272778-12-8

Basic information

• Product Name: 3-[(2R,5S)-5-(4-Fluorophenyl)-2-[(S)-[(4-fluorophenyl(amino)]][4-[trimethylsilyl]-oxy]phenyl]methyl]-1-oxo-5-[(trimethylsily)-oxy]pentyl]-4-phenyl-(4S)-2-oxazolidinone
• Synonyms: 3-[(2R,5S)-5-(4-FLUOROPHENYL)-2-[(S)-[(4-FLUOROPHENYL(AMINO)]] [4-[TRIMETHYLSILYL]-OXY]PHENYL]METHYL]-1-OXO-5-[(TRIMETHYLSILY)-OXY]PENTYL]-4-PHENYL-(4S)-2-OXAZOLIDINONE;2-OXAZOLIDINONE, 3-[(2R,5S)-5-(4-FLUOROPHENYL)-2-[(S)-[(4-FLUOROPHENYL)AMINO][4-[(TRIMETHYLSILYL)OXY]PHENYL]METHYL]-1-OXO-5-[(TRIMETHYLSILYL)OXY]PENTYL]-4-PHENYL-, (4S)-;3-[(2r,5s)-5-(4-Fluorophenyl)-2-[(S)-[(4-Fluorophenyl( Amino)]][4-[Trimethylsilyl]-Oxy]Phenyl]Methyl]-1-Oxo-5-[(Trimethylsilyl)-Oxy]Pentyl]-4-Phenyl-(4s)-2-Oxazolidinone;3-[(2R,5S)-5-(4-fluorophenyl)-2-{(S)-[4-fluorophenyl]Amino}[4-(trimethylsily)-oxy]pentyl]methyl-1-2oxo-5-(trimethylsilyl)-oxo]penyl]-4-phenyl-(4S)-2-oxazolidinone;3-[(2R,5S)-5-(4-FLUOROPHENYL)-2-[(S)-[(4-FLUOROPHENYL( AMINO)]] [4-[TRIMETHYLSILYL]-OXY]PHENYL]METHYL]-1-OXO-5-[(TRIMETHYLSILY) -OXY]PENTYL]-4-PHENYL-(4S)- 2-OXAZOLIDINONE(INTERMEDIATE OF EZETIMIBE);INTERMEDIATE OF EZETIMIBE;3-(2R,5S)-5-(4-fluorophenyl)-2-(S)-(4-fluorophenyl(amino)4-trimethylsilyl-oxyphenylmethyl-1-oxo-5-(trimethylsily)-oxypentyl-4-p
• CAS NO: 272778-12-8
• Molecular Formula: C₃₉H₄₆F₂N₂O₅Si₂
• Molecular Weight: 716.96
• EINECS: 1592732-453-0
• Product Categories: Ezetimibe intermediates;Ezetimibe
• Mol File: 272778-12-8.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 748.9 °C at 760 mmHg
• Flash Point: 406.7 °C
• Appearance: /
• Density: 1.177
• Vapor Pressure: 2.64E-22mmHg at 25°C
• Refractive Index: 1.565
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: Chloroform, Ethyl Acetate, Methanol
• PKA: 3.55±0.50(Predicted)
• CAS DataBase Reference: 3-[(2R,5S)-5-(4-Fluorophenyl)-2-[(S)-[(4-fluorophenyl(amino)]][4-[trimethylsilyl]-oxy]phenyl]methyl]-1-oxo-5-[(trimethylsily)-oxy]pentyl]-4-phenyl-(4S)-2-oxazolidinone(CAS DataBase Reference)
• NIST Chemistry Reference: 3-[(2R,5S)-5-(4-Fluorophenyl)-2-[(S)-[(4-fluorophenyl(amino)]][4-[trimethylsilyl]-oxy]phenyl]methyl]-1-oxo-5-[(trimethylsily)-oxy]pentyl]-4-phenyl-(4S)-2-oxazolidinone(272778-12-8)
• EPA Substance Registry System: 3-[(2R,5S)-5-(4-Fluorophenyl)-2-[(S)-[(4-fluorophenyl(amino)]][4-[trimethylsilyl]-oxy]phenyl]methyl]-1-oxo-5-[(trimethylsily)-oxy]pentyl]-4-phenyl-(4S)-2-oxazolidinone(272778-12-8)

Safety Data

• Hazardous Substances Data: 272778-12-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-white Solid

Uses

Different sources of media describe the Uses of 272778-12-8 differently. You can refer to the following data:
1. (4R)-3-[(2S,5R)-5-(4-Fluorophenyl)-2-[(R)-[(4-fluorophenyl)amino][4-[(trimethylsilyl)oxy]phenyl]methyl]-1-oxo-5-[(trimethylsilyl)oxy]pentyl]-4-phenyl-2-oxazolidinone is an intermediate in the preparat ion of Ezetimibe (E975000).
2. (4S3-[(2R,5S)-5-(4-Fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino][4-[(trimethylsilyl)oxy]phenyl]methyl]-1-oxo-5-[(trimethylsilyl)oxy]pentyl]-4-phenyl-2-oxazolidinone is used in the synthesis of Ezetimibe (E975000), an antihyperlipoproteinemic; a cholesterol absorption inhibitor.

