氟桂利嗪杂质25

实验步骤: 投料: 往三口瓶加入SM1（10g，49.9mmol）和甲醇（10V）； 氮气保护下降温至5~10℃； 加入硼氢化钠（1.50eq）， 加毕，室温搅拌1小时； TLC显示反应完全： 往反应液倒入氯化铵溶液，浓缩除甲醇； 加入水和EA，搅拌30分钟； 静置、分相； 有机相浓缩得白色固体

实验步骤: 投料: 往单口瓶加入SM1（7.7g，38.1 mmol）和异丙醚（10V）； 反应液降温至5~10℃，加入三溴化磷（2.0eq）； 自然回室温搅拌4小时； TLC 显示有少量原料剩余； 往反应液倒入碳酸氢钠溶液淬灭反应，调节pH至5~6，温度最高30℃； 用异丙醚萃取，合并有机相浓缩，红棕色油状物粗品，直接用于下一步

实验步骤: 投料: 09-02 14:11: 往单口瓶加入SM1（1g，4.9mmol）和异丙醚（10mL）； 反应液降温至5~10℃，加入三溴化磷（2.0eq）； 自然回室温搅拌4小时； TLC 显示有少量原料剩余； 往反应液倒入碳酸氢钠溶液淬灭反应； 用EA萃取，合并有机相浓缩，红棕色油状物粗品，直接用于下一步

实验步骤: 投料: 往单口瓶加入SM1（1g，4.9mmol）和异丙醚（10mL）； 反应液降温至5~10℃，加入三溴化磷（2.0eq）； 自然回室温搅拌4小时； TLC 显示有少量原料剩余； 往反应液倒入碳酸氢钠溶液淬灭反应； 用EA萃取，合并有机相浓缩； 粗品过柱得黑色油状物； HNMR显示较杂，推测产品与硅胶接触会变坏；

实验步骤: 投料: 将原料SM1投入瓶中，异丙醚溶解，再滴加PBr3,滴加完毕常温反应。 17：30 TLC监测（PE：EA=10：1），显示没有原料，有产物点产生。 后处理 用饱和碳酸氢钠溶液调PH接近中性，再用EA（50ml*3)和水(100ml)萃取，盐水洗，无水硫酸钠干燥，浓缩有机相，用于下一步反应

实验步骤: 投料: 将原料SM1投入瓶中，异丙醚溶解，再滴加PBr3,滴加完毕常温反应。 17：30 TLC监测（PE：EA=10：1），显示没有原料，有产物点产生。 后处理 用饱和碳酸氢钠溶液调PH接近中性，再用EA和水萃取，盐水洗，无水硫酸钠干燥，浓缩有机相，用于下一步反应

实验步骤: 投料: 将原料SM1投入瓶中，甲醇溶解，再加入NaBH4，常温搅拌反应。 11：00 TLC（PE：EA=10：1）有产物点生成，没有原料，反应完全 后处理 加入饱和NH4Cl溶液淬灭，将反应液浓缩，用EA（50ml*3），水（100ml)萃取，盐水洗，无水硫酸钠干燥，浓缩，用于下一步反应。

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

实验步骤: In dichloromethane (30 mL), (±)-(4-fluorophenyl)phenylmethanol (2.1 g, 10 mmol) synthesized in Production Example 195 was dissolved, and thionyl chloride (5.1 g, 42 mmol) was added dropwise thereto at a room temperature. After the completion of the dropping, the mixture was heated under reflux, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (2.1 g, 94%) was obtained. was dissolved at a room temperature After the completion of the dropping, the mixture was heated under reflux After the completion of the reaction the reaction mixture was concentrated diluted with ethyl acetate washed with water The organic layer was dried over magnesium sulfate the solvent was distilled off

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

实验步骤: Benzaldehyde (8.5 g, 80 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled in an ice bath. Then, a 1.0-M solution (88 mL, 88 mmol) of 4-fluorophenylmagnesium bromide in tetrahydrofuran was added dropwise thereto at 0° C. After the dropping was completed, the mixture was heated to a room temperature, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform/ethanol (volume ratio)=10:1) to give the title compound (13 g, 81%). cooled in an ice bath at 0° C After the completion of the reaction extracted with ethyl acetate The organic layer was washed with water dried over sodium sulfate the solvent was distilled off The resulting residue was purified by silica gel column chromatography (chloroform/ethanol (volume ratio)=10:1)

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

实验步骤: Benzaldehyde (8.5 g, 80 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled in an ice bath. Then, a 1.0-M solution (88 mL, 88 mmol) of 4-fluorophenylmagnesium bromide in tetrahydrofuran was added dropwise thereto at 0° C. After the dropping was completed, the mixture was heated to a room temperature, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform/ethanol (volume ratio)=10:1) to give the title compound (13 g, 81%). cooled in an ice bath at 0° C After the completion of the reaction extracted with ethyl acetate The organic layer was washed with water dried over sodium sulfate the solvent was distilled off The resulting residue was purified by silica gel column chromatography (chloroform/ethanol (volume ratio)=10:1)

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

实验步骤: Thionyl chloride was added to (±)-(4-fluorophenyl)phenylmethanol, and the mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, ethyl acetate was added thereto, and water was added to the mixture. The resulting mixture was neutralized with sodium hydrogen carbonate, and then washed water twice and dried over magnesium sulfate. After the solvent was distilled off, the residue was dissolved in acetonitrile, and piperazine (1.7 g, 20 mmol), potassium iodide (3.3 g, 20 mmol), and potassium carbonate (3.3 g, 24 mmol) were added thereto. The mixture was refluxed overnight. After the completion of the reaction was confirmed by HPLC, the insoluble matter was removed, and the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with water 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (3.9 g, 72.7%) was obtained as a yellowish white solid. was added washed water twice and dried over magnesium sulfate After the solvent was distilled off the residue was dissolved in acetonitrile The mixture was refluxed overnight the insoluble matter was removed the solvent was distilled off The resulting residue was dissolved in ethyl acetate washed with water 3 times The organic layer was dried over magnesium sulfate the solvent was distilled off

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

实验步骤: Thionyl chloride was added to (±)-(4-fluorophenyl)phenylmethanol, and the mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, ethyl acetate was added thereto, and water was added to the mixture. The resulting mixture was neutralized with sodium hydrogen carbonate, and then washed water twice and dried over magnesium sulfate. After the solvent was distilled off, the residue was dissolved in acetonitrile, and piperazine (1.7 g, 20 mmol), potassium iodide (3.3 g, 20 mmol), and potassium carbonate (3.3 g, 24 mmol) were added thereto. The mixture was refluxed overnight. After the completion of the reaction was confirmed by HPLC, the insoluble matter was removed, and the solvent was distilled off. The resulting residue was dissolved in ethyl acetate and washed with water 3 times. The organic layer was dried over magnesium sulfate, and then the solvent was distilled off. Thus the title compound (3.9 g, 72.7%) was obtained as a yellowish white solid. was added washed water twice and dried over magnesium sulfate After the solvent was distilled off the residue was dissolved in acetonitrile The mixture was refluxed overnight the insoluble matter was removed the solvent was distilled off The resulting residue was dissolved in ethyl acetate washed with water 3 times The organic layer was dried over magnesium sulfate the solvent was distilled off