AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Synthesis, characterization and anti-inflammatory evaluation of novel substituted tetrazolodiazepine derivatives

 Uncategorized  Comments Off on Synthesis, characterization and anti-inflammatory evaluation of novel substituted tetrazolodiazepine derivatives
Jul 172017
 
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SRM University
Chennai, Tamil Nadu, India

3b R = NITRO

str1

Dr. S. Sathishkumar

Dr. S. Sathishkumar
Assistant Professor in Chemistry, Kongu Engineering College, Perundurai, Erode – 638052

DR. HELEN P. KAVITHA

Dr. Helen P. Kavitha
Dr. Helen P. Kavitha

Professor and Head of the Department
E-mail: helen.p@rmp.srmuniv.ac.in
Area: Chemistry
Affiliation: Department of Chemistry, Ramapuram Campus, SRM University

Education

Ph.D. Organic Synthesis Bharathidasan University, Tiruchirapalli, 2000
M.Sc. General Chemistry Bharathidasan University, Tiruchirapalli, 1994
B.Sc. General Chemistry Bharathidasan University, 1992

Other Details:

Course

  • Chemistry
  • Principles of Environmental Science

Research Interests

  • Organic Synthesis
  • Medicinal Chemistry
  • Crystal Growth
  • Molecular Docking
  • Nano Synthesis

