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

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

Uses

Used in Pharmaceutical Industry:
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 is used as an intermediate in the preparation of Ezetimibe (E975000), an antihyperlipidemic drug and a cholesterol absorption inhibitor. Its role in the synthesis process is crucial for the development of this medication, which helps in managing high cholesterol levels and reducing the risk of cardiovascular diseases.
Used in Synthesis of Ezetimibe (E975000):
In the pharmaceutical industry, 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 is utilized in the synthesis of Ezetimibe (E975000). 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 serves as a key intermediate in the production process, enabling the creation of a drug that effectively lowers cholesterol levels and supports cardiovascular health.
Chemical Properties:
The compound is an off-white solid, which indicates its stable and solid-state nature. This property is essential for its use in the pharmaceutical industry, as it allows for easy handling and processing during the synthesis of target drugs.

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 
• 10416-59-8 N,O-bis-(trimethylsilyl)-acetamide 
• 3382-63-6 N-(4-hydroxybenzylidene)-4-fluorobenzenamine 

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.

Slurry bed continuous production method of ezetimibe intermediate

The invention discloses a continuous production method of an ezetimibe intermediate 3-[(2R,5S)-5-(4-fluorophenyl)-2-[(S)-[(4-fluorophenyl(amino))][4-R1oxo]phenyl]methyl]-1-oxo-5-[(trimethylsilicon)oxo]phenyl]-4-phenyl-(4S)-2-oxazolidinone. The ezetimibe intermediate is prepared through a contact reaction of raw materials containing a compound A and a compound B with a solid acid catalyst in a slurry bed reactor. The solid acid catalyst is adopted to substitute original titanium tetrachloride and isopropyl titanate catalysts, and a continuous reaction is carried out in the slurry bed reactor, so the method reduces environment pollution and production device requirements, solves the separation and recovery problems of the catalysts, and makes large-scale continuous production of ezetimibe become possible.

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.

Process for the synthesis of azetidinones

A process is provided for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, comprising reacting a β-(substituted-amino)amide, a β-(substituted-amino)acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or the reaction product of: (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.