cas 163222-33-1, Ezetimibe | Articles data

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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.
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(2020/03/03)

METHOD OF PREPARING EZETIMIBE AND INTERMEDIATE THEREOF
Disclosed is a method of preparing ezetimibe, including cross-metathesis using a Grubbs 2nd catalyst and deprotection using a Pearlman's catalyst, and an intermediate thereof. The method of preparing ezetimibe is useful as an efficient ezetimibe synthesis technique in pharmaceutical fields using ezetimibe as a raw material.
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(2019/08/30)

Structural Correction and Process Improvement for Control of a Critical Process Impurity of Ezetimibe
A new process-related impurity of ezetimibe was identified and characterized. The impurity is critical and common to most of the manufacturing routes of ezetimibe. Structural characterization using HMBC indicated the presence of a six-membered ring rather than a nine-membered ring as proposed by the innovator of ezetimibe. Prominently, the existing pharmacopoeial methods for ezetimibe are not capable of detecting this impurity. A control strategy was established by appropriate process control that is capable of purging the impurity to levels comfortably below the regulatory requirement. The formation of the diastereomer impurity during the demonstration of a scale-up batch under the optimized conditions is attributed to epimerization of ezetimibe induced by thermal degradation of the silylating agent.
Mannam, Madhava Rao,Sankareswaran, Srimurugan,Gaddam, Venugopal Reddy,Natarajan, Senthilkumar,Kottapalli, Rajasekhara Prasad,Kumar, Pramod
p. 919 - 925
(2019/05/08)

Preparation method of ezetimibe serving as drug for treating hyperlipidemia
The invention discloses a preparation method of ezetimibe serving as a drug for treating hyperlipidemia and belongs to the field of drug synthesis. Ezetimibe 1 is prepared by carrying out four synthesis steps including carbonyl protection, cyclization, carbonyl reduction and deprotection on a compound 2 serving as a raw material. Compared with a method reported by an existing document, the preparation method is capable of avoiding using a polluting titanium reagent and reducing the synthesis steps, higher in process stability and suitable for large-scale production.
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(2018/05/01)

Preparation method of ezetimibe for treating hyperlipidemia
The invention discloses a preparation method of ezetimibe for treating hyperlipidemia, and belongs to the field of drug synthesizing. The method is characterized in that a compound 2 is treated as theraw material and subjected to four synthesizing steps to prepare ezetimibe 1, wherein the four steps include the step of protection for carbonyl group, cyclizing, carbonyl reduction and hydrogenationdeprotection. Compared with methods in existing documents, the preparation method has the advantages that the use of polluting titanium agents is avoided; the synthesizing steps are decreased; the technology stability is improved; massive production can be performed.
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(2018/03/25)

According to booklet according to booklet mai bu and mai bu intermediates of the synthesis method
The invention relates to an ezetimibe intermediate and a synthesis method of ezetimibe, and mainly solves the technical problems of low yield, low purity, severe conditions and the like in existing methods. According to a technical scheme of the invention, the preparation method includes: subjecting a compound 1 to Aldol condensation reaction under the condition of a self-made isopropoxy titanium trichloride catalyst to generate a compound 2, controlling the Aldol condensation temperature below -5DEG C, in terms of dropwise adding of the catalyst, adding a system A into a catalyst system, conducting ring closing on a compound 2 under the catalysis of TBAF, and removing silicon protecting group under the fluoride salt condition to generate ezetimibe. The synthesis route has mild conditions, the obtained intermediate and end product have high yield, and the purity is high.
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(2018/07/30)

A process for the synthesis of intermediate according to booklet of the mai bu and its preparation method and application
The invention discloses an ezetimibe synthesis intermediate and a preparation method and application thereof, the ezetimibe synthesis intermediate has the structure as shown in formula III, and is synthesized by enzyme-chemical method, a chiral hydroxyl compound is produced by asymmetric reduction reaction of a raw material compound under the catalysis effect of aldehyde ketone reductase, and a product can be obtained by cyclization reaction. The ezetimibe synthesis intermediate is used in the preparation of ezetimibe, the process is simple, the concentration of the obtained product is high, and the product has the advantages of high optical purity, mild reaction conditions, environmental friendliness, simple operation, easy industrial amplification, and very good industrial application prospect.
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(2018/07/07)

