191330-56-0

Basic information

• Product Name: EZM-K
• Synonyms: (3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-2-azetidinone;Ezetimibe Ketone;EZM-K;(3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)azetidin-2-one;EzetiMibe 3-Oxo IMpurity;Monophenyl phosphite diisooctyl;(3R,4S)-1-(4-Fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)-4-(4-hydroxyphenyl)azetidin-2-on;Ezetimibe Impurity 16(SCH57871)
• CAS NO: 191330-56-0
• Molecular Formula: C₂₄H₁₉F₂NO₃
• Molecular Weight: 407.41
• Product Categories: Chiral Reagents;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 191330-56-0.mol

Chemical Properties

• Boiling Point: 656.149 °C at 760 mmHg
• Flash Point: 350.627 °C
• Appearance: white crystalline solid
• Density: 1.325
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.615
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 9.72±0.30(Predicted)
• CAS DataBase Reference: EZM-K(CAS DataBase Reference)
• NIST Chemistry Reference: EZM-K(191330-56-0)
• EPA Substance Registry System: EZM-K(191330-56-0)

Safety Data

• Hazardous Substances Data: 191330-56-0(Hazardous Substances Data)

Usage

Chemical Properties

White to Off-White Solid

Uses

Phase-I metabolite of Ezetimibe (E975000).

InChI:InChI=1/C24H19F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21,23,28H,13-14H2/t21-,23-/m1/s1

Upstream product

• 190595-65-4 (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one 
• 221349-60-6 (3R,4S)-4-(4-Benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[(E)-3-(4-fluoro-phenyl)-3-oxo-propenyl]-azetidin-2-one 
• 953805-34-0 4(S)-(4-hydroxyphenyl)-1-(4-fluorophenyl)-3(R)-{2-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]-dioxan-2-yl]-ethyl}azetidine-2-one 
• 953805-25-9 4(S)-(4-trimethylsilanyloxyl)-1-(4-fluorophenyl)-3(R)-{2-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]-dioxan-2-yl]-ethyl}azetidine-2-one 
• 70627-52-0 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine 
• 221349-58-2 (2S,3S)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxazetidine-3-carbaldehyde 
• 221349-56-0 (3S,4S)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one 
• 231301-00-1 (3S,4S)-4-(4-Benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-1-hydroxy-3-oxo-propyl]-azetidin-2-one 
• 219653-96-0 (Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine 
• 1501-26-4 methyl 4-(chlorocarbonyl)butyrate 
• 99395-88-7 (S)-4-phenyl-2-oxazolidinone 
• 133472-27-2 4-fluorophenylzinc chloride 
• 954109-23-0 (3R,4S)-4-[4-hydroxy-phenyl]-1-(4-fluorophenyl)-3-{2-(2-(4-fluorophenyl)-[1,3]dioxolan-2-yl)-ethyl}-azetidine-2-one 
• 1159183-23-9 C₃₂H₂₅F₂NO₅ 

Downstream Products

• 163222-33-1 ezetemibe 
• 1478664-18-4 (3R,4R)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one 
• 954109-26-3 (3R,4S)-4-(4-(trimethylsilyloxy)phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one 
• 857506-68-4 1-(4-fluorophenyl)-3-(R)-[2-(4-fluorobenzoyl)ethyl]-4-(S)-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one 
• 163222-32-0 (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 
• 163380-16-3 (3R,4S)-1-(4-fluorophenyl)-3-[(3R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one 
• 1159183-23-9 C₃₂H₂₅F₂NO₅ 
• 1042722-98-4 (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-[4-(trityloxy)phenyl]azetidin-2-one 

Relevant articles and documents

Method for preparing ezetimibe degradation impurities

The invention discloses a method for preparing ezetimibe degradation impurities, namely, ring-opened impurities and ketone impurities. According to the method, the ring-opened impurities and the ketone impurities are obtained from ezetimibe through alkali reaction or oxidation reaction respectively. The method is easy to operate, mild in reaction and higher in yield, product purity is high, environmental pollution is effectively reduced, the impurities are suitable for impurity spectrum analysis of the raw material medicine and preparations of ezetimibe and can be used as a reference substance of correlated substances to detect the content of degradation products in ezetimibe and the preparations of ezetimibe, and guarantee is provided for further control of product quality of ezetimibe and the preparations of ezetimibe.

