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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, 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 Open superstar 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 30 year tenure till date Dec 2017, Around 35 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, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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

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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…

View original post 1,474 more words

Overview about API manufacturing for the European market


DRUG REGULATORY AFFAIRS INTERNATIONAL

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. Please read more about the API registrations in EudraGMDP.

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


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


Skeletal formula of linezolidLINEZOLID

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

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

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 C-NMR spectrum

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

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  • 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),

    Figure imgb0001
  • [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 ),

    Figure imgb0002
  • [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 ),
      Figure imgb0003

      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 ),
      Figure imgb0004

      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),
      Figure imgb0005

      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),
      Figure imgb0006

      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),

    Figure imgb0007

    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 C16H20FN3Oand the following structure (1):
Figure US20060252932A1-20061109-C00001
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:
Figure US20060252932A1-20061109-C00002
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 NaNcan 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)
Figure US20060252932A1-20061109-C00003

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)
Figure US20060252932A1-20061109-C00004

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)

Figure US20060252932A1-20061109-C00005

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)

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.20037 (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

Abstract Image
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 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
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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:
Figure imgf000002_0001

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:
Figure imgf000003_0001
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:
Figure imgf000008_0001
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:
Figure imgf000009_0001

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
Figure imgf000015_0001
Figure imgf000015_0002
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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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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)
Figure imgf000011_0001
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.
Figure imgf000012_0001
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.
Figure imgf000012_0002
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. TR (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. TR [title compound] = 3.6 min; TR (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.
Figure imgf000013_0001
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:

      Figure imgb0001
    • [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.

      Figure imgb0002
    • [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

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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
Skeletal formula of linezolid
Linezolid-from-xtal-2008-3D-balls.png
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
  • AU: C
  • US: C
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
165800-03-3 Yes
J01XX08
PubChem CID 441401
DrugBank DB00601 
ChemSpider 390139 Yes
UNII ISQ9I6J12J Yes
KEGG D00947 Yes
ChEMBL CHEMBL126 Yes
NIAID ChemDB 070944
Chemical data
Formula C16H20FN3O4
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”
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]
2 * [Online] June 1995 (1995-06), XP002388489 Retrieved from the Internet: URL:www.emea.eu.int/pdfs/human/ich/38195en .pdf> [retrieved on 2006-07-03]
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)
4 * GLEAVE D M ET AL: “Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 10, 19 May 1998 (1998-05-19), pages 1231-1236, XP004137053 ISSN: 0960-894X
5 * REDDY K V S R K ET AL: “Isolation and characterization of process related impurities in linezolid” JOURNAL OF PHARMACEUTICAL AN BIOMEDICAL ANALYSIS, vol. 30, no. 3, 15 October 2003 (2003-10-15), pages 635-642, XP002388486
WO2001057035A1 * Jan 29, 2001 Aug 9, 2001 Upjohn Co Linezolid-crystal form ii
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WO2005099353A2 * Apr 19, 2004 Oct 27, 2005 Reddy Pingili Krishna A novel process for the preparation of linezolid and related compounds
WO2006008754A1 Jul 20, 2004 Jan 26, 2006 Reddy Pingili Krishna Novel intermediates for linezolid and related compounds
WO2006031179A1 * Sep 12, 2005 Mar 23, 2006 Astrazeneca Ab Process for preparation of phtalimide
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WO2013072923A1 Sep 18, 2012 May 23, 2013 Cadila Healthcare Limited Process for the preparation of crystalline linezolid
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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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
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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
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US8658789 Jan 8, 2010 Feb 25, 2014 Lianhe Chemical Technology Co., Ltd. Method for preparing linezolid and intermediates thereof
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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
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
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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
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
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
US7649096 * Jul 17, 2006 Jan 19, 2010 Glenmark Pharmaceuticals Limited crystallization of linezolid antibacterial agent in solvent and antisolvent
US20060111350 Jun 29, 2005 May 25, 2006 Judith Aronhime Solid forms of linezolid and processes for preparation thereof
US20060142283 Jun 29, 2005 Jun 29, 2006 Judith Aronhime Crystalline form IV of linezolid
US20090156806 Dec 11, 2008 Jun 18, 2009 Dipharma Francis S.R.I. Process for the Preparation of Oxazolidinone Derivatives
WO1995007271A1 Aug 16, 1994 Mar 16, 1995 Michael R Barbachyn Substituted oxazine and thiazine oxazolidinone antimicrobials
WO2005035530A1 Oct 16, 2003 Apr 21, 2005 Reddy Pingili Krishna A novel crystalline form of linezolid
WO2007026369A1 Aug 29, 2005 Mar 8, 2007 Reddy Pingili Krishna A novel amorphous form of linezolid
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.

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.

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


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

(s)-2-aminobutyric Acid Methyl Ester
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).
logo
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
logo
(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.
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.
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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  JALGAON, MAHARASHTRA, INDIA

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MANUDEVI

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


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

………..

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.
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.
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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TIRUPATI, INDIA
Map of tirupati town.

Tirupati
తిరుపతి
City
Clockwise from top: Tirumala Venkateswara Temple, Tirumala ghat road, City skyline and Chandragiri fort

Clockwise from top: Tirumala Venkateswara Temple, Tirumala ghat road, City skyline and Chandragiri fort
Tirupati is located in Andhra Pradesh

Tirupati
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

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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


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

(s)-2-(2-oxopyrrolidin-1-yl)butanoic Acid
CAS No.: 102849-49-0
Synonyms:
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
(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 C-NMR spectrum

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);

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);

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.
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.
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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Levetiracetam industrial process


Levetiracetam industrial process

2 pyrolidinone
Inline image 2
ethyl 2 bromo butyrate
Inline image 1
 (R)-(+)-alpha-methyl-benzylamine
Inline image 3
ethyl chloro formate
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%.
(c) Preparation of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
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 (Cquat),
143.02 (Cquat), 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.

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.

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.

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

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updated

US 7902380, Levetiracetam

Levetiracetam.svgUS 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.
Figure US07902380-20110308-C00005
The following is an exemplary scheme of the process:
Figure US07902380-20110308-C00006

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:
Figure US07902380-20110308-C00009

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.
Levetiracetam.svg

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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vietnam

 

Map of vietnam country.

 

 

 

 

 

 

 

 

 

 

dalat city

hanoi

 

 

 

 

 

 

Levetiracetam Green process construction


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
You might enjoy reading:

– See more at: http://organicsynthesisinternational.blogspot.in/#sthash.ruewyXXk.dpuf

Dr Rakeshwar Bandichhor

Rakeshwar Bandichhor
Associate Director, API, R&D
Dr. Reddy’s Laboratories
India
Dr. Reddys Laboratories
 
BiographyRakeshwar Bandichhor holds a doctorate in Chemistry from University of Lucknow/University of Regensburg, Germany and worked as Postdoctoral Fellow at University of Regensburg, Germany, University of Pennsylvania and Texas A&M University. Dr. Rakeshwar has more than 150 papers including patents and book chapters published/accepted in various International Journals and contributed to more than 60 academic national and international conferences. He has won the various awards in his career
Dr. Rakeshwar has more than 80 papers including patents and book chapters published/accepted in various International Journals. Notably, in the area of Organic Chemistry, Dr. Rakeshwar has coauthored a chapter in the book entitled “Green Chemistry in Pharmaceutical industry”.
He has won the various awards in his career e.g. Chairman Excellence Award in the category of individual functional excellence, Best Cost Leadership Award  for the development of Lopinavir, Ritonavir & their components and Anveshan Award at Dr. Reddy’s. As a part of organizational building efforts, he also supervises master’s & Ph.D. students in their dissertations. He has been invited in several conferences e.g. IIT-Mumbai, IGCW-2009, BIT-Ranchi, BITS Pilani, 9th Heterocyclic Conference, University of Florida, JNTU-Hyderabad, ISCB-2011, Apollo Hospitals Educational & Research Foundation, Hyderabad etc. to deliver  lectures. He is also currently acting as an Associate  Editor of GERF Bulletin of Bioscience.
Recently, he has become a member National Advisory Board of Indian Society of Chemists and Biologists.

Publications

Role of Generic Pharmaceutical Industry in Healthcare
Rakeshwar Bandichhor
Editorial: Chem Sci J 2014, 5:e101
doi: 10.4172/2150-3494.10000e101
Research Perspective in Academia and Generic Pharmaceutical Industry
Rakeshwar Bandichhor
Editorial: Organic Chem Current Res 2012, 1:e104
doi: 10.4172/2161- 0401.1000e104

Innovation Plaza, IPDO, R&D , Dr. Reddy’s Laboratories Ltd.

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MAHABALIPURAM, INDIA

Mahabalipuram – Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Mahabalipuram

Mahabalipuram, also known as Mamallapuram is a town in Kancheepuram district in the Indian state of Tamil Nadu. It is around 60 km south from the city of …Shore Temple – ‎Seven Pagodas – ‎Pancha Rathas – ‎

Map of mahabalipuram.

.

Krishna’s Butter Ball in Mahabalipuram, India. The surface below the rock is …


http://www.weather-forecast.com/locations/Mamallapuram


Come to Mahabalipuram (also known as Mammallapuram), an enchanting beach that is located on the east coast of India.
Moonraikers Restaurant, Mamallapuram
 

Hotel Mamalla Bhavan – Mahabalipuram Chennai – Food, drink and entertainment

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A carving at the Varaha Temple, Mahabalipuram

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The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy


 Developing queen larvae surrounded by royal jelly

Royal jelly is a honey bee secretion that is used in the nutrition of larvae, as well as adult queens.[1] It is secreted from the glands in the hypopharynx of worker bees, and fed to all larvae in the colony, regardless of sex or caste.[2]

When worker bees decide to make a new queen, because the old one is either weakening or dead, they choose several small larvae and feed them with copious amounts of royal jelly in specially constructed queen cells. This type of feeding triggers the development of queen morphology, including the fully developed ovaries needed to lay eggs.[3]

Other Common Names:  Apilak, Gelée Royale, Queen Bee Jelly

Royal Jelly has been called the “Crown Jewel” of the beehive that has become extremely popular since the 1950s as a wonderful source of energy and natural way to increase stamina; perhaps that is the reason why the Queen Bee is so strong and enduring.  It is also thought to be a great nutritional source of enzymes, proteins, sugars and amino acids, but there is no scientific proof to verify the supplement’s efficacy for its use as an overall health tonic.  You’ll have to decide.

History:
Royal Jelly is a thick, milky material that is secreted from the hypopharyngea- salivary glands in the heads of the young nurse bees between the sixth and twelfth days of life, and when honey and pollen are combined and refined within the nurse bee, Royal Jelly is naturally created.  While all larvæ in a colony are fed Royal Jelly, it is the only food that is fed to the Queen Bee throughout her life; other adult bees do not consume it at all.  All female eggs may produce a Queen Bee, but this occurs only when – during the whole development of the larvæ – she is cared for and fed by this material – in large quantities.  As a result of this special nutrition, the Queen develops reproductive organs (while the worker bee develops traits that relate only to work, i.e., stronger mandibles, brood food, wax glands and pollen baskets).  The Queen develops in about fifteen days, while the workers require twenty-one; and finally, the Queen endures for several years, while workers survive only a few months. “10-2 HDA,” thought to be the principle active substance in Royal Jelly, makes the Queen Bee fifty percent larger than the other female worker bees and gives her incredible stamina, ovulation ability and longevity, living four to five years longer than worker bees who only live forty or more days.  Perhaps this is the reason why so many positive qualities have been attributed to Royal Jelly as a truly rare gift of nature, but it should be noted that there is no clinical evidence to support the claims.  There is even great controversy as to the constituents included in the supplement.  Most researchers claim that it includes all the B-vitamins and vitamins A, C, D and E; some disagree.  It does contain proteins, sugars, lipids (essential fatty acids), many essential amino acids, collagen, lecithin, enzymes and minerals, in addition to the very valuable

10-2-HDA (10-Hydroxy-2-Decenoic Acid).  It is said that Royal Jelly may be most effective when combined with honey.  You can decide whether any improvements you derive from Royal Jelly’s use are purely coincidental, but if  (and when) you feel better when using it, just enjoy the benefits.

10-2-HDA (10-Hydroxy-2-Decenoic Acid)

Beneficial Uses:
Many fans claim that Royal Jelly is a great way to increase energy, as well as a remarkable stamina booster.  In addition, it is also considered a means to enhance the immune system and maintain overall health.

Royal Jelly is said to alleviate a variety of problems, such as exhaustion, anxiety, mild depression, insomnia and lack of energy and stamina.   Royal Jelly is also believed to have a calming effect on the nervous system.

Some people maintain that Royal Jelly has helped to improve skin disorders and has slowed down the ageing process.  Royal Jelly’s collagen, lecithin and vitamins A, C, D and E all benefit the skin, helping to moisturize dry skin and soothe dermatitis.

In 1977, scientists at the Beijing Medical University reported that when Royal Jelly was administered to male and female neurasthenia patients, all patients reported very effective (86%) or effective (14%) improvement.  Insomnia was eliminated, quality of sleeping increased and headache and dizziness were alleviated.  It was also said that physical and mental abilities, appetite and working efficiency were improved.

The 10-Hydroxy-2-Decenoic Acid (10-2-HDA) content in Royal Jelly, is said to possess strong inhibition of malignant cell growth, namely transferable AKR leukemia, TA3 breast malignancy, etc., and recent studies indicated immuno-regulation and anti-malignancy activities.  It can promote the growth of T-lymphocyte subsets, Interleukin-2 and the generation of tumor necrosis factor.  Much research is being conducted on this valuable active constituent, which has exhibited positive physiological and pharmacological effects including vasodilative and hypotensive activities, antihypercholesterolemic activity and anti-inflammatory functions.  In addition to these activities, the 10-HDA in Royal Jelly has been suggested to improve menopausal symptoms.

Other benefits attributed to the qualities of Royal Jelly include relief of bronchial asthma, liver, pancreatic and kidney ailments, stomach ulcers and bone fractures.

Contraindications:
Royal Jelly Nutritional Supplement is a natural bee product and may induce allergic reactions in some people and should, therefore, be tested in very small amounts before continued use.  Symptoms of allergy include breathing problems or tightness in your throat or chest, chest pain, skin hives, rash or itchy or swollen skin.

Cultivation

Royal jelly is secreted from the glands in the heads of worker bees, and is fed to all bee larvae, whether they are destined to become drones (males), workers (sterile females), or queens (fertile females). After three days, the drone and worker larvae are no longer fed with royal jelly, but queen larvae continue to be fed this special substance throughout their development. It is harvested by humans by stimulating colonies with movable frame hives to produce queen bees. Royal jelly is collected from each individual queen cell (honey comb) when the queen larvae are about four days old. It is collected from queen cells because these are the only cells in which large amounts are deposited; when royal jelly is fed to worker larvae, it is fed directly to them, and they consume it as it is produced, while the cells of queen larvae are “stocked” with royal jelly much faster than the larvae can consume it. Therefore, only in queen cells is the harvest of royal jelly practical. A well-managed hive during a season of 5–6 months can produce approximately 500 g of royal jelly. Since the product is perishable, producers must have immediate access to proper cold storage (e.g., a household refrigerator or freezer) in which the royal jelly is stored until it is sold or conveyed to a collection center. Sometimes honey or beeswax are added to the royal jelly, which is thought to aid its preservation.

Composition

The overall composition of royal jelly is 67% water, 12.5% crude protein, including small amounts of many different amino acids, and 11% simple sugars (monosaccharides), also including a relatively high amount (5%) of fatty acids. The main acid is the 10-hydroxy-2-decenoic acid or 10-HDA (about 2 – 3%).It also contains many trace minerals, some enzymes, antibacterial and antibiotic components, pantothenic acid (vitamin B5), vitamin B6 (pyridoxine) and trace amounts of vitamin C,[2] but none of the fat-soluble vitamins, A, D, E and K.[4]

Royalactin

The component of royal jelly that causes a bee to develop into a queen appears to be a single protein that has been called royalactin. Jelly which had been rendered inactive by prolonged storage had a fresh addition of each of the components subject to decay and was fed to bees; only jelly laced with royalactin caused the larvae to become queens.[5] Royalactin also induces similar phenotypical change in the fruitfly (Drosophila melanogaster), marked by increased body size and ovary development.

Epigenetic effects

The honey bee queens and workers represent one of the most striking examples of environmentally controlled phenotypic polymorphism. In spite of their identical clonal nature at the DNA level, they are strongly differentiated across a wide range of characteristics including anatomical and physiological differences, longevity of the queen, and reproductive capacity.[6] Queens constitute the sexual caste and have large active ovaries, whereas workers have only rudimentary, inactive ovaries and are functionally sterile. The queen/worker developmental divide is controlled epigenetically by differential feeding with royal jelly; this appears to be due specifically to the protein royalactin. A female larva destined to become a queen is fed large quantities of royal jelly; this triggers a cascade of molecular events resulting in development of a queen.[3] It has been shown that this phenomenon is mediated by an epigenetic modification of DNA known as CpG methylation.[7] Silencing the expression of an enzyme that methylates DNA in newly hatched larvae led to a royal jelly-like effect on the larval developmental trajectory; the majority of individuals with reduced DNA methylation levels emerged as queens with fully developed ovaries. This finding suggests that DNA methylation in honey bees allows the expression of epigenetic information to be differentially altered by nutritional input.

Uses

Citing various potential health benefits seen in lab studies, royal jelly is collected and sold as a dietary supplement for humans, but the European Food Safety Authority has rejected these claims stating that the current evidence does not support consuming royal jelly will give health benefits in humans.[8] In the United States, both the Federal Trade Commission and the Food and Drug Administration have taken legal action against companies that have used unfounded claims of health benefits to market royal jelly products.[9][10][11][12]

Adverse effects

Royal jelly may cause allergic reactions in humans ranging from hives, asthma, to even fatal anaphylaxis.[13][14][15][16][17][18] The incidence of allergic side effect in people who consume royal jelly is unknown. The risk of having an allergy to royal jelly is higher in people who have other allergies.[13]

The benefits of Royal Jelly are truly extensive. The list of benefits is so extensive that it may actually appear to be ‘too good to be true’ to many of us, myself included. I’m still amazed every time I scan the many studies done on this amazing substance.Royal Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!

What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.  Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!  What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.
 Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- See more at: http://www.collective-evolution.com/2013/06/06/the-royal-benefits-of-royal-jelly/#sthash.DPhCubyY.dpufRoyal Jelly is one of the naturally occurring miraculous super foods on the planet that gets very little press!  It packs a powerful health punch and here’s why:Royal Jelly is a substance produced by worker honey bees.  Bee colonies function on a hierarchical system:  Bees all start out as unisex larvae, blank slate bee babies if you will.  Then they break off into 1 of 3 roles within their colony.  The worker bees (females), the drones (males used for reproduction) and The Queen Bee.The workers and drones have a typical life span of 3-4 months, whereas The Queen Been can live for up to 7 years!  What differentiates the role of The Queen Bee from the workers and the drones is quite simply what she is fed!  Keep in mind, she starts off the same as the rest of colony but her diet transforms her into The Queen Bee.
 Workers and drones are fed royal jelly when they hatch, followed by pollen and honey for the following 6 days.  The Queen Bee on the other hand, is exclusively fed royal jelly for the entirety of her life- See more at: http://www.collective-evolution.com/2013/06/06/the-royal-benefits-of-royal-jelly/#sthash.DPhCubyY.dpufRoyal jelly is a substance that is secreted from the glands of worker bees to feed their larvae and queens. It is thick in texture, milky-white in color, and has been harvested by humans for centuries for its rejuvenating properties. Indeed, it is a fact that queen bees – which are fed royal jelly their entire lives – live approximately 40 times longer than drone or worker bees, largely due to the jelly’s nutritiousness.

Cancer-fighting properties – According to a study published in a 2009 edition of the BMC Complementary and Alternative Medicine, royal jelly fights cancer by suppressing the blood supply to tumors. When the Japanese researchers tested various royal jelly types on umbilical vein tissue cultures, all of them inhibited the formation of blood vessels, especially those richest in caffeic acid, a compound responsible for the greatest suppressive levels. Moreover, since the fatty components of royal jelly contain estrogenic effects – as proved by a study published in the December 2010 edition of PLoS One – it is possible that royal jelly can treat breast and cervical cancer.
Improves blood health – A study published in the November 2008 edition of the Biological and Pharmaceutical Bulletin showed that royal jelly can improve insulin resistance and blood pressure. The researchers fed the jelly to rats suffering from high blood pressure and insulin resistance due to a high-fructose diet. After two months, the rats demonstrated noticeably fewer instances of blood vessel constriction, which resulted in lower triglyceride and insulin levels.

Skincare properties – Although Royal jelly is best-known as a health supplement, it is often used in skincare products because it contains DNA and gelatin, two ingredients that aid collagen production (and thus anti-aging activity). For this reason, many people like to apply royal jelly topically and allow it to nourish and invigorate their skin.

Antibacterial components – According to a study published in the July 1990 edition of the Journal of Biological Chemistry, a protein found in royal jelly – unofficially named royalisin – provides numerous antibacterial and antimicrobial properties, and is effective at dealing with certain bacterial cultures at lower levels.