Study on the HPLC-based separation of some ezetimibe stereoisomers and the underlying stereorecognition process
The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode. The use of prohibited solvents as nonstandard mobile phase gave rise to better resolution than that of standard mobile phases (n-hexane/alcohol system). In addition, the presence of ethanol in nonstandard mobile phase has played an important role in enhancing chromatographic efficiency and resolution between ezetimibe stereoisomers. Various attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Moreover, possible solute-mobile phase-stationary phase interactions were derived to explain how stationary and mobile phases affected the separation. Then the method validation with respect to selectivity, linearity, precision, accuracy, and robustness was carried out, which was demonstrated to be suitable and accurate for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug.
Zhu, Bolin,Yao, Yaqi,Zhao, Yu,Sun, Tiemin,Li, Qing
p. 642 - 651
(2018/02/12)

Preparation method of medicine ezetimibe for treating hyperlipidemia
The invention discloses a preparation method of a medicine ezetimibe for treating hyperlipidemia, belonging to the field of pharmaceutical synthesis. According to the preparation method, a compound 2is taken as a raw material, and the ezetimibe 1 is prepared by four steps of carbonyl protection, cyclization, carbonyl reduction and oxidation. Compared with the existing method reported by documents, the preparation method provided by the invention avoids the use of a polluting titanium reagent, and is fewer in synthesis steps, higher in process stability and suitable for large-scale production.
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(2018/03/26)

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)

according to folds Mai Bu and its intermediate synthesis method
The invention provides an Ezetimibe synthesis method comprising the following steps: (a) a compound (5) is subjected to asymmetric reduction reaction to obtain a compound (6), and the compound (6) and tert-butyldimethylsilyl chloride react in an organic solution under the action of alkali to obtain a compound (7); (b) the compound (7) and diisopropylethylamine are dissolved in the organic solution, titanium tetrachloride is added in the organic solution to react at 20-50 DEG C, and a compound (3) is added in the organic solution at minus 20 to minus 60 DEG C to react to obtain a compound (8); (c) the compound (8) and N,O-bis(trimethylsilyl) acetamide react in the organic solution at 20-80 DEG C, tetrabutylammonium fluoride trihydrate is added into the organic solution to react at 20-80 DEG C to obtain a compound (9); (d) the compound (9) is subjected to off-protection reaction to obtain Ezetimibe, wherein R is equal to TBS, Ac or COOCH2CCl3. The invention further provides an Ezetimibe intermediate and a preparation method thereof.
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(2017/07/26)

Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe
The invention provides an ezetimibe intermediate, a synthesis method of the intermediate and a synthesis method of ezetimibe. The method is short in synthetic route. The method includes the steps of making fluorobenzene as the initial raw material sequentially have acylation reaction with glutaric anhydride and 4(S)-4-phenyl oxazolidinone to generate a compound II, protecting carbonyl through 2,2-bis-substituted-1,3-propylene glycol to obtain a compound III, generating a compound V through the compound III and a compound IV under the catalysis of titanium tetrachloride, cyclizing the compound V to generate a compound VI, hydrolyzing the compound VI to obtain a compound VII, and reducing the compound VII through a borane chiral reducing agent and removing a benzyl protecting group in a hydrogenated mode to obtain the ezetimibe. The method is high in yield, little in side reaction and suitable for industrial mass production.
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(2017/07/01)

according to bookletmai Bu midbody and its preparation method
The invention relates to a chemical of formula (VI) and its preparation method, and an intermediate of formula (V) of the chemical of formula (VI) and its preparation method. The method can high-yield synthesize the chemical of formula (V) without need of silyl protectant to further prepare the chemical of formula (VI) and more further prepare ezetimibe, so as to simplify operation and be suitable for industrial production.
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(2017/07/14)

Preparation process of ezetimibe and its intermediate
The invention provides a preparation process of ezetimibe shown as formula II and its intermediate. The process includes the steps of: in an organic solvent, and under the catalysis of (R)-Me-CBS, subjecting compound I to asymmetric reduction reaction shown as the specification in an NaBH4-I2 reduction system so as to obtain II. Specifically, R is hydrogen atom, benzyl, t-butyldimethylsilyl or trimethylsilyl. In the preparation method, the used NaBH4-I2 reduction system is more environment-friendly than borane dimethylsulfide, the operation is safer and more convenient, also the product cost can be reduced, and the obtained product has high yield and chiral purity. Therefore the preparation process can be used for synthesis of ezetimibe smoothly, and is more suitable for industrial production.
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Paragraph 0035-0049

(2017/09/13)

