2-氨基-4-氟苯甲醇

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-amino-4-fluorobenzyl alcohol from Step 1 (2.00 g, 14.17 mmol) and methylene chloride (45 mL), was added N,N,-diisopropylethylamine (3.70 g, 28.34 mmol) followed by hydrocinnamoyl chloride (4.78 g, 28.34 mmol) dropwise over 15 min under an argon atmosphere at 23° C. After 16 h, the reaction was diluted with methylene chloride (100 mL), washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was dissolved in methanol (14 mL) and NaOH (1.5 N, 14 mL) was added at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide (3.40 g, 87.8%) as an oil: 1H NMR (CDCl3) δ2.65 (t, J=7 Hz), 3.05 (t, J=7 Hz), 4.48 (s), 6.68-6.74 (m), 7.00-7.34 (m), 7.83-7.91 (m) 8.72 (br s). MS (EI) 273, 255, 212. IR (neat) 3500-3150, 1667 cm−1. Anal. Calc'd. for C16H16NO2F: C, 70.31; H, 5.90; N, 5.13. Found: C, 70.26; H, 6.11; N, 5.03. washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) dried (MgSO4) After concentration in vacuo the crude residue was dissolved in methanol (14 mL) NaOH (1.5 N, 14 mL) was added at 23° C. under argon After 2 h at 23° C. the reaction was concentrated in vacuo diluted with ether (150 mL) washed with brine (100 mL) dried (MgSO4) After concentration in vacuo the residue was purified by flash chromatography (ethyl acetate:hexane 1:3)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-amino-4-fluorobenzoic acid (3.00 g, 19.3 mmol) and THF (40 mL) at 0° C. under argon, borane-THF complex (1M THF solution, 77.0 mmol) was added dropwise over 30 min. After complete addition, the reaction was warmed to 23° C. After 4 h, the reaction mixture was added slowly (5 min) to ethanol (77 mL). After 20 min, the reaction was concentrated in vacuo, diluted with sat'd NaHCO3 (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by passing through a silica gel pad (1:1 ethyl acetate:hexane). Concentration in vacuo afforded 2.02 g of 2-amino-4-fluorobenzyl alcohol as a yellow solid which was sufficiently pure to take on to the next step: 1H NMR (CDCl3) δ4.54 (br s), 6.28-6.47 (m), 6.93-7.05 (m); 13C NMR (CDCl3) δ62.7, 101.9 (J=24 Hz), 103.4 (J=21 Hz), 121.5, 130.1 (J=10 Hz), 149.1, 163 (J=360 Hz). MS (EI) 141 (M+), 124, 110. IR (neat) 3500-3000 cm−1. After complete addition After 20 min the reaction was concentrated in vacuo diluted with sat'd NaHCO3 (100 mL) extracted with ethyl acetate (2×100 mL) washed with brine (1×100 mL) dried (MgSO4) After concentration in vacuo the residue was purified Concentration in vacuo

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-amino-4-fluorobenzyl alcohol from Step 1 (2.00 g, 14.17 mmol) and methylene chloride (45 mL), was added N,N,-diisopropylethylamine (3.70 g, 28.34 mmol) followed by hydrocinnamoyl chloride (4.78 g, 28.34 mmol) dropwise over 15 min under an argon atmosphere at 23° C. After 16 h, the reaction was diluted with methylene chloride (100 mL), washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) and dried (MgSO4). After concentration in vacuo, the crude residue was dissolved in methanol (14 mL) and NaOH (1.5 N, 14 mL) was added at 23° C. under argon. After 2 h at 23° C., the reaction was concentrated in vacuo, diluted with ether (150 mL), washed with brine (100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:hexane 1:3) to afford N-[5-fluoro-2-hydroxymethylphenyl]benzenepropanamide (3.40 g, 87.8%) as an oil: 1H NMR (CDCl3) δ 2.65 (t, J=7 Hz), 3.05 (t, J=7 Hz), 4.48 (s), 6.68-6.74 (m), 7.00-7.34 (m), 7.83-7.91 (m) 8.72 (br s). MS (EI) 273, 255, 212. IR (neat) 3500-3150, 1667 cm−1. Anal. Calc'd. for C16H16NO2F: C, 70.31; H, 5.90; N, 5.13. Found: C, 70.26; H, 6.11; N, 5.03. washed with KHSO4 (1 N, 1×80 mL), sat'd NaHCO3 (1×80 mL), brine (1×80 mL) dried (MgSO4) After concentration in vacuo the crude residue was dissolved in methanol (14 mL) NaOH (1.5 N, 14 mL) was added at 23° C. under argon After 2 h at 23° C. the reaction was concentrated in vacuo diluted with ether (150 mL) washed with brine (100 mL) dried (MgSO4) After concentration in vacuo the residue was purified by flash chromatography (ethyl acetate:hexane 1:3)

反应条件: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2-amino-4-fluorobenzoic acid (3.00 g, 19.3 mmol) and THF (40 mL) at 0° C. under argon, borane-THF complex (1M THF solution, 77.0 mmol) was added dropwise over 30 min. After complete addition, the reaction was warmed to 23° C. After 4 h, the reaction mixture was added slowly (5 min) to ethanol (77 mL). After 20 min, the reaction was concentrated in vacuo, diluted with sat'd NaHCO3 (100 mL), extracted with ethyl acetate (2×100 mL), washed with brine (1×100 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by passing through a silica gel pad (1:1 ethyl acetate:hexane). Concentration in vacuo afforded 2.02 g of 2-amino-4-fluorobenzyl alcohol as a yellow solid which was sufficiently pure to take on to the next step: 1H NMR (CDCl3) δ 4.54 (br s), 6.28-6.47 (m), 6.93-7.05 (m); 13C NMR (CDCl3) δ 62.7, 101.9 (J=24 Hz), 103.4 (J=21 Hz), 121.5, 130.1 (J=10 Hz), 149.1, 163 (J=360 Hz). MS (EI) 141 (M+), 124, 110. IR (neat) 3500-3000 cm−1. After complete addition After 20 min the reaction was concentrated in vacuo diluted with sat'd NaHCO3 (100 mL) extracted with ethyl acetate (2×100 mL) washed with brine (1×100 mL) dried (MgSO4) After concentration in vacuo the residue was purified Concentration in vacuo