70627-52-0

Basic information

• Product Name: N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline
• Synonyms: 4-BENZYLOXYBENZYLIDENE-(4-FLUORO)ANILINE;4-(4-Benzyloxybenzylidene)Fluoroaniline;N-(4-(benzyloxy)benzylidene)-4-fluorobenzenamine;4-Fluoro-N-[[4-(phenylmethoxy)phenyl]methylene]benzenamine;N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline;4, 4-Benzyloxybenzylidene P- Fluoroaniline;4-Benzyloxybenzylidene-(4-f...;BenzenaMine,4-fluoro-N-[[4-(phenylMethoxy)phenyl]Methylene]-
• CAS NO: 70627-52-0
• Molecular Formula: C₂₀H₁₆FNO
• Molecular Weight: 305.35
• EINECS: 1308068-626-2
• Mol File: 70627-52-0.mol
• Article Data: 8

Chemical Properties

• Melting Point: 136-138 ºC
• Boiling Point: 455.2 °C at 760 mmHg
• Flash Point: 229.1 °C
• Appearance: /
• Density: 1.07
• Vapor Pressure: 4.83E-08mmHg at 25°C
• Refractive Index: 1.558
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: Acetonitrile (Slightly), Chlorofrom (Slightly), Methanol (Slightly, Sonicated)
• PKA: 3.71±0.50(Predicted)
• CAS DataBase Reference: N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline(CAS DataBase Reference)
• NIST Chemistry Reference: N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline(70627-52-0)
• EPA Substance Registry System: N-(4-(Benzyloxy)benzylidene)-4-fluoroaniline(70627-52-0)

Safety Data

• Hazardous Substances Data: 70627-52-0(Hazardous Substances Data)

Usage

Uses

4-Benzyloxybenzylidene 4-Fluoroaniline is an intermediate in the synthesis of Linezolid (L466500).

InChI:InChI=1/C20H16FNO/c21-18-8-10-19(11-9-18)22-14-16-6-12-20(13-7-16)23-15-17-4-2-1-3-5-17/h1-14H,15H2/b22-14+

Synthetic route

p-benzyloxybenzaldehyde (4397-53-9) + 4-fluoroaniline (371-40-4) → 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

Conditions	Yield
In isopropyl alcohol at 40℃;	95%
In toluene Reflux; Large scale;	93.6%
In toluene for 48h; Heating;	75%
With magnesium sulfate In dichloromethane at 20℃; for 2h;

benzyl bromide (100-39-0) + 4-hydroxy-benzaldehyde (123-08-0) + 4-fluoroaniline (371-40-4) → 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

Conditions	Yield
Stage #1: benzyl bromide; 4-hydroxy-benzaldehyde With potassium carbonate at 20℃; for 12h; Stage #2: 4-fluoroaniline In acetone for 4h; Reflux;	92%
Stage #1: 4-hydroxy-benzaldehyde With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 0.25h; Stage #2: benzyl bromide In dichloromethane; water at 25 - 30℃; for 1.5h; Stage #3: 4-fluoroaniline In isopropyl alcohol at 20 - 60℃; for 2.5h;

Reaxys ID: 30143016 + (S)-4-phenyl-2-oxazolidinone (99395-88-7) → Reaxys ID: 30143012 + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

4-hydroxy-benzaldehyde (123-08-0) → 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2: isopropyl alcohol / 40 °C View Scheme

benzyl chloride (100-44-7) → 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 2: isopropyl alcohol / 40 °C View Scheme

N-(4-hydroxybenzylidene)-4-fluorobenzenamine (3382-63-6) + benzyl chloride (100-44-7) → 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	20.3 g

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → C40H36F2N2O5 (1185883-39-9)

Conditions	Yield
Stage #1: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine; (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane at -5℃; for 2h; Inert atmosphere; Stage #2: With titanium tetrachloride In dichloromethane at -30℃; for 2h; Inert atmosphere;	94%

chloro-trimethyl-silane (75-77-4) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → C43H44F2N2O5Si

Conditions	Yield
Stage #1: chloro-trimethyl-silane; 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine; (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane at -5 - 5℃; Inert atmosphere; Stage #2: With titanium tetrachloride In dichloromethane at -5 - 5℃; for 1h;	93%

(S)-3-{4-[2-(4-fluorophenyl)dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one (942485-56-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride In toluene at 60℃;	88.94%

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → N-(4-(benzyloxy)benzyl)-4-fluoroaniline (415960-63-3)

Conditions	Yield
With 4-Fluorothiophenol In toluene for 8h; Sealed tube; Irradiation;	85%

3-{4-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]dioxin-2-yl]butyryl}(4S)-phenyl-1,3-oxazolidin-2-one (953805-20-4) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 3-{(2R,3S)-3-[(4-fluorophenyl)amino]-2-[2-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]-3-[4-(benzyloxy)phenyI]propanoyl}-(4S)-4-phenyl-1,3-oxazolidin-2-one (953805-22-6)

Conditions	Yield
With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -5℃; for 3h;	78%

ethyl 3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propanoate + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → ethyl-3-(4-(benzyloxy)benzyl)-3-((4-fluorophenyl)amino)-2-((S)-2-oxo-4-phenyloxazolidin-3-carbonyl)propanoate

Conditions	Yield
Stage #1: ethyl 3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propanoate; 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine With N-ethyl-N,N-diisopropylamine In dichloromethane at -30℃; for 0.166667h; Inert atmosphere; Stage #2: With titanium tetrachloride In dichloromethane at -30 - -20℃; for 3h;	76%

(-)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one (793673-93-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → trans-1-(4-fluorophenyl)-3-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone

Conditions	Yield
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -50℃; for 0.5h; Stage #2: (-)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one at -50℃; for 0.25h; Stage #3: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; DMF (N,N-dimethyl-formamide); hexane at -50℃; for 1h;	67%

(-)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one (793673-93-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → C31H27F2NO3

Conditions	Yield
Stage #1: (-)-6-(4-fluorophenyl)tetrahydro-2H-pyran-2-one With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -50℃; for 0.916667h; Stage #2: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine In tetrahydrofuran at -50℃; for 2.5h; Reagent/catalyst;	67%

(3S)-hydroxy-γ-butyrolactone (5469-16-9, 58081-05-3, 131432-37-6, 7331-52-4) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3S,4S)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one (221349-56-0) + (3S,4R)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one

Conditions	Yield
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium chloride; lithium diisopropyl amide In tetrahydrofuran; N,N-dimethyl-formamide at -30 - -25℃; for 18h; Cycloaddition;	A 64% B n/a

(4S)-N-acetyl-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one (1375257-24-1) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (R)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)azetidin-2-one

Conditions	Yield
Stage #1: N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl] imidazolidin-2-one With N,N,N,N,-tetramethylethylenediamine; lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Mannich Aminomethylation; Inert atmosphere; Stage #2: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine In tetrahydrofuran at -78 - 0℃; Mannich Aminomethylation; Inert atmosphere; stereoselective reaction;	63%

(S)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one (1185883-41-3) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → C42H40F2N2O6

Conditions	Yield
With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -50℃; for 3.66667h; Inert atmosphere;	62.5%

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → C40H36F2N2O5

Conditions	Yield
With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -30 - -20℃; for 5h;	60.9%

(S)-3-{4-[2-(4-fluorophenyl)dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one (942485-56-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (S)-3-{(R)-2-[(S)-[4-(benzyloxy)phenyl][(4-fluorophenyl)amino]methyl]-4-[2-(4-fluorophenyl)[1,3]dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one (954109-20-7)

Conditions	Yield
Stage #1: (S)-3-{4-[2-(4-fluorophenyl)dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one With titanium(IV) isopropylate; titanium tetrachloride In dichloromethane at 0℃; for 0.666667h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h; Stage #3: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine Product distribution / selectivity;	58%

5-(4-fluorophenyl)pentanoyl chloride (204589-92-4) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-2-azetidinone

Conditions	Yield
With tributyl-amine In toluene for 72h; Heating;	48%

1-(5-methoxy-1,5-dioxopentyl)-4(S)-phenyloxazolidin-2-one (477558-79-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 3-[2-(3-methoxy-3-oxopropyl)-3-(4-fluorophenylamino)-3-(4-benzyloxyphenyl)-1-oxopropyl]-4(S)-phenyloxazolidin-2-one (934245-17-7)

Conditions	Yield
Stage #1: 1-(5-methoxy-1,5-dioxopentyl)-4(S)-phenyloxazolidin-2-one With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at -10℃; for 1h; Stage #2: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine In dichloromethane at -10℃; for 6h; optical yield given as %de;	48%
Stage #1: 1-(5-methoxy-1,5-dioxopentyl)-4(S)-phenyloxazolidin-2-one With titanium(IV) isopropylate; titanium tetrachloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 1h; Stage #2: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine In dichloromethane at -20℃; for 4h; Stage #3: With acetic acid In dichloromethane at -20 - 0℃;

5,6-dihydro-pyran-2-one (3393-45-1) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → anti-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)-4-phenylazetidin-2-one

Conditions	Yield
Stage #1: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine With chloro(1,5-cyclooctadiene)rhodium(I) dimer; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 5,6-dihydro-pyran-2-one With diethylzinc In tetrahydrofuran; hexane at 20℃; for 24h; Catalytic behavior; Reagent/catalyst; Temperature; Solvent; Schlenk technique;	46%

5,6-dihydro-pyran-2-one (3393-45-1) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → C26H26FNO2

Conditions	Yield
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; diethylzinc; aluminum isopropoxide In tetrahydrofuran at 20℃; for 24h; Catalytic behavior; Temperature; Solvent; Reagent/catalyst; Inert atmosphere; Schlenk technique;	9%

pent-4-enoic acid (591-80-0) + 4-fluoro-1-iodobenzene (352-34-1) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-1-E-propenyl)-4-(4-benzyloxyphenyl)-2-azetidinone + 1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-2-E-propenyl)-4-(4-benzyloxyphenyl)-2-azetidinone

Conditions

Yield

Stage #1: pent-4-enoic acid; 4-fluoro-1-iodobenzene With tetrabutyl-ammonium chloride; potassium acetate; triphenylphosphine; palladium diacetate In N,N-dimethyl-formamide at 80℃; Arylation; Stage #2: With oxalyl dichloride In dichloromethane at 22℃; for 1h; Substitution; Stage #3: 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine With tributyl-amine In n-heptane; toluene at 80℃; for 18h; cyclocondensation; Staudinger conditions;

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl)-2-azetidinone

Conditions	Yield
Multi-step reaction with 2 steps 1: 48 percent / tributylamine / toluene / 72 h / Heating 2: 63 percent / ammonium formate / 10 percent Pd/C / methanol / Heating View Scheme
Multi-step reaction with 3 steps 1.1: PPh3; KOAc; n-Bu4NCl / Pd(OAc)2 / dimethylformamide / 80 °C 1.2: oxalyl chloride / CH2Cl2 / 1 h / 22 °C 1.3: NBu3 / toluene; heptane / 18 h / 80 °C 2.1: 68 percent / BCl3*SMe2 / CH2Cl2 / 18 h / 20 °C 3.1: H2 / 10 percent Pd/C / ethyl acetate / 2 h / 760 Torr View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → N-(4-fluorophenyl)-5-(4-fluorophenyl)-2-(4-hydroxybenzyl)pentanamide