Rich in nutrients – As with other bee products such as bee pollen and propolis, royal jelly’s biggest attraction is probably its impressive concentration of vitamins and minerals. Indeed, an average serving of royal jelly contains seventeen different amino acids (including all eight essential amino acids, making it a complete protein), most of the B-vitamins (which are used for the production and synthesis of energy), and respectable levels of iron and calcium, which are essential for superior blood and bone Health. Royal jelly also contains vitamins A, C, and E, which are important antioxidants that can neutralize free radical activity, thus guarding us from degenerative diseases.

Infertility treatment – It is not a coincidence that worker bees are infertile, while queen bees can lay up to 2,000 eggs per day throughout their extensive 4 to 6 year lifespan. This is because royal jelly stimulates estrogen production, thereby stabilizing menstrual cycles in women, improving sperm morphology in men, and increasing the libido of both sexes.

Notes

  1. ^ Jung-Hoffmann L: Die Determination von Königin und Arbeiterin der Honigbiene. Z Bienenforsch 1966, 8:296-322.
  2. ^ a b Graham, J. (ed.) (1992) The Hive and the Honey Bee (Revised Edition). Dadant & Sons.
  3. ^ a b Maleszka, R, Epigenetic integration of environmental and genomic signals in honey bees: the critical interplay of nutritional, brain and reproductive networks. Epigenetics. 2008, 3, 188-192.
  4. ^ “Value-added products from beekeeping. Chapter 6.”.
  5. ^ Kamakura, M. (2011). “Royalactin induces queen differentiation in honeybees”. Nature 473 (7348): 478–483. doi:10.1038/nature10093. PMID 21516106. edit
  6. ^ Winston, M, The Biology of the Honey Bee, 1987, Harvard University Press
  7. ^ Kucharski R, Maleszka, J, Foret, S, Maleszka, R (2008). “Nutritional Control of Reproductive Status in Honeybees via DNA Methylation”. Science 319 (5871): 1827–1833. doi:10.1126/science.1153069.
  8. ^ “Scientific Opinion”. EFSA Journal 9 (4): 2083. 2011.
  9. ^ “QVC to Pay $7.5 Million to Settle Charges that It Aired Deceptive Claims”. Federal Trade Commission. March 19, 2009.
  10. ^ “Complaint in the Matter of CC Pollen Company et al.”. Federal Trade Commission. March 16, 1993.
  11. ^ “Federal Government Seizes Dozens of Misbranded Drug Products: FDA warned company about making medical claims for bee-derived products”. Food and Drug Administration. Apr 5, 2010.
  12. ^ “Inspections, Compliance, Enforcement, and Criminal Investigations: Beehive Botanicals, Inc”. Food and Drug Administration. March 2, 2007.
  13. ^ a b Leung, R; Ho, A; Chan, J; Choy, D; Lai, CK (March 1997). “Royal jelly consumption and hypersensitivity in the community”. Clin. Exp. Allergy 27 (3): 333–6. doi:10.1111/j.1365-2222.1997.tb00712.x. PMID 9088660.
  14. ^ Takahama H, Shimazu T (2006). “Food-induced anaphylaxis caused by ingestion of royal jelly”. J Dermatol. 33 (6): 424–426. doi:10.1111/j.1346-8138.2006.00100.x. PMID 16700835.
  15. ^ Lombardi C, Senna GE, Gatti B, Feligioni M, Riva G, Bonadonna P, Dama AR, Canonica GW, Passalacqua G (1998). “Allergic reactions to honey and royal jelly and their relationship with sensitization to compositae”. Allergol Immunopathol (Madr). 26 (6): 288–290.
  16. ^ Thien FC, Leung R, Baldo BA, Weiner JA, Plomley R, Czarny D (1996). “Asthma and anaphylaxis induced by royal jelly”. Clin Exp Allergy 26 (2): 216–222. doi:10.1111/j.1365-2222.1996.tb00082.x. PMID 8835130.
  17. ^ >Leung R, Thien FC, Baldo B, Czarny D (1995). “Royal jelly-induced asthma and anaphylaxis: clinical characteristics and immunologic correlations”. J Allergy Clin Immunol 96 (6 Pt 1): 1004–1007. doi:10.1016/S0091-6749(95)70242-3. PMID 8543734.
  18. ^ Bullock RJ, Rohan A, Straatmans JA (1994). “Fatal royal jelly-induced asthma”. Med J Aust 160 (1): 44.

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    Disclaimer:
    The information presented herein by this post is intended for educational purposes only. These statements have not been evaluated by the FDA and are not intended to diagnose, cure, treat or prevent disease. Individual results may vary, and before using any supplements, it is always advisable to consult with your own health care provider.