3-氯-2-氟-6-甲氧基苯甲醛

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

实验步骤: To a solution of 3-chloro-2-fluoro-6-methoxy-benzaldehyde (10 g, 53.2 mmol,) in dichloromethane (200 mL) at −78° C. was added a dichloromethane solution (1 M) of BBr3 (159 mL, 159 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give a residue. The reside was triturated with dichloromethane and hexanes to afford 3-chloro-2-fluoro-6-hydroxy-benzaldehyde as a brown solid (Yield: 2.07 g, 22%) quenched with water The mixture was extracted with dichloromethane three times washed with brine dried over MgSO4 concentrated to give a residue The reside was triturated with dichloromethane and hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-chloro-2-fluoro-6-(methyloxy)benzaldehyde (10 g, 53.0 mmol) in 1,2-dimethoxyethane (105 mL) was added potassium carbonate (8.06 g, 58.3 mmol) and O-methylhydroxylamine hydrochloride (4.43 g, 53.0 mmol) and the mixture was stirred and heated at 45° C. for 4 hrs. After cooling, the mixture was filtered and concentrated to ˜40 mL and hydrazine monohydrate (58.3 mL, 1856 mmol) was added and the reaction was refluxed under argon over the weekend. The mixture was concentrated to 10-15 mL on the rotary evaporator and then poured into water and stirred for 10 mins. The precipitated solid was collected by filtration and washed with water (3×), sucked dry and then dried in the vacuum oven at 60° C. for 1 hr to give the title compound (D28) as an off white solid (8.83 g) After cooling the mixture was filtered was added the reaction was refluxed under argon over the weekend The mixture was concentrated to 10-15 mL on the rotary evaporator poured into water stirred for 10 mins The precipitated solid was collected by filtration washed with water (3×) sucked dry dried in the vacuum oven at 60° C. for 1 hr

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 3-chloro-2-fluoro-6-(methyloxy)benzaldehyde (10 g, 53.0 mmol) in 1,2-dimethoxyethane (105 mL) was added potassium carbonate (8.06 g, 58.3 mmol) and O-methylhydroxylamine hydrochloride (4.43 g, 53.0 mmol) and the mixture was stirred and heated at 45° C. for 4 hrs. After cooling, the mixture was filtered and concentrated to ˜40 mL and hydrazine monohydrate (58.3 mL, 1856 mmol) was added and the reaction was refluxed under argon over the weekend. The mixture was concentrated to 10-15 mL on the rotary evaporator and then poured into water and stirred for 10 mins. The precipitated solid was collected by filtration and washed with water (3×), sucked dry and then dried in the vacuum oven at 60° C. for 1 hr to give the title compound (D28) as an off white solid (8.83 g) After cooling the mixture was filtered was added the reaction was refluxed under argon over the weekend The mixture was concentrated to 10-15 mL on the rotary evaporator poured into water stirred for 10 mins The precipitated solid was collected by filtration washed with water (3×) sucked dry dried in the vacuum oven at 60° C. for 1 hr

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

实验步骤: 1-(3-Chloro-2-fluoro-6-methoxyphenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 3-chloro-2-fluoro-6-methoxybenzaldehyde. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.43-7.36 (m, 1H), 6.75-6.56 (m, 2H), 6.13-6.03 (m, 2H), 3.80 (s, 3H).

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

实验步骤: To a solution of 3-chloro-2-fluoro-6-methoxy-benzaldehyde (10 g, 53.2 mmol,) in dichloromethane (200 mL) at −78° C. was added a dichloromethane solution (1 M) of BBr3 (159 mL, 159 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give a residue. The reside was triturated with dichloromethane and hexanes to afford 3-chloro-2-fluoro-6-hydroxy-benzaldehyde as a brown solid (Yield: 2.07 g, 22%) quenched with water The mixture was extracted with dichloromethane three times washed with brine dried over MgSO4 concentrated to give a residue The reside was triturated with dichloromethane and hexanes

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-chloro-3-fluoroanisole (10.2 g, 63.5 mmol, Oakwood) in tetrahydrofuran (100 mL) at −78° C. was added lithium diisopropyl amine (42.3 mL, 1.8 M in THF, 76.2 mmol) dropwise during a period of 15 min. The mixture was stirred at −78° C. for another 20 mins. Then N,N-dimethyl-formamide (5.9 mL, 76.2 mmol) was added in one portion. The mixture was stirred at −78° C. for 10 min, then quenched with acetic acid (15.6 g, 254 mmol) and followed by the addition of water (80 mL). The mixture was partitioned between ethyl acetate and water. The organic layer was separated, concentrated to give 3-chloro-2-fluoro-6-methoxy-benzaldehyde as a yellow solid (Yield: 10 g, 85%) The mixture was stirred at −78° C. for 10 min The mixture was partitioned between ethyl acetate and water The organic layer was separated concentrated