Conditions	Yield
Multi-step reaction with 2 steps 1: 48 percent / tributylamine / toluene / 72 h / Heating 2: 20 percent / ammonium formate / 10 percent Pd/C / methanol / Heating View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-2-E-propenyl]-4-(4-hydroxyphenyl)-2-azetidinone

Conditions	Yield
Multi-step reaction with 2 steps 1.1: PPh3; KOAc; n-Bu4NCl / Pd(OAc)2 / dimethylformamide / 80 °C 1.2: oxalyl chloride / CH2Cl2 / 1 h / 22 °C 1.3: NBu3 / toluene; heptane / 18 h / 80 °C 2.1: 68 percent / BCl3*SMe2 / CH2Cl2 / 18 h / 20 °C View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → 4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-[3-(4-fluorophenyl)propyl]-2-azetidinone

Conditions	Yield
Multi-step reaction with 2 steps 1.1: PPh3; KOAc; n-Bu4NCl / Pd(OAc)2 / dimethylformamide / 80 °C 1.2: oxalyl chloride / CH2Cl2 / 1 h / 22 °C 1.3: NBu3 / toluene; heptane / 18 h / 80 °C 2.1: H2 / 10 percent Pd/C / ethyl acetate / 2 h / 760 Torr View Scheme
Multi-step reaction with 2 steps 1.1: PPh3; KOAc; n-Bu4NCl / Pd(OAc)2 / dimethylformamide / 80 °C 1.2: oxalyl chloride / CH2Cl2 / 1 h / 22 °C 1.3: NBu3 / toluene; heptane / 18 h / 80 °C 2.1: H2 / 10 percent Pd/C / ethyl acetate / 2 h / 760 Torr View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → [14C]-Sch 57871 (191330-56-0)

Conditions

Yield

Multi-step reaction with 5 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 90 percent / hydrogen / 10 percent Pd/C / methanol; ethyl acetate / 3 h / 1551.44 Torr View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 2: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 3: formic acid / dichloromethane / 12 h / Reflux View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → ezetemibe (163222-33-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 90 percent / hydrogen / 10 percent Pd/C / methanol; ethyl acetate / 3 h / 1551.44 Torr 6: 79 percent / bistrimethylsilylurea; BH3-Me2S / CH2Cl2 / 5 h / -20 - -15 °C View Scheme
Multi-step reaction with 7 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 6: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C 7: 79 percent / ammonium formate; HOAc / Pd-C / methanol / 3 h / 45 - 55 °C / pH 3 - 5 View Scheme
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 2: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 3: formic acid / dichloromethane / 12 h / Reflux 4: dimethyl sulfide borane / dichloromethane; toluene; tetrahydrofuran / 12 h / 15 °C 5: acetic acid; ammonium formate; palladium 10% on activated carbon / 6 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 5 h / -30 - -20 °C 2.1: tetrabutyl ammonium fluoride / toluene / 3 h / 60 °C 3.1: sulfuric acid / isopropyl alcohol / 1 h / 20 °C 3.2: 2 h / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride / toluene / 60 °C 2: dimethylsulfide borane complex / dichloromethane; toluene / 3 h / -5 - 0 °C / Inert atmosphere 3: palladium 10% on activated carbon; hydrogen / methanol; tetrahydrofuran / 2 h View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 6: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 2: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 3: formic acid / dichloromethane / 12 h / Reflux 4: dimethyl sulfide borane / dichloromethane; toluene; tetrahydrofuran / 12 h / 15 °C View Scheme
Multi-step reaction with 2 steps 1: N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride / toluene / 60 °C 2: dimethylsulfide borane complex / dichloromethane; toluene / 3 h / -5 - 0 °C / Inert atmosphere View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (2S,3S)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxazetidine-3-carbaldehyde (221349-58-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.17 h / -30 °C / Inert atmosphere 1.2: 3 h / -30 - -20 °C 2.1: N,O-bis-(trimethylsilyl)-acetamide / dichloromethane / 3 h / 50 °C 2.2: 2 h / Reflux 3.1: diisobutylaluminium hydride / tetrahydrofuran; hexane / -45 - 20 °C View Scheme

