New Drug Approvals

Home » PROCESS » Ezetimibe NMR

Ezetimibe NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

PAYPAL DONATIONS

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Categories

Blog Stats

  • 1,309,803 hits

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

add to any

Share

syn2

Ezetimibe

 

 

 

 

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
J. Org. Chem., 2013, 78 (14), pp 7048–7057
Figure

Ezetimibe (1)

 ezetimibe 1 (1.08 g, 80%) as a white solid.
Mp 164–166 °C [lit.(11) 155–157 °C];
99% ee;
[α]20D −28.1 (c 0.15, MeOH) [lit.(11) −32.6 (c 0.34, MeOH)];
1H NMR (600 MHz, DMSO-d6) δ 9.49 (1H, s), 7.28–7.24 (2H, m), 7.19–7.16 (4H, m), 7.11–7.07 (4H, m), 6.75–6.71 (2H, m), 5.25 (1H, d, J 4.3 Hz), 4.77 (1H, d, J 2.2 Hz), 4.49–4.59 (1H, m), 3.07–3.04 (1H, m) 1.84–1.66 (4H, m);
13C NMR (150 MHz, CDCl3) δ 167.8, 162.3, and 160.7 (d, JC–F 240.3 Hz), 159.3, 157.9, 157.7, 142.5, 134.4, 128.7, 128.3, 128.0, 127.9, 118.7, and 118.6 (d, JC–F 8.1 Hz), 116.3, 116.2, 115.2, and 115.0 (d, JC–F 20.7 Hz), 71.5, 60.0, 59.9, 36.8, 24.9;
HRMS (EI, TOF) m/z calcd for C24H21F2NO3 [M] 409.1489 found 409.1478. Anal. Calcd for C24H21F2NO3: C 70.41, H 5.17, F 9.28, N 3.42. Found: C 70.46, H 5.23, F 9.24, N 3.34.

(3S,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3′-hydroxypropyl)azetidin-2-one (20)

Method 1

To a cooled (0 °C) solution of lactone 19 (2.0 g, 4 mmol) in 160 mL of dry diethyl ether was added 12 mL of 1 M solution of t-BuMgCl in diethyl ether. After 2 h, 30 mL of aq NH4Cl was added. The aqueous layer was extracted with ether (160 mL), the organic layer was washed with satd NaHCO3 (50 mL) and dried (MgSO4), and the solvent was removed under reduced pressure. Crude product 20 (1.64 g, 82%) obtained as a yellowish solid was used in the next step without further purification. An analytic sample was obtained by chromatography on silica gel (hexanes/ethyl acetate 7:3). Mp 130–133 °C [lit.(11) 132–134 °C]; [α]20D −42.2 (c 1.2, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.42–7.20 (11H, m), 7.02–6.90 (6H, m), 5,04 (2H, s), 4.72–4.68 (1H, m), 4.55 (1H, d J 2.2 Hz), 3.07 (1H, dt J 7.1, 2.2 Hz), 2.05–1.93 (3H, m) 1.89–1.82 (2H, m); 13C NMR (150 MHz, CDCl3) δ 167.6, 163.0, and 161.4 (d, JC–F 244.2 Hz), 159.8 and 158.1 (d, JC–F 241.8 Hz), 159.0, 140.0, 139.9, 136.6, 133.9, and 133.8 (d, JC–F 2.9 Hz), 129.6, 128.6, 128.1, 127.5, 127.4 and 127.4, (d, JC–F 8.0 Hz), 127.2, 118.4, 118.3, 115.8, 115.8, and 115.7 (d, JC–F 22.0 Hz), 115.5, 115.4, and 115.3 (d, JC–F 21.3 Hz), 73.3, 70.1, 61.1, 60.3, 36.5, 25.0; HRMS (ESI, TOF) m/z calcd for C31H27F2NO3Na [M + Na]+ 522.1851, found 522.1862; IR (KBr) v 3441, 1743, 1609, 1510 cm–1. Anal. Calcd for C31H27F2NO3: C 74.53, H 5.45, N 2.80, F 7.61. Found: C 74.40, H 5.53, N 2.74, F 7.56.
Abstract Image
Org. Process Res. Dev., 2009, 13 (5), pp 907–910
DOI: 10.1021/op900039z
Figure