Novel method for preparing ezetimibe crystal form I
The invention discloses a novel method for preparing ezetimibe crystal form I. The method comprises the following steps: S101, adding methylbenzene to a compound 1, and then adding bi(trimethylsilyl-1-hexyne) acetamide and tetrabutylammonium fluoride to react under nitrogen protection; S102, quenching the reaction solution obtained in step S101 with acetic acid under the nitrogen protection, and performing pressure-reduction distillation to remove a solvent so as to obtain a rough product; S103, adding the obtained rough product to a mixed solution of isopropanol and 2N sulfuric acid solution to precipitate; and S104, filtering, washing and drying to obtain the ezetimibe crystal form I product. The method is convenient to operate; the product quality and the product yield are improved; the cost is saved; and the commercialized production can be realized.
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Paragraph 0039; 0040; 0041; 0042; 0043; 0044; 0045-0054

(2017/07/21)

METHOD FOR PRODUCING EZETIMIBE
PROBLEM TO BE SOLVED: To provide a method for producing high purity (3R, 4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone in which, particularly open ring bodies can be efficiently reduced. SOLUTION: (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl-(4-hydroxyphenyl)-2-azetidinone is crystallized from the inside of a mixed solvent including alcohol, water and acid to produce high purity (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone crystals in which, particularly, the content of open ring bodies is reduced. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 00113-0114

(2017/12/01)

MANUFACTURING METHOD OF (3R,4S)-1-(4-FLUOROPHENYL)-[3(S)-HYDROXY-3-(4-FLUOROPHENYL)PROPYL]-[4-(PHENYLMETHOXY)PHENYL]-2-AZETIDINONE
PROBLEM TO BE SOLVED: To provide a method for effectively manufacturing high purity (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-[4-(phenylmethoxy)phenyl]-2-azetidinone with reduced contents of specific impurities and enantiomers. SOLUTION: When a benzyl protective body is manufactured by reacting a benzyl protective keto body and borane in presence of a CBS catalyst, the benzyl protective keto body is injected under a condition with co-existing a part of borane of needed amount in a reaction system in advance and remaining borane is added later to conduct the reaction. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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(2017/11/18)

PROCESS FOR PREPARING PURE ALLYL PROTECTED KETO DERIVATIVE
The present invention provides an industrially advantageous process for the preparation of pure allyl protected keto derivative of formula I, an intermediate of ezetimibe. by using a novel O-allyl amide derivative of formula II. wherein R is methyl or ethyl
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(2017/11/03)

Ezetimibe preparation method
The invention solves the problem of providing a zetimibe preparation method. The ezetimibe preparation method is high in yield rate, few in impurities, simple in operation and operable and controllable during scale-up. The ezetimibe preparation method improves the preparation method of a key intermediate of EZ2 ((3R, S4)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-benzyloxy-phenyl)-2-azetidinone). The ezetimibe preparation method reduces the reaction temperature, simplifies operation, improves the product yield rate and reduces the content of isomer impurities. Compared with existing preparation methods, the ezetimibe preparation method can avoid low-temperature reaction, improve the production efficiency and the product yield rate and facilitate scale production of ezetimibe. The synthetic route applied in the ezetimibe preparation method is shown as below.
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Paragraph 0053; 0056-0067

(2017/08/29)

Intermediate preparation of mai Buaccording to booklet and its preparation method
The invention provides a preparation midbody for Ezetimibe which is shown in a general formula I, wherein PG is an acetyl group, a T-butyloxycarbonyl group, a benzyl group, a benzyloxycarbonyl group, a trityl group, a trimethylsilyl group or a diphenylmethyl group silicon group. The invention further provides a preparation method of the midbody I, and the application for preparing the medicine Ezetimibe. The method for preparing the Ezetimibe by adopting the compounds shown in the general formula I is different from the method in the conventional document, the newer chirality assistant (S)-4-(2-chlorphenyl)-2-oxazolone is adopted, the productive rate reaches 91%, and the optical purity reaches 100%, so that the productive rate and the optical purity are higher than those of the previously applied (S)-4-phenyl-2-oxazolone. Besides, the selected chirality assistant (S)-4-(2-chlorphenyl)-2- oxazolone can be conveniently prepared by the original commercialized ((S)-2-chlorobenzene glycine potassium).
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(2018/01/19)

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.
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(2016/10/24)

An improved process for preparing according to bookletmai Bu
The invention discloses an improved method for preparing ezetimibe. The method comprises the steps of chirally reducing metal hydride and boride by using a reducing agent; carrying out hydroxy ether protection and condensation reaction by using a one-pot method; and cyclizing, carrying out ether removal protection and the like. The improved method has the advantages that the operation is simple, the reaction selectivity and product stability are good, and the optical purity and yield of the product are high, so that the improved method is suitable for industrial production.
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Paragraph 0029; 0047; 0048

