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Ozonization of Pharmaceutical Water and the Biocidal Products Regulation

April 6, 2015 3:50 am / 2 Comments on Ozonization of Pharmaceutical Water and the Biocidal Products Regulation

With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this directive. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. The ozone registration group is active for this purpose. Read more about the Ozonization of Pharmaceutical Water and the Biocidal Products Regulation.

http://www.gmp-compliance.org/enews_04756_Ozonization-of-Pharmaceutical-Water-and-the-Biocidal-Products-Regulation_9200,9122,9340,9251,Z-PEM_n.html

With the new biocidal products regulation from 2013 in-situ generated ozone now also falls into the scope of this regulation. Ozone generation systems with a biocide application (such as disinfection of pharma water) thus require an approval after the transitional period expires in the September 2017. We already reported about the impact of the new Biocidal Products Regulation – please see the GMP News “Pharmaceutical Water: Uncertainty caused by the New Biocidal Products Regulation” from 21 May 2014.

Admission will take place in two stages. In the first step, ozone is certified as an active ingredient and registered in the list of active substances authorised in the EU. In the second step, the ozone generation system is approved as a biocidal product. The major manufacturers of ozone generation systems have joined forces for this in the ozone registration group (ORG). It aims at relieving users of ozone systems from the registration procedure. That means the documents should be provided to the users. The access to the marketing authorisation dossier is supposed to be assured through a Letter of Access (LoA). One of the open questions seems to be resolved now: the question whether an authorisation document will be required for each ozone precurser (i.e. water, oxygen or air). As this seems to be unnecessary, only one authorisation document is currently being processed.

The question with regard to how reasonable it is to include ozone from pharmaceutical water systems in the biocidal products regulation cannot be clarified at this point. The same is true with regard to the question on who is supposed to control pharmaceutical companies and whether their ozone comes from approved ozone systems.

You can find more information on the page Ozone registration group.

New EU GMP Annex 15 Revision published – Valid as of 1 October 2015

April 6, 2015 3:42 am / 1 Comment on New EU GMP Annex 15 Revision published – Valid as of 1 October 2015

DRUG REGULATORY AFFAIRS INTERNATIONAL

In February 2014 the draft for the revision of Annex 15 was published. Compared with the currently valid version the changes were partly significant. Now the draft was published as final document and will be valid as of 1 October 2015. Read more about the Changes in Annex 15.

http://www.gmp-compliance.org/enews_04792_New-EU-GMP-Annex-15-Revision-published—Valid-as-of-1-October-2015_9184,9266,9185,9322,Z-QAMPP_n.html

In February 2014 the draft for the revision of EU GMP Annex 15 was published (see the GMP-News from 11 February 2014 “Revision of the EU GMP Annex 15 for Qualification and Validation published“). Compared with the currently valid version the changes were significant in some parts (see also the GMP-News from 21 March 2014 “Detailed Analysis of Annex 15 Draft“. Now the draft was published as final document and will be valid as of 1 October 2015.

What will change? Following you will find an overview about the changes.

With 16 pages the document is much…

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Overview about API manufacturing for the European market

April 6, 2015 3:23 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

http://www.gmp-compliance.org/enews_04767_Overview-about-API-manufacturing-for-the-European-market_9188,S-WKS_n.html

EudraGMDP provides some interesting information about the API manufacturing sites as well as about importers, distributors of APIs to be used as starting material in Medicinal Products for human use in Europe. Although the database is still not complete (not all competent authorities in Europe have established a system to make sure that all registration data will be entered into EudraGMDP in a timely manner) the current information is already very interesting.

Currently (as per 19 March 2015) the database counts 3.275 API manufacturing sites, importers or distributors located outside Europe. On the other side 936 API manufacturing sites, importers or distributors are located in EEA countries (EU Member states…

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A surprising source of serotonin could affect antidepressant activity

April 6, 2015 1:23 am / Leave a comment

Lyra Nara Blog

This schematic drawing of a serotonergic neuron shows exocytotic release of serotonin from vesicles (red arrow) and the nonexocytotic release described by Mlinar and colleagues (blue arrow). Reuptake of serotonin (green arrow) is blocked by SSRI antidepressants, increasing the extracellular serotonin concentration. Credit: Adell 2015

Depression affects an estimated 350 million people worldwide and poses a major public health challenge, according to the World Health Organization. Researchers have discovered an unconventional way that serotonin is released from neurons that could play an important role in the mechanism through which antidepressant drugs work. The Journal of General Physiology study is highlighted in the April issue.

Serotonin is a chemical in the brain that plays a key role in regulating various emotions and behaviors. Like other neurotransmitters, which relay signals between neurons, serotonin is stored in small sacs called vesicles in the presynaptic terminal of one neuron and released into the synapse…

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LINEZOLID

April 5, 2015 1:30 pm / Leave a comment

LINEZOLID

N- [[(5S) – 3 – [3 -Fluoro-4- (4-morpholinyl)phenyl] -2-oxo- 5 -oxazolidinyl] methyl] acetamide and marketed by Pfizer in US under brand name Zyvox. Linezolid is a synthetic antibacterial agent of the oxazolidinone class. It is used for the treatment of infections caused by multi-resistant bacteria including streptococci and methicillin-resistant Staphylococcus aureus.

(S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide.

N-[[(5s)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide PRODUCT PATENTUS5688792 (1997 to Pharmacia & Upjohn)
CAS No.:	165800-03-3
Synonyms:	View More Zyvoxam; linezolid; Zyvoxid; Zyvox; Zyvoxa; Linezolid; Linezlid;
Formula:	C16H20FN3O4
Exact Mass:	337.14400

13C

1H NMR AND 13C PREDICT

1H NMR PREDICT

N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide NMR spectra analysis, Chemical CAS NO. 165800-03-3 NMR spectral analysis, N-[[(5S)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide H-NMR spectrum

13C NMR PREDICT

COSY
PREDICT

HMBC

ORIGINAL 1H NMR…………...http://www.selleckchem.com/products/Linezolid(Zyvox).html

INTERMEDIATES USED

Arkivoc, , vol. 2012, # 6 p. 45 – 56

WO2011/137222 A1, ;

Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 11 ;

THE REGENTS OF THE UNIVERSITY OF CALIFORNIA; GARG, Neil K.; RAMGREN, Stephen D.; SILBERSTEIN, Amanda L.; QUASDORF, Kyle W. Patent: WO2012/94622 A2, 2012 ; Location in patent: Page/Page column 31-32 ;

Lianhe Chemical Technology Co., Ltd. Patent: EP2388251 A1, 2011 ; Location in patent: Page/Page column 11 ;

Tammana, Rajesh; Vemula, Kiran Kumar; Guruvindapalli, Ramadasu; Yanamandr, Ramesh; Gutta, Madhusudhan Arkivoc, 2012 , vol. 2012, # 6 p. 45 – 56

Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 10 ;

Song, Lirong; Chen, Xiaobei; Zhang, Shilei; Zhang, Haoyi; Li, Ping; Luo, Guangshun; Liu, Wenjing; Duan, Wenhu; Wang, Wei Organic Letters, 2008 , vol. 10, # 23 p. 5489 – 5492

Union Quimico Farmaceutica, S.A. (UQUIFA) Patent: EP2163547 A1, 2010 ; Location in patent: Page/Page column 10 ;

JUBILANT LIFE SCIENCES LIMITED; BISWAS, Sujay; PANDA, Atulya, Kumar; GUPTA, Ashish, Kumar; SINGH, Shishupal; TIWARI, Praveen; VIR, Dharam; THOMAS, Saji Patent: WO2013/111048 A1, 2013 ; Location in patent: Page/Page column 24; 25 ;

Perrault, William R.; Pearlman, Bruce A.; Godrej, Delara B.; Jeganathan, Azhwarsamy; Yamagata, Koji; Chen, Jiong J.; Lu, Cuong V.; Herrinton, Paul M.; Gadwood, Robert C.; Chan, Lai; Lyster, Mark A.; Maloney, Mark T.; Moeslein, Jeffery A.; Greene, Meredith L.; Barbachyn, Michael R. Organic Process Research and Development, 2003 , vol. 7, # 4 p. 533 – 546

US6362334 B1, ; Example 13 ;

NMR OF INTERMEDTIATES

………….

…….

………

……………

Linezolid is a pharmaceutically active compound useful as an antibacterial agent, e.g. for the treatment of diabetic food infections caused by Gram-positive bacteria. It is represented by the formula (I),
[0003]

The marketed pharmaceutical compositions are a sterile isotonic solution for an i.v. infusion, a tablet for oral administration and an aqueous suspension for oral administration. They are marketed, i.e., under brand name ZYVOX by Pfizer.
[0004]

The molecule of linezolid has one asymmetric carbon in the molecule allowing for 2 enantiomers; the marketed compound is the (S)-enantiomer. In the above-marketed compositions, linezolid is present as a free base.
[0005]

Hereinunder, the name linezolid will be used as the generic name for N-(3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)acetamide, unless indicated to the contrary.
[0006]

Linezolid was first disclosed in WO 95/07271 ( EP 0717738 , US 5,688,792 ) of the Upjohn Company.
[0007]

Various processes for making linezolid are known in the art. In particular, the important ones are these, the final step of which comprises acetylation of an amine precursor of the formula (II) with an acetylhalide or acetic anhydride (see, e.g., WO 2005 099353 ),
[0008]
This amine precursor (II) may be made from various starting materials, e.g.:
1. a) By a reduction of an azide compound of formula (III) by a suitable reductant ( WO2006/091731 , WO 95/07271 , US 5837870 , WO2009/063505 , US 7291614 ),
  
  The starting compound (III) may be made from the corresponding tosylate or chloride of general formula (VII) below ( WO 2005/099353 ).
2. b) By a decomposition of a phthalimide compound of formula (IV), e.g. by methylamine ( WO95/07271 ) or by hydrazine ( US 5837870 ),
  
  The starting compound (IV) may be made from the same tosylate or chloride as sub a) ( WO2005/099353 ) or by a cyclization of the oxazolidine ring ( WO 99/24393 , WO2006/008754 ).
3. c) From a sulfonate compound of formula (V),
  
  by treatment with ammonium hydroxide in isopropanol or THF ( WO 95/07271 ) or by treatment with ammonia under enhanced pressure ( WO 97/37980 ).
4. d) By a reduction of an imine (VI),
  
  wherein R2 is a chlorophenyl, bromophenyl or 2,4,-dichlorophenyl moiety ( WO 2007/116284 ).
[0009]

Except of the imine (VI), each of the preceded synthetic approaches is based on a step of converting a starting material of the general formula (VII),

wherein L is a suitable leaving group, for instance a halogen or an alkyl-or aryl sulfonyloxy group,
by a reaction with a nitrogen nucleophile (an azide salt, phthalimide salt, ammonia or ammonium hydroxide), followed, if necessary, by a next step of conversion of the formed reaction intermediate (e.g., compound (III) or compound (IV)) into the amino/compound (II). Apparently, making the starting amine-compound (II) in a good yield and purity is the key aspect of commercial success of any of the above synthetic routes yielding linezolid. However, the known approaches have various drawbacks, for instance serious toxicity and explosion hazard of the azide salts, long reaction times and hazardous agents (hydrazine, methyl amine) in using the phthalimide intermediate, low yields and many side products at the ammonium hydroxide approach, or harsh reaction conditions in reaction with ammonia.

