(2-amino-6-fluorophenyl)methanol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: A solution under argon of 2-amino-6-fluorobenzoic acid (5 g; 32 mmol) in anhydrous tetrahydrofuran (100 ml) is treated with lithium aluminium hydride (1M in tetrahydrofuran; 64 ml; 64 mmol) at ambient temperature. The reaction medium is agitated for 3 hours, then hydrolyzed at 0° C. with a saturated aqueous solution of ammonium chloride (100 ml). The resulting mixture is extracted with ethyl acetate (2×70 ml). The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and concentrated to produce 3.8 g of the desired product, a white solid (m.p.: 93° C.). The resulting mixture is extracted with ethyl acetate (2×70 ml) The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride dried over magnesium sulphate concentrated

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

実験手順: To (2-amino-6-fluoro-phenyl)-methanol (2.49 g, 17.3 mmol) in dichloromethane (30 mL) was added MnO2 (3.01 g, 34.7 mmol, activated). The mixture was refluxed for 3 hrs and then filtered over celite. The mixture was concentrated and purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 2-amino-6-fluoro-benzaldehyde as a yellow solid (1.23 g). tR=2.20 min. (method 1) The mixture was refluxed for 3 hrs filtered over celite The mixture was concentrated purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane)

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

実験手順: To (2-amino-6-fluoro-phenyl)-methanol (2.49 g, 17.3 mmol) in dichloromethane (30 mL) was added MnO2 (3.01 g, 34.7 mmol, activated). The mixture was refluxed for 3 hrs and then filtered over celite. The mixture was concentrated and purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 2-amino-6-fluoro-benzaldehyde as a yellow solid (1.23 g). tR=2.20 min. (method 1) The mixture was refluxed for 3 hrs filtered over celite The mixture was concentrated purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane)

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

実験手順: LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO410H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M−OH]+: 124.1; tR=0.57 min. (method 1) cooled to 0° C. again Na2SO410H2O (10 g) was added slowly with stirring for 20 minutes The mixture was filtered the solid was washed with THF The solution was concentrated

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

実験手順: To (2-amino-6-fluoro-phenyl)-methanol (2.49 g, 17.3 mmol) in dichloromethane (30 mL) was added MnO2 (3.01 g, 34.7 mmol, activated). The mixture was refluxed for 3 hrs and then filtered over celite. The mixture was concentrated and purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane) to give 2-amino-6-fluoro-benzaldehyde as a yellow solid (1.23 g). tR=2.20 min. (method 1) The mixture was refluxed for 3 hrs filtered over celite The mixture was concentrated purified via silica gel flash chromatography (eluting with 30% ethyl acetate in hexane)

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

実験手順: LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO4. 10H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M−OH]+: 124.1; tR=0.57 min. (method 1) cooled to 0° C. again 10H2O (10 g) was added slowly with stirring for 20 minutes The mixture was filtered the solid was washed with THF The solution was concentrated

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

実験手順: LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO4. 10H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M−OH]+: 124.1; tR=0.57 min. (method 1) cooled to 0° C. again 10H2O (10 g) was added slowly with stirring for 20 minutes The mixture was filtered the solid was washed with THF The solution was concentrated

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

実験手順: Trimethylacetyl chloride (0.25 mL, 1.99 mmol) was added to a solution of (2-amino-6-fluorophenyl)methanol (268 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). The mixture was stirred for 1 hr, followed by normal aqueous work-up to afford the expected crude product, N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415 mg, 97% yield), which was used directly in the next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 2.64 (s, 1 H), 4.78 (d, J=4.78 Hz, 2 H), 6.75-6.84 (m, 1 H), 7.23 (td, J=8.62, 5.92 Hz, H), 7.86 (d, J=8.31 Hz, 1 H), 8.97 (s, 1 H); Mass spec. 226.11 (MH+), Calc. for C12H16FNO2 225.12.

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

実験手順: Trimethylacetyl chloride (0.25 mL, 1.99 mmol) was added to a solution of (2-amino-6-fluorophenyl) methanol (268 mg, 1.90 mmol) in CH2Cl2 (10 mL) at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). The mixture was stirred for 1 hr, followed by normal aqueous work-up to afford the expected crude product, N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415 mg, 97% yield), which was used directly in the next step; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 9 H), 2.64 (s, 1 H), 4.78 (d, J=4.78 Hz, 2 H), 6.75-6.84 (m, 1 H), 7.23 (td, J=8.62, 5.92 Hz, 1 H), 7.86 (d, J=8.31 Hz, 1 H), 8.97 (s, 1 H); Mass spec. 226.11 (MH+), Calc. for C12H16FNO2 225.12.

反応条件: temp:0.00; pressure:0.00; stir: