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Friday, 6 March 2015

R-Enantiomer in Ezetimibe



R-Enantiomer in Ezetimibe


ABOVE 1H NMR OF R ENANTIOMER




Isolation and Characterization of R-Enantiomer in Ezetimibe

www.scirp.org/journal/PaperDownload.aspx?paperID=36901

by K Chimalakonda - ‎2013 - ‎Related articles
HPLC1H and 13C NMR. The purity of isolated R-Isomer is about 98%. Keywords: Isolation; Characterization; (R)-Isomer; Ezetimibe; Supercritical Fluid  ...


http://file.scirp.org/Html/10-2200417_36901.htm

1H NMR VALUES FOR R ENANTIOMER

13C NMR OF R ENANTIOMER





13C NMR VALUES OF R ENANTIOMER









IR OF R ENANTIOMER












Ezetimibe for reference

Ezetimibe


Ezetimibe
Ezetimibe.svg
Systematic (IUPAC) name
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Clinical data
Trade namesZetia
AHFS/Drugs.commonograph
MedlinePlusa603015
Legal status
RoutesOral
Pharmacokinetic data
Bioavailability35–65%
Protein binding>90%
MetabolismIntestinal wall, hepatic
Half-life19–30 hours
ExcretionRenal 11%, faecal 78%
Identifiers
CAS number163222-33-1 Yes
ATC codeC10AX09
PubChemCID 150311
DrugBankDB00973
ChemSpider132493 Yes
UNIIEOR26LQQ24 Yes
KEGGD01966 Yes
ChEBICHEBI:49040 Yes
ChEMBLCHEMBL1138 Yes
Chemical data
FormulaC24H21F2NO3 
Molecular mass409.4 g·mol−1
Physical data
Melting point164 to 166 °C (327 to 331 °F)
 Yes (what is this?)  (verify)






1H NMR OF R ENANTIOMER PREDICTED


Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe H-NMR spectrum

13C NMR OF R ENANTIOMER PREDICTED


Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe C-NMR spectrum


cosy






.
Ezetimibe has the chemical name 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (hereinafter referred to by its adopted name “ezetimibe”) and is structurally represented by Formula I.
Figure US20070049748A1-20070301-C00001
Ezetimibe is in a class of lipid lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related phytosterols. It is commercially available in products sold using the trademark ZETIA as a tablet for oral administration containing 10 mg of ezetimibe, and in combination products with simvastatin using the trademark VYTORIN.
U.S. Pat. No. 6,096,883 discloses generically and specifically ezetimibe and its related compounds along with their pharmaceutical compositions. The patent also describes a process for the preparation of ezetimibe.
The process described in the patent involves the use of methyl-4-(chloroformyl) butyrate and also involves isolation of the compound (3R,4S)-1-(4-fluorophenyl)-3-[3-(chloroformyl)-3-oxo-propyl]-4-(4-benzyloxyphenyl)-2-azetidinone as an intermediate. Chlorinated compounds are unstable and difficult to handle in large scale productions. The process described in the patent also involves the purification of intermediates using column chromatography, thus making the process difficult to be scaled up.

Processes for preparation of ezetimibe and its intermediates have also been described in U.S. Pat. Nos. 6,207,822, 5,856,473, 5,739,321, and 5,886,171, International Application Publication No. WO 2006/050634, and in Journal of Medicinal Chemistry 1998, 41, 973-980, Journal of Organic Chemistry 1999, 64, 3714-3718, and Tetrahedron Letters, 44(4), 801-804.





http://www.google.com/patents/US20070049748



EXAMPLE 10 PREPARATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)
50 g of (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(s)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone and 475 ml of methanol were taken into a round bottom flask. A mixture of 15 g of 5% palladium on carbon and 25 ml of water was added to it. The reaction mass was flushed with hydrogen gas and a hydrogen pressure of 3 to 5 kg/cm2 was applied. The reaction mass was stirred for 3 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the pressure was released and the reaction mass was filtered through perlite. The filter bed was washed with 100 ml of methanol. The filtrate was distilled completely at 70° C., and 400 ml of isopropanol was added to it. The reaction mass was heated to 45° C. and maintained for 10 minutes. The reaction mass was then allowed to cool to 28° C. 400 ml of water was added to the reaction mass and stirred for 1 hour, 20 minutes. The separated compound was filtered and washed with 100 ml of water. The wet cake was taken into another round bottom flask and 500 ml of chlorobenzene and 40 ml of methanol were added to it. The reaction mass was heated to 65° C. and maintained for 15 minutes. 25 ml of water was added to the reaction mass and stirred for 2 hours. The separated compound was filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 375 ml of chlorobenzene, and 30 ml of methanol were added to it. The reaction mass was heated to 62° C. and maintained for 10 minutes. The reaction mass was then cooled to 28° C. and 20 ml of water was added to it. The reaction mass was stirred for 20 minutes and then filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 400 ml of isopropanol was added to it. The reaction mass was heated to 46° C. and maintained for 15 minutes. 800 ml of water was added to the reaction mass at 45 to 46° C. and stirred for one hour. The separated solid was filtered and washed with water. The process of recrystallization in a combination of isopropanol and water was repeated and the obtained compound was dried at 70° C. for 5 hours to get 19.8 g of the title compound. (Yield 49.2%)
Purity by HPLC: 99.68%.
EXAMPLE 11 PURIFICATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)
15.0 g of ezetimibe obtained above and 120 ml of isopropanol were taken into a round bottom flask and the reaction mass was heated to 48° C. The reaction mass was filtered through a perlite bed in the hot condition to make the solution particle free. The filtrate was taken into another round bottom flask and heated to 47° C. 240 ml of water was added at 47° C. After completion of the addition, the reaction mass was maintained at 47° C. for 1 hour. The separated solid was filtered and washed with 30 ml of water. The wet compound was dried at 70° C. for 8 hours to get 13.4 g of the title compound. (Yield 89%)
Purity by HPLC: 99.92.
benzyl ezetimibe impurity: less than 0.0003 area-%,
benzyl ezetimibe diol impurity: 0.004 area-%,
lactam cleaved alcohol impurity: 0.003 area-%,
lactam cleaved acid impurity: 0.01 area-%,
ezetimibe diol impurity: less than 0.0007 area-%.
Residual solvent content by gas chromatography:
Isopropyl alcohol: 1454 ppm
All other solvents: Less than 100 ppm.
WO1997045406A1 *May 28, 1997Dec 4, 1997Schering Corp3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
WO2004099132A2May 5, 2004Nov 18, 2004Ram Chander AryanProcess for the preparation of trans-isomers of diphenylazetidinone derivatives
WO2008032338A2 *Sep 10, 2007Mar 20, 2008Reddy Maramreddy SahadevaImproved process for the preparation of ezetimibe and its intermediates
EP0720599A1Sep 14, 1994Jul 10, 1996Schering CorporationHydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US20070049748Aug 25, 2006Mar 1, 2007Uppala Venkata Bhaskara RPreparation of ezetim

Citing PatentFiling datePublication dateApplicantTitle
US7470678Jul 1, 2003Dec 30, 2008Astrazeneca AbDiphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684Apr 25, 2007Nov 30, 2010Astrazeneca AbDiphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
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US8013150 *Feb 17, 2006Sep 6, 2011Msn Laboratories Ltd.Process for the preparation of ezetimibe
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WO2005021497A2 *Aug 27, 2004Mar 10, 2005Eduardo J MartinezTethered dimers and trimers of 1,4-diphenylazetidn-2-ones
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