Preparation of 1-(4-Fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone 1 (Ezetimibe)

 of compound 1. 1H NMR (300 MHz, DMSO-d6, δ) 1.72−1.84 (m, 4H), 3.08 (m, 1H), 4.45 (m, 1H), 4.8 (d, 1H, J = 2.0 Hz), 5.25 (d, 1H, J = 4.8), 6.75 (d, 2H, J = 8.4 Hz), 7.05−7.4 (m, 10H, Ar), 9.48 (s, 1H); IR: 3270.0, 2918, 1862, 1718.4, 1510 cm−1. MS: m/z 409.2 (M+). Anal. Calcd for C15H17NO5: C, 70.41; H, 5.17; N, 3.42. Found: C, 70.38; H, 5.27; N, 3.34.

Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 10

compound 9 as a white solid. 1H NMR (200 MHz, DMSO-d6, δ) 1.6−1.9 (m, 4H), 2.0−2.2 (bs, 1H), 3.0−3.2 (m, 1H), 4.4−4.6 (m, 1H), 4.74 (m, 1H), 5.05 (s, 2H), 6.95−7.9 (m, 17H, Ar); IR: 3492, 2922, 2852, 1719 cm−1; MS: m/z 499.3 (M+).
 ….

Synthesis of ezetimibe and desfluoro ezetimibe impurity.

Scheme 1.

Synthesis of ezetimibe and desfluoro ezetimibe impurity.

Comparison of 1H, 13C and 19F NMRs of ezetimibe and desfluoro ezetimibe ...

Fig. 4.Structures of ezetimibe, desfluoro impurity and intermediates.

Fig. 2.

Structures of ezetimibe, desfluoro impurity and intermediates.

 

 

Comparison of 1H, 13C and 19F NMRs of ezetimibe and desfluoro ezetimibe impurity.

Table 2.1H and 13C NMR assignments for Eze-1 and desfluoro Eze-1.

Positiona 1H–δ ppm


13C–δ ppm (DEPT)


Eze-1b Desfluoro Eze-1b Eze-1b Desfluoro Eze-1b
1 10.15 (br, OH) 10.13 (br, OH)
2 161.3 (C) 161.3 (C)
3 6.87 (d, J=8.5 Hz, 2H) 6.87 (dd, J=8.4, 1.8 Hz, 2H) 116.3 (2CH) 116.3 (2CH)
4 7.74 (d, J=8.5 Hz, 2H) 7.75 (dd, J=8.4, 1.8 Hz, 2H) 131.4 (2CH) 131.4 (2CH)
5 128.1 (C) 128.2 (C)
6 8.43 (s, 1H) 8.43 (s, 1H) 160.8 (CH) 160.8 (CH)
7 149.0 (d, 4J=2.6 Hz, C) 152.7 (C)
8 7.15–7.26 (m, 4H) 7.36 (dd, J=8.1, 7.5 Hz, 2H) 123.3 (d, 3J=8.4 Hz, 2CH) 121.6 (2CH)
9 7.17 (d, J=7.8 Hz, 2H) 116.5 (d, 2J=22 Hz, 2CH) 129.8 (2CH)
10 7.18 (t, J=6.3 Hz, 1H) 160.8 (d, 1J=242 Hz, C) 126.0 (CH)
Assignments: s: singlet; d: doublet; t: triplet; m: multiplet; br: broad singlet. Mean values used for coupled signals.

aNumbering of all compounds shown in Fig. 2 and copies of NMR spectra are presented in Appendix A.
bSolvent is DMSO-d6.

