163222-32-0Relevant articles and documents
Chiral amino-pyridine-phosphine tridentate ligand, manganese complex, and preparation method and application thereof
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Paragraph 0597-0600; 0603, (2020/07/13)
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.
METHOD OF PREPARING EZETIMIBE AND INTERMEDIATE THEREOF
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, (2019/08/30)
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.
Lutidine-Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones
Zhang, Linli,Tang, Yitian,Han, Zhaobin,Ding, Kuiling
supporting information, p. 4973 - 4977 (2019/03/17)
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.
Preparation method of ezetimibe for treating hyperlipidemia
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, (2018/03/25)
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.
Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis
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)
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.
Ezetimibe intermediate, synthesis method of intermediate and synthesis method of ezetimibe
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, (2017/07/01)
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.
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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Page/Page column 18; 19; 20, (2018/03/23)
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.
MANUFACTURING METHOD OF (3R,4S)-1-(4-FLUOROPHENYL)-[3(S)-HYDROXY-3-(4-FLUOROPHENYL)PROPYL]-[4-(PHENYLMETHOXY)PHENYL]-2-AZETIDINONE
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, (2017/11/18)
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
Ezetimibe preparation method
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Paragraph 0053; 0054; 0055; 0058; 0060; 0062; 0064; 0067, (2017/08/29)
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.
Preparation process of ezetimibe and its intermediate
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Paragraph 0053-0055, (2017/09/13)
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.