(2018/01/19)

Synthesis method of ezetimibe
The invention discloses a synthesis method of ezetimibe, which comprises the following steps: under the protection of inert gas, adding N,O-dimethylhydroxylamine hydrochloride and EZE-5 into a solvent, and dropwisely adding a DEAC toluene solution to react, thereby obtaining EZE-15; adding magnesium chips and THF (tetrahydrofuran), and dropwisely adding a 4-fluorobromobenzene THF solution to obtain oily EZE-8; adding ethyl benzene, and stirring; dropwisely adding a prepared triethylamine-formic acid mixed reagent, and adding a catalyst to react, thereby obtaining EZE-9; adding THF and EtOH, stirring, adding 5% Pd/C, replacing air in a reaction bulb with high-purity nitrogen, introducing high-purity hydrogen, and carrying out LC until the reaction is complete, thereby obtaining a crude product EZE-10; and refining the crude product with isopropanol and water to obtain the white crystalline powder high-purity EZE-10. The method has the advantages of high synthesized ezetimibe purity, simple used equipment, simplified steps and low production cost, and is suitable for industrial production.
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(2016/10/31)

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)

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe
An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium-hydride complex (Rh-H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor.
Isoda, Motoyuki,Sato, Kazuyuki,Kunugi, Yurika,Tokonishi, Satsuki,Tarui, Atsushi,Omote, Masaaki,Minami, Hideki,Ando, Akira
supporting information
p. 1608 - 1615
(2016/10/05)

Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-β-Lactams
Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding α-alkylidene-β-aryl-
Humpl, Marek,Tauchman, Ji?í,Topolov?an, Nikola,Kretschmer, Jan,Hessler, Filip,Císa?ová, Ivana,Kotora, Martin,Vesely, Jan
p. 7692 - 7699
(2016/09/09)

METHOD FOR PRODUCING (3R,4S)-1-(4-FLUOROPHENYL)-[3(S)-HYDROXY-3-(4-FLUOROPHENYL)PROPYL]-(4-HYDROXYPHENYL)-2-AZETIDINONE
PROBLEM TO BE SOLVED: To provide a method for efficiently producing high purity (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone in which the amount of specified impurities is reduced. SOLUTION: In the presence of palladium carbon in a catalyst quantity, the deprotection of (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-[4-(phenyl methoxy)-phenyl]-2-azetidinone is performed, and to produce (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone, at this time, reaction is performed in such a manner that the pH of a reaction solvent is controlled to 5 or lower. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0055

(2017/04/03)

MANUFACTURING METHOD OF EZETIMIBE
PROBLEM TO BE SOLVED: To provide a method for effectively manufacturing high purity (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone with reducing the amount of specific impurities. SOLUTION: A reaction is conducted with using formic acid and formate as hydrogen sources during manufacturing (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-hydroxyphenyl)-2-azetidinone by deprotecting (3R,4S)-1-(4-fluorophenyl)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl]-(4-phenylmethoxy)-2-azetidinone in a presence of palladium carbon with catalysts quantity. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0060; 0061

(2017/06/08)

PROCESS FOR SYNTHESIS OF EZETIMIBE AND INTERMEDIATES USED IN SAID PROCESS
A process for the production of ezetimibe and intermediates used in said process are disclosed. A kind of Morita-Baylis-Hillman adduct can be altered to chiral carboxylic acid derivatives of β-arylamino α-methylene with high activity and selectivity by means of ally lamination reaction, and the above carboxylic acid derivatives of β-arylamino α-methylene can be altered to the chiral intermediates of ezetimibe by means of simple conversion and further synthesized into the chiral drug ezetimibe. The synthesis route introduces chirality through the use of a chiral catalysis method, thereby avoiding the use of the chiral auxiliary oxazolidinone; and the route is economical and eco-friendly.
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(2015/06/03)

PROCESS FOR SYNTHESIS OF EZETIMIBE AND INTERMEDIATES USED IN SAID PROCESS
A process for the production of ezetimibe and intermediates used in said process are disclosed. A kind of Morita-Baylis-Hillman adduct can be altered to chiral carboxylic acid derivatives of β-arylamino α-methylene with high activity and selectivity by means of ally lamination reaction, and the above carboxylic acid derivatives of β-arylamino α-methylene can be altered to the chiral intermediates of ezetimibe by means of simple conversion and further synthesized into the chiral drug ezetimibe. The synthesis route introduces chirality through the use of a chiral catalysis method, thereby avoiding the use of the chiral auxiliary oxazolidinone; and the route is economical and eco-friendly.
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(2015/06/24)