Linezolid [(S)-N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C₁₆H₂₀FN₃O₄and the following structure (1):

Linezolid (1) is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°. Linezolid (1), as well as a process for its preparation, is disclosed in U.S. Pat. No. 5,688,792 (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and International Patent Publication WO 95/07271.

U.S. Pat. No. 5,688,792 discloses the antibacterial agent linezolid as well as a process for its preparation. EXAMPLE 5 reports the linezolid produced had a mp of 181.5-182.5°.

There are many other disclosures of processes to prepare linezolid. J. Med. Chem., 39(3), 673-9 (1996) reports the linezolid was, “recrystallized from ethyl acetate and hexanes . . . white crystals, m.p. 181.5-182.5C.” It also sets forth the IR spectrum as “3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435”.

Tetrahedron Lett., 40(26), 4855 (1999) discloses linezolid and a process to prepare linezolid. However, this document does not set forth the melting point or IR spectrum of the linezolid prepared.

U.S. Pat. No. 5,837,870 (International Publication WO97/37980 of PCT/US97/03458) discloses a process to prepare linezolid. Linezolid is described in EXAMPLE 18, which does not set forth the melting point or IR spectrum of the linezolid prepared.

International Publication WO99/24393 of PCT/US98/20934 discloses a process to prepare linezolid. Linezolid is described in EXAMPLES 8, 9 and 12 which do no set forth the melting point or IR spectrum of the linezolid prepared.

The form of linezolid being used in the clinical trials to support the filing of the NDA is Form II.

Linezolid (1) is marketed in the United States by Pfizer, Inc. as an injection, tablets, and oral suspension under the name ZYVOX®. Its main indications are nosocomial pneumonia, skin and skin-structure infections, and vancomycin-resistant Enterococcus faecium infections.

U.S. Pat. No. 5,688,792 claims linezolid (1) and its use for the treatment of microbial infections. This patent also discloses, but does not claim, the following method of preparation:

This method of preparation was also disclosed in Bricker, et al., J. Med. Chem., 39 673 -679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use of NaN₃can be avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine.

In the above-described synthesis, the intermediate amine, S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (2)

is reacted without isolation with acetic anhydride as an oily product, or in solution, to produce the acetamide, linezolid (1). This is followed by procedures for isolating the linezolid (1) such as those described in U.S. Pat. No. 5,688,792, at col. 15, 11. 22-28 (chromatography and separation of the desired fraction, followed by evaporation and trituration of the product to obtain pure linezolid (1)).

In the above-described syntheses, the intermediate azide R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (3)

is reduced to its corresponding amine, S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (2) in the solvent ethyl acetate by hydrogenation using hydrogen gas and a palladium/carbon catalyst. These reaction conditions lead to the production of an undesirable level of reaction by-products, and, following the acetylation of the intermediate amine (2) to linezolid (1), to undesirably high levels of bis-linezolid (4)

http://www.google.com/patents/US20060252932

FIG. 1 shows the ¹H-NMR spectrum of bis-linezolid (4)

FIG. 2 shows the ¹³C-NMR spectrum of bis-linezolid (4)

FIG. 3 shows the IR spectrum of bis-linezolid (4)

A Novel Synthesis of Oxazolidinone Derivatives (A Key Intermediate of Linezolid)

Volume 29, Number 3

Pingili Krishna Reddy1,2, K. Mukkanti2 and Dodda Mohan Rao1*

1Symed Research Centre, Plot No. 89/A, Phase-I, Shapoornagar, IDA Jeedimetla, Hyderabad, Andhra Pradesh, India
2Center for Pharmaceutical sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad, India

http://www.orientjchem.org/vol29no3/a-novel-synthesis-of-oxazolidinone-derivatives-a-key-intermediate-of-linezolid/

Reddy P. K, Mukkanti K, Rao D. M. A Novel Synthesis of Oxazolidinone Derivatives (A Key Intermediate of Linezolid). Orient J Chem 2013;29(3). doi : http://dx.doi.org/10.13005/ojc/290322

N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (7a):

IR (KBr, cm-1): 3338 (N-H stretching), 3117, 3066 (aromatic C-H stretching), 2971, 2863, 2818 (aliphatic C-H stretching), 1738, 1662 (C=O stretching), 1545, 1516,1453 (aromatic C=C stretching), 1425 (C-N stretching), 1381 (aliphatic C-H bending), 1334 (C-F stretching), 1274 (C-O stretching), 1198, 1177 (C-N bending), 1117, 1081 (aromatic C-H bending).

1H NMR (CDCl3) δ ppm: 7.44 (m, 1H), 7.26 (m, 1H), 6.99 (m, 1H), 6.01 (t,1H), 4.76 (m, 1H), 4.02 (m, 2H), 3.80 (m, 4H), 3.61(m, 2H), 3.05 (m, 4H), 2.02 (t, 3H):

C13NMR(CDCl3) δppm: 171.33, 156.87, 154.44, 136.40, 132.84, 118.67, 113.81, 107.52, 71.96, 66.76, 50.79, 47.46, 41.68, 22.81. MS: 338 (M++H);

……………………………………………………………………….

ARKIVOC 2012 (vi) 45-56 Page 45 ©ARKAT-USA, Inc.

An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: a short and efficient synthesis of Linezolid

Rajesh Tammana,a,b Kiran Kumar Vemula,a Ramadasu Guruvindapalli,a Ramesh Yanamandra,c and Madhusudhan Gutta* a
aDepartment of Research & Development, Inogent Laboratories Pvt. Ltd.,

A GVK BIO Company, 28A, IDA, Nacharam, Hyderabad 500 076, Andhra Pradesh, India

bCentre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad 500 072, Andhra Pradesh, India

cDepartment of Analytical Research & Development, GVK Biosciences Pvt. Ltd., 28A, IDA, Nacharam, Hyderabad 500 076, Andhra Pradesh, India

E-mail: madhusudhan.gutta@inogent.com

http://www.arkat-usa.org/get-file/42622/
N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide 1 (Linezolid) 1 was prepared according to the method described in literature.12,15

Mp 182-183 °C, (lit.12a 181.5- 182.5 °C); enantiomeric purity 99.9% (by chiral HPLC);

IR (KBr): ν 3343 (NH), 3075 (Ar-H), 2967 (CH), 1741 (C═O), 1660 (C═O) cm-1 ;

1H NMR (CDCl3): δ 2.03 (s, 3H), 3.04-3.07 (t, 4H), 3.56-3.77 (m, 3H), 3.86-3.89 (t, 4H), 4.00-4.06 (t, 1H), 4.74-4.79 (m, 1H), 5.96 (s, 1H), 6.90- 6.96 (t, 1H), 7.06-7.10 (d, 1H), 7.43-7.48 (d, 1H).

13C NMR (DMSO-d6): δ 22.4, 41.4, 47.3, 50.6, 66.1, 71.5, 106.4, 114.0, 119.1, 133.3, 135.5, 154.0, 156.2, 170.0;

ESI-MS (C16H20FN3O4): m/z (%) 338.18 (100, M+ +1).

12. (a) Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanowicz, D. A.;
Garmon, S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. J.
Med. Chem. 1996, 39, 673. (b) Barbachyn, M. R.; Brickner, S. J.; Hutchinson, D. K. U.S.
patent 5688792; 1997; Chem. Abstr. 1995, 123, 256742. (c) Dhananjay, G. S.; Nandu, B. B.;
Avinash, V. N.; Kamlesh, D. S.; Anindya, S. B.; Tushar, A. N. PCT Int. Appl. 063505, 2009;
Chem. Abstr. 2009, 150, 515152.
13. (a) Imbordino, R. J.; Perrault, W. R.; Reeder, M. R. PCT Int. Appl. 116284, 2007; Chem.
Abstr. 2007, 147, 469356. (b) Pearlman, B. A.; Perrault, W. R.; Barbachyn, M. R.;
Manninen, P. R.; Toops, D. S.; Houser, D. J.; Fleck, T. J. U.S. Patent 5837870, 1998; Chem.
Abstr. 1998, 130, 25061. (c) Perrault, W. R.; Pearlman, B. A.; Godrej, D. B.; Jeganathan, A.;
Yamagata, K.; Chen, J. J.; Lu, C. V.; Herrinton, P. M.; Gadwood, R. C.; Chan, L.; Lyster, M.
A.; Maloney, M. T.; Moeslein, J. A.; Greene, M. L.; Barbachyn, M. R. Org. Proc. Res. Dev.
2003, 7, 533.
14. (a) Yu, D. S.; Huang, L.; Liang, H.; Gong, P. Chin. Chem. Lett. 2005, 16, 875. (b) Pearlman,
B. A. PCT Int. Appl. 9924393, 1999; Chem. Abstr. 1999, 130, 338099. (c) Weigert, F. J. J.
Org. Chem. 1973, 38, 1316.
15. (a) Wang, M.; Tong, H. CN patent 101220001, 2008. (b) Mohan Rao, D.; Krishna Reddy, P.
PCT Int. Appl. 099353, 2005; Chem. Abstr. 2005, 143, 440395. (c) Mohan Rao, D.; Krishna
Reddy, P. PCT Int. Appl. 008754, 2006; Chem. Abstr. 2006, 144, 170978.

……………………………………

Org. Proc. Res. Dev., 2003, 7 (4), pp 533–546

DOI: 10.1021/op034028h

Organic Process Research and Development, 2003 , vol. 7, # 4 p. 533 – 546

http://pubs.acs.org/doi/abs/10.1021/op034028h

Since 1993, a significant process research and development effort directed towards the large-scale synthesis of oxazolidinone antibacterial agents has been ongoing in both Early Chemical Process Research and Development, and Chemical Process Research and Development at Pharmacia. This work has led to the successful development of the current commercial process to produce Zyvox (linezolid), recently approved by the FDA as an antibacterial. While this synthesis is appropriate for the preparation of linezolid in particular, a more convergent and versatile synthesis was developed for the rapid preparation of numerous other oxazolidinone analogues. Toward this end, economical methods for the large-scale preparation of N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide 3 and tert-butyl [(2S)-3-chloro-2-hydroxypropyl]carbamate 27 from commercially available (S)-epichlorohydrin via the common intermediate (2S)-1-amino-3-chloro-2-propanol hydrochloride 2a were developed. Also, general methods for coupling these reagents with N-aryl carbamates to giveN-aryl-5(S)-aminomethyl-2-oxazolidinone derivatives in one step were developed. These reagents and procedures have proven widely applicable in the preparation of a diverse array of oxazolidinone analogues such as 23 and 28 in both process and medicinal chemistry research.

(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo- 5-oxazolidinyl]methyl]acetamide: Linezolid: Zyvox

HPLC analyses showed the first and second crops to be 98.9 and 94.6 wt % linezolid, respectively, with <0.2% enantiomer in each; also, an additional 9.7% yield of linezolid was detected in the filtrate by external standard HPLC (total ) 80.6%). Analysis data for 1st crop material: mp ) 73-76 °C;

1 H NMR (CDCl3, 400 MHz)
δ 7.43 (dd, J ) 14.4, 2.4 Hz, 1H), 7.07 (dd, J ) 8.8, 2.0 Hz, 1H), 6.91 (t, J ) 8.8 Hz, 1H), 6.43 (br t, 1H), 4.77 (m, 1H), 4.02 (t, J ) 9.2 Hz, 1H), 3.86 (t, J ) 4.4 Hz, 4H), 3.76 (dd, J ) 8.8, 6.8 Hz, 1H), 3.66 (m, 2H), 3.05 (t, J ) 4.8 Hz, 4H), 2.02 (s, 3H);

13C NMR (CDCl3, 100 MHz)
δ 23.07 (q), 41.93 (t), 47.66 (t), 51.00 (t), 66.95 (t), 71.99 (d), 107.56 (dd, JC-F ) 26.16 Hz), 113.97 (dd, JC-F ) 3.02 Hz), 118.85 (dd, JC-F ) 4.03 Hz), 132.90 (sd, JC-F ) 4.03 Hz), 136.58 (sd, JC-F ) 9.06 Hz), 154.42 (s), 155.50(sd, JC-F ) 246.53 Hz), 171.19 (s)

MS (EI) m/z (relative intensity) 337 (90), 293 (81), 209 (100);

[R]25D ) -16 (c ) 1.05, ethanol).

Anal. Calcd for C16H20FN3O4: C, 56.97; H, 5.97; N, 12.46; found: C, 56.86; H, 6.05; N, 12.44

HPLC (99.0 wt %, 98.9 area % linezolid, tR 1.60 min) conditions: InertsilODS-2 5.0 µm 150 mm × 4.6 mm, flow rate ) 2.0 mL/ min, gradient elution from 40:60 A:B to 80:20 A:B over 10 min; A ) acetonitrile; B ) water. External standard HPLC analysis of the filtrate showed
d 12.9% and 7.6% yield of linezolid and 8, respectively.
SEE HPLC AT http://file.selleckchem.com/downloads/hplc/S140801-Linezolid-Zyvox-HPLC-Selleck.pdf
………………………….
http://www.google.com/patents/WO2007064818A1?cl=en

Linezolid [(S)-N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyljmethyl] acetamide} is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C₁₆H₂₀FN₃O₄ and the following structure:

Linezolid

Linezolid is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5⁰C. Linezolid, as well as a process for its preparation, is described in U.S. Patent No. 5,688,792 (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and International Patent Publication WO 95/07271. Linezolid is marketed in the United States by Pfizer, Inc. as an injection, as tablets, and as an oral suspension under the name ZYVOX^®. Its main indications are nosocomial pneumonia, skin and skin-structure infections, and vancomycin-resistant Enterococcus faecium infections.

U.S. Patent No. 5,688,792 describes linezolid and its use for the treatment of microbial infections. This patent also describes the following method for the preparation of linezolid:

This method of preparation was also described in Bricker, et al., J. Med. Chem., 39, 673 — 679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use OfNaN₃ can be avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine.

An analysis of the commercial tablet ZYVOX^® shows the presence of desfluoro linezolid as an impurity of linezolid. An HPLC chromatogram of ZYVOX^® is depicted in Figure 1. The desfluoro linezolid haviong a relative retention time (RRT) of 0.69 compared to the retention time of linezolid.

desfluoro linezolid of the following structure:

Desfluoro linezolid

As illustrated in Figure 1, this impurity is ideal for use as a reference standard since it is detectable by HPLC, and yet it is present in much less amounts than linezolid, having a RRT of 0.69 compared to the retention time of linezolid.

The isolated desfluoro linezolid is pure. Preferably it has about 95% purity by weight with respect to other compounds, including linezolid. Preferably, the desfluoro linezolid is isolated in about 99.3% purity by weight. Thus, the isolated desfluoro linezolid contains less than about 5%, preferably less than about 2%, and even more preferably less than about 1%, by weight, linezolid.

The isolated desfluoro linezolid of the present invention can be characterized by data selected from: ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.8a (s), 3.04 (brt), 3.40 (t), 3.68 (m), 3.72 (brt), 4.04 (t), 4.67 (m), 6.95 (d), 6.95 (d), 737 (d), 7.37 (d) and 8.21 (t); ¹³C NMR (lOOMHz, DMSO-d6) δ (ppm): 22.8, 41.9, 48.0, 49.2, 66.5, 71.7, 115.9, 115.9, 119.9, 119.9, 130.9, 148.0, 154.7, 170.0; EI+m/z (MH⁺): 319; and IR spectra on KBr at 1523, 1555, 1656, 1731, 2830, 2926, 2968 and 3311 cm^‘1.

The isolated desfluoro linezolid of the present invention may be characterized by a ¹H NMR, substantially as depicted in figure 2. The isolated desfluoro linezolid of the present invention may be characterized by ¹³C NMR, substantially as depicted in figure 3. The isolated desfluoro linezolid of the present invention may be characterized by an IR spectrum substantially as depicted in figure 4. The isolated, desfluoro linezolid of the present invention may be characterized by an Mass spectrum substantially as depicted in figure 5. The isolated desfluoro linezolid of the present invention may be prepared by performing the process described in U.S. Patent No. 5,688,792, with l-fluoro-4- nitrobenzene instead of 3,4-difluoronitrobenzene, according to the following scheme:

Desfluoro Linezolid

The desfluoro linezolid of the present invention is isolated by a process comprising the following steps; a) combining (5R)-[[3-[4-(4-morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]methyl]azide with an organic solvent, preferably a C₁-C₄ alkyl ester or a C₆ to C₁₂ aromatic hydrocarbon, more preferably toluene or ethylacetate, most preferably toluene, and hydrogen gas in the presence of a catalyst to obtain a reaction mixture containing (5S)-[[3-[4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl] amine; b) filtering the reaction mixture to obtain a solution containing (5S)-[[3-[4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl}methyl]amine; c) adding acetic anhydride to the solution to obtain a precipitate; and d) recovering and drying the precipitate to obtain isolated desfluoro linezolid. Preferably, recovering of the precipitate in step d) is carried out by filtering or decanting. Preferably, the catalyst in step a) is selected from the group consisting of Pd/C, Raney Nickel, and noble metal catalysts, more preferably the catalyst is Pd/C. The isolated desfluoro linezolid of the present invention is useful as a reference marker for linezolid. As such, it may be used in order to detect the desfluoro linezolid impurity in a linezolid sample.

Step 7. Preparation of N-rr(5S)-3-r4-(4-moφholinyl)phenyl1-2-oxo-5- oxazolidinyl]methyl1acetamide (des-fluoro-linezolid). In a IL reactor, 6 g (5R)-[[ 3-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]azide were charged with 0.7L toluene followed by 0.6 g Pd/C (10% Pd/C containing 52% water). The system was bubbled with ammonia (gas) during 2 h, and then flushed three times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 arm. The reaction mixture was stirred at RT and the reaction followed up until completion. The reaction mixture was filtered and the solution was treated with 60 ml acetic anhydride at RT. The precipitate was filtered and dried to obtain 3.3 g of desfluoro linezolid (purity: 99.3%). Desfluorolϊnezolid ¹H-NMR and ¹³C-NMR identification

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HTTP://WWW.GOOGLE.COM/PATENTS/US6559305

Example 1 Preparation of Crystal Form II of Linezolid

Linezolid with better than 99.8% enantiomeric purity, less than 0.2% of the R enantiomer, (1.99 grams) is mixed with ethyl acetate (100 mL). The flask is stoppered and heated to 65° with constant stirring in a temperature controlled oil bath. The linezolid is completely dissolved and the mixture is stirred for an additional 10 minutes. The temperature is maintained at 55° in the flask and one neck of the flask is unstoppered to allow slow evaporation of the solvent. A gentle stream of nitrogen is blown across the open neck to aid in evaporation. Solids spontaneously precipitated from solution and the volume is reduced by about 25% of the initial volume. The flask is sealed and mixed for 90 minutes while maintaining the mixture at 55°. The mixture was then cooled to about 23° while being stirred. The solids are isolated by vacuum filtration using a sintered glass funnel to give linezolid in crystal form. Analysis by powder X-ray diffraction indicates that the solids are linezolid crystal Form II.

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US7989618

HTTP://WWW.GOOGLE.COM/PATENTS/US7989618

Example 1 Linezolid Dihydrochloride

20 g of linezolid are dissolved in 750 ml of acetone at about 30° C. The solution is kept at about 30° C. and 8 ml of concentrated hydrochloric acid (37% w/w aqueous solution) are added, thus immediately causing linezolid dihydrochloride to precipitate as a white solid. The mixture is kept under stirring at about 30° C. for approximately 30 minutes, then refluxed under stirring for about 2 hours. The mixture is left to cool to room temperature, then cooled on ice-water bath, under stirring, for about 2 hours. A white solid precipitates which is filtered with suction, washed with 30 ml of acetone and dried under vacuum at about 50° C.

A solid water-soluble crystalline product is obtained, characterized by an XRPD spectrum substantially as reported in FIG. 3, wherein the most intense diffraction peaks fall at 13.9; 18.2; 19.1; 19.7; 22.2; 22.9; 23.6; 25.3; 27.1; 28.4±0.2° in 2θ; and by a DSC thermogram substantially as reported in FIG. 4, characterized by an exothermic peak around 178±2° C. The acid-base potentiometric titre is double while the argentimetric one is 17.71% (theor. dihydrochloride 17.77%). Purity 99.8% as determined by HPLC.

¹H NMR (300 MHz, DMSO-d6), ppm: 8.37 (bt, 1H), 7.50 (dd, 1H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1H), 4.05 (t, 1H, J=9.0 Hz), 3.70 (m, 5H), 3.36 (t, 2H, J=5.1 Hz), 3.07 (t, 4H, J=4.5 Hz), 1.80 (s, 3H).

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http://www.google.com/patents/EP2690100A1?cl=en

Example 3

[0034]

To a 25 ml, round-bottomed flask equipped with a magnetic stirring bar was charged “amine” (0.49 g) followed by water (8.30 ml). A heterogeneous mixture was stirred and hydrochloric acid (0.12 mL, 35 %) was added. A homogenous solution was obtained. The solution was cooled down in an ice-water bath to 0°C. Acetic anhydride (0.31 mL) was added followed by sodium bicarbonate (0.45 g). Carbon dioxide was immediately released and a formation of white precipitate was observed. The precipitate was filtered off and the filter cake was washed with water (10 ml). The filter cake was collected and dried (100 mbar) at 70°C overnight. An off-white solid linezolid (0.26 g) was isolated.

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PATENT

http://www.google.com/patents/WO2007116284A1?cl=en

Example 3 Preparation of (S)~N-[3-(3-fiuoro~4~morpholin-4-yI-ρhenyI)~2-oxo- oxazolidin-5~ylmethyl]-acetarnide (Linezo!id)

Method A

To (S)-5-{[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 mL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCl (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic. After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, eluting with CH₃CN /water + 0.1% TFA from 20% CH₃CN to 80% CH₃CN in 8 min at 0.5 mL/min, detecting at 254nm, Retention time of (S)-N-[3-(3-fluoro-4-morpholin-4-yl- phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL). CH₂Cl₂ (900 mL) is added and the pH is adjusted to 6.7 with ~ 25 mL aq. 50% aq. NaOH. With constant stirring, Ac₂O (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CHiCl₂ (800 mL) and the organics are combined and concentrated to ~1L in volume. Ethyl acetate (IL) is added and the volume is reduced to 1.5 L under vacuum. Another IL of ethyl acetate is added and volume is reduced again to IL under vacuum. The resultant slurry is cooled to 0⁰C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 50⁰C for 2 hours to give the title compound as Hnezolid crystalline Form I.

Following the general procedure of method A and making non-critical variations, but substituting (S)-5- { [2,4-dichloro-benzylidene)-amino]-methyl } -3-(3-fluoro-4-morphoIin-4-yl- phenyl)-oxazolidin-2-one (example 11) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morρholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.

Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino] -methyl }-3-(3-fluoro-4-morpholin-4-yl~ phenyl)-oxazolidin-2-one (example 9) for (S)-5-{[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morph.olin-4-yl-phenyl)-oxazoIidin-2-one, the title compound is obtained.

Example 4 Trituration (convert linezolid crystalline Form I to linezolid crystalline Form E) The product from Example (89.18 g) is transferred to a 3L round bottom flask equipped with a mechanical stirrer, thermocouple and heating mantel. Ethyl acetate (2.23 L, 15 mL/g) is added and seeded with Linezolid form II crystals and the slurry is heated to ca. 50⁰C. A slight exotherm of 3⁰C is observed. After 30 minutes of heating the form change is observable as the solid is changing to long needles. Stirring is continued for 2 hours at 50⁰C, at which time the contents are cooled to ambient temperature and stirred for an additional 30 minutes. The contents are then cooled to 3⁰C for 1.5 hours, filtered and washed with cold ethyl acetate (300 mL total). The resultant solids are dried under vacuum at 50°C for 18 hours to give Linezolid (78.12 g) Form II by XRD, 99.8 wt%, 99.9% ee. HPLC conditions: YMC 5μ ODS-AM 150 nm X 4.6 nm column, etuting with CH₃CN /water + 0.1% TFA from 20% CH₃CN to 80% CH₃CN in 8 min at 0.5 mL/min, detecting at 254nm. T_R (Linezolid) = 4.4 min; HPLC conditions: Chiralcel OJ-H 250 nm X 4.6 nm column, eluting with 90% CO₂/ 10%MeOH at 3.0 mL/min, detecting at 255 nm. T_R [title compound] = 3.6 min; T_R (enantiomer of title compound) = 4.1 rain
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http://www.google.com/patents/EP2516408A1?cl=en

The polymorphic form obtained by following process disclosed in U.S. Pat. No. 5,688,792 is designated as Form I. Figure- 1 depicts the PXRD graph of Form I obtained by following prior art process. [15] Disadvantage of the process disclosed in U.S. Pat. No. 5,688,792 is that it involves use of n-butyl lithium. Due to its explosive nature it is difficult to handle at plant scale. Also, the said reaction is carried out at temperature of -78°C, which is difficult to attain during commercial production. Further the intermediate obtained requires purification by column chromatography. Column chromatography is a cumbersome technique and difficult to practice during commercial scale production.
The process for the preparation of Linezolid is also disclosed in Journal of Medicinal Chemistry (1996), 39(3), 673-9, U.S. Pat. Nos. 6,492,555, 5,837,870, 6,887,995, 7,307,163, 7,429,661, etc.

Linezolid was first disclosed in U.S. Pat. No. 5,688,792. The process for synthesis is as disclosed in Scheme-I

The synthetic reaction scheme of the present invention is as shown below.

Scheme-ll

Example 6: Synthesis of Linezolid Crude.

[140] Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)- [N- 3 – (3 -Fluoro-4-morpholinylphenyl) -2-oxo- 5 -oxazolidinyl] methyl azide (lOOg) at 20-30°C. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20°C for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate

(100mlx2). Then add the Triethyl amine (35. lg) & Acetic anhydride (29.9g) slowly at 25-30°C under stirring. Cool the mix, filter it and wash the solid with chilled (0-5°C) Ethyl acetate (100 ml) followed by water (100mlx2). Finally product is dried at 55-60° C. Yield: 0.85.: Percentage 81%w/w.

[141]

[142] Example 7: Synthesis of Linezolid Pure

[143] Reflux the Acetone (1020ml) and Linezolid crude (lOOg) at 55-60°C for the 30

minutes. Filter the hot turbid solution & wash it with hot (55-60°C) acetone (50ml). Cool the reaction mixture at -5 to 0°C for 1 hour, wash the solid with chilled (-5 to 0°C) acetone (50ml). After drying the Linezolid semi pure (77g) add n-Propanol (308ml) reflux it at 95-100°C for 30 min & filter it by hot solution through hyflo bed. Cool the mix to 0-5°C for 1 hour and wash the solid with chilled (0-5°C) n-Propanol (77ml). Dry the material at 55-60°C. Yield: 0.73.: Percentage 73%w/w.

[144]

[145] Example 8: Synthesis of Linezolid

[146] Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)- [N- 3 – (3 -Fluoro-4-morpholinylphenyl) -2-oxo- 5 -oxazolidinyl] methyl azide (lOOg) at 20-30°C. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20°C for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate. Distill out ethyl acetate at 75-90°C and then cool the reaction mass to 0-5°C. Add acetone (1000ml) & acetic anhydride (29.9g) at 0-5°C. Further, add Triethyl amine (37.8g) slowly at 0-5°C under stirring. Maintain the reaction mass at 0-5°C for 1-2 hrs. Heat the reaction mass to reflux at 65-75°C for 1 hr. Again cool the reaction mass to 0-5°C fori hr. Filter the solid wash it with acetone and water and dry it at 55-60C. Yield: 0.80.: Percentage 80 w/w.

Example 9: Synthesis of Linezolid Form I

[149] Reflux n-propanol (400ml) and Linezolid (lOOg) at 95-100°C till all solid gets

dissolved. Add activated charcoal (2.0g) and heat for 30 mins. Filter thro hyflo bed. Heat the filtrate and concentrate the solution by partially removing n-propanol. Cool to 0-5°C and filter the solid and dry it at 55-60°C under vacuum. Yield: 0.9. : Percentage 90 w/w.

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https://acs.confex.com/acs/green08/techprogram/P52019.HTM

Wednesday, June 25, 2008 – 2:00 PM
New York (Capital Hilton)
128

Convergent Green Synthesis of Linezolid (Zyvox)

William R. Perrault, James B. Keeler, William C. Snyder, Christian L. Clark, Michael R. Reeder, Richard J. Imbordino, Rebecca M. Anderson, Nabil Ghazal, Stephen L. Seacrest, and Bruce A. Pearlman. Pfizer, Kalamazoo, MI

Pfizer has developed a novel, convergent, green, second generation synthesis of Linezolid (the active ingredient in ZyvoxTM). The second generation process will replace the launch process after approval by appropriate regulatory agencies and has numerous green chemistry benefits: overall yield is increased by 8%; total waste is reduced by 56%; non-recycled w is eliminated. At current volumes, total waste will be reduced 1.9 million kilograms per year and 1.7 million kg per year non-recyclable waste will be eliminated. The improved process utilizes a highly efficient low dilution convergent synthesis to replace the more dilute linear synthesis utilized in the launch process. The key chlorohydrin imine reagent 1 contains both the chiral center and the key 5-S-aminomethyl moiety of linezolid. In the launch process, S-1-chloro-2,3-propanediol was utilized to install the oxazolidinone functionality. However, this yielded a 5-S-hydroxymethyl group which required activation as the 3-nitrobenzenesulfonate and displacement with excess ammonia to generate the corresponding aminomethyl group of linezolid. The second generation process affords the oxazolidinone imine 3 in the convergent step. The penultimate 5-S-aminomethyl oxazolidinone 4 is then easily formed via hydrolysis with stoichiometric hydrochloric acid. Acylation of this amine with acetic anhydride, utilizing an improved Schotten Baumann reaction, affords high purity linezolid.

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http://www.google.com/patents/EP2072505A2?cl=en

WO 95/07271 , which specifically describes the synthesis of linezolid, namely [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide], according to the following scheme:
[0003]

Other synthetic routes for the preparation of linezolid are reported for example in US 6107519 and in Tetrahedron Letters, Vol 37, N° 44, pages 7937-7940, wherein the chiral compound shown below is used instead of glycidyl butyrate as a synthon containing the molecule stereocenter.
[0004]

It should be appreciated that all of the known approaches to the preparation of linezolid make use of chiral synthons for the construction of the stereocenter. These are small molecules characterized by a high cost, therefore they are not suitable for the production of the compound on an industrial scale.
[0005]

There is therefore the need for an alternative synthesis which provides oxazolidinone derivatives, linezolid included, from inexpensive starting materials, and which does not require a chiral synthon for the construction of the molecule, so that it can be used for the industrial preparation of such derivatives.

