioned between aqueous 1N HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.35 (s, 1H); 3.73 (s, 3H); 1.43 (s, 6H). the reaction mixture was stirred overnight at 50° C The reaction was partitioned between aqueous 1N HCl and EtOAc The organic phase was washed with brine dried over MgSO4 filtered concentrated to give the indicated product

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

実験手順: 400 mg (1.11 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 277 mg (1.33 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 175 mg (1.56 mmol) of potassium tert-butoxide, and the mixture was heated to reflux for 24 h. A little water was added and the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). The product-containing fractions were concentrated and the residue was stirred with water/isopropanol. The solids were filtered off and purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 170 mg (35% of theory) of the target compound were obtained. to reflux for 24 h the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5) The product-containing fractions were concentrated The solids were filtered off purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0) 170 mg (35% of theory) of the target compound were obtained

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

実験手順: 400 mg (1.11 mmol) of 1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 277 mg (1.33 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 175 mg (1.56 mmol) of potassium tert-butoxide, and the mixture was heated to reflux for 24 h. A little water was added and the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5). The product-containing fractions were concentrated and the residue was stirred with water/isopropanol. The solids were filtered off and purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 170 mg (35% of theory) of the target compound were obtained. to reflux for 24 h the reaction solution was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→95:5) The product-containing fractions were concentrated The solids were filtered off purified again by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0) 170 mg (35% of theory) of the target compound were obtained

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

実験手順: 200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide were admixed with 3 ml of tert-butanol, 146 mg (0.70 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 1.5 ml of tert-butanol and 94 mg (0.84 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, and the organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theory) of the target compound were obtained. under reflux for 48 h the precipitate was filtered off The filtrate was extracted with dichloromethane the organic phase was dried over sodium sulphate concentrated on a rotary evaporator The solid was filtered off dried under high vacuum 102 mg (34% of theory) of the target compound were obtained

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

実験手順: 300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide were admixed with 2 ml of tert-butanol, 287 mg (1.38 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 181 mg (1.61 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 72 h. The mixture was concentrated to dryness and the residue was stirred with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theory) of the target compound were obtained. under reflux for 72 h The mixture was concentrated to dryness The solid was filtered off dried under high vacuum 385 mg (80% of theory) of the target compound were obtained

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

実験手順: In THF (91 ml), 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil) were admixed gradually with 3 g (45.411 mmol) of malononitrile. Subsequently, 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the reaction mixture was stirred at room temperature overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the reaction mixture was heated to 50° C. overnight. Then yet another 1.762 ml (13.623 mmol) of methyl 2-bromo-2-methylpropanoate were added and the reaction mixture was heated to 50° C. for a further 4 h. The mixture was then admixed with saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (4:1 cyclohexane-ethyl acetate). the reaction mixture was heated to 50° C. overnight the reaction mixture was heated to 50° C. for a further 4 h extracted three times with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulphate filtered concentrated to dryness This gave 8.9 g of crude product, which was purified by chromatography on silica gel (4:1 cyclohexane-ethyl acetate)

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

実験手順: 3 ml tert.-butanol, a solution of 146 mg (0.70 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 1.5 ml tert.-butanol and 94 mg (0.84 mmol) of potassium tert.-butylate were added to 200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide and it was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, the organic phase was dried over sodium sulphate and concentrated in a rotary evaporator. The residue was mixed with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theor.) of the target compound was obtained. was heated under reflux for 48 h the precipitate was filtered off The filtrate was extracted with dichloromethane the organic phase was dried over sodium sulphate concentrated in a rotary evaporator The residue was mixed with water/ethanol The solid was filtered off dried under high vacuum 102 mg (34% of theor.) of the target compound was obtained

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

実験手順: 300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide was dissolved with 2 ml tert.-butanol, 287 mg (1.38 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 2 ml tert.-butanol and 181 mg (1.61 mmol) of potassium tert.-butylate was added and it was heated under reflux for 72 h. It was evaporated to dryness and the residue was mixed with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theor.) of the target compound was obtained. was added it was heated under reflux for 72 h It was evaporated to dryness the residue was mixed with water/isopropanol (v/v=3:1) The solid was filtered off dried under high vacuum 385 mg (80% of theor.) of the target compound was obtained

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

実験手順: In THF (91 ml), 3 g (45.411 mmol) of malonic acid dinitrile was slowly added to 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil). Then 5.876 ml (45.411 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was stirred overnight at RT. Then a further 5.876 ml (45.411 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was heated overnight to 50° C. Then once again, 1.762 ml (13.623 mmol) of methyl-2-bromo-2-methylpropanoate was added and it was heated for a further 4 h to 50° C. Saturated aqueous sodium hydrogen carbonate solution was then added to the mixture and it was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and evaporated to dryness. 8.9 g of raw product was obtained, and was purified by silica gel chromatography (cyclohexane-ethyl acetate 4:1). it was heated overnight to 50° C it was heated for a further 4 h to 50° C was extracted three times with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulphate filtered evaporated to dryness

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 liter 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen bubbler, was charged with malononitrile (251 g, 3.802 moles) and THF (2 liters). Potassium t-butoxide (1M THF, 3.802 L, 3.802 moles) was then added. The mixture was stirred at 50° C. for 30 min. Methyl 2-bromoisobutyrate (688 g, 3.80 moles) was added and the reaction mixture was stirred overnight at 50° C. The reaction was partitioned between aqueous 1N HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.35 (s, 1H); 3.73 (s, 3H); 1.43 (s, 6H). the reaction mixture was stirred overnight at 50° C The reaction was partitioned between aqueous 1N HCl and EtOAc The organic phase was washed with brine dried over MgSO4 filtered concentrated to give the indicated product

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 12 liter 3 neck round bottom flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen bubbler, was charged with malononitrile (251 g, 3.802 moles) and THF (2 liters). Potassium t-butoxide (1M THF, 3.802 L, 3.802 moles) was then added. The mixture was stirred at 50° C. for 30 min. Methyl 2-bromoisobutyrate (688 g, 3.80 moles) was added and the reaction mixture was stirred overnight at 50° C. The reaction was partitioned between aqueous 1N HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.35 (s, 1H); 3.73 (s, 3H); 1.43 (s, 6H). the reaction mixture was stirred overnight at 50° C The reaction was partitioned between aqueous 1N HCl and EtOAc The organic phase was washed with brine dried over MgSO4 filtered concentrated to give the indicated product

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

実験手順: In THF (91 ml), 1.816 g (45.411 mmol) of sodium hydride (60% in mineral oil) were admixed gradually with 3 g (45.411 mmol) of malononitrile. Subsequently, 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was stirred at room temperature overnight. Thereafter, another 5.876 ml (45.411 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated to 50° C. overnight. Then yet another 1.762 ml (13.623 mmol) of methyl 2-bromo-2-methylpropanoate were added and the mixture was heated to 50° C. for a further 4 h. The mixture was then admixed with saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. This gave 8.9 g of crude product, which was purified by chromatography on silica gel (4:1 cyclohexane-ethyl acetate). the mixture was heated to 50° C. overnight the mixture was heated to 50° C. for a further 4 h extracted three times with ethyl acetate The combined organic phases were washed with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated to dryness This gave 8.9 g of crude product, which was purified by chromatography on silica gel (4:1 cyclohexane-ethyl acetate)