METHOD OF PREPARING EZETIMIBE
A method of preparing ezetimibe. The method includes converting a compound of formula (II) to a compound of formula (III) as shown below: in which R1-R5, A1, and A2 are defined in the specification.
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Paragraph 0059; 0060; 0061; 0062; 0063

(2015/02/18)

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)

Total synthesis of ezetimibe, a cholesterol absorption inhibitor
Ezetimibe (1), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl) -nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N-O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1.
Sniezek, Marcin,Stecko, Sebastian,Panfil, Irma,Furman, Bartlomiej,Chmielewski, Marek
p. 7048 - 7057
(2013/08/23)

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.
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Page/Page column 23-24

(2012/02/01)

METHOD OF PREPARING EZETIMIBE AND INTERMEDIATES USED THEREIN
Disclosed is a method for preparing ezetimibe which is effective for preventing or treating arteriosclerosis, and novel intermediates used therein. In accordance with the method which does not use expensive reagents, unwanted diastereoisomers can be easily removed by a step-by-step crystallization procedure, and the ezetimibe of formula 1 can be prepared in a high yield without the use of a hydrogenation procedure under a high pressure.
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Page/Page column 18-19

(2010/08/05)

PROCESSES FOR PREPARING EZETIMIBE AND INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION THEREOF
The invention relates, in general, to an improved process for converting compounds of Formula II (below) to compounds of Formula III (below), which are key intermediates for the synthesis of ezetimibe, or to ezetimibe itself, wherein in Formulas II and III, R represents hydrogen, alkyl, or a hydroxyl protecting group (e.g., benzyl group, a substituted benzyl group, or a silyl group). The invention further includes the use of the described process and the use of compounds of Formula III made by the described process for the preparation of ezetimibe.
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Page/Page column 6

(2010/07/08)

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)

SYNTHESIS OF EZETIMIBE
The present disclosure relates to processes for the preparation of Ezetimibe (1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone) and related azetidine compounds.
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Page/Page column 60

(2010/12/29)

(Z)-5-(4-fluorophenyl)pent-4-enoic acid: A precursor for convenient and efficient synthesis of the antihypercholesterolemia agent ezetimibe
A convenient and efficient total synthesis of ezetimibe, an intestinal cholesterol absorption inhibitor and useful anticholesteremic agent, is described. Based on (Z)-5-(4-fluorophenyl)pent-4-enoic acid as a starting compound, and taking the synthesis through further Z-configured intermediates, the total yield is remarkably increased, compared with the use of the corresponding E-configured starting substances or intermediates. Georg Thieme Verlag Stuttgart.
Sova, Matej,Mravljak, Janez,Kovac, Andreja,Pecar, Slavko,Casar, Zdenko,Gobec, Stanislav
experimental part
p. 3433 - 3438
(2010/11/21)

Process for the synthesis of ezetimibe and intermediates useful therefor
The present invention discloses novel and useful intermediates for the synthesis of ezetimibe (EZT), which intermediates share a characteristic Z-isomeric structure. Based on Z-5-(4-fluorophenyl)-pent-4-enoic acid, and proceeding the synthesis through further Z-intermediates, a total synthesis is presented to obtained final ezetimibe in high yields.
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Page/Page column 15

(2010/03/02)

A PROCESS FOR THE PREPARATION OF AN ALDEHYDE BETA-LACTAM COMPOUND
The invention relates to a process for the preparation of an aldehyde beta-lactam compound of formula (I), wherein P1 is H or a protecting group, useful in the preparation of ezetimibe, from a nitrone compound of formula (II). The nitrone compound Il is prepared by reacting 4-fluorophenylhydroxyloamine with OH- protected 4-hydroxybenzaldehyde. The nitrone compound of formula (II) is reacted with an acetylene compound of formula (III) to form a compound of formula (IV), and the compound of formula (IV), after optional deprotection, is oxidized to obtain an aldehyde of formula (V), which undergoes isomerisation to the compound of formula (I). The subject of the invention are also novel compounds of formulas (II) and (IV).
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Page/Page column 33-34

(2010/09/17)

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 15

(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)

PROCESS FOR PREPARING EZETIMIBE USING NOVEL ALLYL INTERMEDIATES
The present invention provides an efficient and industrially advantageous process for the preparation of ezetimibe of formula (I), using novel intermediates.
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Page/Page column 23-24

