4-Fluoro-N-[[4-(phenylmethoxy)phenyl]methylene]benzenamine

P-Fluoroaniline (100 g, 1.1 eq) and isopropanol (1730 ml, 10 V) were added and heated to 40 ° C. with mechanical stirring to precipitate a large amount of a pale yellow crystalline solid gradually, Stir over time and monitor until reaction is complete. The heating was stopped, the temperature was naturally lowered to room temperature while stirring, extraction and filtration were carried out, the filter cake was washed off with cold isopropanol, and after drying, a pale yellow crystalline substance SM 2 was obtained, the mass was 238 g , The yield is 95percent, and the purity is 99percent.The p-fluoroaniline (1.11kg, 10mol) and 4-benzyloxybenzaldehyde (2.12kg, 10mol) were added to 10L of toluene and refluxed. After the reaction was completed, the solvent was evaporated and the solvent was normal. n-hexane and ethyl acetate 10:1 Crystallization gave Compound 4 (2.85 kg) in 93.6percent yield.100 ml of DMF, p-hydroxybenzaldehyde (12.2 g, 0.1 mol), potassium carbonate (16.6 g, 0.12 mol) were successively added to a 250 ml three-necked flask, Benzyl bromide (20.4 g, 0.12 mol) was added dropwise, Room temperature reaction for 12 hours, The reaction solution was poured into ice water, Solid precipitation, filter, Washed cake, The filter cake is dry. To give benzyl-protected p-hydroxybenzaldehyde (26.2 g)Yield 91percent. And then take another 250ml single neck round bottom flask, Followed by adding 100 ml of acetone, benzyl-protected p-hydroxybenzaldehyde (14.4 g, 0.05 mol), p-fluoroaniline (5.55 g, 0.05 mol) After the reaction was refluxed for 4 h, the reaction solution was cooled to 5 ° C to precipitate a solid, filter, The solid was washed with cold acetone, The solid was dried to give N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (Compound IV) 14g, Yield 92percent.P-Fluoroaniline (100 g, 1.1 eq) and isopropanol (1730 ml, 10 V) were added and heated to 40 ° C. with mechanical stirring to precipitate a large amount of a pale yellow crystalline solid gradually, Stir over time and monitor until reaction is complete. The heating was stopped, the temperature was naturally lowered to room temperature while stirring, extraction and filtration were carried out, the filter cake was washed off with cold isopropanol, and after drying, a pale yellow crystalline substance SM 2 was obtained, the mass was 238 g , The yield is 95percent, and the purity is 99percent.The p-fluoroaniline (1.11kg, 10mol) and 4-benzyloxybenzaldehyde (2.12kg, 10mol) were added to 10L of toluene and refluxed. After the reaction was completed, the solvent was evaporated and the solvent was normal. n-hexane and ethyl acetate 10:1 Crystallization gave Compound 4 (2.85 kg) in 93.6percent yield.100 ml of DMF, p-hydroxybenzaldehyde (12.2 g, 0.1 mol), potassium carbonate (16.6 g, 0.12 mol) were successively added to a 250 ml three-necked flask, Benzyl bromide (20.4 g, 0.12 mol) was added dropwise, Room temperature reaction for 12 hours, The reaction solution was poured into ice water, Solid precipitation, filter, Washed cake, The filter cake is dry. To give benzyl-protected p-hydroxybenzaldehyde (26.2 g)Yield 91percent. And then take another 250ml single neck round bottom flask, Followed by adding 100 ml of acetone, benzyl-protected p-hydroxybenzaldehyde (14.4 g, 0.05 mol), p-fluoroaniline (5.55 g, 0.05 mol) After the reaction was refluxed for 4 h, the reaction solution was cooled to 5 ° C to precipitate a solid, filter, The solid was washed with cold acetone, The solid was dried to give N-(4-fluorophenyl)-4-benzyloxybenzylideneamine (Compound IV) 14g, Yield 92percent.The formula EZ-2 is a structural formula of 4-[[(4-fluorophenyl)imino]methyl]-phenol.4-[[(4-Fluorophenyl)imino]methyl]-phenol (21.5 g, 0.1 mol) was dissolved in 20 ml of DMF.Potassium carbonate (27.6 g, 0.2 mol) was added in sequenceChlorobenzyl (12.6 g, 0.1 mol), After the addition, the mixture was stirred at room temperature for 2 h.TLC judged the end of the reaction, poured the reaction solution into ice water, and filtered by suction.The filter cake was dried in vacuo to give a white solid (20.3 g).P-Fluoroaniline (100 g, 1.1 eq) and isopropanol (1730 ml, 10 V) were added and heated to 40 C. with mechanical stirring to precipitate a large amount of a pale yellow crystalline solid gradually, Stir over time and monitor until reaction is complete. The heating was stopped, the temperature was naturally lowered to room temperature while stirring, extraction and filtration were carried out, the filter cake was washed off with cold isopropanol, and after drying, a pale yellow crystalline substance SM 2 was obtained, the mass was 238 g , The yield is 95%, and the purity is 99%.The p-fluoroaniline (1.11kg, 10mol) and 4-benzyloxybenzaldehyde (2.12kg, 10mol) were added to 10L of toluene and refluxed. After the reaction was completed, the solvent was evaporated and the solvent was normal. n-hexane and ethyl acetate 10:1 Crystallization gave Compound 4 (2.85 kg) in 93.6% yield.The formula EZ-2 is a structural formula of 4-[[(4-fluorophenyl)imino]methyl]-phenol.4-[[(4-Fluorophenyl)imino]methyl]-phenol (21.5 g, 0.1 mol) was dissolved in 20 ml of DMF.Potassium carbonate (27.6 g, 0.2 mol) was added in sequenceChlorobenzyl (12.6 g, 0.1 mol), After the addition, the mixture was stirred at room temperature for 2 h.TLC judged the end of the reaction, poured the reaction solution into ice water, and filtered by suction.The filter cake was dried in vacuo to give a white solid (20.3 g).Preparation of TiCl4+Ti(O-i-Pr)4 mixed solution:The TiCl4 (21.3g, 0.112mol) dissolved in 100ml dichloromethane.Ti(O-i-Pr)4 (10.6 g, 0037 mol) was added dropwise at 0 C.The reaction was kept for 30 minutes.Intermediate A1-2 (53.4 g, 0.1 mol) andIntermediate A1-3 (61.4 g, 0.2 mol)Soluble in 250ml dichloromethane, DIPEA (25.8g, 0.2mol) was added dropwise at -15 C.TiCl4+Ti(O-i-Pr)4 mixed solution, After the addition is completed, the reaction is continued for 2 hours.Then glacial acetic acid (30 g, 0.5 mol) was added dropwise.After cooling in an ice bath, the reaction solution was poured into a 7% aqueous solution of tartaric acid.Stir for 1 h, naturally warm to room temperature, Add 100ml of 20% sodium bisulfite solution, Stirring was continued for 2 h, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated.50 ml of methanol was beaten and the white solid was 62.1 g.Preparation of TiCl4+Ti(O-i-Pr)4 mixed solution:TiCl4 (21.3 g, 0.112 mol)Soluble in 100ml dichloromethane, Ti(O-i-Pr)4 (10.6 g, 0037 mol) was added dropwise at 0 C.The reaction was kept for 30 minutes.Intermediate A10-1 (47.1 g, 0.1 mol) andIntermediate A10-2 (61.4 g, 0.2 mol)Soluble in 250ml dichloromethane, DIPEA (25.8g, 0.2mol) was added dropwise at -15 C.TiCl4+Ti(O-i-Pr)4 mixed solution, After the addition is completed, the reaction is continued for 2 hours.Then glacial acetic acid (30 g, 0.5 mol) was added dropwise.After cooling in an ice bath, the reaction solution was poured into a 7% aqueous solution of tartaric acid.Stir for 1 h, naturally warm to room temperature, Add 100ml of 20% sodium bisulfite solution, Stirring was continued for 2 h, the organic layer was separated and washed with water.Dry over anhydrous sodium sulfate, suction filtration, concentrate the filtrate, beat with 50 ml of methanol, White solid 60.2 g.

Used in the synthesis of cardiovascular drug etimibe

Molecular Weight:305.3
XLogP3:4.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:305.121592296
Monoisotopic Mass:305.121592296
Topological Polar Surface Area:21.6
Heavy Atom Count:23
Complexity:351
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes