6-chlorohex-1-yne

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

実験手順: To a solution of n-BuLi/hexane (7.28 mL, 18.2 mmol, 2.5 M) at −5° C. was added tetrahydrofuran dropwise, maintaining the temperature below +9° C. 6-Chloro-1-hexyne (1.00 mL, 8.92 mmol) was added at +5° C., and the solution was stirred for six hours. The reaction was quenched by the addition of tri-n-butyltin chloride (2.66 mL, 9.81 mmol), and was allowed to stir for an additional 10 minutes. The solution was poured into hexane, washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a colorless liquid which was used without further purification. maintaining the temperature below +9° C to stir for an additional 10 minutes washed with saturated NaHCO3 solution and brine dried (Na2SO4) filtered concentrated in vacuo The product was isolated as a colorless liquid which was used without further purification

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

実験手順: To a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) in anhydrous Et2O (500 mL) at −78° C., n-butyllithium (2.5 M in hexane, 360 mL, 0.90 mol) was added over 40 minutes. The resulting mixture was stirred for 30 minutes at −78° C. Chlorotrimethylsilane (125 mL, 1.0 mol) was then added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature and extracted with Et2O (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (144 g, yield 93%). 1H NMR (DMSO-d6, 400 MHz): δ 3.65 (t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s, 9H). to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature extracted with Et2O (2×200 mL) The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SO4 concentrated in vacuo

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

実験手順: To a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) in anhydrous Et2O (500 mL) at −78° C., n-butyllithium (2.5 M in hexane, 360 mL, 0.90 mol) was added over 40 minutes. The resulting mixture was stirred for 30 minutes at −78° C. Chlorotrimethylsilane (125 mL, 1.0 mol) was then added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature and extracted with Et2O (2×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the title compound (144 g, yield 93%). 1H NMR (DMSO-d6, 400 MHz): δ 3.65 (t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s, 9H). to warm to room temperature stirred for 16 h The reaction mixture was carefully quenched with saturated aqueous NH4Cl (300 mL) at room temperature extracted with Et2O (2×200 mL) The combined organic layers were washed with brine (200 mL) dried over anhydrous Na2SO4 concentrated in vacuo

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

実験手順: To potassium phthalimide (37.5 g) in dimethylformamide (400 ml) at 100° C,. was added dropwise 1-chloro-5-hexyne (23.67 g) in dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for a further hour, cooled and stirred at room temperature overnight. The mixture was poured on to ice/water to give an oil, which on trituration gave as a white solid N-5-hexynyl phthalimide (18.35 g), m.p. 74°-6° C. (recrystallisation from ethanol). at 100° C cooled stirred at room temperature overnight to give an oil, which on trituration

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

実験手順: To potassium phthalimide (37.5 g) in dimethylformamide (400 ml) at 100° C,. was added dropwise 1-chloro-5-hexyne (23.67 g) in dimethylformamide (100 ml). The reaction mixture was stirred at 100° C. for a further hour, cooled and stirred at room temperature overnight. The mixture was poured on to ice/water to give an oil, which on trituration gave as a white solid N-5-hexynyl phthalimide (18.35 g), m.p. 74°-6° C. (recrystallisation from ethanol). at 100° C cooled stirred at room temperature overnight to give an oil, which on trituration

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1.0 g of 6-chloro-1-hexyne and 1.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and then at 90° C. for 2 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.70 g of 2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (23)). at 90° C. for 2 hours to stand near room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated under reduced pressure

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1.0 g of 6-chloro-1-hexyne and 1.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and then at 90° C. for 2 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.70 g of 2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (23)). at 90° C. for 2 hours to stand near room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated under reduced pressure

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1.0 g of 6-chloro-1-hexyne and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 0.3 g of sodium hydride (60% in oil) was added at room temperature. The mixture was stirred at room temperature for 12 hours, at 60° C. for 2 hours and then at 90° C. for 10 hours. The reaction mixture was allowed to stand near room temperature, and 10% hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.50 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-7-octynoate (hereinafter referred to as the present compound (1)). at 90° C. for 10 hours to stand near room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate concentrated under reduced pressure

