AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK- GENERICS LTD, Research centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments 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 25 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

May 122017
 

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KemInnTek Laboratories

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Welcome to Keminntek Laboratories

Keminntek Laboratories is a Hyderabad (India) based Contract Research Organization in Pharmaceutical sector in specific Pharmaceutical Intermediates, Speciality Chemicals, Impurities and Active Pharmaceutical Ingredients. Promoters of Keminntek Laboratories are Young and Dynamic Technocrats and established with a vision to provide a best-in class pharmaceutical services. Keminntek Laboratories would be a value-added and innovative-in –approach business partner. It has a strong talent pool of qualified and experienced scientists drawn from the national and international institutes and industry. It has a capability to synthesize in mg to multi-kg scale.

About Us

Vision
Our vision is to build Keminntek Laboratories into a world class leading pharmaceutical service provider based on innovation while keeping health and prosperity in mind. Imperatively, we will continue our business with high standards of ethics in the interest of society and environment.Mission
We are committed towards improving people’s health through science and innovation. Our mission is to provide better access of the affordable medicines to the patients and positively impact prosperity.

Team

  • Promoters of this company are very well qualified and experienced personalities in Pharmaceutical sector

  • We have a team consisting

    • Ph.Ds from premier Indian Institutes and postdocs from abroad

    • M. Sc (Chemistry) with 2-12 years pharmaceutical industry experience

  • Our team expertise lies in process R&D of pharmaceutical intermediates, NCEs (Medicinal Chemistry) development, pharmaceutical impurities, and custom synthesis of specialty chemicals

http://keminnteklabs.com/

keminnteklabs@gmail.com

 

Kolupula Srinivas

Kolupula Srinivas

Co-Founder & Chief Scientific Officer at Keminntek Laboratories

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Plot No: 10/11, Road No: 5,
IDA Nacharam, Hyderabad,
India – 500076.
 +91 9515 053 169 / 68
 keminnteklabs@gmail.com
 keminnteklabs@gmail.com

 

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//////////////KemInnTek Laboratories, srinivas kolupula, hyderabad, blog, cro, custom, synthesis

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May 062017
 

Novel diarylheptanoids as inhibitors of TNF-α production

Sameer Dhurua, Dilip Bhedia, Dnyaneshwar Gophanea, Kiran Hirbhagata, Vijaya Nadara, Dattatray Morea, Sapna Parikha, Roda Dalala, Lyle C. Fonsecaa, Firuza Kharasa, Prashant Y. Vadnala, Ram A. Vishwakarmaa, H. Sivaramakrishnana*

 

aDepartment of Medicinal Chemistry, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India

bDepartment of Pharmacology, Piramal Life Sciences Limited, 1 Nirlon Complex, Off Western Express Highway, Goregaon (E), Mumbai 400 063, India 

Bioorg. Med. Chem. Lett. 21 (2011) 3784–3787

 

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

 

Graphical abstract

 

Synthesis and anti-inflammatory activity of novel diarylheptanoids [5-hydroxy-1-phenyl-7-(pyridin-3-yl)-heptan-3-ones and 1-phenyl-7-(pyridin-3-yl)hept-4-en-3-ones] as inhibitors of tumor necrosis factor-α (TNF-α production is described in the present article. The key reactions involve the formation of a β-hydroxyketone by the reaction of substituted 4-phenyl butan-2-ones with pyridine-3-carboxaldehyde in presence of LDA and the subsequent dehydration of the same to obtain the α,β-unsaturated ketones. Compounds 4i, 5b, 5d, and 5g significantly inhibit lipopolysaccharide (LPS)-induced TNF-α production from human peripheral blood mononuclear cells in a dose-dependent manner. Of note, the in vitro TNF-α inhibition potential of 5b and 5d is comparable to that of curcumin (a naturally occurring diarylheptanoid). Most importantly, oral administration of 4i, 5b, 5d, and 5g (each at 100 mg/kg) but not curcumin (at 100 mg/kg) significantly inhibits LPS-induced TNF-α production in BALB/c mice. Collectively, our findings suggest that these compounds may have potential therapeutic implications for TNF-α-mediated auto-immune/inflammatory disorders.

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Scheme 1. Synthetic scheme

 

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Table 1.

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Table 2.

 

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Highlights

 

  • Designed and synthesized a novel series of diarylheptanoids.
  • Compounds 4i, 5b, 5d, and 5g significantly inhibit in vitro TNF-α production from human cells.
  • Oral administration of these compounds significantly inhibits TNF-α production in mice.
  • These compounds may have potential therapeutic implications for TNF- α -mediated auto-immune/inflammatory diseases.

 

ABOUT GUEST BLOGGER

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Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, gophane@gmail.com

 

Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry. These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

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May 032017
 

Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids

Dnyaneshwar B. Gophane and Snorri Th. Sigurdsson* 

a Department of Chemistry, Science Institute, University of Iceland, Dunhaga 3, 107 Reykjavik, Iceland 

Chem. Commun., 2013, 49, 999—1001

[Link: http://pubs.rsc.org/en/content/articlelanding/2013/cc/c2cc36389e#!divAbstract]

 

Graphical abstract

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Two new nitroxide-modified nucleosides, OxU and ImU, were synthesized and incorporated into DNA. ImU has lower mobility in duplex DNA due to an intramolecular hydrogen bond.

Abstract 

Nucleosides spin-labelled with isoindoline-derived benzimidazole (ImU) and benzoxazole (OxU) moieties were synthesized and incorporated into DNA oligonucleotides. Both labels display limited mobility in duplex DNA but ImU was less mobile, which was attributed to an intramolecular hydrogen bond between the N-H of the imidazole and O4 of the uracil nucleobase.

Scheme 1. Literature methods for synthesis of diamino isoindoline 6.

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Scheme 2. Improved synthesis of diamino isoindoline 6.

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Scheme 3. Synthesis of benzimidazole derivative phosphoramidites 10.

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Scheme 4. Synthesis of benzoxazole derivative phosphoramidites 14.

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Highligts

 

  • Synthesized novel nitroxide-labelled benzimidazole (ImU) and benzoxazole (OxU) derivatives of 2′-deoxyuridine as spin probes for nucleic acids.
  • Both ImU and OxU had limited mobility in duplex DNA, in particular ImU, indicating that rotation around the single bond linking the spin label to the uracil is restricted.
  • ImU is the first example of using intramolecular hydrogen-bonding to restrict spin label mobility.
  • ImU should not only be a good label for accurate distance measurements in oligonucleotides, but also yield information about the relative orientation of the labels.


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ABOUT GUEST BLOGGER

 

Dr. Dnyaneshwar B. Gophane, Ph. D.

Post doc fellow at Purdue university and university of Iceland

Email, gophane@gmail.com

Dr. Dnyaneshwar Gophane

Phone: +917083553405 and +917558215379

Dr. Dnyaneshwar B. Gophane completed his B.Sc. (Chemistry) at Anand college of science, Pathardi (Ahmednagar, Maharashtra, India) in 2000 and M.Sc. (Organic Chemistry) at Department of Chemistry, University of Pune (India) in 2003. From 2003 to 2008, he worked in research and development departments of pharmaceutical companies like Dr. Reddy’s Laboratories and Nicholas Piramal India Limited, where he involved in synthesizing novel organic compounds for in vitro and in vivo screening and optimizing process for drug molecule syntheses. In 2008, Dnyaneshwar joined Prof. Sigurdsson’s laboratory for his Ph.D. study at the University of Iceland. His Ph.D. thesis mainly describes syntheses of nitroxide spin-labeled and fluorescent nucleosides and their incorporation into DNA and RNA using phosphoramidite chemistry.

These modified nucleosides are useful probes for studying the structure and dynamics of nucleic acids by EPR and fluorescence spectroscopies. In 2014, after finishing his Ph.D., he worked as post doc fellow in same laboratory and mainly worked on spin labelling of RNA. At the university of Purdue in his second post doc, he was totally dedicated to syntheses of small molecules for anti-cancer activity and modification of cyclic dinucleotides for antibacterial activity. During his research experience, he has authored 8 international publications in peer reviewed journals like Chemical Communications, Chemistry- A European Journal, Journal of organic chemistry and Organic and Biomolecular Chemistry.

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May 012017
 

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Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinl Chemistry Letters, Elsevier Publications. Congratulation Sir !

Click here for details. https://www.journals.elsevier.com/bioorganic-and-medicinal-chemistry-letters

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GUEST BLOGGER, Dr Pravin Patil, A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

 Uncategorized  Comments Off on GUEST BLOGGER, Dr Pravin Patil, A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone
Apr 292017
 

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As a GUEST BLOGGER, myself Dr Pravin Patil,  presenting my paper as below

A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

 Pravin C Patil*a and Krishnacharya G Akamanchi

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019.

aPresent address: Department of Chemistry, University of Louisville, Louisville, KY, USA.

*Corresponding Author: Email-pravinchem@gmail.com

Tetrahedron Letters 2017, 58 (19), 1883-1886 (Recently published)

[Link: http://www.sciencedirect.com/science/article/pii/S004040391730429X]

 

Graphical Abstract:

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Abstract: The present paper demonstrate a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.

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Scheme: Literature methods for synthesis of parvaquone

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Scheme:  IBX mediated oxidative arylation towards synthesis of 1 (Parvaquone)

 

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Scheme :  Cyclohexyl radical mediated postulated mechanism for formation of Parvaquone, 1

Synthesis of 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone (parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one lot and stirred for 5 min at room temperature. To this was added dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL of acetonitrile over the course of 20 min. During the addition of 8 exotherm (up to 35 °C) was observed with evolution of nitrogen gas in the form of bubbles. Reaction progress was monitored by TLC (using mobile phase, hexane: ethyl acetate/5:95). After satisfactory TLC, water (20 mL) was added to the reaction mixture and acetonitrile was evaporated using rotary evaporator. To the residue obtained was added dichloromethane (30 mL). Oganic layer was separated and washed with saturated sodium bicarbonate solution followed by saturated solution of sodium sulphite. Separated organic layer was dried over anhydrous sodium sulphate and evaporated to obtain crude 1 which was further purified by column chromatography (mobile phase – hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g, 60% yield); mp 136-138 °C (lit.18 135-136°C); FT-IR (KBr): 3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm-1;

1H NMR (300 MHz; CDCl3): δ 8.10-8.06 (d, J = 12 Hz, 2H), 7.74-7.67 (d, J = 22 Hz, 2H, 7.45 (s, 1H, OH), 3.11-3.03 (t, J = 16 Hz, 1H), 1.99-1.34 (m, 10H); 13C NMR (75 MHz; CDCl3): δ 184.5, 181.9, 152.8, 135.1, 134.9, 132.7, 129.2, 127.9, 126.9, 125.9, 35.1, 29.2, 26.7, 25.9.

Highlights

  • New method of generating cyclohexyl radical by using IBX and cyclohexylhydrazine.
  • Parvaquone synthesized in 60% yield using metal, hazardous peroxide free conditions.
  • Described method has advantages of single step and mild reaction conditions.
  • The mechanism for cyclohexyl radical mediated synthesis of parvaquone is postulated.

 

please note………

Image result for A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of parvaquone

 

ABOUT GUEST BLOGGER

Dr. Pravin C. Patil

Dr. Pravin C. Patil

Postdoctoral Research Associate at University of Louisville

Email, pravinchem@gmail.com

    see…….http://oneorganichemistoneday.blogspot.in/2017/04/dr-pravin-patil.html

    Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.

    After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.

    During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.

    //////////////Parvaquone, guest blogger, pravin patil

     

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    Dr. Vinayak Pagar( GUEST BLOGGER) Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds

     cancer, new drugs, spectroscopy, SYNTHESIS  Comments Off on Dr. Vinayak Pagar( GUEST BLOGGER) Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds
    Apr 282017
     

    Discussing my paper……..

    Metal-catalyzed cycloadditions of alkenyldiazo reagents are useful tools to access carbo- and heterocycles.[1] These diazo compounds are chemically sensitive toward both Brønsted orLewis acids. Their reported cycloadditions rely heavily on the formation of metal carbenes to initiate regio- and stereoselective [3+n] cycloadditions (n=2–4) with suitable dipolarophiles.[2–4] A noncarbene route was postulated for a few copper-catalyzed cycloadditions of these diazo species, but they resulted in complete diazo decomposition.[3a, 4a, 5] oyle and co-workers reported[4a] a [3+2] cycloaddition of the alkenylrhodium carbene A with imines to give dihydropyrroles (Scheme 1a). We proposed a cycloaddition the tetrahydroquinoline derivatives 3 and 3’, as well as the tetrahydro-1H-benzo[b]azepine species 4. Access to these frameworks are valuable

    Access to these frameworks are valuable for the preparation of several bioactive molecules including 2-phenyl-2,3-
    dihydroquinolone,[8a] L-689,560,[8b] torcetrapib,[8c] martinellic acid,[8d] OPC-31260,[8e] OPC-51803,[8f] and tetraperalone A (Figure 1).[8g] Their specific biological functions have been well documented.[8]

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    Spectral data for ethyl 2-diazo-2-(2-phenyl-1,2,3,4-tetrahydroquinolin-4-yl) acetate (2a)

    Yellow Semi-Solid;

    IR (KBr, cm-1 ): 3542 (m), 2117 (s), 3015 (s), 1737 (s), 1564 (s), 1334 (m), 1137 (s), 817 (s);

    1H NMR (600 MHz, CDCl3): δ 7.41 (d, J = 7.3 Hz, 2 H), 7.36 ~ 7.33 (m, 2 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H) 4.56 (dd, J = 11.0, 2.3 Hz, 1H ), 4.25 (q, J = 7.1 Hz, 2H ), 4.21 (dd, J = 11.0, 5.3 Hz, 1H ), 4.01 (s, 1H) 2.36 ~ 2.33 (m, 1H), 2.00 (dd, J = 11.8, 2.3 Hz, 1H ), 1.28 (t, J = 7.1 Hz, 3H);

    13C NMR (150 MHz, CDCl3): δ 167.2, 145.3, 142.9, 128.6, 128.0, 127.8, 126.5, 126.4, 118.8, 117.9, 114.4, 60.9, 59.5, 56.2, 36.8, 32.6, 14.4.

    HRMS calcd for C19H19N3O2: 321.1477; found: 321.1483.

    Development of a Povarov Reaction/Carbene Generation Sequence for Alkenyldiazocarbonyl Compounds

    Authors, Appaso Mahadev Jadhav, Vinayak Vishnu Pagar, and Rai-Shung Liu*, DOI: 10.1002/anie.201205692

     We thank the National Science Council, Taiwan, for financial support of this work., [*] A. M. Jadhav, V. V. Pagar, Prof. Dr. R.-S. Liu

    Department of Chemistry, National Tsing Hua University
    Hsinchu (30013) (Taiwan)
    E-mail: rsliu@mx.nthu.edu.tw

    Abstract

    original image

    Rings aplenty: A HOTf-catalyzed (Tf=trifluoromethanesulfonyl) Povarov reaction of alkenyldiazo species has been developed and delivers diazo-containing cycloadducts stereoselectively (see scheme). The resulting cycloadducts provide access to six- and seven-membered azacycles through the generation of metal carbenes as well as the functionalization of diazo group.

    [1] Selected reviews: a) M. P. Doyle,M. A. McKervy, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds,  Wiley, New York, 1998; b) A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223; c) H. M. L. Davies, J. R. Denton, Chem. Soc. Rev. 2009, 38, 3061; d) M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704; e) H. M. L. Davies, D. Morton, Chem. Soc. Rev. 2011, 40, 1857; f) Z. Zhang, J. Wang, Tetrahedron
    2008, 64, 6577.
    [2] Selected examples for carbocyclic cycloadducts, see: a) L. Deng, A. J. Giessert, O. O. Gerlitz, X. Dai, S. T. Diver, H. M. L. Davies, J. Am. Chem. Soc. 2005, 127, 1342; b) H. M. L. Davies, Adv. Cycloaddit. 1999, 5, 119; c) H. M. L. Davies, B. Xing, N. Kong, D. G. Stafford, J. Am. Chem. Soc. 2001, 123, 7461; d) H. M. L. Davies, T. J. Clark, H. D. Smith, J. Org. Chem. 1991, 56, 3819; e) Y. Liu, K. Bakshi, P. Zavalij, M. P. Doyle, Org. Lett. 2010, 12, 4304; f) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573.
    [3] For oxacyclic cycloadducts, see: a) X. Xu, W.-H. Hu, P. Y. Zavalij, M. P. Doyle, Angew. Chem. 2011, 123, 11348; Angew. Chem. Int. Ed. 2011, 50, 11152; b) M. P. Doyle, W. Hu, D. J. Timmons, Org. Lett. 2001, 3, 3741.

    [4] For azacyclic cycloadducts, see selected reviews: a) M. P. Doyle, M. Yan, W. Hu, L. Gronenberg, J. Am. Chem. Soc. 2003, 125, 4692; b) J. Barluenga, G. Lonzi, L. Riesgo, L. A. Lpez, M. Tomas, J. Am. Chem. Soc. 2010, 132, 13200; c) M. Yan, N. Jacobsen, W. Hu, L. S. Gronenberg, M. P. Doyle, J. T. Colyer, D. Bykowski, Angew. Chem. 2004, 116, 6881; Angew. Chem. Int. Ed. 2004, 43, 6713; d) X.Wang, X. Xu, P. Zavalij, M. P. Doyle, J. Am.
    Chem. Soc. 2011, 133, 16402; e) Y. Lian, H. M. L. Davies, J. Am. Chem. Soc. 2010, 132, 440; f) X. Xu, M. O. Ratnikov, P. Y. Zavalij, M. P. Doyle, Org. Lett. 2011, 13, 6122; g) V. V. Pagar, A. M. Jadhav, R.-S. Liu, J. Am. Chem. Soc. 2011, 133, 20728; h) R. P. Reddy, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129, 10312.

    [5] Y. Qian, X. Xu, X.Wang, P. Zavalij,W. Hu, M. P. Doyle, Angew. Chem. 2012, 124, 6002; Angew. Chem. Int. Ed. 2012, 51, 5900.
    [6] Povarov reactions refer to the formal [4+2] cycloadditions of Naryl imines with enol ethers or enamines. See reviews: a) L. S. Povarov, Russ. Chem. Rev. 1967, 36, 656; b) V. V. Kouznetsov, Tetrahedron 2009, 65, 2721; c) D. Bello, R. Ramn, R. Lavilla, Curr. Org. Chem. 2010, 14, 332; d) M. A. McCarrick, Y. D. Wu, K. N. Houk, J. Org. Chem. 1993, 58, 3330; e) A. Whiting, C. M. Windsor, Tetrahedron 1998, 54, 6035.

    [7] For Povarov reactions catalyzed by Brønsted acids, see selected examples: a) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobson, Science 2010, 327, 986; b) T. Akiyama, H. Morita, K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070; c) H. Liu, G. Dagousset, G. Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009, 131, 4598; d) G. Dagousset, J. Zhu, G. Masson, J. Am. Chem. Soc. 2011, 133, 14804; e) H. Ishitani, S. Kobayashi, Tetrahedron Lett. 1996, 37, 7357; f) G. Bergonzini, L. Gramigna, A. Mazzanti, M. Fochi, L. Bernardi, A. Ricci, Chem. Commun.
    2010, 46, 327; g) L. He, M. Bekkaye, P. Retailleau, G. Masson, Org. Lett. 2012, 14, 3158.

    [8] a) Y. Xia, Z.-Y. Yang, P. Xia, K. F. Bastow, Y. Tachibana, S.-C. Kuo, E. Hamel, T. Hackl, K.-H. Lee, J. Med. Chem. 1998, 41, 1155; b) R.W. Carling, P. D. Leeson, A. M. Moseley, J. D. Smith, K. Saywell, M. D. Trickelbank, J. A. Kemp, G. R. Marshall, A. C. Foster, S. Grimwood, Bioorg. Med. Chem. Lett. 1993, 3, 65;
    c) D. B. Damon, R. W. Dugger, R.W. Scott, U.S. Patent 6,689,897, 2004; d) D. A. Powell, R. A. Batey, Org. Lett. 2002, 4, 2913; e) A. Matsuhisa, K. Kikuchi, K. Sakamoto, T. Yatsu, A. Tanaka, Chem. Pharm. Bull. 1999, 47, 329; f) M. Y. Christopher, E. A. Christine, D. M. Ashworth, J. Barnett, A. J. Baxter, J. D. Broadbridge, R. J. Franklin, S. L. Hampton, P. Hudson, J. A. Horton, P. D. Jenkins, A. M. Penson, G. R.W. Pitt, P. Rivire,
    P. A. Robson, D. P. Rooker, G. Semple, A. Sheppard, R. M.Haigh, M. B. Roe, J. Med. Chem. 2008, 51, 8124; g) C. Li, X. Li, R. Hong, Org. Lett. 2009, 11, 4036.

    About author( Me)

    Dr. Vinayak Pagar

    Dr. Vinayak Pagar

    Postdoctoral Research Fellow at The Ohio State University

    Vinayak Vishnu Pagar was born in Nasik, Maharashtra (India) in 1983. He obtained his BSc and MSc degrees in chemistry from the University of Pune (India) in 2004 and 2006, respectively. From 2006–2010, he worked as Research Associate in pharmaceutical companies like Jubilant Chemsys Ltd. and Ranbaxy Laboratories Ltd. (India). In 2010, he joined the group of Professor Rai-Shung Liu to pursue his PhD degree in National Tsing Hua University (Taiwan) and completed it in 2014. Subsequently, he worked as a postdoctoral fellow in the same group for one year. Currently, he is working as a Research Scientist at The Ohio State University, Columbus, Ohio USA. His research focused on the development of new organic reactions by using transition-metal catalysis such Gold, Silver, Rhodium, Zinc, Cobalt, Nickel and Copper metals which enables mild, diastereoselective, enantioselective and efficient transformations of variety of readily available substrates to wide range of synthetically useful nitrogen and oxygen containing heterocyclic products which are medicinally important. He published his research in a very high impact factor international Journals includes  J. Am. Chem. Soc.,  Angew. Chem. Int. Ed.,  J. Org. Chem.,  Chem- A. Eur. Journal,  Org. Biomol. Chem., and Synform (Literature Coverage).

    Dr. Vinayak Pagar

    Postdoctoral Researcher

    Department of Chemistry and Biochemistry

    The Ohio State University

    100 West 18th Avenue

    Columbus, Ohio 43210 USA

    vinayak.pagar@gmail.com

    /////////Vinayak Pagar, Postdoctoral Research Fellow, The Ohio State University, blog, Povarov Reaction, Carbene Generation Sequence,  Alkenyldiazocarbonyl Compounds

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    Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

     spectroscopy, SYNTHESIS  Comments Off on Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile
    Apr 222017
     

    Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

     Green Chem., 2017, Advance Article
    DOI: 10.1039/C7GC00602K, Communication
    Katharina J. Hock, Robin Spitzner, Rene M. Koenigs
    Applications of diazo acetonitrile in cyclopropa(e)nation reactions are realized in a slow-release protocol with bench-stable reagents. Cyclopropyl nitriles are obtained in one step in good diastereoselectivity on a gram-scale providing an efficient entry into this class of fragrances and drug-like molecules.
    STR1
    STR2
    trans-2-phenylcyclopropane-1-carbonitrile
    colorless solid (46 mg, 81%);
    m.p. = 29°C;
    1 H-NMR (600 MHz, CDCl3): δ = 7.34 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 7.12 – 7.08 (m, 2H), 2.63 (ddd, J = 9.2, 6.7, 4.7 Hz, 1H), 1.62 (dt, J = 9.2, 5.4 Hz, 1H), 1.55 (ddd, J = 8.7, 5.5, 4.8 Hz, 1H), 1.45 (ddd, J = 8.8, 6.7, 5.3 Hz, 1H);
    13C-NMR (151 MHz, CDCl3): δ = 137.55, 128.76, 127.41, 126.31, 121.05, 24.90, 15.24, 6.63;
    HRMS (ESI): m/z calc. for [C10H9NNa]: 166.06272, found 166.06276;
    IR (KBr): νmax/cm-1 = 3044, 2235, 2098, 1761, 1600, 1461, 1220, 1051, 920, 705.
    The analytical data is in correspondence with the literature [2]
    STR1 STR2
    [2] M. Gao, N. N. Patwardhan, P. R. Carlier, J. Am. Chem. Soc., 2013, 135 (38), 14390–14400

    Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile

    Author affiliations

    Abstract

    Diazo acetonitrile has long been neglected despite its high value in organic synthesis due to a high risk of explosions. Herein, we report our efforts towards the transient and safe generation of this diazo compound, its applications in iron catalyzed cyclopropanation and cyclopropenation reactions and the gram-scale synthesis of cyclopropyl nitriles.

    Graphical abstract: Towards nitrile-substituted cyclopropanes – a slow-release protocol for safe and scalable applications of diazo acetonitrile
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    Dimethylcarbamoyl Chloride, a known carcinogen

     PROCESS  Comments Off on Dimethylcarbamoyl Chloride, a known carcinogen
    Mar 142017
     
    Dimethylcarbamoylchlorid Strukturformel.svg
    Identifiers
    79-44-7
    ECHA InfoCard 100.001.099
    PubChem 6598
    Properties
    C3H6ClNO

    Dimethylcarbamoyl Chloride

    Figure

    Mechanisms for the Formation of Dimethylcarbamoyl Chloride

    Thionyl chloride is the most common reagent in process chemistry for the conversion of a carboxylic acid to an acid chloride. One of the primary factors is cost, since the reagent is inexpensive and represents one of the most cost-efficient ways of preparing acid chlorides. However, one disadvantage of thionyl chloride is the potential formation of dimethylcarbamoyl chloride, a known carcinogen in animal models, when used in combination with DMF as catalyst.

    Dimethylcarbamoyl chloride is a reagent for transferring a dimethylcarbonyl group to alcoholic or phenolic hydroxyl groups forming dimethyl carbamates, usually having pharmacological or pesticidal activities. Because of its high toxicity and its carcinogenic properties shown in animal experiments and presumably also in humans,[1] dimethylcarbamoyl chloride can only be used under stringent safety precautions.

    Production and occurrence

    The production of dimethylcarbamoyl chloride from phosgene and dimethylamine (DMA) was reported as early as 1879 (reported as “Dimethylharnstoffchlorid” – dimethylurea chloride).[2]

    Synthese von Dimethylcarbamoylchlorid (DMCC) mit Dimethylamin

    Dimethylcarbamoyl chloride can be produced in high yields (90%) at 275 °C by reacting phosgene with gaseous dimethylamine in a flow reactor.[3] To suppress the formation of ureas excessive phosgene is used (in a 3:1 ratio).

    The reaction can also be carried out at the laboratory scale with diphosgene or triphosgene and a aqueous dimethylamine solution in the two-phase system benzene+xylene/water in a stirred reactor with sodium hydroxide as an acid scavenger. However, considerably lower yields (56%) are achieved due to the hydrolysis sensitivity of dimethylcarbamoyl chloride .[4]

    Dimethylcarbamoyl chloride is also formed (together with methyl chloride) when reacting phosgene with trimethylamine.[5]

    Synthese von Dimethylcarbamoylchlorid (DMCC) mit Trimethylamin

    A more recent process is based on dimethylamine chloride, which is converted practically quantitatively to dimethylcarbamoyl chloride on a palladium catalyst under pressure with carbon monoxide at room temperature.[6]

    Synthese von Dimethylcarbamoylchlorid (DMCC) aus Chloramin

    Dicarbamoyl chloride can also be formed in small amounts (0-20 ppm) from dimethylformamide (DMF) in the Vilsmeier-Haack reaction[7] or when DMF is used as a catalyst in the reaction of carboxylic acids with thionyl chloride to the corresponding carboxylic acid chlorides.[8]

    Synthese von Dimethylcarbamoylchlorid (DMCC) mit Dimethylformamid (DMF)

    The tendency towards dicarbamoyl chloride formation depends on the chlorination reagent (thionyl chloride> oxalyl chloride> phosphorus oxychloride) and is higher in the presence of a base. However, dicarbamoyl chloride hydrolyses very quickly to dimethylamine, hydrochloric acid and carbon dioxide (with a half-life of about 6 minutes at 0 °C) so that less than 3 ppm of dicarbamoyl chloride are found in the Vilsmeier product after aqueous work-up.[9]

    Properties[edit]

    Dimethylcarbamoyl chloride is a clear, colorless, corrosive and flammable liquid with a pungent odor and a tear-penetrating effect, which decomposes rapidly in water.[10]Because of its unpleasant, toxic, mutagenic and carcinogenic properties[11][12] it has to be used under extreme precautions.

    Dimethylcarbamoyl chloride behaves like an acid chloride whose chlorine atom can be exchanged for other nucleophiles. Therefore, it reacts with alcohols, phenols and oximes to the corresponding N, N-dimethylcarbamates, with thiols to thiolourethanes, with amines and hydroxylamine to substituted ureas, and with imidazoles and triazoles to carbamoylazoles.[13]

    Reaktionen von Dimethylcarbamoylchlorid (DMCC) mit Nukleophilen

    Dimethylcarbamoyl chloride is less reactive and less selective to substrates with multiple nucleophilic centers than conventional acid chlorides.

    Unsaturated conjugated aldehydes such as (2E)-butenal react with dimethylcarbamoyl chloride forming dienyl carbamates, which can be used as dienes in Diels-Alder reactions.[14]

    Synthese von Dienylcarbamaten mit Dimethylcarbamoylchlorid (DMCC)

    Alkali metal carboxylates react with dimethylcarbamoyl chloride forming the corresponding dimethylamides. Dimethylcarbamoyl chloride reacts with anhydrous sodium carbonate[15] or with excess dimethylamine to tetramethylurea.[16]

    The reaction of dimethylcarbamoyl chloride with DMF forms tetramethylformamidinium[17] chloride which is a major intermediate in the preparation of tris(dimethylamino)methane, a reagent for the introduction of enamine functions in conjunction with activated methylene groups[18] and the preparation of amidines.[19]

    Synthese von Tris(dimethylamino)methan mit Diemthylcarbamoylchlorid (DMCC)

    Dimethylcarbamoyl chloride is a starting material for the insecticide class of the dimethyl carbamates[20] which act as inhibitors of acetylcholinesterase, including dimetilane,[21]and the related compounds isolane, pirimicarb and triazamate.

    Synthesis of Dimetilan mit Dimethylcarbamoylchlorid

    The quaternary ammonium compounds neostigmine[22] finds pharmaceutical applications as acetylcholinesterase inhibitors. It is obtained from 3-dimethylaminophenol and dimethylcarbamoyl chloride and subsequent quaternization with methyl bromide or dimethyl sulfate[23]

    Synthese von Neostigmin mit Dimethylcarbamoylchlorid

    and pyridostigmine, which is obtainable from 3-hydroxypyridine and dimethylcarbamoyl chloride and subsequent reaction with methyl bromide.[24]

    Synthese von Pyridostigmin mit dimethylcarbamoylchlorid

    Dimethylcarbamoyl chloride is also used in the synthesis of the benzodiazepine camazepam.[25]

    Synthese von Camazepam mit Dimethylcarbamoylchlorid

    Image result for Dimethylcarbamoyl Chloride

    13c NMR

    MASS

    RAMAN

    References

    1. Jump up^ R.P. Pohanish (2011) (in German), Sittig’s Handbook of Toxic and Hazardous Chemicals and Carcinogens, 6th Edition, Amsterdam: Elsevier, pp. 1045–1047, ISBN 978-1437778694
    2. Jump up^ W. Michler; C. Escherich (1879), “Ueber mehrfach substituirte Harnstoffe” (in German), Ber. Dtsch. Chem. Ges. 12 (1): pp. 1162–1164, doi:10.1002/cber.187901201303
    3. Jump up^ R.J. Slocombe; E.A. Hardy; J.H. Saunders; R.L. Jenkins (1950), “Phosgene derivatives. The preparation of isocyanates, carbamyl chlorides and cyanuric acid” (in German), J. Am. Chem. Soc. 72 (5): pp. 1888–1891, doi:10.1002/ja01161a009
    4. Jump up^ G. Karimipour; S. Kowkabi; A. Naghiha (2015), “New aminoporphyrins bearing urea derivative substituents: synthesis, characterization, antibacterial and antifungal activity” (in German), Braz. Arch. Biol. Technol. 58 (3), doi:10.1590/S1516-891320500024
    5. Jump up^ H. Babad; A.G. Zeiler (1973), “Chemistry of Phosgene” (in German), Chem. Rev. 73 (1): pp. 75–91, doi:10.1021/cr60281a005
    6. Jump up^ T. Saegusa; T. Tsuda; Y. Isegawa (1971), “Carbamoyl chloride formation from chloramine and carbon monoxide” (in German), J. Org. Chem. 36 (6): pp. 858–860, doi:10.1021/jo00805a033
    7. Jump up^ M. Stare; K. Laniewski; A. Westermark; M. Sjögren; W. Tian (2009), “Investigation on the formation and hydrolysis of N,N-dimethylcarbamoyl chloride (DMCC) in Vilsmeier reactions using /GC/MS as the analytical detection method” (in German), Org. Process Res. Dev. 13 (5): pp. 857–862, doi:10.1021/op900018f
    8. Jump up^ D. Levin (1997), “Potential toxicological concerns associated with carboxylic acid chlorination and other reactions” (in German), Org. Process Res. Dev. 1 (2): pp. 182, doi:10.1021/op970206t
    9. Jump up^ A. Queen (1967), “Kinetics of the hydrolysis of acyl chlorides in pure water” (in German), Canad. J. Chem. 45 (14): pp. 1619–1629, doi:10.1139/v67-264
    10. Jump up^ C.B. Kreutzberger; R.A. Olofson (2001), “Dimethylcarbamoyl Chloride” (in German), e-EROS Encyclopedia of Reagents for Organic Synthesis, doi:10.1002/047084289X.rd319
    11. Jump up^ P. Jäger; C.N. Rentzea; H. Kieczka (2014) (in German), Carbamates and Carbamoyl Chloride, in Ullmann’s Fine Chemicals, Weinheim: Wiley-VCH, pp. 57–58, ISBN 978-3-527-33477-3
    12. Jump up^ “Dimethylcarbamoyl Chloride, CAS No. 79-44-7” (PDF). Report on Carcinogens, Thirteenth Edition (in German). National Toxicology Program, Department of Health and Human Services. Retrieved 2016-09-25.
    13. Jump up^ C.B. Kreutzberger, R.A. Olofson (2007-02-01). “Dimethylcarbamoyl Chloride” (in German). John Wiley&Sons, Ltd. Retrieved 2016-09-27.
    14. Jump up^ P.F. De Cusati; R.A. Olofson (1990), “A simple synthesis of 1-(1,3-butadienyl)carbonates and carbamates” (in German), Tetrahedron Lett. 31 (10): pp. 1405–1408, doi:10.1016/S0040-4039(00)88817-6
    15. Jump up^ J.K. Lawson Jr.; J.A.T. Croom (1963), “Dimethylamides from alkali carboxylates and dimethylcarbamoyl chloride” (in German), J. Org. Chem. 28 (1): pp. 232–235, doi:10.1021/jo1036a513
    16. Jump up^ US 3597478, M.L. Weakly, “Preparation of tetramethylurea”
    17. Jump up^ Z. Arnold (1959), “The preparation of tetramethylformamidinium salts and their vinylogues” (in German), Coll. Czech. Chem. Commun. 24: pp. 760–765, doi:10.1135/cccc19590760
    18. Jump up^ H. Meerwein; W. Florian; N. Schön; G. Stopp (1961), “Über Säureamidacetale, Harnstoffacetale und Lactamacetale” (in German), Justus Liebigs Ann. Chem. 641 (1): pp. 1–39, doi:10.1002/jlac.19616410102
    19. Jump up^ H. Bredereck; F. Effenberger; Th. Brendle (1966), “Synthese und Reaktionen von Trisdimethylaminomethan” (in German), Angew. Chem. 78 (2): pp. 147–148, doi:10.1002/ange.19660780212
    20. Jump up^ “Compendium of Pesticide Common Names” (in German). Alan Wood. Retrieved 2016-09-27.
    21. Jump up^ US 3452043, T. Grauer, H. Urwyler, “Production of 1-N,N-dimethylcarbamoyl-5-methyl-3-N,N-dimethyl-carbamoyl-oxy-pyrazole”
    22. Jump up^ J.A. Aeschlimann; M. Reinert (1931), “Pharmacological action of some analogues of physostigmine” (in German), J. Pharmacol. Exp. Ther. 43 (3): pp. 413–444
    23. Jump up^ US 1905990, J.A. Aeschlimann, “Disubstituted carbamic acid esters of phenols containing a basic constituent”
    24. Jump up^ US 2572579, “Disubstituted carbamic acid esters of 3-hydroxy-1-alkyl-pyridinium salts”
    25. Jump up^ DOS 2448015, “Verfahren zur Herstellung des 3-N,N-Dimethylcarbamoyl-oxy-1-methyl-5-phenyl-7-chlor-1,3-dihydro-2H-1,4-benzodiazepin-2-on”