(2010/01/30)

METHOD OF PRODUCING (3R,4S)-L-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)- HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE
Method of producing (3R,4S)-l-(4-fiuorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone (ezetimibe) of formula I, in which alcohol-oxazolidide of general formula II, wherein PG is a phenol protecting group, such as a carbonate group, for instance benzyloxycarbonyl or tert-butyloxycarbonyl, or an arylmethyl group, for instance benzyl, benzhydryl or trityl, or a silyl group, for instance tert- butyldimethylsilyl or thexyldimethylsilyl, is silylated by silylation agents in an inert organic solvent in the temperature range of -10 0C to the boiling temperature of the mixture; the obtained silylether-oxazolidide of general formula III, wherein PG is as defined above and X is a silyl group of general formula SiR1R2R3, wherein R1 to R3 are identical or different alkyl groups with 1 to 5 carbon atoms or the phenyl group, is cyclized by action of bis(trimethylsilyl)acetamide and a base in an inert organic solvent in the temperature range of -20 to 40 0C; and, finally, the obtained protected azetidinone of general formula IV, wherein PG is as defined above and Y is hydrogen or the group X as defined above, is deprotected by action of deprotecting hydrogenolytic agents and/or acidic agents in an inert organic solvent.
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Page/Page column 10-11

(2009/12/27)

Ezetimibe process and composition
The present invention describes a process for producing ezetimibe (EZT) from a protected compound, including a step of deprotecting the 4-(p-hydroxyphenyl) protection group by catalytic hydrogenation, wherein the catalyst is used in an amount of 0.7 wt.-% or lower, relative to the weight of the compound used for the deprotection reaction. After carrying out a step of deprotection reaction, the process preferably comprises: (a) the reaction product is dissolved or extracted in ethyl acetate, and (b) the ethyl acetate solution is washed with an aqueous salt solution. The invention further describes a process for obtaining pure EZT, wherein raw EZT is dissolved in a solvent at a concentration of lower than 0.1 g/ml, and a crystallization step is carried out from this solution. These measures, respectively alone and particularly in combination contribute to attain ezetimibe (EZT) free of critical impurities described herein, and thus to use exceptionally pure ezetimibe (EZT) to be formulated into a pharmaceutical composition together with a pharmaceutically acceptable carrier or excipient.
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Page/Page column 5-6

(2009/12/23)

A METHOD OF MANUFACTURING (3R,4S)-L-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3- HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE AND ITS INTERMEDIATES
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, in which a protected ketone of general formula II, wherein R stands for a protective group, such as benzyloxycarbonyl, tert-butoxycarbonyl, benzhydryl or trityl, is reduced with asymmetrical borane agents in an inert organic solvent in the temperature range of -30 to +40 °C, and finally the obtained protected alcohol of general formula III, wherein R has the same meaning as above, is deprotected by the action of hydro genolytic or acidic agents in an inert organic solvent.
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Page/Page column 11

(2009/07/03)

PROCESS FOR THE MODIFICATION OF THE SOLID STATE OF A COMPOUND AND CO-AMORPHOUS COMPOSITIONS PRODUCED WITH SAME
The invention provides a process for preparing non-crystalline organic compositions and non-crystalline, co-amorphous blends of organic compounds.
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Page/Page column 25-28

(2009/05/28)

An improved and scalable process for the synthesis of ezetimibe: An antihypercholesterolemia drug
An efficient, cost-effective and large-scale synthesis of ezetimibe 1, an antihypercholesterolemia drug, is described. Chiral oxazolidinone chemistry was used to fix the required stereochemistry of the β-lactam ring, and the chiral oxazaborolidine chemistry was used to fix the hydroxyl group stereochemistry. The synthesis significantly lowers the cost and provides easy access to ezetimibe on large scale.
Sasikala,Padi, Pratap Reddy,Sunkara, Vishnuvardhan,Ramayya, Pattabhi,Dubey,Uppala, Venkata Bhaskar Rao,Praveen, Cherukupally
experimental part
p. 907 - 910
(2010/04/22)

Process for the preparation of ezetimibe and derivatives thereof
The present invention relates to the method of preparing of ezetimibe and in particular to novel intermediates for its synthesis and an improved process for preparing such intermediates. Said intermediates may be obtained in high yields and purity in a fast and cost efficient manner. The present invention relates to a novel crystalline form of ezetimibe as well.
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Page/Page column 26

(2008/12/07)