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-4-(4-Benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[(E)-3-(4-fluoro-phenyl)-3-oxo-propenyl]-azetidin-2-one (221349-60-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C View Scheme

Upstream product

• 99395-88-7 (S)-4-phenyl-2-oxazolidinone 
• 123-08-0 4-hydroxy-benzaldehyde 
• 100-44-7 benzyl chloride 
• 3382-63-6 N-(4-hydroxybenzylidene)-4-fluorobenzenamine 
• 100-39-0 benzyl bromide 
• 371-40-4 4-fluoroaniline 
• 4397-53-9 p-benzyloxybenzaldehyde 

Downstream Products

• 917392-16-6 N-{2-[3-(methoxy)-3-(oxo)-propyl]-3-(4-fluorophenylamino)-3-(4-benzyloxyphenyl)-1-oxo-propyl}-4-(S)-phenyloxazolidin-2-one 
• 1046809-84-0 (R)-4-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-oxo-5-((S)-2-oxo-4-phenyl-oxazolidin-3-yl)pentanoic acid benzyl ester 
• 954109-20-7 (S)-3-{(R)-2-[(S)-[4-(benzyloxy)phenyl][(4-fluorophenyl)amino]methyl]-4-[2-(4-fluorophenyl)[1,3]dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one 
• 163380-15-2 (3R,4S,3'R)-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[3'-(4-fluorophenyl)-3'-hydroxy-propyl]-azetidin-2-one 
• 1185883-39-9 C₄₀H₃₆F₂N₂O₅ 
• 415960-63-3 N-(4-(benzyloxy)benzyl)-4-fluoroaniline 
• 953805-24-8 4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-3(R)-{2-[2-(4-fluorophenyI)-5,5-dimethyl-[1,3]-dioxan-2-yl]-ethyl}azetidine-2-one 
• 953805-22-6 3-{(2R,3S)-3-[(4-fluorophenyl)amino]-2-[2-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]-3-[4-(benzyloxy)phenyI]propanoyl}-(4S)-4-phenyl-1,3-oxazolidin-2-one 
• 221349-56-0 (3S,4S)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one 

Relevant articles and documents

A new class of ezetimibe derivative and its preparation method (by machine translation)

The present invention provides a new class of ezetimibe derivatives, characterized in that its structural formula as shown in formula I: The invention the ezetimibe derivatives improves the water-solubility of ezetimibe, more conducive to clinical use. (by machine translation)

Visible-Light Photocatalytic Synthesis of Amines from Imines via Transfer Hydrogenation Using Quantum Dots as Catalysts

CdSe/CdS core/shell quantum dots (QDs) can be used as stable and highly active photoredox catalysts for efficient transfer hydrogenation of imines to amines with thiophenol as a hydrogen atom donor. This reaction proceeds via a proton-coupled electron transfer (PCET) from the QDs conduction band to the protonated imine followed by hydrogen atom transfer from the thiophenol to the α-aminoalkyl radical. This precious metal free transformation is easy to scale up and can be carried out by a one-pot protocol directly from aldehyde, amine, and thiophenol. Additional advantageous features of this protocol include a wide substrate scope, high yield of the amine products, extremely low catalyst loading (0.001 mol %), high turnover number (105), and the mild reaction conditions of using visible light or sun light at room temperature in neutral media.

METHOD FOR PRODUCING EZETIMIBE AND INTERMEDIATE THEREOF

PROBLEM TO BE SOLVED: To provide a method for producing ezetimibe that is a cholesterol-lowering agent. SOLUTION: The present invention provides a method for producing ezetimibe (I) that generates intermediate (M1) and eliminates a protecting group. [R1 is a benzyl group and others, R2 is an ether protecting group such as a silyl ether protecting group]. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT