cas 189028-95-3, (4S)-3-[(5R)-5-(4-FLUOROPHENYL)-5-HYDROXYPENTANOYL]-4-PHENYL-1,3-OXAZOLIDIN-2-ONE

Articles about 189028-95-3Total 25 be found

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Process for preparing Ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction
The S alcohol in the benzylic position of compound 2, a key feature of a novel cholesterol lowering agent Ezetimibe, was introduced by the (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 1 using borane tetrahydrofuran complex (BTHF) as the reducing agent. The chemo- and enantioselectivity was dramatically enhanced by using an acid as a scavenger of the stabilizer sodium borohydride present in the commercially supplied pure BTHF. The effect of the critical reaction parameters such as addition mode of reagent, temperature, acids as well as water content on the selectivity has been examined. This reaction has been successfully applied in the commercial process for the preparation of the key intermediate 2 for Ezetimibe.
Fu, Xiaoyong,McAllister, Timothy L.,Thiruvengadam,Tann, Chou-Hong,Su, Dan
p. 801 - 804
(2003)
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Process for preparing Ezetimibe intermediate by enantioselective CBS catalyzed ketone reduction with BH3-DEA prepared in situ
The (S) alcohol in the benzylic position of compound 2, a key intermediate in the synthesis of the cholesterol lowering agent Ezetimibe, was introduced by the (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 1 using borane diethylaniline complex (BDEA) as the reducing agent. The latter was prepared in situ from sodium borohydride (NaBH4), diethylaniline (DEA) and dimethylsulfate (DMSO4). BDEA prepared in situ offers considerable advantages from the industrialization standpoint (cost and stability on storage of the reagents) over commercial solutions of BH3-THF (BTHF) or BH3-DMS (BMS). The effect of critical reaction parameters such as addition mode of reagent, temperature, solvent, reaction quenching as well as LiCl addition on the selectivity has been examined. This reaction has been successfully applied in the process for the preparation of key intermediate 2 for Ezetimibe.
Bertrand, Blandine,Durassier, Sonia,Frein, Stéphane,Burgos, Alain
p. 2123 - 2125
(2007)
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Synthesis method of cholesterol absorption selective inhibitor drug intermediate
The invention discloses a synthesis method of a cholesterol absorption selective inhibitor drug intermediate, and is characterized in that the synthesis method comprises the following steps of: dissolving a raw material ezetimibe intermediate (4S)-3-[5-(4-fluorophenyl)-1, 5-dioxopentyl]-4-phenyl-2-oxazolidinone in an organic solvent according to a proper proportion, adding a glucose aqueous solution into the system, rapidly stirring, adjusting the pH to a required value, adding enzyme and coenzyme to continue reaction, controlling the pH of the system in the reaction process until the reaction is finished, adjusting the pH to be acidic after the reaction is finished, extracting, washing with water, concentrating, and evaporating to dryness to remove the solvent, thereby obtaining an oily matter which is a target compound (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl valeryl]-4-phenyl-1, 3-oxazacyclopentane-2-ketone. The synthesis method of the cholesterol absorption selective inhibitor drug intermediate has the advantages of being environmentally friendly, high in yield and purity, simple in preparation process, high in economic profit and the like.
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Paragraph 0021-0048

(2021/07/08)

Ezetimibe intermediate and preparation method of ezetimibe
The invention relates to an ezetimibe intermediate and a preparation method of ezetimibe. The ezetimibe intermediate has a structure as represented by a formula (I). The preparation method comprises the following steps: providing a compound represented by a formula (II); subjecting the compound as shown in a formula (II) to an asymmetric catalytic hydrogenation reaction under the action of a P-BIAMH catalyst to prepare a compound shown as the formula (I), wherein the P-BIAMH catalyst has a structure as shown in a formula (A) which is described in the specification. In the formula (A), X and Yare halogen independently; R1 is H or a C1-9 alkyl group; R2 is a high-molecular polymer; and a fragment as described in the specification represents a diphosphorus ligand. The method has the advantages of high conversion rate and high safety, and is especially suitable for industrial production.
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Paragraph 0098; 0100-0110

(2020/08/27)

Crystal form of ezetimibe key intermediate and preparation method of crystal form
The invention provides a crystal form of an ezetimibe key intermediate and a preparation method of the crystal form. The invention relates to the crystal form of (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-2-oxazolidinone and a preparation method thereof. Specifically, the invention provides the crystal form of a compound represented as in a formula (1), and the characteristic diffraction peaks exist in an X-ray powder diffraction pattern at the following 2[theta] angles: 6.195+/-0.2 degrees, 7.640+/-0.2 degrees, 8.289+/-0.2 degrees, 12.847+/-0.2 degrees, 18.394+/-0.2 degrees,19.871+/-0.2 degrees, 21.548+/-0.2 degrees and 25.062+/-0.2 degrees.
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Paragraph 0027

(2019/08/30)

According to booklet mai bu synthesis of intermediates method
The invention discloses a according to the method for synthesizing intermediate folds mai bu, comprises the following steps: in under the nitrogen atmosphere, of formula (2) compound are added to in tetrahydrofuran to obtain solution A, A the solution temperature to 5 °C to 10 °C, and to the solution of (-) - A dropping two different pine pinane base chlorine borane, stirring the reaction, after the reaction is finished to obtain solution B, the solution B cooling to - 20 °C to 0 °C, aqueous solution of [...], adjusting solution B of pH=5 - 8, the ethyl acetate extract adjusting pH of the solution B, evaporate ethyl acetate to obtain the residue C, to the remainder of the organic solvent is added in the C, standing, pouring the organic solvent, the residue obtained D, D to the residue in toluene is added to obtain solution E, heating and stirring solution after E, natural cooling, the solution is put into the freezing environment in E, filtering, drying formula (1) compound of the solid, the method is simple and easy, and the cost is low. The reaction is shown as follows:
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Paragraph 0028; 0030; 0035; 0036

(2018/10/11)

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)

Synthetic method for ezetimibe intermediate
The invention discloses a synthetic method for an ezetimibe intermediate. The synthetic method comprises: by taking a compound I as a raw material, mixing the compound I with a reaction solution; under the action of an acid-binding agent, firstly activating the compound I by pivaloyl chloride; then coupling the compound with S-4-phenyl-2-oxazolidinone; then carrying out reduction reaction through (R)-2-mehtyl-CBS-oxazole borane; and then carrying out post-treatment to prepare (4S)-3-[(5S)-5-(4-fluorophenyl-5-hydroxyl valeryl)-4-phenyl-1,3- azacyclocyclopentane-2-(one) (II), wherein the formula is as shown in the description, and the reaction solution comprises tetrahydrofuran, chloroform, dioxane or dichloromethane. The synthetic method for the ezetimibe intermediate disclosed by the invention has the advantages of being simple to operate, short in synthetic line and relatively low in synthetic cost, and is suitable for large-scaled industrial production.
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Paragraph 0021-0034

(2016/12/01)

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 0018; 0033; 0034; 0036; 0038

(2018/01/19)

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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(2015/02/18)

NOVEL PROCESS FOR THE PREPARATION OF EZETIMIBE INTERMEDIATES
The present invention provides a novel process for the preparation of compounds useful as intermediates for the production of Ezetimibe.
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Page/Page column 12; 13

(2015/04/15)

PROCESS FOR PREPARING EZETIMIBE INTERMEDIATE
The present invention refers to [...] which can inhibit the cholesterol absorption and are (ezetimibe) used in the manufacture of an intermediate manufacturing method relates to compounds of formula 4, a chelatable metal compounds, and metal of formula 2 in one direction so that at step low id id compound of formula 3 to the asymmetrically reducing according to including of the present invention manufacturing method, a method that of the prior art compared to compounds of formula 4 economically, purity can be produced: Said in formula, The X and Ph as defined during specification.
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Paragraph 0036; 0038

(2016/11/07)