    /////////////

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    Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

     Uncategorized  Comments Off on Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease
    Mar 132017
     

    Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

    Med. Chem. Commun., 2017, Advance Article
    DOI: 10.1039/C6MD00707D, Research Article
    E. Lattmann, J. Sattayasai, R. Narayanan, N. Ngoc, D. Burrell, P. N. Balaram, T. Palizdar, P. Lattmann
    Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using a range of assays.

    Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

    *Corresponding authors
    aSchool of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
    E-mail: e.lattmann@aston.ac.uk
    bDepartment of Pharmacology, Faculty of Medicine, Khon Kaen University, 40002 Khon Kaen, Thailand
    cDepartment of Medicine, University of Tennessee Health Science Center, Memphis, USA
    dPNB Vesper Life Science PVT, Cochin, India
    Med. Chem. Commun., 2017, Advance Article

    DOI: 10.1039/C6MD00707D

    Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC50 of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg−1 PNB-001 was equivalent to 40 mg kg−1 tramadol. The CCK2-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg−1 dose of prednisolone, which served as a standard.

    General Method: The relevant amine (2.5 times excess) was added to a solution of lactone A – E (0.7 mol) in ether (10 ml) and stirred on ice for 30 minutes, allowing to warm up to RT over the time. The resultant mixture was poured into 5 ml water and separated by separating funnel. The mixture was washed with water three times. The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. All compounds gave an oily solid which were passed through a column (80% ether, 20% petrol ether). The resulting fractions were dried from excess solvent under vacuum to yield crystals. 4-Chloro-1-cyclopropyl-5-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one 1 Yield = 83 %; mp: 177-179 oC;
    MS (APCI(+)): 193/195 (M+1), 250/252 (M+) m/z
    1H NMR (CDCl3) 250 MHz:  = 7.41 (m, 5H), 6.09 (s, 1H), 3.50 (m, 1H), 2.18 (m, 1H), 0.95-1.04 & 0.38-0.69 (m, 4H);
    13C NMR (CDCl3) 167.4, 154.8, 135.2, 129.2, 128.8, 126.1, 122.2, 93.5, 22.6 , 3.8, 5.1;
    IR (KBr-disc)  max: 3416, 3260, 3105, 3011, 2363, 2338, 1671, 1602, 1490, 1450, 1409, 1369, 1256, 1144, 1032, 939, 833, 752, 702 cm-1 .
    /////////////////Cholecystokinin-2/gastrin antagonists, 5-hydroxy-5-aryl-pyrrol-2-ones,  anti-inflammatory analgesics, inflammatory bowel disease
    Holi Festival 2017
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