1185883-41-3Relevant academic research and scientific papers
Efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe
Zhu, Yijun,Pan, Jing,Zhang, Shunli,Liu, Zhenren,Ye, Deyong,Zhou, Weicheng
, p. 1687 - 1693 (2016)
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.
INTERMEDIATES FOR THE PREPARATION OF (3R, 4S)-1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE
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Page/Page column 4, (2011/04/14)
A method for the preparation of (S)-alcohol oxazolidides of general formula II, in which PG represents hydrogen or a hydroxyl protecting group, such as trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, benzhydryl or
METHOD OF PRODUCING (3R,4S)-L-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)- HYDROXYPROPYL)]-4-(4-HYDROXYPHENYL)-2-AZETIDINONE
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Page/Page column 15-16, (2009/12/27)
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.
INTERMEDIATES FOR THE PREPARATION OF (3R, 4S) -1- (4-FLUOROPHENYL) -3- [ (3S) -3- (4-FLUOROPHENYL) -3-HYDROXYPROPYL) ] -4- (4-HYDROXYPHENYL) -2-AZETIDINONE
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Page/Page column 10, (2009/10/21)
A method for the preparation of (S)-alcohol oxazolidides of general formula II, in which PG represents hydrogen or a hydroxyl protecting group, such as trimethylsilyl, tert-butyldimethylsilyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, benzhydryl or trityl, in which a ketal oxazolidide of general formula III, where PG has the same meaning as above and R means an alkyl with 1-4 carbon atoms, linear or branched, such as methyl, ethyl, isopropyl or butyl, or R+R together represents a divalent alkyl, or substituted with 1 or 2 alkyl groups, e.g. 1,2-ethylene, 1,2-propylene, 1,2-butylene, 1,3-propylene or 2,2-dimethyl-l,3- propylene, is deprotected by the action of acidic reagents in a mixture of water and a water- miscible solvent in the temperature range of 0 to 100 °C (stage A), and the obtained ketone oxazolidide of general IV, in which PG has the same meaning as above, is reduced with asymmetrical reagents in an inert organic solvent in the temperature range of -30 to +40 °C (stage B).
