4-chloro-2-fluorobenzaldehyde

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:

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: Dissolve 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.20 mmol) in methanol (1 mL). Add triethylamine (90 μL, 0.65 mmol) and 4-chloro-2-fluorobenzaldehyde (35 mg, 0.22 mmol), vortex and let sit overnight at room temperature. Add sodium borohydride (15 mg, 0.39 mmol) and let sit 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200 (1.5 g). Wash with methanol and discard the washing, then elute with 5% triethylamine in methanol. Concentrate to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in vacuum oven at 50° C. overnight to give the title compound as its hydrochloride salt (53 mg, 74%). 1H NMR (400 MHz, MeOH-d4) δ 7.63 (t, 1H, J=8.0 Hz), 7.58-7.57 (m, 1H), 7.45 (dd, 1H, J=9.6, 2.0 Hz), 7.40 (dd, 1H, J=8.0, 2.0 Hz), 7.36-7.32 (m, 1H), 7.00 (dd, 1H, J=8.8, 2.8 Hz), 4.44 (s, 2H), 4.21-4.15 (m, 1H), 3.74-3.61 (m, 3H), 3.42-3.36 (m, 1H), 2.68-2.60 (m, 1H), 2.38-2.29 (m, 1H), MS (ES): m/z=324 [M+H]. Wash with methanol elute with 5% triethylamine in methanol Concentrate

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

実験手順: Dissolve 1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (43 mg, 0.20 mmol) in methanol (1 mL). Add triethylamine (90 μL, 0.65 mmol) and 4-chloro-2-fluorobenzaldehyde (35 mg, 0.22 mmol), vortex and let sit overnight at room temperature. Add sodium borohydride (15 mg, 0.39 mmol) and let sit 1 h. Dilute the mixture with methanol and pour onto a column of Dowex® 50wx4-200 (1.5 g). Wash with methanol and discard the washing, then elute with 5% triethylamine in methanol. Concentrate to give the title compound as a residue. Dissolve the residue in methanol and add 1 N HCl in methanol (0.75 mL). Concentrate and dry in vacuum oven at 50° C. overnight to give the title compound as its hydrochloride salt (53 mg, 74%). 1H NMR (400 MHz, MeOH-d4) δ 7.63 (t, 1H, J=8.0 Hz), 7.58-7.57 (m, 1H), 7.45 (dd, 1H, J=9.6, 2.0 Hz), 7.40 (dd, 1H, J=8.0, 2.0 Hz), 7.36-7.32 (m, 1H), 7.00 (dd, 1H, J=8.8, 2.8 Hz), 4.44 (s, 2H), 4.21-4.15 (m, 1H), 3.74-3.61 (m, 3H), 3.42-3.36 (m, 1H), 2.68-2.60 (m, 1H), 2.38-2.29 (m, 1H), MS (ES): m/z=324 [M+H]. Wash with methanol elute with 5% triethylamine in methanol Concentrate

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

実験手順: First, 25 g of 4-chloro-2-fluorobenzaldehyde was dissolved in a mixed solvent consisting of 250 ml of 1,4-dioxane and 25 ml of methanol, to which 2.4 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After completion of the reaction, a small amount of diluted aqueous hydrochloric acid was added, and the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 25 g of 4-chloro-2-fluorobenzyl alcohol. was added under ice cooling After completion of the reaction extracted with ethyl acetate The organic layer was washed with saturated sodium chloride solution dried concentrated

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5% yield). The reaction was concentrated in half eluting with 5% ethyl acetate/hexanes

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5% yield). The reaction was concentrated in half eluting with 5% ethyl acetate/hexanes

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

実験手順: 5.5 g (0.12 mol) of methylhydrazine were added to a solution of 19 g (0.12 mol) of 4-chloro-2-fluorobenzaldehyde in 120 ml of ethanol. After 1 hour, the mixture was concentrated, and the residue was subsequently treated with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and finally concentrated. Yield: 94% the mixture was concentrated the residue was subsequently treated with ethyl acetate The organic phase was washed with water dried over magnesium sulfate finally concentrated

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

実験手順: A mixture of 4-chloro-2-fluoro-benzoaldehyde (Matrix Sci, 3.17 g, 20.0 mmol) and methyl amine (2.0 M in THF, Aldrich, 15 mL, 15.0 mmol) in CH2Cl2 (20 mL) was stirred at rt overnight. The reaction mixture was concentrated and the residue was dried under reduced pressure to afford [[1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-methyl-amine (3.32 g, 97.0%) as colorless oil which was used in the next step without further purification. The reaction mixture was concentrated the residue was dried under reduced pressure