2,3-二氟苯乙腈

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M−OEt). to cool to ambient temperature The crude mixture was purified by silica gel chromatography eluting with a gradient of hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound (12.0 g). MS 377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 221 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M−OEt). to cool to ambient temperature The crude mixture was purified by silica gel chromatography eluting with a gradient of hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to −10° C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to −78° C. and a solution of 2.00 g (13 mmol) 2,3-difluorophenyl-acetonitrile in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at −78° C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+.), 152.1 (((M-CH3)+.), 100%). the cooling bath was removed after 5 min The mixture was stirred for 2.5 h at room temperature aqueous ammonium chloride solution was added The mixture was extracted twice with ethyl acetate The combined organic layers were dried over MgSO4 filtered evaporated The residue was purified

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to −10° C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to −78° C. and a solution of 2.00 g (13 mmol) 2,3-difluorophenyl-acetonitrile in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at −78° C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+.), 152.1 (((M-CH3)+.), 100%). the cooling bath was removed after 5 min The mixture was stirred for 2.5 h at room temperature aqueous ammonium chloride solution was added The mixture was extracted twice with ethyl acetate The combined organic layers were dried over MgSO4 filtered evaporated The residue was purified

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2,3-Difluorophenylacetonitrile (23 mg, 0.15 mmol) was dissolved in EtOH (1 ml). Hydroxylamine hydrochloride (14 mg, 0.20 mmol) was added, followed by water (0.5 ml) and potassium carbonate (41 mg, 0.3 mmol). The mixture was heated at reflux overnight and then cooled and partitioned between EtOAc and brine. The organic phase was evaporated and the crude amidoxime thus obtained was dissolved in EtOH (1 ml). Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (43 mg, 0.12 mmol) and 21% by wt. ethanolic sodium ethoxide ((0.067 ml, 0.18 mmol) was added and the mixture heated in the microwave reactor at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase evaporated and the product purified by MDAP to provide the title compound as a solid (13 mg). The mixture was heated at reflux overnight cooled partitioned between EtOAc and brine The organic phase was evaporated the crude amidoxime thus obtained The mixture was partitioned between EtOAc and 2M HCl the organic phase evaporated the product purified by MDAP

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2,3-Difluorophenylacetonitrile (23 mg, 0.15 mmol) was dissolved in EtOH (1 ml). Hydroxylamine hydrochloride (14 mg, 0.20 mmol) was added, followed by water (0.5 ml) and potassium carbonate (41 mg, 0.3 mmol). The mixture was heated at reflux overnight and then cooled and partitioned between EtOAc and brine. The organic phase was evaporated and the crude amidoxime thus obtained was dissolved in EtOH (1 ml). Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (43 mg, 0.12 mmol) and 21% by wt. ethanolic sodium ethoxide ((0.067 ml, 0.18 mmol) was added and the mixture heated in the microwave reactor at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl, the organic phase evaporated and the product purified by MDAP to provide the title compound as a solid (13 mg). The mixture was heated at reflux overnight cooled partitioned between EtOAc and brine The organic phase was evaporated the crude amidoxime thus obtained The mixture was partitioned between EtOAc and 2M HCl the organic phase evaporated the product purified by MDAP

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M-OEt). to cool to ambient temperature The crude mixture was purified by silica gel chromatography eluting with a gradient of hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (2,3-difluorophenyl)acetonitrile (18.6 g, 122 mmol) in N,N-dimethylformamide (243 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (4.37 g, 109 mmol). After 20 min, methyl N-(tert-butoxycarbonyl)-3-iodo-D-alaninate (20.0 g, 60.8 mmol) was added, and the resulting mixture stirred 50 min. Saturated aqueous sodium bicarbonate was added, and the mixture was warmed to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate) gave the title compound. MS: m/z=377.3 (M+Na). the mixture was extracted with ethyl acetate (3×) The combined organic extracts were washed with water (3×), brine dried over magnesium sulfate filtered concentrated Purification by silica gel chromatography (100% hexanes→20% hexanes/ethyl acetate)

反应条件: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (2,3-difluorophenyl)acetonitrile (40.5 g, 265 mmol), ethyl acrylate (24 mL, 220 mmol), and hydroquinone (50 mg, 0.45 mmol) was added KOH (2 M in MeOH, 2.0 mL, 4.0 mmol) and the resulting mixture was heated at 160° C. for 16 h and then allowed to cool to ambient temperature. The crude mixture was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=207.9 (M−OEt). to cool to ambient temperature The crude mixture was purified by silica gel chromatography eluting with a gradient of hexanes