Asymmetric synthesis of optically active methyl-2-benzamido-methyl-3-hydroxy-butyrate by robust short-chain alcohol dehydrogenases from Burkholderia gladioli
Three short-chain alcohol dehydrogenases from Burkholderia gladioli were discovered for their great potential in the dynamic kinetic asymmetric transformation of methyl 2-benzamido-methyl-3-oxobutanoate, and their screening against varied organic solvents and substrates. This is the first report of recombinant enzymes capable of achieving this reaction with the highest enantio- and diastereo-selectivity.
Chen, Xiang,Liu, Zhi-Qiang,Huang, Jian-Feng,Lin, Chao-Ping,Zheng, Yu-Guo
p. 12328 - 12331
(2015/07/27)

Lipase catalyzed kinetic resolution for the production of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one: An intermediate for the synthesis of ezetimibe
Efficient enzymatic methods were developed for the synthesis of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one, by transesterification of (RS)-3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4(S)-4- phenyl-1,3-oxazolidin-2-one [(R,S)-FOP alcohol] and hydrolysis of (RS)-1-(4-fluorophenyl)-5-oxo-5-[(S)-2-oxo-4-phenyloxazolidin-3-yl] pentyl acetate [(R,S)-FOP acetate] using lipase as enzyme source. The synthesized S-diastereomer is an intermediate for the potent cholesterol absorption inhibitor, ezetimibe. Among various lipases tried, Candida rugosa lipase in diisopropyl ether was best for both the reactions. Vinyl acetate was found as suitable acyl donor in transesterification reaction. A higher amount of enzyme (500 mg) was required for the transesterification of 10 mM substrate; it may be due to the enzyme denaturation by acetaldehyde formed in the reaction. The ester hydrolysis reaction worked well, excellent conversion and de were obtained at 40 °C, pH 7. The 300 mg enzyme hydrolyzed 120 mg (R,S)-FOP acetate with 50% conversion and 99.5% de.
Singh, Amit,Goel, Yogesh,Rai, Amit Kumar,Banerjee
p. 99 - 104
(2013/01/15)

KETOREDUCTASE POLYPEPTIDES FOR THE STEREOSELECTIVE PRODUCTION OF (4S)-3-[(5S)-5-(4-FLUOROPHENYL)-5-HYDROXYPENTANOYL]-4-PHENYL-1,3-OXAZOLIDIN-2-ONE
The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme including the capability of reducing 5-((4S)-2-oxo-4-phenyl(1,3-oxazolidin-3-yl))-1-(4-fluorophenyl)pentane-1,5-dione to (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize the intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one in a process for making Ezetimibe.
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(2010/04/23)

KINETIC RESOLUTION OF (4S)-4-PHENYL-3-[5(RS)-(4-FLUOROPHENYL)-5-HYDROXYPENTANOYL] -1,3 OXAZOLIDIN 2-ONE TO (5S) ISOMER VIA LIPASE CATALYZED ENANTIOSELECTIVE ESTERIFICATION OF THE (5R) ISOMER
A process for synthesis of 4S-phenyl -3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one comprising resolution of 4S-phenyl -3-[(5RS)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one by selective esterification of 4S-phenyl -3-[(5R)-5-(4-fluorophenyl)-5-hydroxypentanoyl] -1,3 oxazolidin 2-one using appropriate esterification reagent in an organic solvent in presence of Lipase enzyme at a temperature ranging from 0° to 100°C, and further isolation.
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Page/Page column 10

(2010/11/03)

Anti-hypercholesterolemic biaryl azetidinone compounds
This invention provides cholesterol absorption inhibitors of Formula I: and the pharmaceutically acceptable salts thereof, wherein R12 is an alkyl, alkeny or alkynyl group mono- or poly-substituted with —OH, —COOH or a combination of —OH and —COOH, and R9 contains an alkyl, alkeny or alkynyl group substituted with a heterocyclic ring, amino or sulfonyl. The compounds are useful for lowering plasma cholesterol levels, particularly LDL cholesterol, and for treating atherosclerosis and preventing atherosclerotic disease events.
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Page/Page column 19

(2008/12/08)

