- Chiral amino-pyridine-phosphine tridentate ligand, manganese complex, and preparation method and application thereof
-
The invention discloses a chiral amino-pyridine-phosphine tridentate ligand, a manganese complex, and a preparation method and application thereof. The chiral amino-pyridine-phosphine tridentate ligand is shown as a formula II, and the manganese complex of the chiral amino-pyridine-phosphine tridentate ligand can be used for efficiently catalyzing and hydrogenating ketone compounds to prepare chiral alcohol compounds in a high enantioselectivity mode. The chiral amino-pyridine-phosphine tridentate ligand and the manganese complex are simple in synthesis process, good in stability, high in catalytic activity and mild in reaction conditions.
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Paragraph 0597-0600; 0603
(2020/07/13)
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- 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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-
- Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones
-
A series of MnI complexes containing lutidine-based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; TON=turnover number), broad substrate scope (81 examples), good functional-group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth-abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer-sphere mode of substrate–catalyst interactions probably dominates the catalysis.
- Zhang, Linli,Tang, Yitian,Han, Zhaobin,Ding, Kuiling
-
supporting information
p. 4973 - 4977
(2019/03/17)
-
- 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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-
- Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis
-
1,1′-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1′-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α′-bis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1S,2S,2′S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1S,2S,2′S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a-c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.
- Zheng, Zhiyao,Cao, Yuxi,Chong, Qinglei,Han, Zhaobin,Ding, Jiaming,Luo, Chenguang,Wang, Zheng,Zhu, Dongsheng,Zhou, Qi-Lin,Ding, Kuiling
-
supporting information
p. 10374 - 10381
(2018/08/03)
-
- Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe
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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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- 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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- Ezetimibe preparation method
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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; 0054; 0055; 0058; 0060; 0062; 0064; 0067
(2017/08/29)
-
- 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 0053-0055
(2017/09/13)
-
- Substituted phosphoramidate derivative, method for preparing thereof, and use thereof definitions of substituent groups in general formula (I) are the same as those defined in the specification
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The present invention relates to a substituted phosphoramidate derivative represented by general formula (I), a method for preparing therefor, and use thereof. In the general formula (I), A is selected from a phenyl group or a naphthyl group, and the phenyl group or the naphthyl group is optionally further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, an amino group, a hydroxy group, a carboxy group, a C1-4 alkyl group or a C1-4 alkoxy group. B is ; E is selected from -CH(CH2F)CH2-, CH2CH(CH3)OCH2- or -CH2-CH2OCH2-; R1 is selected from H or a C1-4 alkyl group; R2 is a natural or pharmaceutically acceptable amino acid side chain, if the side chain contains a carboxyl group, the carboxyl group may be optionally esterified with an alkyl group or an aryl group; R3 is ; R4 is a group selected from H, a methylacyl group, a C1-4 alkyl group, a -(CH2)n-C3-6 carbocyclic ring, a -(C= O)-C1-4 alkyl group or a -(C = O)-C1-4 carbocyclic ring; n is selected from 0, 1 or 2.
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Page/Page column 18; 19; 20
(2018/03/23)
-
- 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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- MANUFACTURING METHOD OF EZETIMIBE
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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 0055
(2017/06/08)
-
- according to bookletmai Bu intermediate preparation method
-
The invention discloses a preparation method of an Ezetimibe intermediate. The preparation method comprises the following steps: adding (3R,4S)-4-[4-(benzyloxy) phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxo propyl] azacyclobutane-2-one which is called RM1 for short into a borane/dimethylsulfide reaction system; and then adding an oxidizing agent to react to generate the Ezetimibe intermediate. According to the preparation method, the RM1 is taken as a raw material, a dichloromethane solvent is taken as a raw material solvent and a (R)-MeCBS/methylbenzene solution is taken as a reaction catalyst, so that the reaction can be accelerated and the Ezetimibe intermediate yield can be improved.
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-
Paragraph 0026; 0027
(2017/05/26)
-
- PROCESS FOR SYNTHESIS OF EZETIMIBE AND INTERMEDIATES USED IN SAID PROCESS
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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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-
- 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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-
- Total synthesis of ezetimibe, a cholesterol absorption inhibitor
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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)
-
- IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE
-
The present invention provides an improved process for the preparation of compound of Formula II, which is a key intermediate for the preparation of Ezetimibe, through stereoselective addition of an organometallic reagent to novel aldehyde intermediates under chiral catalysis.
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-
- (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 14-15
(2010/03/02)
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- PROCESSES FOR PREPARING EZETIMIBE AND INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION THEREOF
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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 5
(2010/07/08)
-
- A PROCESS FOR THE PREPARATION OF AN ALDEHYDE BETA-LACTAM COMPOUND
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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
(2010/09/17)
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- INTERMEDIATES IN THE PREPARATION OF 1,4-DIPHENYL AZETIDINONE
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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 14-15
(2010/11/03)
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- PROCESSES FOR PREPARING INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION OF EZETIMIBE
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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)
-
- An improved and scalable process for the synthesis of ezetimibe: An antihypercholesterolemia drug
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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
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experimental part
p. 907 - 910
(2010/04/22)
-
- Process for preparing intermediates of ezetimibe by microbial reduction
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Processes of preparing an ezetimibe intermediate by microbial reduction and further converting the intermediate to ezetimibe are provided. Also provided is an ezetimibe intermediate with high diastereomeric excess.
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Page/Page column 5
(2009/04/24)
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- Process for the preparation of ezetimibe and derivatives thereof
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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 19
(2008/12/07)
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- IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE AND ITS INTERMEDIATES
-
The present invention provides an improved process for the preparation of ezetimibe through novel organic amine salt compounds of general formula (1). The present invention also relates to a highly pure ezetimibe and 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl) azetidin-3-yl)propionic acid compound.
