5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile

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

実験手順: To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (175 mg, 0.90 mmol) in dichloromethane (4 mL) was added Dess-Martin periodinane (530 mg, 1.3 mmol) at RT. The mixture stirred at roomtemperature for 2 h, then was diluted with saturated sodium bicarbonate and saturated sodium thiosulfate and stirred 30 min. The mixture was extracted with dichloromethane (3×) and the combined organics dried (MgSO4), filtered and concentrated to provide 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile which was used without further purification. LC-MS (IE, m/z): 194.2 [M+1]+. stirred 30 min The mixture was extracted with dichloromethane (3×) the combined organics dried (MgSO4) filtered concentrated

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

実験手順: To a solution of methyl(4-cyano-2-fluoro-5-methoxyphenyl)acetate (212 mg, 0.95 mmol) in tetrahydrofuran (4 mL) at 0° C. was added lithium borohydride (2.0 M solution in tetrahydrofuran, 0.62 mL). The mixture warmed slowly to room temperature and was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (2×). The combined organics were washed with water and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (MPLC, 5-60% Ethyl Acetate:Hexanes) to provide 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (m, 1H), 6.92 (m, 1H), 3.93 (s, 3H), 3.88 (m, 2H), 2.95 (m, 2H), 2.29 (br s, 1H). was quenched with saturated sodium bicarbonate diluted with ethyl acetate The layers were separated the aqueous extracted with ethyl acetate (2×) The combined organics were washed with water and brine dried (Na2SO4) filtered concentrated The residue was purified by column chromatography (MPLC, 5-60% Ethyl Acetate:Hexanes)

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

実験手順: To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (0.68 g, 3.5 mmol) and Et3N (0.82 mL, 5.9 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.33 mL, 4.2 mmol) at 0° C. After 15 min. the reaction mixture was poured into saturated ammonium chloride and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in dichloromethane (5 mL), treated with DBU (0.79 mL, 5.2 mmol) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The resulting olefin was dissolved in dichloromethane (5 mL) and treated with meta-chloro perbenzoic acid (0.72 g, 4.2 mmol) at 0° C. After 3 h, the mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (twice). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude epoxide was purified by silica gel column chromatography (5->80% EtOAc:hexane) to provide 5-fluoro-2-methoxy-4-oxiran-2-ylbenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.32 (d, J=5.3 Hz, 1H), 6.82 (d, J=5.4 Hz, 1H), 4.19 (m, 1H), 3.96 (s, 3H), 3.27 (m, 1H), 2.76 (m, 1H); extracted with dichloromethane The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine dried (MgSO4) concentrated in vacuo The residue was re-dissolved in dichloromethane (5 mL) extracted with dichloromethane The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine dried (MgSO4) concentrated in vacuo The resulting olefin was dissolved in dichloromethane (5 mL) After 3 h extracted with dichloromethane (twice) The combined organic extracts were washed with brine dried (MgSO4) filtered concentrated in vacuo The crude epoxide was purified by silica gel column chromatography (5->80% EtOAc:hexane)

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

実験手順: To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (175 mg, 0.900 mmol) in Dichloromethane (4 mL) was added Dess-Martin Periodinane (0.53 g, 1.2 mmol). The solution was stirred for 2 h at ambient temperature, then was diluted with NaHCO3 (sat.) and Na2S2O3 (sat.) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired aldehyde, which was used directly without further purification. stirred for 30 min The layers were separated the aqueous layer was extracted with dichloromethane twice The combined organics were washed with brine dried (MgSO4) filtered concentrated

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

実験手順: To a solution of methyl (4-Cyano-2-fluoro-5-methoxyphenyl)acetate (5.0 g, 22 mmol) in THF (50 mL) at 0° C. was added lithium borohydride (14.6 mL, 29.1 mmol). The reaction was stirred for 12 h, then was diluted with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Silica gel column chromatography (50->100% EtOAc:hex.) provided 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.19 (d, J=5.3 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H), 4.21 (br s, 1H), 3.88 (s, 3H), 3.82 (m, 2H), 2.92 (m, 2H); LC/MS: [(M+1)]+=196.2; tR=0.58 min. extracted three times with ethyl acetate The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated

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

実験手順: To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (0.68 g, 3.5 mmol) and Et3N (0.82 mL, 5.9 mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (0.33 mL, 4.2 mmol) at 0° C. After 15 min. the reaction mixture was poured into saturated ammonium chloride and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in dichloromethane (5 mL), treated with DBU (0.79 mL, 5.2 mmol) and stirred for 2 h. TLC monitoring showed conversion to the olefin. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried (MgSO4) and concentrated in vacuo. The resulting olefin was dissolved in dichloromethane (5 mL) and treated with meta-chloro perbenzoic acid (0.72 g, 4.2 mmol) at 0° C. After 3 h, the mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane (twice). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude epoxide was purified by silica gel column chromatography (5→80% EtOAc:hexane) to provide 5-fluoro-2-methoxy-4-oxiran-2-ylbenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.32 (d, J=5.3 Hz, 1H), 6.82 (d, J=5.4 Hz, 1H), 4.19 (m, 1H), 3.96 (s, 3H), 3.27 (m, 1H), 2.76 (m, 1H); extracted with dichloromethane The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine dried (MgSO4) concentrated in vacuo The residue was re-dissolved in dichloromethane (5 mL) extracted with dichloromethane The combined organics were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine dried (MgSO4) concentrated in vacuo The resulting olefin was dissolved in dichloromethane (5 mL) After 3 h extracted with dichloromethane (twice) The combined organic extracts were washed with brine dried (MgSO4) filtered concentrated in vacuo The crude epoxide was purified by silica gel column chromatography (5→80% EtOAc:hexane)

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

実験手順: To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (175 mg, 0.900 mmol) in Dichloromethane (4 mL) was added Dess-Martin Periodinane (0.53 g, 1.2 mmol). The solution was stirred for 2 h at ambient temperature, then was diluted with NaHCO3 (sat.) and Na2S2O3 (sat.) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired aldehyde, which was used directly without further purification. stirred for 30 min The layers were separated the aqueous layer was extracted with dichloromethane twice The combined organics were washed with brine dried (MgSO4) filtered concentrated

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

実験手順: To a solution of methyl(4-Cyano-2-fluoro-5-methoxyphenyl)acetate (5.0 g, 22 mmol) in THF (50 mL) at 0° C. was added lithium borohydride (14.6 mL, 29.1 mmol). The reaction was stirred for 12 h, then was diluted with saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. Silica gel column chromatography (50→100% EtOAc:hex.) provided 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H NMR (500 MHz, CD3OD) δ 7.19 (d, J=5.3 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H), 4.21 (br s, 1H), 3.88 (s, 3H), 3.82 (m, 2H), 2.92 (m, 2H); LC/MS: [(M+1)]+=196.2; tR=0.58 min. extracted three times with ethyl acetate The combined organic layers were washed with brine dried (Na2SO4) filtered concentrated