cas 191330-56-0, EZM-K | Articles data

Articles about 191330-56-0Total 16 be found

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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.
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(2017/09/13)

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.
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(2018/04/02)

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.
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Paragraph 0065; 0074; 0075; 0076; 0086; 0097; 0108; 0119

(2018/04/02)

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.
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Paragraph 0075; 0076; 0087; 0098; 0109; 0120

(2018/04/02)

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.
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Paragraph 0050; 0051

(2018/03/24)

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.
Zhu, Yijun,Pan, Jing,Zhang, Shunli,Liu, Zhenren,Ye, Deyong,Zhou, Weicheng
p. 1687 - 1693
(2016/10/21)

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.
Ren, Yun,Duan, Yan-Jun,Li, Ren-Jun,Deng, Yong,Hai, Li,Wu, Yong
p. 1157 - 1160
(2014/08/18)

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.
Kyslikova, Eva,Babiak, Peter,Maresova, Helena,Palyzova, Andrea,Hajicek, Josef,Kyslik, Pavel
experimental part
p. 266 - 270
(2011/02/22)

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.
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Page/Page column 14

(2010/11/03)

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.
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Page/Page column 18

(2009/09/26)

METHOD OF MANUFACTURING (3R, 4S) -1- (4-FLUOROPHENYL) -3- [ (3S) -3- (4 -FLUOROPHENYL) -3-HYDROXYPROPYL) ] -4- (4-HYD ROXYPHENYL) -2-AZETIDINONE
A method of manufacturing (3R,4S)-l-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (Ezetimibe) of formula I, starting from the optically active (S)-N-acyl-oxazolidide of formula II, which is reacted with an alkyleneglycol of general formula III, (stage 1), and the obtained acetal-oxazolidide of general formula IV, is subjected to reaction with a silyl-imine of general formula V the produced amino-oxazolidide of general formula VI, (stage 3), and the obtained silylated azetidinone of general formula VII, is desilylated (stage 4), and the ketal of general formula VIII produced this way, is deketalized formula IX is finally reduced.
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Page/Page column 12

(2008/12/07)

PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES
The present invention relates to an industrially advantageous process for the preparation of ezetimibe of formula (I) in high yields by using novel benzyl ester intermediates. The present invention further provides a process for the purification of ezetimibe of formula (I).
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Page/Page column 21-22

(2008/12/08)

PROCESSES FOR THE SYNTHESIS OF AZETIDINONE
Provided are intermediates useful for the synthesis of hydroxyl-alkyl substituted azetidinones, processes of their preparation, and processes for the synthesis of certain hydroxyl-alkyl substituted azetidinones. Also provided are processes for the synthesis ofl-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)- hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone, or ezetimibe.
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Page/Page column 75

(2008/06/13)

Combinations of substituted azetidinones and CB1 antagonists
The present invention provides compositions, therapeutic combinations and methods including: (a) at least one selective CB1 antagonist; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity, metabolic syndrome and lowering plasma levels of sterols or 5α-stanols.
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Page/Page column 26-27

(2008/06/13)

A novel one-step diastereo- and enantioselective formation of trans- azetidinones and its application to the total synthesis of cholesterol absorption inhibitors
An efficient and practical asymmetric process was developed for the synthesis of azetidinone-based cholesterol absorption inhibitors. Key to this synthesis was the discovery of a novel one-step diastereo- and enantioselective formation of trans β-lactams starting from commercially available 3(S)-hydroxy-γ-lactone. Various trans β-lactams can be prepared in good yields and with better than 95:5 enantio- and diastereoselctivity. A Lewis acid-catalyzed aldol condensation and a highly enantioselective oxazaborolidine-catalyzed chiral reduction completes the side chain.
Wu,Wong,Chen,Ding
p. 3714 - 3718
(2007/10/03)

Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption
(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]- (4S)-(4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.
Rosenblum, Stuart B.,Huynh, Tram,Afonso, Adriano,Davis Jr., Harry R.,Yumibe, Nathan,Clader, John W.,Burnett, Duane A.
p. 973 - 980
(2007/10/03)