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http://pubs.rsc.org/en/content/articlelanding/2010/md/c0md00015a/unauth

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RSC Adv., 2013,3, 24946-24951

DOI: 10.1039/C3RA45186K

http://pubs.rsc.org/en/content/articlelanding/2013/ra/c3ra45186k#!divAbstract

Graphical abstract: Concise asymmetric synthesis of Linezolid through catalyzed Henry reaction
A new asymmetric synthesis of the antibiotic Linezolid was performed through a copper-catalyzed Henry reaction as the key step. The use of camphor-derived aminopyridine ligands helped to improve the yields of the chiral precursor and to obtain Linezolid in good overall yield and enantiomeric excess.

Linezolid 1. Mp: 181–182 C [lit. 181.5–182.5 C];
1 H-NMR (300 MHz; CDCl3) d 2.02 (s, 3H), 3.06 (t, J ¼ 4.7 Hz, 4H), 3.61– 3.78 (m, 3H), 3.87 (t, J ¼ 4.7 Hz, 4H), 4.03 (t, J ¼ 9.0 Hz, 1H), 4.72–4.82 (m, 1H), 6.17 (bt, 1H, exch. with D2O), 6.93 (t, J ¼ 9.0 Hz, 1H), 7.08 (dd, J1 ¼ 9.0 Hz, J2 ¼ 2.5 Hz, 1H), 7.44 (dd, J1 ¼ 14.4 Hz, J2 ¼ 2.5 Hz, 1H); ee ¼ 71%;

HPLC (Daicel CHIRALPAK-IA, hexane/i-PrOH ¼ 70 : 30, ow rate 0.8 mL min 1 , l ¼ 254 nm); tR (major) ¼ 14.1 min; tR (minor) ¼ 16.4 min. A true sample of (S)-Linezolid (ee > 98%) under the same HPLC conditions gave a tR ¼ 14.1 min.

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http://www.slideshare.net/vishwajeeta/introduction-new-ppt

Introduction new ppt! from vishwajeeta

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http://www.slideshare.net/pushechnikov/linezolid-case-study

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http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc15503b#!divAbstract

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http://www.mdpi.com/1424-8247/3/7/1988/htm

Pharmaceuticals 03 01988 g001 1024

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Numbered structure of linezolid, showing the pharmacophore required for good activity (in blue) and desirable structural features (in orange).

Title: Linezolid

CAS Registry Number: 165800-03-3

CAS Name:N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide

Manufacturers’ Codes: PNU-100766; U-100766

Trademarks: Zyvox (Pharmacia & Upjohn); Zyvoxid (Pharmacia & Upjohn)

Molecular Formula: C16H20FN3O4

Molecular Weight: 337.35

Percent Composition: C 56.96%, H 5.98%, F 5.63%, N 12.46%, O 18.97%

Literature References: Prototype of the oxazolidinone antimicrobials; inhibits bacterial mRNA translation. Prepn: M. R. Barbachyn et al.,WO9507271 (1995 to Upjohn); eidem,US5688792 (1997 to Pharmacia & Upjohn); S. J. Brickner et al.,J. Med. Chem.39, 673 (1996).

Antibacterial spectrum: C. W. Ford et al.,Antimicrob. Agents Chemother.40, 1508 (1996). Mechanism of action study: D. L. Shinabarger et al.,ibid.41, 2132 (1997).

HPLC determn in plasma: C. Buerger et al.,J. Chromatogr. B796, 155 (2003). Clinical comparison with vancomycin, q.v., for MRSA infections: D. L. Stevens et al., Clin. Infect. Dis.34, 1481 (2002).

Review of pharmacology: L. D. Dresser, M. J. Rybak, Pharmacotherapy18, 456-462 (1998); and clinical experience: R. Norrby, Expert Opin. Pharmacother.2, 293-302 (2001).

Properties: White crystals from ethyl acetate and hexanes, mp 181.5-182.5°. [a]D20 -9° (c = 0.919 in chloroform).

Melting point: mp 181.5-182.5°

Optical Rotation: [a]D20 -9° (c = 0.919 in chloroform)

Therap-Cat: Antibacterial.

Keywords: Antibacterial (Synthetic); Oxazolidinones.

Linezolid
Systematic (IUPAC) name


(S)-N-({3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
Clinical data
Trade names	Zyvox, Zyvoxam, Zyvoxid
AHFS/Drugs.com	monograph
MedlinePlus	a602004
Licence data	US FDA:link
Pregnancy category	AU: C US: C
Legal status	AU:Prescription Only (S4) CA: ℞-only UK:POM US:℞-only
Routes of administration	Intravenous infusion, oral
Pharmacokinetic data
Bioavailability	~100% (oral)
Protein binding	Low (31%)
Metabolism	Hepatic (50–70%, CYPnot involved)
Half-life	4.2–5.4 hours (shorter in children)
Excretion	Nonrenal, renal, and fecal
Identifiers
CAS Registry Number	165800-03-3
ATC code	J01XX08
PubChem	CID 441401
DrugBank	DB00601
ChemSpider	390139
UNII	ISQ9I6J12J
KEGG	D00947
ChEMBL	CHEMBL126
NIAID ChemDB	070944
Chemical data
Formula	C₁₆H₂₀F N₃O₄
Molecular mass	337.346 g/mol

Cited Patent	Filing date	Publication date	Applicant	Title
WO1995007271A1 *	Aug 16, 1994	Mar 16, 1995	Michael R Barbachyn	Substituted oxazine and thiazine oxazolidinone antimicrobials
AU2001100437A4 *	Title not available
EP0963980A2 *	Mar 10, 1999	Dec 15, 1999	The Wellcome Foundation Limited	1,2,4-Triazine derivative, its preparation and its use as reference marker for testing purity and stability of “lamotrigine”

* Cited by examiner

Reference
1	*	[Online] August 2002 (2002-08), XP002388488 Retrieved from the Internet: URL:www.emea.eu.int/pdfs/human/ich/273799e n.pdf> [retrieved on 2006-07-03]
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3	*	DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; LIU, JUN ET AL: “Preparation of oxazolidone derivatives as antibacterial agents” XP002429969 retrieved from STN Database accession no. 2003:576097 -& CN 1 355 165 A (INSTITUTE OF MEDICAL AND BIOLOGICAL TECHNOLOGY, CHINESE ACADEMY OF MED) 26 June 2002 (2002-06-26)
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WO2013111048A1	Jan 22, 2013	Aug 1, 2013	Jubilant Life Sciences Limited	Improved process for the preparation of stable crystalline form-i of linezolid, substantially free of residual solvent
WO2014071990A1	Nov 9, 2012	May 15, 2014	Synthon Bv	Process for making linezolid
EP1403267A1 *	Sep 25, 2003	Mar 31, 2004	Daiso Co., Ltd.	Process for preparing glycidylphthalimide
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EP2100884A1	Oct 16, 2003	Sep 16, 2009	Symed Labs Limited	Crystalline form of linezolid
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US6444813	Jan 29, 2001	Sep 3, 2002	Pharmacia & Upjohn Company	Mixing linezolid of an >98% enantomeric purity in a solvent at >80 degrees; separating a crystal (ii) of >99% purity; analysis by the powder x-ray diffraction spectrum/infrared spectrum as a mineral oil mull; bactericides; stability
US6514529	Mar 15, 2001	Feb 4, 2003	Pharmacia & Upjohn Company	A compressed tablet of antibacterial oxazolidinone selected from the group consisting of linezolid, eperezolid and (S)-N-((3-(3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl-2-o xo-5-oxazolidinylmethyl)acetamide S,S-dioxide
US6544991	Jun 21, 2001	Apr 8, 2003	Pharmacia & Upjohn Company	Compositions and methods for treating bacterial infections
US6559305	May 23, 2002	May 6, 2003	Pharmacia & Upjohn Company	Linezolid—crystal form II
US6617339	Jun 3, 1999	Sep 9, 2003	Syngenta Limited	Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
US6796975	Mar 15, 2001	Sep 28, 2004	Pharmacia & Upjohn Company	Container for linezolid intravenous solution
US6833453	Oct 17, 2001	Dec 21, 2004	Pharmacia & Upjohn Company	As an example, manufacturing a 5-(tert-butylcarbamoyl)-amino-methyl-oxazolidinone by condensing a carbamate with a tert-butylcarbamoyl protected derivative of glycidylamine or a 3-amino-1-halopropanol
US6875875	Sep 25, 2003	Apr 5, 2005	Daiso Co., Ltd.	Process for preparing glycidylphthalimide
US6887995	Apr 15, 2002	May 3, 2005	Pharmacia & Upjohn Company	Reacting N-aryl-O-alkylcarbamate with an amide derivative in the presence of a lithium cation, a base, and a nucleophile
US6989381	Aug 20, 2001	Jan 24, 2006	Pharmacia Corporation	Containing s cyclodextrin compound in a concentration sufficient to maintain the drug in solution at such a drug concentration.
US7087784	Mar 25, 2004	Aug 8, 2006	Pharmacia & Upjohn	Process to prepare oxazolidinones
US7128928	Feb 20, 2003	Oct 31, 2006	Pharmacia Corporation	Ophthalmic formulation with novel gum composition
US7135576	Jan 7, 2005	Nov 14, 2006	Daiso Co., Ltd.	Process for preparing glycidylphthalimide
US7307163	Apr 19, 2004	Dec 11, 2007	Symed Labs Limited	Process for the preparation of linezolid and related compounds
US7351824	Oct 8, 2007	Apr 1, 2008	Symed Labs Limited	Intermediates for oxazolidinone antibacterials; N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline
US7429661	Jul 20, 2004	Sep 30, 2008	Symed Labs Limited	Intermediates for linezolid and related compounds
US7524954	Oct 8, 2007	Apr 28, 2009	Symed Labs Limited	Reacting 3-fluoro-4-morpholinyl aniline derivative with epichlorohydrin; converting chloromethyl oxazolidinone to aminomethyl oxazolidinone; carbonylation ; reacting with potassium phthalimide, hydrazine hydrate, and acetic anhydride; cyclization, carbamylation
US7714128	Oct 16, 2003	May 11, 2010	Symed Labs Limited	crystalline linezolid form III (N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide) an antibacterial agent; thermal stability
US7718799	Sep 26, 2007	May 18, 2010	Symed Labs Limited	Crystalline form of linezolid
US7718800	Sep 26, 2007	May 18, 2010	Symed Labs Limited	Prepared by mixing linezolid with solvent or mixture of solvents, cooling contents to below 15 degrees C., optionally seeding contents with linezolid form III, stirring, and collecting linezolid form III crystals by filtration or centrifugation; antibacterial agent; thermally stable
US7732597	Sep 26, 2007	Jun 8, 2010	Symed Labs Limited	Prepared by acetylating (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine in a solvent, optionally in presence of an organic base to form linezolid, seeding reaction mixture, and isolating linezolid form III; antibacterial agent; thermally stable
US7741480	Oct 8, 2007	Jun 22, 2010	Symed Labs Limited	Process for the preparation of linezolid and related compounds
US8658789	Jan 8, 2010	Feb 25, 2014	Lianhe Chemical Technology Co., Ltd.	Method for preparing linezolid and intermediates thereof