InChI:InChI=1/C39H46F2N2O5Si2/c1-49(2,3)47-33-22-14-29(15-23-33)37(42-32-20-18-31(41)19-21-32)34(24-25-36(48-50(4,5)6)28-12-16-30(40)17-13-28)38(44)43-35(26-46-39(43)45)27-10-8-7-9-11-27/h7-23,34-37,42H,24-26H2,1-6H3/t34-,35-,36+,37-/m1/s1

Synthetic route

chloro-trimethyl-silane (75-77-4) + N-(4-hydroxybenzylidene)-4-fluorobenzenamine (3382-63-6) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → (4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (272778-12-8)

Conditions	Yield
Stage #1: chloro-trimethyl-silane; N-(4-hydroxybenzylidene)-4-fluorobenzenamine; (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - 0℃; Inert atmosphere; Stage #2: With titanium tetrachloride In dichloromethane at -30 - -25℃; Inert atmosphere;	66.6%
With triethylamine In dichloromethane at -20℃; Reagent/catalyst; Solvent;

chloro-trimethyl-silane (75-77-4) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → (4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (272778-12-8)

Conditions	Yield
Stage #1: (E)-(4-hydroxy-benzylidene)-(4-fluorophenyl)-amine; (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - -5℃; Stage #2: chloro-trimethyl-silane In dichloromethane at -5℃; for 1.5h; Stage #3: With titanium tetrachloride In dichloromethane at -30 - -25℃; for 3h;	65%

chloro-trimethyl-silane (75-77-4) + N,O-bis-(trimethylsilyl)-acetamide (10416-59-8) + N-(4-hydroxybenzylidene)-4-fluorobenzenamine (3382-63-6) + (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one (189028-95-3) → (4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (272778-12-8)

Conditions	Yield
Stage #1: chloro-trimethyl-silane; N-(4-hydroxybenzylidene)-4-fluorobenzenamine; (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one With N-ethyl-N,N-diisopropylamine In dichloromethane at -10 - -5℃; for 1h; Stage #2: With titanium tetrachloride In dichloromethane at -30℃; for 20h; Stage #3: N,O-bis-(trimethylsilyl)-acetamide	60%

(4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (272778-12-8) → (3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-(trimethylsilyloxy)propanyl)-4-(4-(trimethylsiloxy)phenyl)azetidinone

Conditions	Yield
With N,O-bis-(trimethylsilyl)-acetamide; tetrabutylammonium acetate In tert-butyl methyl ether at 20℃; for 0.25h; Product distribution / selectivity;
With N,O-bis-(trimethylsilyl)-acetamide; potassium acetate In tetrahydrofuran at 20 - 60℃; for 5.5h; Product distribution / selectivity;
Stage #1: (4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one With N,O-bis-(trimethylsilyl)-acetamide; potassium acetate In tetrahydrofuran at 20℃; for 0.5h; Stage #2: With tetrabutylammomium bromide In tetrahydrofuran at 20℃; for 0.7h; Product distribution / selectivity;

(4S)-3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl)amino]({4-[(trimethylsilyl)oxy]phenyl})methyl]-5-[(trimethylsilyl)oxy]pentanoyl]-4-phenyl-1,3-oxazolidin-2-one (272778-12-8) → ezetemibe (163222-33-1)

Conditions	Yield
With N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride In toluene at 28℃; for 2.66667h; Temperature; Inert atmosphere; Large scale;

Upstream product

• 75-77-4 chloro-trimethyl-silane 
• 189028-95-3 (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidine-2-one 
• 3382-63-6 N-(4-hydroxybenzylidene)-4-fluorobenzenamine 
• 10416-59-8 N,O-bis-(trimethylsilyl)-acetamide 

Downstream Products

• 163222-33-1 ezetemibe 
• 272778-13-9 (3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-(trimethylsilyloxy)propanyl)-4-(4-(trimethylsiloxy)phenyl)azetidinone 

Relevant articles and documents

Preparation method of ezetimibe and intermediate thereof

The invention discloses a preparation method of ezetimibe and an intermediate thereof. The invention provides a preparation method of an ezetimibe intermediate IV. The preparation method comprises thefollowing steps: an ezetimibe intermediate II and an ezetimibe intermediate III are subjected to a cyclization reaction to obtain the ezetimibe intermediate IV in the presence of a trialkylchlorosilane, an organic base, a chiral catalyst and lithium diisopropylamide in an organic solvent, wherein R is methyl, ethyl or propyl. The preparation method is short in route steps, mild in reaction conditions and simple in post-treatment steps, and avoids the connection of a substrate with a chiral group, and the obtained product is high in purity, achieves the standard of bulk drugs, is high in yield, low in production cost, high in atomic utilization rate, and suitable for industrial production.

NEW METHOD FOR PREPARING EZETIMIBE

The present invention relates to a new method for preparing ezetimibe comprising a step of cyclizing the compound (4S)-phenyl-3-[(5S)-(4-fluorophenyl)-(2R)-[(1S)-(4-fluorophenylamino)-1-(4-nitrophenyl)methyl]-5-hydroxypentanoyl]oxazolidin-2-one or the derivatives thereof in which the hydroxyl group is protected. The invention also relates to new intermediates used in this method.