 

R-Enantiomer in Ezetimibe

R-Enantiomer in Ezetimibe

ABOVE 1H NMR OF R ENANTIOMER

Isolation and Characterization of R-Enantiomer in Ezetimibe

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 names Zetia
AHFS/Drugs.com monograph
MedlinePlus a603015
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 35–65%
Protein binding >90%
Metabolism Intestinal wall, hepatic
Half-life 19–30 hours
Excretion Renal 11%, faecal 78%
Identifiers
CAS number 163222-33-1 Yes
ATC code C10AX09
PubChem CID 150311
DrugBank DB00973
ChemSpider 132493 Yes
UNII EOR26LQQ24 Yes
KEGG D01966 Yes
ChEBI CHEBI:49040 Yes
ChEMBL CHEMBL1138 Yes
Chemical data
Formula C24H21F2NO3 
Molecular mass 409.4 g·mol−1
Physical data
Melting point 164 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, 1997 Dec 4, 1997 Schering Corp 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
WO2004099132A2 May 5, 2004 Nov 18, 2004 Ram Chander Aryan Process for the preparation of trans-isomers of diphenylazetidinone derivatives
WO2008032338A2 * Sep 10, 2007 Mar 20, 2008 Reddy Maramreddy Sahadeva Improved process for the preparation of ezetimibe and its intermediates
EP0720599A1 Sep 14, 1994 Jul 10, 1996 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US20070049748 Aug 25, 2006 Mar 1, 2007 Uppala Venkata Bhaskara R Preparation of ezetim
Citing Patent Filing date Publication date Applicant Title
US7470678 Jul 1, 2003 Dec 30, 2008 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684 Apr 25, 2007 Nov 30, 2010 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265 Jun 19, 2006 Jan 4, 2011 Astrazeneca Ab N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine, used as anticholesterol agents
US7871998 Dec 21, 2004 Jan 18, 2011 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048 Jun 21, 2006 Feb 22, 2011 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502 Jun 21, 2006 Mar 15, 2011 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8013150 * Feb 17, 2006 Sep 6, 2011 Msn Laboratories Ltd. Process for the preparation of ezetimibe
US8383810 Dec 12, 2011 Feb 26, 2013 Merck Sharp & Dohme Corp. Process for the synthesis of azetidinones
US20110130378 * May 26, 2009 Jun 2, 2011 Lek Pharmaceuticals D.D. Ezetimibe process and composition
US20110183956 * Jul 29, 2009 Jul 28, 2011 Janez Mravljak Process for the synthesis of ezetimibe and intermediates useful therefor
EP2128133A1 May 26, 2008 Dec 2, 2009 Lek Pharmaceuticals D.D. Ezetimibe process and composition
WO2008096372A2 * Feb 6, 2008 Aug 14, 2008 Pranav Gupta Process for preparing highly pure ezetimibe using novel intermediates
WO2009150038A1 May 26, 2009 Dec 17, 2009 Lek Pharmaceuticals D.D. Process for the preparation of ezetimibe and composition containing it
WO2009157019A2 * Jun 23, 2009 Dec 30, 2009 Ind-Swift Laboratories Limited Process for preparing ezetimibe using novel allyl intermediates
WO2005021497A2 * Aug 27, 2004 Mar 10, 2005 Eduardo J Martinez Tethered dimers and trimers of 1,4-diphenylazetidn-2-ones
WO2006127893A2 * May 25, 2006 Nov 30, 2006 Microbia Inc Processes for production of 4-(biphenylyl)azetidin-2-one phosphonic acids
WO2008096372A2 * Feb 6, 2008 Aug 14, 2008 Pranav Gupta Process for preparing highly pure ezetimibe using novel intermediates
US20070049748 * Aug 25, 2006 Mar 1, 2007 Uppala Venkata Bhaskara R Preparation of ezetimibe
/////

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

Paypal Donate

DR ANTHONY CRASTO

Follow New Drug Approvals on WordPress.com

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 1,782 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

View Full Profile →

TWITTER

bloglovin

Follow my blog with Bloglovin The title of your home page You could put your verification ID in a comment Or, in its own meta tag Or, as one of your keywords Your content is here. The verification ID will NOT be detected if you put it here.
%d bloggers like this: