1,2-bis(bromomethyl)-3-fluorobenzene

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

実験手順: To a solution of ethyl isocyanoacetate (3.85 mL, 35.0 mmol) in anhydrous ACN (300 mL) is added finely ground anhydrous K2CO3 (K2SO4, 29.0 g, 210 mmol), TBAHS (tetrabutyl ammonium hydrogen sulfate, 2.34 g, 7.0 mmol), and 1,2-bis(bromomethyl)-3-fluorobenzene (9.87 g, 35 mmol). The resulting heterogeneous mixture is stirred at 80° C. overnight. The reaction mixture is cooled down to RT and filtered to remove the unwanted salts. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane) to give a pure product as colorless oil (4.5 g, 55%). The reaction mixture is cooled down to RT filtered to remove the unwanted salts The filtrate is concentrated in vacuo The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane)

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

実験手順: To a solution of ethyl isocyanoacetate (3.85 mL, 35.0 mmol) in anhydrous ACN (300 mL) is added finely ground anhydrous K2CO3 (K2SO4, 29.0 g, 210 mmol), TBAHS (tetrabutyl ammonium hydrogen sulfate, 2.34 g, 7.0 mmol), and 1,2-bis(bromomethyl)-3-fluorobenzene (9.87 g, 35 mmol). The resulting heterogeneous mixture is stirred at 80° C. overnight. The reaction mixture is cooled down to RT and filtered to remove the unwanted salts. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane) to give a pure product as colorless oil (4.5 g, 55%). The reaction mixture is cooled down to RT filtered to remove the unwanted salts The filtrate is concentrated in vacuo The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane)

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

実験手順: A solution of 1,2-bis-bromomethyl-3-fluoro-benzene (4.4 g, 15.6 mmol) in MeCN (10 ml) was added to stirred solution of 1-cyclopent-1-enyl-pyrrolidine (2.3 ml, 15.6 mmol) and DIPEA (5.4 ml, 31.2 mmol) in MeCN (20 ml). The mixture was stirred at room temperature for 18 hours and then filtered. Washing with cold MeCN afforded an off-white solid 1.02 g (19%). m/z 258 (M+). filtered Washing with cold MeCN

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%) to warm to RT then cooled to 0° C. quenched with water extracted with ethylacetate The combined organic phases were washed with water dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (SiO2, heptane/ethyl acetate)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%) to warm to RT then cooled to 0° C. quenched with water extracted with ethylacetate The combined organic phases were washed with water dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (SiO2, heptane/ethyl acetate)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%) to warm to RT then cooled to 0° C. quenched with water extracted with ethylacetate The combined organic phases were washed with water dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (SiO2, heptane/ethyl acetate)

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

実験手順: To a solution of ethyl isocyanoacetate (3.85 mL, 35.0 mmol) in anhydrous ACN (300 mL) is added finely ground anhydrous K2CO3 (K2SO4, 29.0 g, 210 mmol), TBAHS (tetrabutyl ammonium hydrogen sulfate, 2.34 g, 7.0 mmol), and 1,2-bis(bromomethyl)-3-fluorobenzene (9.87 g, 35 mmol). The resulting heterogeneous mixture is stirred at 80° C. overnight. The reaction mixture is cooled down to RT and filtered to remove the unwanted salts. The filtrate is concentrated in vacuo. The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane) to give a pure product as colorless oil (4.5 g, 55%). The reaction mixture is cooled down to RT filtered to remove the unwanted salts The filtrate is concentrated in vacuo The residue is purified by flash column chromatography (200 g silica gel; gradient elution: 0-25% EtOAc in heptane)

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

実験手順: A solution of 1,2-bis-bromomethyl-3-fluoro-benzene (4.4 g, 15.6 mmol) in MeCN (10 ml) was added to stirred solution of 1-cyclopent-1-enyl-pyrrolidine (2.3 ml, 15.6 mmol) and DIPEA (5.4 ml, 31.2 mmol) in MeCN (20 ml). The mixture was stirred at room temperature for 18 hours and then filtered. Washing with cold MeCN afforded an off-white solid 1.02 g (19%). m/z 258 (M+). filtered Washing with cold MeCN

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a RT suspension of 0.61 mmol sodium hydride (50% in mineral oil) in 0.5 ml dry DMF, a solution of 0.29 mmol 2-Isopropoxy-5-methanesulfonyl-benzamide (example B20) in 1 ml dry DMF was added dropwise. After 15 minutes at RT and 15 minutes at 50° C., the reaction mixture was cooled to 0° C., and treated by a solution of 0.29 mmol 1,2-Bis-bromomethyl-3-fluoro-benzene (CAS: 62590-16-3) in 1 ml dry DMF. The reaction mixture was allowed to warm to RT and stirred for 15 minutes then cooled to 0° C., quenched with water and extracted with ethylacetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (27% yield). MS (m/e): 378.3 [M+H+], 100%) to warm to RT then cooled to 0° C. quenched with water extracted with ethylacetate The combined organic phases were washed with water dried over sodium sulfate filtered concentrated in vacuo The residue was purified by chromatography (SiO2, heptane/ethyl acetate)