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US6492555	Jan 15, 2002	Dec 10, 2002	Pharmacia & Upjohn Company	Reaction of a carbamate with either a (s)-secondary alcohol or (s)-epoxide or (s)-ester; bactericides
US6559305	May 23, 2002	May 6, 2003	Pharmacia & Upjohn Company	Linezolid—crystal form II
US6716980	Jun 27, 2003	Apr 6, 2004	Pharmacia & Upjohn Company	Cyclization and acylation of carbamate
US6740754	Apr 24, 2003	May 25, 2004	Pharmacia & Upjohn Company	Process to produce oxazolidinones
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US6887995	Apr 15, 2002	May 3, 2005	Pharmacia & Upjohn Company	Reacting N-aryl-O-alkylcarbamate with an amide derivative in the presence of a lithium cation, a base, and a nucleophile
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Citing Patent	Filing date	Publication date	Applicant	Title
WO2009032294A2 *	Sep 5, 2008	Mar 12, 2009	Teva Pharma	Processes for the preparation of a linezolid intermediate, linezolid hydroxide
WO2011076678A1 *	Dec 17, 2010	Jun 30, 2011	F. Hoffmann-La Roche Ag	Substituted benzamide derivatives

……………

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

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

https://newdrugapprovals.org/

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Methyl (S)-aminobutyrate hydrochloride…..Levetiracetam intermediate

April 5, 2015 6:24 am / Leave a comment

Methyl (S)-aminobutyrate hydrochloride…..Levetiracetam intermediate

(s)-2-aminobutyric Acid Methyl Ester
CAS No.: 15399-22-1

PATENT

http://www.google.im/patents/WO2003014080A2?cl=en

(S)-amino butyric acid

Step 1 – Synthesis of methyl (S)-aminobutyrate hydrochloride

……………………………(23) …………………………………………………….(24)

5.0g of (S)-amino butyric acid (23) was suspended in 50 ml of methanol and stirred at 0-5°C. 6.35g of thionyl chloride was added dropwise over 45 min to form a clear solution. After stirring for 20 hours at room temperature, the reaction was concentrated under reduced pressure to dryness and the almost colourless residue solidified to give the required product which was dried in an oven at 50°C under vacuum (7.6g; 102% crude yield). The same reaction was scaled-up from 200g of the amino acid and provided 296g (99.5% yield) of product (24). Analysis gave the following results:

1H NMR (DMSO-de) : d 0.94 (3H, t) 1.88 (2H, q) 3.75 (3H, s) 3,9 (1H, m) 8,8

(3H, m). m.p. : 107°C-110°C IR : 2876 cm ¹, 1742 cm ¹.

TLC : Si0₂, 20%MeOH/80%EtOAc/ l%NH OH, UV & IR. (TLC is an abbreviation for thin layer chromatography).

1H NMR PREDICT

(S)-2-aminobutyric acid methyl ester NMR spectra analysis, Chemical CAS NO. 15399-22-1 NMR spectral analysis, (S)-2-aminobutyric acid methyl ester H-NMR spectrum

13C PREDICT

(S)-2-aminobutyric acid methyl ester NMR spectra analysis, Chemical CAS NO. 15399-22-1 NMR spectral analysis, (S)-2-aminobutyric acid methyl ester C-NMR spectrum

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

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

amcrasto@gmail.com

JALGAON, MAHARASHTRA, INDIA

Image result for jalgaon railway station

MANUDEVI

(S)-2-amino-butanamide hydrochloride………. Key intermediate of Levetiracetam

April 5, 2015 6:22 am / Leave a comment

(S)-2-amino-butanamide hydrochloride………. Key intermediate of Levetiracetam

(S)-2-amino-butanamide hydrochloride

Key intermediate of Levetiracetam

CAS Number 7682-20-4

Linear Formula CH₃CH₂CH(NH₂)CONH₂ · HCl

Stage B

(S)-2-aminobutyramide hydrochloride Preparation

Into the above (S)-2-aminobutyric acid methyl ester hydrochloride is added Isopropanol is then added, followed by the introduction of ammonia gas at a pressure about 60 psi (413 kPa) until the reaction is complete. After filtering to remove formed ammonium chloride, the solvent is partially evaporated and isopropanol hydrochloride is added. The mixture is stirred while solid product forms, then the solid is separated by filtration and washed with isopropanol.

The product was characterized by the following ¹H NMR data (200 MHz, DMSO-d₆): 0.9-1.0(t,3H), 1.8-1.9(Q,2H), 3.7-3.8(t, 1H), 7.5-7.7(Br,NH₂), 8.0-8.2(Br,NH₂)

1H NMR PREDICT

………..

13C NMR PREDICT

(2S)-2-aminobutanamide,hydrochloride NMR spectra analysis, Chemical CAS NO. 7682-20-4 NMR spectral analysis, (2S)-2-aminobutanamide,hydrochloride C-NMR spectrum

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

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

https://newdrugapprovals.org/

amcrasto@gmail.com

TIRUPATI, INDIA
Map of tirupati town .

Tirupati తిరుపతి
City
Clockwise from top: Tirumala Venkateswara Temple, Tirumala ghat road, City skyline and Chandragiri fort
Tirupati Location in Andhra Pradesh, India
Coordinates: 13.65°N 79.42°ECoordinates: 13.65°N 79.42°E
Country	India
State	Andhra Pradesh
Region	Rayalaseema
District	Chittoor
Government
• Member of Parliament	Varaprasad Rao Velagapalli
Area
• City	24 km² (9 sq mi)
Elevation	161 m (528 ft)
Population (2011)^[1]
• City	287,035
• Density	12,000/km² (31,000/sq mi)
• Metro^[2]	459,985
Languages
• Official	Telugu
Time zone	IST (UTC+5:30)
PIN	517501
Telephone code	+91–877
Vehicle registration	AP 03
Website	Tirupati Mucnicipal Corporation

.
Kapila Theertham in Tirupati

Food Service During Tirumala Tirupati Devastanam’s ‘Srinivasa Kalyanam Utsavam’ at MARG Swarnabhoomi

(2S)-2- Oxopyrrolidin-1-yl)butanoic acid………….Key Levetiracetam intermediate

April 5, 2015 6:18 am / Leave a comment

(2S)-2- Oxopyrrolidin-1-yl)butanoic acid………….Key Levetiracetam intermediate

(s)-2-(2-oxopyrrolidin-1-yl)butanoic Acid
CAS No.:	102849-49-0
Synonyms:	(2S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid;
Formula:	C8H13NO3
Exact Mass:	171.09000

1H NMR PREDICT

1H NMR (CDCl3, 400 MHz): δ 0.93 (t, J = 7.7 Hz, 3H), 1.67–1.76 (m, 1H), 1.99–2.13 (m, 3H), 2.49 (t, J = 7.7 Hz, 2H), 3.37 (m, J = 8.7, 5.8 Hz, 1H), 3.52-3.58 (m, 1H), 4.64 (dd, J = 10.6, 4.8 Hz, 1H);
Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994

(S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid NMR spectra analysis, Chemical CAS NO. 102849-49-0 NMR spectral analysis, (S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid H-NMR spectrum

13 C NMR PREDICT

13C NMR (CDCl3, 125 MHz) : δ 10.8, 18.2, 21.9, 30.8, 43.9, 55.4, 173.7, 177.2;
Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994

Cosy predict.BELOW

SYNTHESIS AS IN PAPER

Asymmetric synthesis of chiral amines by highly diastereoselective 1,2-additions of organometallic reagents to N-tert-Butanesulfinyl Imines

Chandra Babu K1,2*, Buchi Reddy R3 , Mukkanti K2 , Madhusudhan G1 and Srinivasulu P1
1 Inogent Laboratories (A GVK BIO Company), 28A, IDA, Nacharam, Hyderabad 500 076, India 2Centre for Pharmaceutical Sciences, JNT University, Kukatpally, Hyderabad 500 072, India
3Orchid Chemicals & Pharmaceuticals Ltd, 476/14, R&D Centre, Chennai -600 119, India __________________________________________________________________________
http://jocpr.com/vol4-iss12-2012/JCPR-2012-4-12-4988-4994.pdf

ABSTRACT We report an asymmetric synthesis of chiral amines (4S,5S)-Cytoxazone, Taxol side chain moiety and (S)- Levetiracetam starting from versatile new chiral N- sulfinimine (4). The key step, stereoselective 1,2-addition of Grignard reagent to chiral N-sulfinimine derived from (R)-glyceraldehyde acetonide and (S)-t-BSA gave the corresponding sulfonamide in high diastereoselectivity. Subsequent reactions yielded the targeted biological active and pharmaceutical important compounds with high purity (>99%) and yield

Journal of Chemical and Pharmaceutical Research, 2012, 4(12):4988-4994

(S)-2-(2-oxopyrrolidin-1-yl)butanoic acid, 16 Potassium hydroxide (1.0 g, 0.017 mol)) was dissolved into water (18.0 ml). Tetra-n-butyl ammonium bromide (0.2 g, 0.0062 mol)) and (S)-15 (1.0 g, 0.0063 mol)) in methylene chloride (10 ml) were charged in 30 min. charged Potassium permanganate (1.5 g, 0.094 mol)). After completion of reaction filtered through a celite bed and washed with water (10.0 ml). The aqueous layer pH was adjusted to 3 using hydrochloric acid (2 ml). Added sodium phosphate (2.5 g, 0.0152 mol) and toluene (25.0 ml). The reaction mixture extracted with dichloromethane (5 x 25 ml). The organic solution was dried with (Na2SO4) distilled under vacuo to give compound 16 as oil. To the residue toluene (10 ml) was added and stirred at 0 °C for about 30 min. The solid was filtered and washed with toluene (5 ml) afford the pure compound 16 (0.83g, 76%);

Mp: 124–125 °C; [α] 25 D = – 24.3 (c l.0, acetone);

13C NMR (CDCl3, 125 MHz) : δ 10.8, 18.2, 21.9, 30.8, 43.9, 55.4, 173.7, 177.2;

IR (CHCl3) ν max : 2975, 1731, 1620 cm–1; ESI-MS: m/z 170.0 [M- +1].

Orchid Chemicals & Pharmaceuticals Ltd

Centre for Pharmaceutical Sciences, JNT University

Inogent Laboratories (A GVK BIO Company)

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

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

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Levetiracetam industrial process

April 3, 2015 2:02 pm / Leave a comment

Levetiracetam industrial process

2 pyrolidinone

ethyl 2 bromo butyrate

(R)-(+)-alpha-methyl-benzylamine

ethyl chloro formate

US4943639.

http://www.google.co.in/patents/US4943639

cut paste

note………….racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid is obt by rxn of 2 pyrolidinone with ethyl 2 bromo acetate

+/-)-(R,S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid methyl ester. CAS# 33978-83-5

EXAMPLE 1 (a) Preparation of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

8.7 kg (50.8 moles) of racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 21.5 liters of anhydrous benzene in a 50 liter reactor. To this suspension is added gradually a solution containing 3.08 kg (25.45 moles) of (R)-(+)-alpha-methyl-benzylamine and 2.575 kg (25.49 moles) of triethylamine in 2.4 liters of anhydrous benzene. This mixture is then heated to reflux temperature until complete dissolution It is then cooled and allowed to crystallize for a few hours. 5.73 kg of the (R)-alpha-methyl-benzylamine salt of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are thus obtained.

Melting point: 148°-151° C. Yield: 77.1%.

This salt may be purified by heating under reflux in 48.3 liters of benzene for 4 hours. The mixture is cooled and filtered to obtain 5.040 kg of the desired salt. Melting point: 152°-153.5° C. Yield: 67.85%.

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

5.04 kg of the salt obtained in (a) above are dissolved in 9 liters of water. 710 g of a 30% sodium hydroxide solution are added slowly so that the pH of the solution reaches 12.6 and the temperature does not exceed 25° C. The solution is stirred for a further 20 minutes and the alpha-methylbenzylamine liberated is extracted repeatedly with a total volume of 18 liters of benzene.

The aqueous phase is then acidified to a pH of 1.1 by adding 3.2 liters of 6N hydrochloric acid. The precipitate formed is filtered off, washed with water and dried.

The filtrate is extracted repeatedly with a total volume of 50 liters of dichloromethane. The organic phase is dried over sodium sulfate and filtered and evaporated to dryness under reduced pressure.

The residue obtained after the evaporation and the precipitate isolate previously, are dissolved together in 14 liters of hot dichloromethane. The dichloromethane is distilled and replaced at the distillation rate, by 14 liters of toluene from which the product crystallizes.

The mixture is cooled to ambient temperature and the crystals are filtered off to obtain 2.78 kg of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid.

Melting point: 125.9° C. [alpha]_D²⁰ =-26.4° (c=1, acetone). Yield: 94.5%.

34.2 g (0.2 mole) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid are suspended in 225 ml of dichloromethane cooled to -30° C. 24.3 g (0.24 mole) of triethylamine are added dropwise over 15 minutes. The reaction mixture is then cooled to -40° C. and 24.3 g (0.224 mole) of ethyl chloroformate are added over 12 minutes. Thereafter, a stream of ammonia is passed through the mixture for 41/2 hours. The reaction mixture is then allowed to return to ambient temperature and the ammonium salts formed are removed by filtration and washed with dichloromethane. The solvent is distilled off under reduced pressure. The solid residue thus obtained is dispersed in 55 ml toluene and the dispersion is stirred for 30 minutes and then filtered. The product is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of 0,4 nm molecular sieve in powder form.

24.6 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide are obtained.

Melting point: 115°-118° C. [alpha]_D²⁵ =-89.7° (c=1, acetone). Yield: 72.3%.

Analysis for C₈ H₁₄ N₂ O₂ in % calculated: C 56.45. H 8.29. N 16.46. found: 56.71. 8.22. 16.48.

The racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid used in this synthesis has been prepared in the manner described below.

A solution containing 788 g (19.7 moles) of sodium hydroxide in 4.35 liters of water is introduced over 2 hours into a 20 liter flask containing 3.65 kg (18.34 moles) of ethyl (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetate at a temperature not exceeding 60° C. When this addition is complete, the temperature of the mixture is raised to 80° C. and the alcohol formed is distilled off until the temperature of the reaction mixture reaches 100° C.

The reaction mixture is then cooled to 0° C. and 1.66 liter (19.8 moles) of 12N hydrochloric acid is added over two and a half hours. The precipitate formed is filtered off, washed with 2 liters of toluene and recrystallized from isopropyl alcohol. 2.447 kg of racemic (±)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid, melting at 155°-156° C., are thus obtained. Yield: 78%.

Analysis for C₈ H₁₃ NO₃, in % calculated: C 56.12. H 7.65. N 8.18. found: 55.82. 8.10. 7.97.

EXAMPLE 2 (a) Preparation of ethyl (S)-4-[[1-(aminocarbonyl)propyl]amino]butyrate

143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]_D²⁵ : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.

The reaction mixture is maintained at 80° C. for 10 hours and then filtered hot to remove the triethylamine salts. The filtrate is then evaporated under reduced pressure and 59 g of an oily residue consisting essentially of the monoalkylation product but containing also a small amount of dialkylated derivative are obtained.

The product obtained in the crude state has been used as such, without additional purification, in the preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide by cyclization.

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

54 g of the crude product obtained in a) above are dissolved in 125 ml of toluene in the presence of 2 g of 2-hydroxypyridine. The mixture is heated at 110° C. for 12 hours.

The insoluble matter is filtered off hot and the filtrate is then evaporated under reduced pressure.

The residue is purified by chromatography on a column of 1.1 kg of silica (column diameter: 5 cm; eluent: a mixture of ethyl acetate, methanok and concentrated ammonia solution in a proportion by volume of 85:12:3).

The product isolated is recrystallized from 50 ml of ethyl acetate to obtain 17.5 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

Melting point: 117° C. [alpha]_D²⁵ : -90.0° (c=1, acetone). Yield: 41%.

EXAMPLE 3 (a) Preparation of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutanamide

345.6 g (2.5 moles) of ground potassium carbonate are mixed with 138.5 g (1 mole) of (S)-2-amino-butanamide hydrochloride in 2.5 liters of acetonitrile. The reaction mixture is cooled to 0° C. and a solution of 129.2 g (1.2 mole) of 4-chlorobutyryl chloride in 500 ml of acetonitrile is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 1.2 liter of anhydrous ether for 30 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 225 ml of ether and dried in vacuo to obtain 162.7 g of (S)-N-[1-(aminocarbonyl)propy]-4-chlorobutanamide.

Melting point: 118°-123° C. [alpha]_D²⁵ : -18° (c=1, methanol). Yield: 78.7%.

The crude product thus obtained is very suitable for the cyclization stage which follows. It can however be purified by stirring for one hour in anhydrous ethyl acetate.

Melting point: 120°-122° C. [alpha]_D²⁵ : -22.2° (c=1, methanol).

(b) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide

6.2 g (0.03 mole) of (S)-N-[1(aminocarbonyl)propyl]-4-chlorobutamine and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 45 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes, at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is then stirred for one hour, after which a further 0.1 g (0.0018 mole) of ground potassium hydroxide is added and stirring continued for 30 minutes at 0° C. The mixture is allowed to return to ambient temperature. The insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue obtained is recrystallized from 40 ml of ethyl acetate in the presence of 1.9 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.10 g of (S)-alphaethyl-2-oxo-1-pyrrolidineacetamide.

Melting point: 116.7° C. [alpha]_D²⁵ : -90.1° (c=1, acetone). Yield: 60.7%.

EXAMPLE 4 Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide……levetiracetam

This example illustrates a variant of the process of Example 3, in which the intermediate 4-chlorobutanamide obtained in situ is not isolated. 84 g of anhydrous sodium sulfate are added to a suspension of 69.25 g (0.5 mole) of (S)-2-amino-butanamide hydrochloride in 600 ml of dichloromethane at ambient temperature. The mixture is cooled to 0° C. and 115 g of ground potassium hydroxide are added, followed by 8.1 g (0.025 mole) of tetrabutylammonium bromide dissolved in 100 ml of dichloromethane. A solution of 77.5 g of 4-chlorobutyryl chloride in 100 ml of dichlorometha is added dropwise at 0° C., wih vigorous stirring. After 5 hours’ reaction, a further 29 g of ground potassium hydroxide are added. Two hours later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure. The residue (93.5 g) is dispersed in 130 ml of hot toluene for 45 minutes. The resultant mixture is filtered and the filtrate evaporated under reduced pressure. The residue (71.3 g) is dissolved hot in 380 ml of ethyl acetate to which 23 g of 0,4 nm molecular sieve in powder form are added. This mixture is heated to reflux temperature and filtered hot. After cooling the filtrate, the desired product crystallizes to give 63 g of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

Melting point: 117° C. [alpha]_D²⁵ : -91.3° (c=1, acetone). Yield: 74.1%.

—

FROM MY OLD POST

(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide a key levetiracetam intermediate

(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

methyl (±)-(R,S)-alpha-ethyl-2-oxo-l -pyrrolidine acetate with (+)-(R)-(l-phenylethyl)- amine in toluene in the presence of a base such as sodium hydride or methoxide; crystallization- induced dynamic resolution of the resultant (±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

(R)-(+)-1-Phenylethylamine

33978-83-5
1-Pyrrolidineacetic acid, α-ethyl-2-oxo-, methyl ester

Ebd414139

1004767-60-5
1-Pyrrolidineacetamide, α-ethyl-2-oxo-N-[(1R)-1-phenylethyl]-
(±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide

Example 1

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide.

In a 100 ml reactor equipped with mechanical stirring, thermometer and bubble condenser, 13.4 g of (±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (71.6 mmol), 8.8 g of (+)-(R)-(l-phenylethyl)-amine (72.5 mmol) and 45 ml of tetrahydrofuran were charged. 3.4 g of NaH (60% dispersion in mineral oil, 85.6 mmol) was added in small portions under nitrogen atmosphere. Reaction mixture was maintained at room temperature for about 2 h. Then, it was heated up to 35⁰C and kept under stirring overnight. Reaction was controlled by TLC (Rf = 0.5, AcOEt/silica gel).

At reaction completed, one night at 35°C temperature, reaction mixture was cooled to room temperature and 30 ml of water was slowly charged. It was transferred into a separatory funnel and was diluted with 30 ml of water and 80 ml of dichloromethane. Phases were separated and the aqueous one was washed with 50 ml of dichloromethane. Collected organic phases were washed with an aqueous acid solution, dried on Na₂SO₄, filtered and concentrated under vacuum. 19.5 g of an oil residue was obtained which slowly solidified. Solid was suspended in 20 ml of a hexane/dichloromethane 9/1 v/v mixture. It was then filtered, washed with 10 ml of the same solvent mixture and dried at 40⁰C to give 12.1 g of the title compound (44.1 mmol, 61.6% yield) as dry solid.

