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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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Process Development for Low Cost Manufacturing


sciupnew logo-master

Process Development for Low Cost Manufacturing on 23-24 nov 2015 , Hyderabad, INDIA

23.11.2015 – 24.11.2015

 

Hotel Green Park – Hyderabad, India
View Brochure
or click
https://scientificupdate.co.uk/index.php/training/scheduled-training-courses/details/213-Low-Cost-Manufacturing.html?utm_source=Scientific+Update+News&utm_campaign=d31c03d4e3-India_Courses_Hyderabad7_22_2015&utm_medium=email&utm_term=0_08c5e1fb69-d31c03d4e3-78584097

Chemical process research and development is recognised as a key function during the commercialisation of a new product particularly in the generic and contract manufacturing arms of the chemical, agrochemical and pharmaceutical industries.

The synthesis and individual processes must be economic, safe and must generate product that meets the necessary quality requirements.

This 2-day course presented by highly experienced process chemists will concentrate on the development and optimisation of efficient processes to target molecules with an emphasis on raw material cost, solvent choice, yield improvement, process efficiency and work up, and waste minimisation.

Process robustness testing and reaction optimisation via stastical methods will also be covered.

A discussion of patent issues and areas where engineering and technology can help reduce operating costs.

The use of engineering and technology solutions to reduce costs will be discussed and throughout the course the emphasis will be on minimising costs and maximising returns.

 

    • Young Chemists who have just started work in industry as development chemists
    • Organic Chemists/Medicinal Chemists in Research and Development who would like to gain an appreciation of development and scale up and who are perhaps contemplating moving into chemical development.
    • Development and Production Chemists in industry who would like to improve their efficiency and gain an insight into alternative approaches to chemical development.
    • Chemical Engineers who wish to understand a chemist’s approach to chemical development of batch processes. (Engineers would, however, need a good grounding in organic chemistry)
    • Students who are about to enter the industry and can obtain company sponsorship.
    • Experienced Chemists looking to refresh and/or augment their knowledge of chemical development
    • Analytical Chemists who wish to gain a broader appreciation of process chemistry
    • Managers who might benefit from a comprehensive and up to date overview of chemical development

    • Introduction
      Route selection, raw material choice
      • Choosing the best route
      • Using the cheapest raw materials and reagents, back integration of raw material supply
      • Reducing the number of steps vs. reagent choice / yield and cost

      Solvent selection
      • Solvent cost, recyclability
      • Solvent reactivity and solvent swapping
      • Solvent choice for reaction and work up

      Reaction optimisation
      • Reaction understanding
      • Improving conversion, selectivity
      • Telescoping

      Process optimisation
      • Reaction quench
      • Work up
      • Product isolation (crystallisation, filtration and drying)

      Statistical methods of optimisation
      • Design of experiments
      • Factorial and fractional factorial design
      • Response surface analysis
      • Robustness testing

      Regulatory and Quality issues
      • Impurity control and tracking
      • Process validation and QbD
      • Vessel cleaning

      Patent issues
      • Patents basics
      • Patent definition
      • Where patents are in force
      • How to work around patents

      Use of technology and engineering
      • Flow chemistry
      • SMB chromatography
      • Separation technologies

      At the end of the course participants will have gained:

      • A logical investigative approach to chemical development and optimisation
      • An insight into the factors involved in development and scaleup
      • A preliminary knowledge of statistical methods of optimisation
      • Improved ability to decide which parts of the chemical process to examine in detail.
      • Ideas for efficient resource allocation
      • Improved troubleshooting and problem solving ability
      • A basic outline of the patent system
      • An appreciation of how to assess the main cost contributors in a process

    • https://scientificupdate.co.uk/images/eventlist/brochures/7649_su_23-24_nov_2015_doe_hyderabad(v2f)_1433342973.pdf

///////////

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Indian Generics 2016


The generic APIs market is expected to continue to rise faster than the branded/innovative APIs, by 7.7%/year to reach $30.3 billion in 2016. Asia-Pacific is expected to show the fastest growth rates (10.8%/year). The 24 fastest growing markets will include 11 in Asia-Pacific, seven in Eastern Europe and CIS, four in Africa-Middle East and two in Latin America (Figure ).

Figure  – Top growth markets for generic APIs to 2016

By 2016, China will account for 27.7% of the global generic API merchant market, while the US will have fallen to 23.8%; the mature markets as a whole will see their share fall from 41.8% in 2012 to 36.9%. India will be the third largest, with a 7.2% share.

 

 

 

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

 

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

 

TOFACITINIB 的合成, トファシチニブ, Тофацитиниб, توفاسيتين يب SPECTRAL VISIT


Tofacitinib Citrate, 的合成

托法替布,  トファシチニブクエン酸塩, Тофацитиниба Цитрат

 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

ROTATION +

Tofacitinib; Tasocitinib;

477600-75-2 base ; CP-690550;

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt

CP 690550 Tofacitinib; CP-690550; CP-690550-10; Xeljanz; Jakvinus; Tofacitinib citrate

Trademarks: Xeljanz; Jakvinus

MF: C16H20N6O

CAS : 477600-75-2 BASE ; 540737-29-9(citrate) 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

Molecular Weight: 312.369

SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

Activity: Treatment of Rheumatoid Arthritis; RA Treatment, JAK Inhibitor; Protein Kinase Inhibitor; JAK3 Inhibitor; Janus Kinase 3 Inhibitor; JAK-STAT Signaling Pathway; JAK1 Kinase Inhibitor; Selective Immunosuppressants

Status: Launched 2012

Originator: Pfizer
Pfizer Inc’s oral JAK inhibitor tofacitinib was approved on November 6, 2012 by US FDA for the treatment of rheumatoid arthritis.
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,[1] CP-690550[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Publication Date (Web): November 17, 2014 (Article)
DOI: 10.1021/op500274j
 
MS m/z 313 (M+ + 1);
mp 201–202 °C;  
1H NMR (CDCl3) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).
Print
09338-acsnews1-pfizercxd
TEAMWORK
Part of the Pfizer group responsible for Xeljanz: Front row, from left: Sally Gut Ruggeri, Chakrapani Subramanyam, Eileen Elliott Mueller, and Frank Busch. Second row, from left: Matthew Brown, Mark Flanagan, and Robert Dugger. Back row, from left: Elizabeth Kudlacz and Douglas Ball.
Credit: Pfizer
Mark Flanagan, who was on the team at Pfizer that discovered Xeljanz, (tofacitinib citrate), an oral treatment for rheumatoid arthritis, remembers testing the drug in a rat model and seeing the drug decrease the level of inflammation in the rats’ footpads. “What we look for is physical measurements of the size of the joint. In the control animals, there was quite a bit of inflammation in the joints, whereas animals treated with different doses of the drug showed a dose-dependent decrease in the size of the joint. “Tofacitinib showed robust efficacy in the first such study run. I can remember the excitement that this data generated on the team,” he says.

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Figure imgf000002_0001

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Figure imgf000020_0001

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. The potential significance of JAK3 inhibition was first discovered in the laboratory of John O’Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).[5] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.[5] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the “health and safety needs of the public.”[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.[6] A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.[7] It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3) , which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.[3] Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)
To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.
1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.
PAPER
3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (1) Monocitrate
J. Med. Chem., 2010, 53 (24), pp 8468–8484
DOI: 10.1021/jm1004286
1monocitrate as a white crystalline solid (mp = 201 dec).
LRMS: m/z 313.2 (MH+).
1H NMR (400 MHz) (D2O) δ HOD: 0.92 (2 H, d, J = 7.2 Hz), 0.96 (1 H, d, J = 7.6 Hz), 1.66 (1 H, m), 1.80 (1 H, m), 2.37 (1 H, m), 2.58 (2 H, 1/2 ABq, J = 15.4 Hz), 2.70 (2 H, 1/2 ABq, J = 15.4 Hz), 3.23 (2 H, s), 3.25 (1 H, s), 3.33 (1 H, m), 3.46 (1 H, m), 3.81 (4 H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).
Anal. Calcd for C22H28N6O8: C, 52.38; H, 5.59; N, 16.66. Found: C, 52.32; H, 5.83; N, 16.30. For additional characterization of the monocitrate salt of 1 see WO 03/048162.
NMR PREDICT
References:
Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidinesOrganic Process Research & Development 2005, 9, 51−56
Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1
Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012
Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efficient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006
MORE NMR PREDICT

tofacitinib Molbase str

Tofacitinib TOFA  1H proton NMR spectra

tofacitinib 1h values

13C NMR PREDICT  TOFA  13C NMR spectra

 

 

SEE…….https://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

 

 

COSY PREDICT COSY NMR prediction सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

 

NMR PICTURE FROM THE NET

tofacitinib ABMOLE NMR BASE

 

PAPER

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

Asymmetric total synthesis of Tofacitinib

  • a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
  • b Laboratory of Natural Products, Department of Chemistry, University of Antofagasta, P.O. Box 170, Antofagasta, Chile

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

Abstract

A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b.


Graphical abstract

Image for unlabelled figure

…………………. Tofacitinib synthesis: US2001053782A1

Tofacitinib synthesis: WO2002096909A1
 
Tofacitinib synthesis: Org Process Res Dev 2014, 18(12), 1714-1720 (also from a chinese publication, same procedure just slight changes in reagents/conditions)
 
References:
1. Blumenkopf, T. A.; et. al. Pyrrolo[2,3-d]pyrimidine compounds. US2001053782A1
2. Flanagan, M. E.; et. al. Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors. WO2002096909A1
3. Das, A.; et. al. An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Org Process Res Dev2014, 18(12), 1714-1720.

 

PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Figure imgf000005_0001
Figure imgf000005_0002

Scheme 2

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. 1H NMR (400 MH2)(D20) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, 1/2 ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

 

Patent

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)2/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-300C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-900C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. 1H NMR (400 MHz, CDCI3): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). 13C NMR (400 MHz, CDCI3): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

 

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

 

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 1000C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.00C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O0C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O0C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-650C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-850C for a minimum of 4 hours. The mixture was cooled to 20-300C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 500C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. 1H NMR (500 MHz, CZ6-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

 

 

PAPER

Org. Lett., 2009, 11 (9), pp 2003–2006
DOI: 10.1021/ol900435t

http://pubs.acs.org/doi/full/10.1021/ol900435t Figure

 

PATENT

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799   …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

Clinical trials

Rheumatoid arthritis

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.[8] The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) andneutropenia.[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[9] In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.[10] By April 2011, three phase III trials for RA had reported positive results.[11] In November 2012, the U.S. FDA approved tofacitinib “to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate.”[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[15]

Development of Safe, Robust, Environmentally Responsible Processes for New Chemical Entities

– Dr. V. Rajappa, Director & Head-Process R&D, Bristol-Myers Squibb, India

A PRESENTATION

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  1. Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
  2.  Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo”. Arthritis & Rheumatism 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. edit
  3.  “Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
  4.  Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
  5. ^ Jump up to:a b c “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
  6. Ken Garber (9 January 2013). “Pfizer’s first-in-class JAK inhibitor pricey for rheumatoid arthritis market”. Nature Biotechnology 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910.
  7. Jump up^ Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. DOI 10.1038/ncb3075
  8.  “EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
  9.  Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
  10.  Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
  11.  “Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
  12.  “FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
  13.  “Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
  14.  https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
  15. “This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
  16. Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
  17. “”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib
Tofacitinib2DACS.svg
Systematic (IUPAC) name
3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names Xeljanz, Jakvinus
AHFS/Drugs.com entry
Licence data US FDA:link
Pregnancy category
  • US: C (Risk not ruled out)
Legal status
Routes of administration Oral
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Hepatic (via CYP3A4 andCYP2C19)
Biological half-life 3 hours
Excretion Urine
Identifiers
CAS Registry Number 477600-75-2
ATC code L04AA29
PubChem CID: 9926791
IUPHAR/BPS 5677
DrugBank DB08183
ChemSpider 8102425
UNII 87LA6FU830
ChEBI CHEBI:71200 Yes
ChEMBL CHEMBL221959
Synonyms CP-690550
Chemical data
Formula C16H20N6O
Molecular mass 312.369 g/mol

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..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.

 

 

Special Olympics World Games 2015

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

 

 

//////

How flow chemistry can make processes greener…………Supercritical fluids


Safe, small scale access to supercritical fluids

The ability to safely access high temperatures and pressures in flow reactors has implications not only on the rate of chemical reactions, but also on the types of solvents one can use. Many greensolvents such as methanol and acetone have boiling points too low for certain batch applications, whereas performing reactions at high pressure in a flow reactor may allow for their safe use at elevated temperatures.

Supercritical fluids are particularly interesting, since these solvents are entirely inaccessible without high pressure conditions. The use of supercritical fluids in a flow system offers numerous advantages over batch reactors.

Reactions may be performed on a small scale, improving safety and reducing the amount of material required. Depending on the type of reactor, it may be possible to visualize the reaction to evaluate the phase behaviour. Moreover, the reaction can be analyzed and the temperature and pressure subsequently changed without stopping the reaction and cleaning the vessel, as is necessary in a simple autoclave.

Continuous methods for utilizing supercritical fluids for extraction,1 chromatography,2 and as a reaction medium3 have all been commercialized, particularly for supercritical carbon dioxide (scCO2).4 Academic examples using scMeOH, scH2O, and scCO2 for continuous reactions such as hydrogenations, esterifications, oxidations, and Friedel–Crafts reactions have been reported.5

A recent example that illustrates many of the green advantages of performing supercritical fluid chemistry in flow is in the ring opening of phthalic anhydride with methanol by Verboom and co-workers (Scheme 1).6 They designed a microreactor with a volume of just 0.32 μL that can withstand very high pressures.

The exceptionally small channel causes a large build-up of pressure, and supercritical conditions with pressures of up to 110 bar and temperatures up to 100 °C can occur inside the reactor, giving an ‘on-chip’ phase transition. The channel size increases near the outlet, allowing the fluid to expand to atmospheric conditions.

Thus, the total volume of scCO2 under high pressure is exceptionally small, alleviating the major hazards of operating under supercritical conditions. The reaction was thoroughly studied on this small scale, allowing the authors to determine rate constants at several different temperatures and pressures.

Small scale continuous use of supercritical fluids.
Scheme 1 Small scale continuous use of supercritical fluids.

Near- and supercritical water (scH2O) can be an interesting green solvent only obtainable at very high temperature (Tc = 374 °C) and pressure (Pc = 221 bar). It is commonly used for completeoxidation of organic waste materials to CO2; however, it has also been shown to be an effective solvent for selective oxidations.7 Given the harshness of the reaction conditions, it is not surprising that side product formation is common and highly dependent on the reaction time. For fast reactions in a batch reactor, precise control of reaction time is challenging, as the vessel takes time to heat and cool. In contrast, rapid heating, cooling, and quenching can be accomplished in a continuous process, allowing for well defined reaction times.

Fine tuning of the temperature, pressure, and time is also easier in a continuous process, as these variables can be changed without stopping and starting the reaction between samples. Thus, more data points can be obtained with less material and fewer heating and cooling cycles.

The Poliakoff group used these advantageous to perform a detailed study on the oxidation of p-xylene to terephthalic acid in scH2O, a reaction carried out on industrial scale in acetic acid (Scheme 2).8 By using a flow reactor, reaction times as low as 9 seconds could be used. The equivalents of oxygen could also be finely varied on a small scale through the controlled thermal decomposition of H2O2.

