2-fluoro-6-methoxybenzaldehyde

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone was prepared from 2-fluoro-6-methoxybenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the General Procedure C. MS m/z: 281.0 (M+Na).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (158 mg, 0.33 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added isopropylmagnesium chloride (2 M solution in THF, 0.4 mL, 0.8 mmol) via dropwise addition. The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-fluoro-6-methoxy-benzaldehyde (96.6 mg, 0.63 mmol) at −30° C. The mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (110 mg) as yellow syrup in 60% yield. ESMS m/z: 549 (M+H). via dropwise addition The mixture was stirred at room temperature for 3 h quenched with saturated aqueous NH4Cl solution (5 mL) extracted with EtOAc (2×25 mL) The combined organic extracts were washed with saturated aqueous NH4Cl solution (25 mL) and brine (25 mL) dried (Na2SO4) concentrated under reduced pressure The obtained residue was purified by flash column chromatography on silica gel (30% EtOAc-hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (459 mg, 1.00 mmol) in anhydrous THF (5 mL) at −10° C. was added 2 M isopropylmagnesium chloride in THF (1.1 mL, 2.2 mmol) and stirred at the same temperature for 30 min. 2-Fluoro-6-methoxy-benzaldehyde (308 mg, 2.00 mmol) was subsequently added in one portion, and the reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z 535.4 (M+H). stirred overnight (18 h) It was then quenched with saturated aqueous NH4Cl (10 mL) extracted with EtOAc (3×75 mL) The combined extracts were washed with aqueous NaHCO3 and brine dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The solution of 3-Fluoro anisole (2.2 g, 17.44 mmol) in anhydrous THF (40 ml) under a nitrogen atmosphere was cooled to −78° C., and then n-BuLi (1.6 M, 19.18 mmol) was slowly added thereto. The reaction mixture was stirred at −78° C. for 1 hour, slowly added with DMF (1.6 ml, 20.93 mmol), and then stirred for 1 hour. After the termination of the reaction, the resulting reaction solution was added with dilute H2SO4, extracted two times with ethyl acetate, washed with brine, dried over MgSO4, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1), thus obtaining the title compound as a white solid (1.48 g, 9.6 mmol, 55%). stirred for 1 hour After the termination of the reaction the resulting reaction solution extracted two times with ethyl acetate washed with brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-fluoro-6-methoxy-benzaldehyde (947 mg, 6.14 mmol) was reacted to give the title compound (1.21 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.30 (m, 6H), 6.91-6.79 (m, 2H), 5.97-5.94 (m, 1H), 5.90-5.87 (d, 1H), 3.86 (s, 3H). was reacted

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-fluoro-6-methoxy-benzaldehyde (947 mg, 6.14 mmol) was reacted to give the title compound (1.21 g, 77%). 1H NMR (400 MHz, DMSO-d6): δ 7.41-7.30 (m, 6H), 6.91-6.79 (m, 2H), 5.97-5.94 (m, 1H), 5.90-5.87 (d, 1H), 3.86 (s, 3H). was reacted