¹H NMR (400.13 MHz, CDCl₃, 25 ⁰C): δ (ppm, TMS)
7.35-7.19 (1OH, m),
6.49 (2H, br s),
5.09-5.00 (2H, m),
4.41 (IH, dd, J = 8.3, 7.4 Hz),
4.36 (IH, dd, J = 8.6, 7.1 Hz),
3.49 (IH, ddd, J = 9.8, 7.7, 6.6 Hz),
3.41 (IH, ddd, J = 9.8, 7.7, 6.2 Hz),
3.30 (IH, ddd, J = 9.6, 8.3, 5.5 Hz),
3.13 (IH, ddd, 9.7, 8.5, 6.1 Hz), 2.47-2.38 (2H, m), 2.41 (IH, ddd, J = 17.0, 9.6, 6.3 Hz), 2.26 (IH, ddd, 17.0, 9.5, 6.6 Hz), 2.10-1.98 (2H, m), 2.01-1.89 (IH, m), 1.99-1.88 (IH, m), 1.98-1.85 (IH, m), 1.88-1.78 (IH, m), 1.75- 1.62 (IH, m), 1.72-1.59 (IH, m), 1.45 (3H, d, J = 7.1 Hz), 1.44 (3H, d, J = 7.1 Hz), 0.90 (3H, t, J = 7.4 Hz), 0.86 (3H, t, J = 7.4 Hz).

¹³C NMR (100.62 MHz, CDCl₃, 25 ⁰C): δ (ppm, TMS)
176.05 (CO), 176.00 (CO), 169.08 (CO),
168.81 (CO), 143.59 (C_quat),
143.02 (C_quat), 128.66 (2 x CH), 128.55 (2 x CH),
127.33 (CH), 127.19 (CH), 126.05 (2 x CH),
125.80 (2 x CH), 56.98 (CH), 56.61 (CH),
48.90 (CH), 48.84 (CH), 44.08 (CH₂),
43.71 (CH₂), 31.19 (CH₂), 31.07 (CH₂), 22.08 (CH₃),
22.04 (CH₃), 21.21 (CH₂), 20.68 (CH₂),
18.28 (CH₂), 18.08 (CH₂), 10.50 (CH₃), 10.45 (CH₃).

Example 2 (±)-(R.S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 1).

In a 500 ml reactor equipped with mechanical stirring, thermometer and condenser, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0⁰C temperature under nitrogen atmosphere, 9.5 g of NaH (60% mineral oil suspension, 237.50 mmol) was added in small portions. At the same temperature, 190.0 g of a toluene solution of (±)-(R,S)- alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 35°C and maintained in that condition till complete disappearing of methyl ester reagent (about 14 h; checked by HPLC).

At reaction completed, reaction mixture was cooled and when room temperature was reached, 100 ml of water was slowly charged. Aqueous phases were separated and extracted with toluene (2 x 75 ml). Collected organic phases were treated with acid water till neuter pH. Solvent was evaporated and residue was suspended in about 100 ml of heptane for about 30 minutes. Product was isolated by filtration and dried in oven at 40⁰C temperature under vacuum overnight to give 45.2 g of the title compound (164.54 mmol, 83.2% yield, d.e. 0.0%) as white dusty solid.

Example 3

(±)-(R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide (alternative 2).

In a 500 ml reactor equipped with mechanical stirring, thermometer and Dean-Stark distiller, 24.2 g of (+)-(R)-(l-phenylethyl)-amine (199.51 mmol) and 40 ml of toluene were charged. By keeping the reaction mixture at 0⁰C temperature, 42.7 g of sodium methoxide (30% solution in methanol, 237.14 mmol) was added under nitrogen atmosphere. At the same temperature, 190.0 g of a toluene solution of (±)- (R,S)-alpha-ethyl-2-oxo-l-pyrrolidineacetic acid methyl ester (19.28% equal to 36.63 g, 197.77 mmol) was charged. Reaction mixture was then heated up to 65- 70⁰C and maintained in that condition till complete disappearing of methyl ester reagent (about 4 h; checked by HPLC). After a work-up carried out according to the procedure described in example 2, 40.2 g of the title compound (146.53 mmol, 74.1% yield, d.e. 0.0%) as white dusty solid was obtained.

http://www.google.com/patents/WO2008012268A1?cl=en

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

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US 7902380, Levetiracetam

US 7902380, Levetiracetamhttp://www.google.im/patents/US7902380

preparation of both the (S)— and (R)-enantiomers of alpha-ethyl-2-oxo-1-pyrrolidineacetamide of formula 1 from (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid of formula 2.

The following is an exemplary scheme of the process:

Suitable resolving agents include optically pure bases such as alpha-methylbenzylamine and dehydroabietylamine, of which alpha-methylbenzylamine is preferred. (S)-2 can be prepared by forming the salt with (R)-alpha-methylbenzylamine and the (R)-2 can be prepared by forming the salt with (S)-alpha-methylbenzylamine.
NOTE……R)-alpha-methylbenzylamine is desired agent to get levetiracetam

The optical resolution of 2 may be carried out by, for example, the formation of a salt of (S)-2 with the optically active base (R)-alpha-methylbenzylamine or dehydroabietylamine (S. H. Wilen et al. Tetrahedron, 33, (1997), 2725-2736). Likewise, the (R)-2 can be prepared by forming the salt with (S)-alpha-methylbenzylamine. The racemic (RS)-2 used as starting material can be prepared by the known procedure described in GB 1309692.

Surprisingly we have found that the undesired (R) or (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid or their mixture can be epimerized by treating it with an acid anhydride, preferably acetic anhydride, propionic anhydride and butyric anhydride, to furnish a mixture of (R) and (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid in excellent yield. The recovered (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid can be optically resolved by the same procedure above. In this way, we are able to obtain almost complete conversion of the (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid to the desired (R) or (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid.

Figure US07902380-20110308-C00007

Figure US07902380-20110308-C00008

The process is depicted below:

EXAMPLE 1
Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide from (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

A suspension of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (45 g, 0.26 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (53 g, 0.53 mol) and methanesulfonyl chloride (39 g, 0.34 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was crystallized from methyl isobutyl ketone to give 36 g (80%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

EXAMPLE 2
Preparation of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide from (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid

A suspension of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (35 g, 0.20 mol) in methylene chloride (225 ml) was cooled to 0° C. and triethylamine (41 g, 0.40 mol) and methanesulfonyl chloride (29 g, 0.26 mol) were added dropwise. The mixture was stirred at 0° C. for 30 min., then a stream of ammonia was purged in the solution at 0° C. for 2 hours. The insoluble solids were filtered and the filtrate was concentrated. The product was recrystallized from methyl isobutyl ketone to give 27.5 g (78%) of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.

EXAMPLE 3
Preparation of (S)-alpha-Ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt

A solution of (R)-alpha-methylbenzylamine (106 g) and triethylamine (89 g) in toluene (100 ml) was added to a suspension of (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (300 g, 1.75 mol) in toluene (1 L). The mixture was heated until complete dissolution, cooled to room temperature and stirred for 3 hours. The solids were filtered and rinsed with toluene (300 ml) to give 250 g of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt. The solids were crystallized from toluene and 205 g (yield 41%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt was obtained. The isolated solid was treated with hydrochloric acid solution and the enantiomerically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid could be isolated in 90% yield.

EXAMPLE 4
Recovery and Epimerization of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid from the Mother Liquor

The combined mother liquors from above were concentrated to half volume and water (200 ml) and 50% sodium hydroxide (52 g) were added sequentially and the mixture was stirred at 20° C. for 30 min. and then was separated. The aqueous layer was washed with toluene (150 ml), acidified with 32% hydrochloric acid until pH=2-3. The resulting suspension was cooled to 0-5° C. and stirred for 2 h. The solids were collected by filtration, and were rinsed with cold water. The damp solids were dried under vacuum oven at 40-50° C. for 4 h to give 160 g of (R)-enriched ethyl-2-oxo-1-pyrrolidineacetic acid. To the above solids, toluene (640 ml) and acetic anhydride (145 g) were added and the mixture was heated to reflux for 10 h. The solution was cooled to 20° C. and stirred for another 2 h. The solids were collected by filtration and rinsed with toluene (150 ml) to give (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (152 g).

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Levetiracetam Green process construction

April 3, 2015 10:14 am / Leave a comment

Dr. Rakeshwar Bandichhorl Director API – R&D,

Dr Reddys

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LEVETIRACETAM GREEN PROCESS

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An alternate synthesis of levetiracetam
Ravikumar Mylavarapu a , Ramasamy Vijaya Anand a , Golla China Mala Kondaiah a , Lekkala
Amarnath Reddy a , Gade Srinivas Reddy a , Arnab Roy a , Apurba Bhattacharya a , Kagga
Mukkanti b & Rakeshwar Bandichhor a
a Innovation Plaza, IPDO, R&D , Dr. Reddy’s Laboratories Ltd. , Survey Nos. 42, 45,46 & 54,
Bachupally, Qutubullapur, 500073, R.R. Dist, Andhra Pradesh, India
b Center for Environmental Science, Institute of Science and Technology , J.N.T. University ,
Kukatpally, Hyderabad, 500 072, Andhra Pradesh, India

Email: rakeshwarb@drreddys.com

Green Chemistry Letters and Reviews
Vol. 3, No. 3, September 2010, 225230

Ravikumar Mylavarapu , Ramasamy Vijaya Anand , Golla China Mala Kondaiah , Lekkala Amarnath Reddy ,
Gade Srinivas Reddy , Arnab Roy , Apurba Bhattacharya , Kagga Mukkanti & Rakeshwar Bandichhor (2010)

An alternate
synthesis of levetiracetam, Green Chemistry Letters and Reviews, 3:3, 225-230, DOI: 10.1080/17518251003716568
To link to this article: http://dx.doi.org/10.1080/17518251003716568

Publications

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Editorial: Chem Sci J 2014, 5:e101

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Research Perspective in Academia and Generic Pharmaceutical Industry

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Editorial: Organic Chem Current Res 2012, 1:e104

doi: 10.4172/2161- 0401.1000e104

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A Novel Synthesis of Oxazolidinone Derivatives (A Key Intermediate of Linezolid)

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Convergent Green Synthesis of Linezolid (Zyvox)

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(±)-(R,S)-alpha-ethyl-2- oxo-l-pyrrolidineacet-N-(+)-(R)-(l-phenylethyl)-amide a key levetiracetam intermediate

(R)-(+)-1-Phenylethylamine

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