Studying this aerobic oxidation with such precision in a batch process would prove highly challenging. Under optimal conditions, excellent selectivity for the desired product could be obtained. Further research by the same group identified improved conditions for this transformation.9

Selective oxidation in supercritical water.
Scheme 2 Selective oxidation in supercritical water.

 

Schematic Diagram of sample Supercritical CO2 system

Table 1. Critical properties of various solvents (Reid et al., 1987)
Solvent Molecular weight Critical temperature Critical pressure Critical density
g/mol K MPa (atm) g/cm3
Carbon dioxide (CO2) 44.01 304.1 7.38 (72.8) 0.469
Water (H2O) (acc. IAPWS) 18.015 647.096 22.064 (217.755) 0.322
Methane (CH4) 16.04 190.4 4.60 (45.4) 0.162
Ethane (C2H6) 30.07 305.3 4.87 (48.1) 0.203
Propane (C3H8) 44.09 369.8 4.25 (41.9) 0.217
Ethylene (C2H4) 28.05 282.4 5.04 (49.7) 0.215
Propylene (C3H6) 42.08 364.9 4.60 (45.4) 0.232
Methanol (CH3OH) 32.04 512.6 8.09 (79.8) 0.272
Ethanol (C2H5OH) 46.07 513.9 6.14 (60.6) 0.276
Acetone (C3H6O) 58.08 508.1 4.70 (46.4) 0.278
Nitrous oxide (N2O) 44.013 306.57 7.35 (72.5) 0.452

Table 2 shows density, diffusivity and viscosity for typical liquids, gases and supercritical fluids.

Comparison of Gases, Supercritical Fluids and Liquids
Density (kg/m3) Viscosity (µPa∙s) Diffusivity (mm²/s)
Gases 1 10 1–10
Supercritical Fluids 100–1000 50–100 0.01–0.1
Liquids 1000 500–1000 0.001
  1. F. Sahena, I. S. M. Zaidul, S. Jinap, A. A. Karim, K. A. Abbas, N. A. N. Norulaini and A. K. M. Omar, J. Food Eng., 2009, 95, 240–253
  2. D. J. Dixon and K. P. Jhonston, in Encyclopedia of Separation Technology, ed. D. M. Ruthven, John Wiley, 1997, 1544–1569
  3. P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliakoff, Green Chem., 2003, 5, 99–104
  4. X. Han and M. Poliakoff, Chem. Soc. Rev., 2012, 41, 1428–1436
  5. S. Marre, Y. Roig and C. Aymonier, J. Supercrit. Fluids, 2012, 66, 251–264
  6. F. Benito-Lopez, R. M. Tiggelaar, K. Salbut, J. Huskens, R. J. M. Egberink, D. N. Reinhoudt, H. J. G. E. Gardeniers and W. Verboom, Lab Chip, 2007, 7, 1345–1351
  7. R. Holliday, B. Y. M. Jong and J. W. Kolis, J. Supercrit. Fluids, 1998, 12, 255–260
  8. P. A. Hamley, T. Ilkenhans, J. M. Webster, E. García-Verdugo, E. Vernardou, M. J. Clarke, R. Auerbach, W. B. Thomas, K. Whiston and M. Poliakoff, Green Chem., 2002, 4, 235–238
  9. E. Pérez, J. Fraga-Dubreuil, E. García-Verdugo, P. A. Hamley, M. L. Thomas, C. Yan, W. B. Thomas, D. Housley, W. Partenheimer and M. Poliakoff, Green Chem., 2011, 13, 2397–2407

Phase change - en.svg

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये। औकात बस इतनी देना, कि औरों का भला हो जाये।
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09b37-misc2b027LIONEL MY SON
He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
औकात बस इतनी देना,
कि औरों का भला हो जाये।

Practical Process Research and development; Development..Optimizing the Reaction by Minimizing Impurities


 