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

実験手順: A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 g, 107 mmol), 6-chloro-1-hexyne (18.71 g, 160 mmol), triethylamine (22.37 mL, 160 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.63 g, 8.02 mmol) and copper(I) iodide (3.04 g, 15.94 mmol) in N,N-Dimethylformamide (1000 mL) under nitrogen was heated to 70° C. for 4 hours. The cooled solution was evaporated and the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes. Appropriate fractions were evaporated to give the title compound as a yellow foam (25.5 g). The cooled solution was evaporated the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes Appropriate fractions were evaporated

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

実験手順: A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 g, 107 mmol), 6-chloro-1-hexyne (18.71 g, 160 mmol), triethylamine (22.37 mL, 160 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.63 g, 8.02 mmol) and copper(I) iodide (3.04 g, 15.94 mmol) in N,N-Dimethylformamide (1000 mL) under nitrogen was heated to 70° C. for 4 hours. The cooled solution was evaporated and the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes. Appropriate fractions were evaporated to give the title compound as a yellow foam (25.5 g). The cooled solution was evaporated the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes Appropriate fractions were evaporated

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

実験手順: A nitrogen degassed stirred mixture of 5-butyl-N-(3,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (4.58 g, 9.7 mmol), copper(I) iodide (278 mg, 1.46 mmol) and bis(triphenylphosphine)palladium(II)dichloride (515 mg, 0.734 mmol) in anhydrous N,N-dimethylformamide (105 mL) was warmed to 60° C. under a nitrogen atmosphere before addition of a solution of 6-chloro-1-hexyne (1.712 g, 14.69 mmol) and triethylamine (2.047 mL, 14.69 mmol) in anhydrous nitrogen degassed N,N-dimethylformamide (15 mL), dropwise over 5 minutes. The reaction was stirred at 60° C. for 6 hours. The cooled reaction mixture was evaporated in-vacuo and the resultant oil partitioned between 1:1 water/brine and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield an orange oil. The oil was dissolved in the minimum volume of dichloromethane, loaded onto a 330 g silica pre-conditioned cartridge and purified by chromatography using cyclohexane over 1 column volume followed by 0-100% ethyl acetate in cyclohexane gradient over 14 column volumes followed by ethyl acetate over 2 column volumes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a yellow foam (3.334 g) A nitrogen degassed degassed N,N-dimethylformamide (15 mL) The reaction was stirred at 60° C. for 6 hours The cooled reaction mixture was evaporated in-vacuo the resultant oil partitioned between 1:1 water/brine and ethyl acetate The organic layer was separated evaporated in-vacuo to yield an orange oil purified by chromatography evaporated in-vacuo

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (4.97 g, 15.62 mmol) in N,N-dimethylformamide (100 mL) was added bis(triphenylphosphine)palladium(II)dichloride (1.228 g, 1.750 mmol) and copper(I) iodide (0.595 g, 3.12 mmol). The solution was stirred and degassed with nitrogen for 5 minutes then the reaction mixture placed under a nitrogen atmosphere. A solution of 6-chloro-1-hexyne (3.64 g, 31.2 mmol) and triethylamine (4.36 mL, 31.2 mmol) in N,N-dimethylformamide (30 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for a further 10 minutes then heated to 60° C. for 2.5 hours. The reaction mixture was concentrated in vacuo at 60° C. and the resulting residue partitioned between ethyl acetate (250 mL) and a 1:1 mixture of water:brine (500 mL). The organic layer was separated and the aqueous layer back extracted with ethyl acetate (250 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a brown solid (8.0 g). The residue was dissolved in a 1:1 mixture of MeOH:DCM and absorbed onto Florisil. The solid was loaded and purified by chromatography on silica (330 g) using a 0-100% ethyl acetate-cyclohexane gradient over 10 column volumes followed by flushing with ethyl acetate for 9 column volumes. The appropriate fractions were combined and evaporated in vacuo to give a yellow solid (3.55 g). The solid was triturated with diisopropyl ether, filtered and dried in vacuo at 50° C. to give the title compound as a pale yellow solid (3.14 g). degassed with nitrogen for 5 minutes The reaction mixture was stirred at ambient temperature for a further 10 minutes The reaction mixture was concentrated in vacuo at 60° C. the resulting residue partitioned between ethyl acetate (250 mL) a 1:1 mixture of water The organic layer was separated the aqueous layer back extracted with ethyl acetate (250 mL) The combined organic phases were dried through a hydrophobic frit concentrated in vacuo