Process for the preparation of 1,3,2-oxazaborolidine compounds
A process is used for the preparation of 1,3,2-oxazaborolidine compounds. This process prepares compounds of formula (I) or (IA): in which: R1 is an alkyl or an aryl; and R2, R3, R4 and R5 are especially a hydrogen atom or an alkyl, wherein the following are reacted in two steps: a) a boric precursor compound with an acetal compound to give a boronate compound; and b) the boronate compound with an amino alcohol compound. This process avoids by-products and exhibits a very good stereospecificity.
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Page/Page column 8

(2008/12/06)

METHOD OF PRODUCING OPTICALLY ACTIVE ALCOHOL
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 11-12

(2008/12/08)

Process For Production Of 4-Biphenylyazetidin-2-Ones
The present invention relates to processes for the production of 4-biphenylylazetidin-2-one derivatives of formula
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Page/Page column 20-21

(2008/12/09)

Process for the synthesis of azetidinones
A process is provided for preparing azetidinones useful as intermediates in the synthesis of penems and as hypocholesterolemic agents, comprising reacting a β-(substituted-amino)amide, a β-(substituted-amino)acid ester, or a β-(substituted-amino)thiolcarbonic acid ester with a silylating agent and a cyclizing agent selected from the group consisting of alkali metal carboxylates, quaternary ammonium carboxylates, quaternary ammonium hydroxides, quaternary ammonium alkoxides, quaternary ammonium aryloxides and hydrates thereof, or the reaction product of: (i) at least one quaternary ammonium halide and at least one alkali metal carboxylate; or (ii) at least one quaternary ammonium chloride, quaternary ammonium bromide, or quaternary ammonium iodide and at least one alkali metal fluoride, wherein a quaternary ammonium moiety of the cyclizing agent is unsubstituted or substituted by one to four groups independently selected from the group consisting of alkyl, arylalkyl and arylalkyl-alkyl.
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Page/Page column 16

(2008/06/13)

PROCESSES FOR PRODUCTION OF PHENOLIC 4-BIPHENYLYLAZETIDIN-2-ONES
The present invention relates to processes for the production of phenolic 4-biphenylylazetidin-2-one derivatives Formula (1)
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Page/Page column 42-43

(2010/11/24)

PROCESS FOR THE SYNTHESIS OF AZETIDINONES
This invention provides a process for preparing the hypocholesterolemic compound (I) comprising: (a) reacting p-fluorobenzoylbutyric acid with pivaloyl chloride and acylating the product with a chiral auxiliary to obtain a ketone of formula (IV); (b) reducing the ketone of formula (IV) in the presence of a chiral catalyst to an alcohol; (c) reacting the chiral alcohol of step (b), an imine and a silyl protecting agent, then condensing the protected compounds to obtain a beta -(substituted-amino)amide of formula (VII); (d) cyclizing the beta -(substituted-amino)amide of formula (VII) with a silylating agent and a fluoride ion catalyst to obtain a protected lactam of formula (VIII); and removing the protecting groups. The intermediates of formulas (VII and VIII) are also claimed.
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Page/Page column 7

(2010/02/11)

PROCESS FOR ASYMMETRIC SYNTHESIS OF HYDROXY-ALKYL SUBSTITUTED AZETIDINONE DERIVATIVES OF INTERMEDIATES THEREOF
Provided herein are processes for asymmetric synthesis of hydroxyalkyl-substituted azetidinone derivatives or intermediates thereof via stereoselective reduction of benzylic ketone using (-)-B-chlorodiisopinocampheylborane. Also provided herein are processes for preparing ezetimibe.
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Page/Page column 17

(2008/06/13)

Synthesis of 3H, 14C and 13C6 labelled Sch 58235
3H-Sch 58235 was prepared at a specific activity of 29.1 Ci/mmol by Ir(COD)(Cy3P)PyPF6 catalysed exchange with tritium gas. 14C-Sch 58235 was prepared in three steps from p-hydroxy[ring-U-14C]benzaldehyde with an overall radiochemical yield of 21%. 13C6-Sch 58235 was similarly prepared in three steps from p-hydroxy[ring-U-13C6]benzaldehyde in an overall yield of 41%. Copyright
Hesk,Bignan,Lee,Yang,Voronin,Magatti,McNamara,Koharski,Hendershot,Saluja,Wang
p. 145 - 155
(2007/10/03)