Chapter 8 – Optimizing the Reaction by Minimizing Impurities

  • Process Solutions L.L.C., Nicasio, California

The goals of process optimization change with the successful development of a project from early process research through scale-up into dedicated manufacturing. This general order of optimization may differ according to the nature of the process being considered; for instance, a process generating an inordinate amount of waste may be optimized to decrease waste before scaling up to the pilot plant. The initial goal of all process research and development is to maximize the amount of product generated under the reaction conditions. This is done by driving the reaction to completion, that is, by consuming any starting material that is charged in limiting amounts and by generating product with a minimal amount of by-products. Once the in-process yield has been optimized, the maximum yield of isolated product is expected. Rapid optimization is possible by judiciously changing solvents, reagents, catalysts, and ligands; investigations in this area allow the chemist considerable room for creativity and simplifying a process. Such changes may generate different impurities in the isolated intermediates, and it may be necessary to examine the tolerance of subsequent processes for the new impurities.

I consult to the pharmaceutical and fine chemical industries on developing and trouble-shooting processes to efficiently prepare drug substances and intermediates on large scale.  Anticipating and avoiding problems are key for effective and efficient scale-up.  For 17 years I have been consulting and presenting short courses internationally on process chemistry R & D for “small molecules” (over 1400 participants from more than 160 companies).  Prior to consulting I worked at Bristol-Myers Squibb for 17 years.  During that time I had extensive hands-on experience with chemical process development in the lab, pilot plant, and manufacturing sites, including 12 manufacturing start-ups and process development for four major drugs and many new drug candidates.  I wrote Practical Process Research & Development (Academic Press, 2000; 2nd edition 2012).

Practical Process Research & Development describes the development of chemical processes for the pharmaceutical and fine chemicals industries.  It provides a comprehensive, step-by-step approach to process R & D, and it is designed for those who want insights into generating rugged, practical, cost-effective processes.  Guidelines for industrial process R & D are rarely taught in academia, although this book has been used as a textbook.  It is primarily used by those in industry.

The second edition updates the first edition and includes topics not covered in the first editionPPR&D 2nd ed Japanese cover, such as genotoxins, biocatalysis, green solvents, predicting effective solvent combinations, and process validation.  Almost 85% of the references cited were published after the first edition was published, and virtually all examples in the Figures are new.  Trevor Laird kindly wrote a forward for this edition.

The second edition has been translated into Japanese and graced with a handsome cover.  Noriaki Murase was the translation supervisor, and the translators were Shohei Imachi, Koreaki Imura, Dai Tatsuta, Taro Tsukude, Toyoharu Numata, Yujiro Furuya, Akira Manaka, and Noriaki Murase. Sayaka Nukatsuka was the editor. I am very grateful to these people for their hard work to translate my book.

I am grateful to Barry Sharpless and Jerry Moniot for writing forwards to the first edition  I am also grateful to the following people for their translations of the first edition of my book.  Noriaki Murase, Yoshinori Murata, Toyoharu Numata, Mio Sakai, and Tatsuo Ueki translated Practical Process Research & Development into Japanese.  Kwang-Hyun Ahn, Yeung-Ho Park, and Sung-Kwan Hwang  translated Practical Process Research & Development into Korean.  Zhinong Gao and Wenhao Hu translated Practical Process Research & Development into Chinese.


 

In the foreword to Neal Anderson’s second edition of Practical process research and development, Trevor Laird states that, in his opinion, this is the best book on process chemistry. Having just co-edited a book with similar subject matter, I agree that this is one of the best available, and would add that it is an exceptionally clear, well written and researched book. This edition is also special for its chronological flow from discovery to production. The author achieves this by having a good understanding of the subject from the process chemist perspective, though consequently the complementary area of process engineering is less well covered.
The book communicates the excitement of this highly creative subject, but also the responsibility that lies with every process development job. This is a timely update with discussions covering contemporary issues such as product safety, process waste, catalysis, continuous operations, optimisation and validation. The updated introduction has a fascinating discussion of recent events that are shaping the direction of the pharma industry. And new chapters on Process safety, Effects of water, Organometallic reactions and Work-up are highly pertinent and will be recognised by all those involved in process development day-to-day. I like the fact that green chemistry and chirality are woven into chapters, reflecting their status within the field.
The book is packed with useful facts and information making it very dense, yet its structure makes it easy to read and find them. Many of the figures and schemes provide contemporary illustrative examples, and the use of text boxes to highlight key facts facilitates browsing. I already recommend the first edition as essential reading to process chemistry and engineering students and academic staff, and am certain this second edition will rapidly establish itself with this audience and those in the wider process chemical industry. Congratulations to Anderson, and thank you; the hard work that has clearly gone into this book has been very worthwhile.
free look
Below my own thoughts of process chemist
  • Evaluate the existing synthesis and identify steps, or sequences in the route that may pose a problem for large scale synthesis
  • Propose alternatives to any problematic steps or sequences and then implement these alternatives bases upon laboratory experimentation using Ph.D. level chemists with process research expertise
  • Ensure the synthesis is suitable for the immediate needs of the project, which maybe for only a few kilograms of API
  • Ensure the synthesis is suitable for long term, large scale manufacturing
  • Optimize reagent charges, operating temperatures, concentrations, work-up conditions and volumes, and solvent use in general
  • Identify which steps can be combined to result in a “through process” and implement the through process
  • Optimize purification schemes by identifying key crystalline intermediates and remove chromatographies from the synthesis
  • Optimize recrystallization parameters to ensure consistently high purity with similar impurity profiles from batch to batch, with low mother liquor losses
  • Institute appropriate analytical controls for in-process assays, end of reaction specifications, and acceptable intermediate or API purity
  • The process research team works closely with the analytical team to integrate the chemistry and analytical controls into the process at an early stage of the development cycle. The process research is then documented into a JACS style development report that outlines the chemistry and synthetic approaches that were tried as part of the synthetic development effort. This development report also includes a detailed experimental with supporting analytical data for the successful chemistry that results from our effort.The experimental that is part of these development reports is much more detailed than any journal publication. When coupled with our analytical and cGMP capabilities, the process research we provide is an essential groundwork for any compound that is just advancing from nomination at the discovery phase into clinical trial development. The process we develop provides the foundation of the ultimate manufacturing process, and should not need any changes (at a later date), to the synthetic strategy or bond forming steps used to prepare the API.

Critical Assessment of Pharmaceutical Processes, A Rationale for Changing the Synthetic Route


Changing the Synthetic Route - Chemical Reviews  ACS Publications -    --

Critical Assessment of Pharmaceutical ProcessesA Rationale for Changing the Synthetic Route

AstraZeneca, Process R&D, Avlon/Charnwood, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, U.K., GlaxoSmithKline, Synthetic Chemistry, Old Powder Mills, Tonbridge, Kent TN11 9AN, U.K., and Pfizer, Chemical R&D, PGR&D, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.
Chem. Rev., 2006, 106 (7), pp 3002–3027
DOI: 10.1021/cr050982w
Publication Date (Web): March 8, 2006

Table of Contents

  • 1. Introduction
  • 2. Criteria for Process Assessment
    • 2.1. Safety Issues2.1.1. Potential Safety Issues and Their Significance
  • 2.1.2. Prediction and Assessment of Safety Issues
  • 2.1.3. Options To Manage Safety Issues
  • 2.1.4. Designing a Safer New Route
    • 2.2. Environmental Issues
  • 2.2.1. Potential Environmental Issues and Their Significance
  • 2.2.2. Prediction and Assessment of Environmental Issues
  • 2.2.3. Options To Manage Environmental Issues
  • 2.2.4. Designing a New “Greener” Route
    • 2.3. Legal Issues
  • 2.3.1. Potential Legal Issues and Their Significance
  • 2.3.2. Prediction and Assessment of Legal Issues Associated with Regulated Substances
  • 2.3.3. Prediction and Assessment of Legal Issues Associated with Patent Infringement
  • 2.3.4. Options To Manage Patent Issues
  • 2.3.5. Designing a New Route with Freedom To Operate
    • 2.4. Economic Issues
  • 2.4.1. Potential Economic Issues and Their Significance
  • 2.4.2. Prediction and Assessment of Economic Issues
  • 2.4.3. Options To Manage Economic Issues
  • 2.4.4. Designing a Cost-Effective New Route
    • 2.5. Control Issues
  • 2.5.1. Potential Control Issues and Their Significance
  • 2.5.2. Prediction and Assessment of Control Issues
  • 2.5.3. Options To Manage Control Issues
  • 2.5.4. Designing a New Route with Adequate Control Measures
    • 2.6. Throughput Issues
  • 2.6.1. Potential Throughput Issues and Their Significance
  • 2.6.2. Prediction and Assessment of Throughput Issues
  • 2.6.3. Options To Manage Throughput Issues
  • 2.6.4. Designing a New Route with High Throughput
  • 3. Interrelationships between Process Issues
  • 4. Conclusions
  • 5. Acknowledgments
  • 6. References

Cadila reports Stable amorphous form of vortioxetine hydrobromide…WO 2015044963


Vortioxetine

O N Sept. 30, 2013 — The U.S. Food and Drug Administration today approved Brintellix (vortioxetine) to treat adults with major depressive disorder.

Major depressive disorder (MDD),

Commonly referred to as depression, is a mental disorder characterized by mood changes and other symptoms that interfere with a person’s ability to work, sleep, study, eat and enjoy once-pleasurable activities. Episodes of depression often recur throughout a person’s lifetime, although some may experience a single occurrence.

READ ALL AT

http://www.drugs.com/newdrugs/fda-approves-brintellix-major-depressive-disorder-3918.html

SYNTHESIS……..https://newdrugapprovals.org/2013/10/01/vortioxetine-fda-approves-brintellix-to-treat-major-depressive-disorder/

 

NEW PATENT

WO 2015044963

An amorphous vortioxetine and salts thereof

Cadila Healthcare Ltd

Singh, Kumar Kamlesh; Gajera, Jitendra Maganbhai; Raikwar, Dinesh Kumar; Khera, Brij; Dwivedi, Shri Prakash Dhar

The present invention relates to an amorphous vortioxetine and salts thereof. In particular, the invention relates to a process for the preparation of an amorphous vortioxetine hydrobromide. Further, the invention also relates to a process for preparation of amorphous vortioxetine free base. The invention also relates topharmaceutical compositions comprising an amorphous vortioxetine or hydrobromide salt thereof for oral administration for treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).

Stable amorphous form of vortioxetine hydrobromide, useful for treating depression, major depressive disorder (MDD) and generalized anxiety disorder. Also claims a process for preparing the amorphous form and solid dispersions comprising the same.

This API, which was originally developed and launched by Lundbeck and Takeda for treating MDD.

A phase IV trial (NCT02357797) for schizophrenia was scheduled to begin in March 2015. Family members of the product case, WO03029232, hold SPC protection in the EP until 2027 and one of its Orange Book listed filings, US7144884, expire in the US in 2023 with US154 extension.

The US FDA Orange Book also lists patents describing crystalline forms of vortioxetine/Brintellix, US8722684 and US8969355, that are due to expire in 2030 and 2027 respectively. The drug also has NCE exclusivity expiring in September 2018.

Cadila is potentially interested in vortioxetine hydrobromide.

 

 

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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COCK SAYS MOM CAN TEACH YOU NMR

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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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 Image result for jalgaon railway station

 

 

 

 

 

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http://www.aai.aero/allAirports/jalgaon_airport.jpg

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MANUDEVI

(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.



COCK WILL TEACH YOU NMR
COCK SAYS MOM CAN TEACH YOU NMR

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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.

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COCK SAYS MOM CAN TEACH YOU NMR

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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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