Preparation method of ezetimibe and key intermediates thereof of lipid-lowering drugs

The invention relates to a preparation method of ezetimibe and key intermediates thereof of lipid-lowering drugs. The preparation method is applicable to industrial production.

Ezetimibe intermediate and synthesis method thereof

The invention provides a new ezetimibe intermediate and a preparation method thereof. The preparation method comprises: (1) converting 4-(4-fluoro-benzoyl)-butyric acid into 4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyric acid through a un-separated intermediate compound; and (2) carrying out acylation on chiral oxazolidone by using the 4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyric acid to obtain the oxazolidone derivative VI. According to the present invention, the route is simple, cheap and efficient, and the obtained product has advantages of less impurity, high purity, and high yield.

Intermediate compound of ezetimibe

The invention provides a novel intermediate compound of ezetimibe and a preparation method thereof. The preparation method comprises a step of converting 4-(4-fluoro-benzoyl)-butyric acid into 4-[2-(4-fluoro-phenyl)-[1,3]dithiolan-2-yl]-butyric acid by using an unseparated intermediate compound. The method provided by the invention is simple in route, low in price and high in efficiency; and in order to better protect functional groups, the method employs the selectively removable protective group, so the method has the advantages of few impurities, high product purity and high product yield.

Ezetimibe intermediate compound

The invention provides a new ezetimibe intermediate and a preparation method thereof, wherein the ezetimibe intermediate is prepared from 4-(4-fluoro-benzoyl)-butyric acid in one step. According to the present invention, the route is simple, cheap and efficient; and in order to well protect the functional group, the route uses the protection group capable of being selectively removed, and the obtained product has advantages of less impurity, high purity, and high yield.

Efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe

An efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe through chiral Evans auxiliary (S)-4-phenyl-2-oxazolidinone is described. The key steps in this process are the condensation of (S)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one and N-(4-((tert-butyldimethylsilyl)oxy)benzylidene)-4-fluoroaniline, and the stereoselective reduction of ezetimibe-ketone with NaBH4/I2, which is first applied in the synthesis of ezetimibe. The process is concise, mild, easy to operate, and highly stereoselective (99.6% of de value of ezetimibe). In addition, three diastereomers of ezetimibe are synthesized and served as the references in quality control of the product.

First synthesis and characterization of key stereoisomers related to Ezetimibe

During the laboratory optimization and the late phase manufacturing studies of the cholesterol absorption inhibitor Ezetimibe 1, the formation of several stereoisomers was observed. To study the complete stereoisomer profile of Ezetimibe 1, we have synthesized and completely characterized several key stereoisomers of Ezetimibe 1 for the first time. This study will provide an access to the reference standard of these stereoisomers and may have some implications in the development of new medicines.

Diastereoselective reduction of 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4- fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one to Ezetimibe by the whole cell catalyst Rhodococcus fascians MO22

The asymmetric microbial reduction of 1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4- fluorophenyl)-propyl]-4(S)-(4-hydroxyphenyl)azetidin-2-one to 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)-propyl]-4(S) -(4-hydroxyphenyl)azetidin-2-one (Ezetimibe) by Rhodococcus fascians MO22 is described. The catalytic capability of the microorganism for reduction has been examined also with protected ketone, an intermediate from chemical synthesis of Ezetimibe. Various parameters of the bioreduction have been optimized: the strain converted 94.8% of ketone and 63% of protected ketone into Ezetimibe with the same de of 99.9%. In the later case, two chemical steps are replaced with a single biotransformation.

INTERMEDIATES IN THE PREPARATION OF 1,4-DIPHENYL AZETIDINONE

The process of the present invention relates to a method for the synthesis of a 1,4-diphenylazetidinone of formula (VIII) by using novel oxime intermediates.

PROCESSES FOR PREPARING INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION OF EZETIMIBE

The invention relates, in general, to an improved process for the preparation of the compounds (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one and (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-(4-hydroxyphenyl)-azetidin-2-one, which are key intermediates for the synthesis of ezetimibe, as well as the use of these intermediates for the preparation of ezetimibe.