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Page/Page column 20-21; 21
(2008/06/13)
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- PROCESS FOR PREPARING HIGHLY PURE EZETIMIBE USING NOVEL INTERMEDIATES
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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 20-21
(2008/12/08)
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- METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL
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This invention relates to a process for producing optically active alcohols using asymmetric reduction of aromatic ketones. This process gives optically active alcohols in high enantioselectivity at large scale production. Aromatic ketones represented by formula (I) [wherein, R1 are selected from hydrogen atom, halogen atom, lower alkyl group etc. R2 is -(CH2)n-R3 [wherein, n is 1 to 5 integer. R3 are selected from hydrogen atom, halogen atom, lower alkoxycarbonyl group etc. and formula (II) and (III). {wherein, R4 is selected from lower alkyl group (1 to 5 carbon atom) etc. R5 and R6 are the same or different and are selected from hydrogen atom, halogen atom, lower alkyl group etc.}]] are reduced by sodium borohydride, chlorotrimethylsilane and optically active 2-[bis(4-methoxyphenyl)hydroxymethyl]pyrrolidine represented by formula (IV) to give optically active alcohol represented by formula (V) stereoselectively. (wherein, R1 and R2 are as defined above.)
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Page/Page column 13-14
(2008/12/08)
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- PROCESSES FOR THE PREPARATION OF (3R,4S)-4-((4-BENZYLOXY)PHENYL)-1-(4-FLUOROPHENYL)-3-((S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL)-2-AZETIDINONE, AN INTERMEDIATE FOR THE SYNTHESIS OF EZETIMIBE
-
The invention encompasses (3R,4S)-4-((4-benzyloxy)phenyl)-l-(4-fluorophenyl)-3- (3-(4-fluorophenyl)-3-oxopropyl)-2-azetidinone (Compound 2a) having an enantiomeric purity of at least about 97.5%. The invention also encompasses Compound 2a having a chemical purity of at least about 97%. The invention further encompasses processes for preparing Compound 2a from Compound 1 having the following formula (I). Compound 1. The invention also encompasses processes for preparing a compound having the formula(II). from a compound having the following formula (III), wherein R is selected from the group consisting of: H or a hydroxyl protecting group. The invention also encompasses processes for preparing Compound 2a, preferably to form Compound 2a-Form 01. Also included are processes for preparing ezetimibe from Compound 2a-Form 01 or Compound 2a prepared according to the invention, compositions containing such ezetimibe, and methods for reducing cholesterol using such compositions.
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Page/Page column 23; 24; 27
(2008/06/13)
-
- PREPARATION OF EZETIMIBE
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A process for preparing ezetimibe.
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Page/Page column 10
(2010/11/26)
-
- PROCESSES FOR THE SYNTHESIS OF AZETIDINONE
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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 65
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF EZETIMIBE VIA A NOVEL INTERMEDIATE
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The present invention relates to a process for the preparation of Ezetimibe via a novel intermediate. Trans-3(R)-(3-[2-oxo-4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-azetidinyl]propanoic acid is converted to trans-N-methoxy-N-methyl-3(R)-3-[2-oxo-4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-azetidinyl]propanamide and the resultant intermediate is subjected to Grignard reaction to obtain trans-1-(4-fluorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl)propyl]-4(S)-(4-benzyloxyphenyl)-2-azetidinone. Reduction of trans-1-(4-JGiuorophenyl)-3(R)-[3-oxo-3-(4-fluorophenyl) propyl]-4(S)-(4-benzyloxyphenyl)-2-azetidinone, followed by debenzylation provides Ezetimibe. The invention also relates to the preparation of the intermediate occurring in the above process.
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Page/Page column 9-10
(2010/11/28)
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- SUBSTITUTED PIPERAZINES AS CB1 ANTAGONISTS
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Compounds of Formula (I): Chemical formula should be inserted here as it appears on the abstract in paper form. or pharmaceutically acceptable salts, solvates, or esters thereof, are useful in treating diseases or conditions mediated by CB1 receptors, such as metabolic syndrome and obesity, neuroinflammatory disorders, cognitive disorders and psychosis, addiction (e.g., smoking cessation), gastrointestinal disorders, and cardiovascular conditions.
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Page/Page column 305
(2010/11/08)
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- Combinations of substituted azetidinones and CB1 antagonists
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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 27
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF EZETIMIBE
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The present invention relates to a cost effective and industrially advantageous process for the preparation of (3R,4S)-l-(4-Fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3 - hydroxypropyl)]-4-(4-hydroxyρhenyl)-2-azetidinone, referred to here as Ezetimibe, it is represented as formula (1).
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Page/Page column 13
(2008/06/13)
-
- Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
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The present invention provides compositions, therapeutic combinations and methods including: (a) at least one lipid modulating agent; and (b) at least one substituted azetidinone or substituted β-lactam sterol absorption inhibitor which can be useful for treating vascular conditions, diabetes, obesity and lowering plasma levels of sterols or 5α-stanols.
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Page/Page column 24
(2008/06/13)
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- A novel one-step diastereo- and enantioselective formation of trans- azetidinones and its application to the total synthesis of cholesterol absorption inhibitors
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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
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p. 3714 - 3718
(2007/10/03)
-
- Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-(?phenyl or 4-fluorophenyl!)-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone
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A process for preparing a compound of the formula STR1 wherein X is H or F, comprising: (a) alkylation of a 3-unsubstituted chiral azetidinone of the formula STR2 with cinnamyl bromide or 4-fluorocinnamyl bromide; (b) Wacker oxidation of the product of step (a); (c) reduction of the ketone product of step (b); and (d) debenzylation of the ketone of step (c).
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- 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
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(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.
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p. 973 - 980
(2007/10/03)
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