Selected PublicationS

  • A. Santhoshkumar, Helen P. Kavitha*, R. Suresh, Hydrothermal Synthesis, Characterization and Antibacterial Activity of NiO Nanoparticles, Journal of Advanced Chemical Sciences-Article in press
  • R. Kavipriya, Helen P. Kavitha, B. Karthikeyan, and A. Nataraj,” Molecular structure, spectroscopic (FT-IR, FT-Raman), NBO analysis of N,N0-diphenyl-6-piperidin-1-yl-[1,3,5]-triazine-2,4-diamine, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 150 (2015) 476–487.
  • S. Sathishkumar, Helen P. Kavitha and S. Arulmurugan, In-silico anti-inflammatory evaluation of some novel tetrazolo and triazolodiazepine derivatives against COX-2 protien,  International Journal of Advanced Chemical Science and Applications, 3(1), 2015
  • S. Arulmurugan and Helen P Kavitha, S. Sathishkumar and R. Arulmozhi.       Review on biologically active benzimidazole, Miniriveviews in organic chemistry, 12(1), 178-195, 2015.
  • S. Sathishkumar and Helen P. Kavitha, Synthesis, Characterization and Anti-inflammatory Activity of Novel Triazolodiazepine Derivatives, IOSR Journal of Applied Chemistry, 8(1),47-52, 2015.
  • A. Silambarasan, Helen P. Kavitha, S. Ponnusamy, M. Navaneethan, Y. Hayakawa, Investigation of photocatalytic behavior of l-aspartic acid stabilized Zn(1−x)MnxS solid solutions on methylene blue Applied Catalysis A: General, 476, 22,1-8, 2014.
  • S. Sathish Kumar and Helen P. Kavitha, Synthesis and Biological Applications of Triazole Derivatives-A Review      Mini-Reviews in Organic Chemistry, 10(1), 2013.
  • Helen P. Kavitha and S. Arulmurugan     Synthesis, characterization and cytotoxic activity of benzoxazole, benzimidazole, imidazole and tetrazole      Acta pharmaceutica  63(2), 253-264, 2013
  • Jasmine P. Vennila, Jhon Thiruvadigal,  Helen P Kavitha,  G. Chakkaravarthi and V. Manivannan, N-[2-(3,4-Dimeth-oxy¬phenyl)eth¬yl]-N-methyl-naphthalene-1-sulfonamide, Acta Crystallogr Sect E, 68(Pt 3): o890, 2012.
  • Jasmine P. Vennila, D. Jhon Thiruvadigal,  and Helen P. Kavitha           Antibacterial evaluation of some organic compounds as potential inhibitors for glucosamine-6-phospate synthase            Journal of Pharmacy Research, 5(4), 1963-1966, 2012.
  • Helen P. Kavitha and R. Arulmozhi , Synthesis, Characterization and Anti inflammatory Activity of Some New Tetrazoles Derived from Quinazoline-4-one , International Journal of Chemistry, 1-6, 2012.
  • S. Arulmurugan, Helen P. Kavitha and S. Sathish Kumar.          Synthesis, characterization and molecular docking studies of some new benzoxazole, benzimidazole, imidazole and tetrazole compounds as potential inhibitors for thymidylate synthase, International Journal of Science and Technology, 1, 1-11 2012.
  • Jasmine P. Vennila, Jhon Thiruvadigal, G. E. Theboral Sugi Kamala,  Helen P Kavitha, Chakkaravarthi and V. Manivannan          N-[2-(3,4-Dimeth-oxy¬phen¬yl)eth¬yl]-N-methyl¬benzene-sulfonamide” Acta Crystallogr Sect E Struct Rep Online. 68(Pt 3), o882, 2012.
  • Helen P Kavitha, A. Silambarasan, S. Ponnusamy, M. Navaneethan and Y, Hayakawa, Monodispersed synthesis of hierarchical wurtzite ZnS nanostructures and its functional properties” Materials Letters 81, 209-211, 2012.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-(4-Bromophenyl)-3-(4-hydroxyphenyl)-1,3-thiazolidin-4-one”  Acta Cryst., E67, o1902, 2011.
  • Jasmine P. Vennila, D Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan    2,4-Bis(morpholin-4-yl)-6-phenoxy-1,3,5-triazine”  Acta Cryst. E67, o2451, 2011.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, G. Chakkaravarthi and V. Manivannan, 2-Chloro-4,6-bis(piperidin-1-yl)-1,3,5-triazine”  Acta Cryst. E67, o312, 2011.
  • Helen P. Kavitha, Samiappan Sathish kumar and Ramachandran Balajee           Antimicrobial Activity and Molecular Docking Studies of Some Novel Tetrazolo Diazepine Derivatives, Journal of Pharmacy Research,4(9), 2946-2949, 2011
  • Helen P. Kavitha and R. Arulmozhi  Study of Antimicrobial and Analgesic Activities of Novel Tetrazoles Derived from Quinazolin-4-one, Journal of Pharmacy Research , 4(12), 4696-4698, 2011.
  • R.Thilagavathy, Helen.P.Kavitha, R.Amrutha and Bathey.R.Venkatraman       Structural parameters, charge distribution and vibrational frequency analysis using theoretical SCF methods, Elixir Comp. Chem. 40, 5514-5516, 2011.
  • S. Sathish Kumar, Helen P. Kavitha, S. Arulmurugan  and B. R. Venkatraman, Review on Synthesis of Biologically Active Diazepam Derivatives           Mini-Reviews in Organic Chemistry, 8, 1-17, 2011.
  • Jasmine P. Vennila, Jhon Thiruvadigal, Helen P Kavitha, B. Gunasekaran and V. Manivannan, (E)-4-{(4-Bromopenzylidene) amino} phenol, Acta Cryst, E66, O316, 2010.
  • Subramaniyan Arulmurugan and Helen P. Kavitha, 2-Methyl-3-{4-[-(1H-tetrazol-5-yl)ethylamino]phenyl}-3H-quinazolin-4-one”,     Molbank, M695,1-5, 2010.
  • S. Arulmurugan, Helen P. Kavitha and B. R. Venkatraman        Biological Activities of Schiff Base and its Complexes”: A Review,           Rasayan Journal of Chemistry, 3(3), 385-410, 2010.
  • R. Thilagavathy, Helen P Kavitha and B. R. venkatraman          Isolation, Characterization and Anti-Inflammatory Property of Thevetia Peruviana     E-journal of Chemistry,7(4), 1584-1590, 2010.
  • Subramaniyan  Arulmurugan, Helen P. Kavitha, B. R. Venkatraman, Synthesis, Characterization and Study of antibacterial activity of some novel tetrazole derivatives” ,  Orbital Elec. J. Chem,  2(3), 271-276, 2010.
  • With R. Thilagavathi “Synthesis of 3-{4-[4-(benzylideneamino) benzene sulfonyl]-phenyl}-2-phenylquinazoline-4(3H)-one” Molbank, M589, 2009.
  • With S.Sathish Kumar “Synthesis of 3-Methyl-1-Morpholin-4-ylmethyl-2,6-Diphenylpiperidin-4-One”, Molbank, M617, 2009.
  • With S. Sathish Kumar “6-Methyl-2,7-Diphenyl-1,4-Diazepan-5-One”, Acta Cryst., E65, (o3211), 2009.
  • With R. Thilagavathi “2-phenyl-4H-3,1-benzoxazian-4-one”, Acta., Cryst. (E), E65, (o127), 2009.
  • With Suneel Manohar Babu “4-Bromo-3-{N[2-(3,4-dimethoxy phenyl)ethyl]-N-methyl-sulfamoyl}-5-methyl benzoic acid mono hydrate”, Acta., Cryst. (E), E65, (o1568), 2009.
  • With Suneel Manohar Babu “2,4-Dichloro-N-phenethyl benzene Sulfonamide” , Acta., Cryst. (E), E65, (o921), 2009.
  • With Suneel Manohar Babu “N-(5-Bromo-2-Chlorobenzyl)-N-cyclopropylnaphthlene-2-sulfonamide”,  Acta. Cryst. (E), E65, (o1098), 2009.
  • With Jasmine P. Vennila “4-nitrophenyl napthalene-1-sulfonate”, Acta Cryst. (E), (o1848), E64, 2008.
  • With R. Arulmozhi,”1- Naphthyl-9-HCarbazole-4-Sulphonate”, Acta Cryst., E66, 010208, 2008.
  • With T. Nithya “Antibacterial activity of Solanum Trilobatum”, Journal of  Ecotoxicol.Environ. Monit., 14, (237-239), 2004.
  • “Synthesis and Antimicrobial activity of1-(9’Acridinyl)-5-substituted phenyl Tetrazoles”, Asian Journal of chemistry, 16, (1191-1192), 2004.
  • With S. V. Selva bala “Study of Hypoglysemic Activity of Solanum Xanthocarpum L. on Alloxanised Diabetic Rats”, Adv. Pharmacol Toxicol., 4, (19-24), 2003.
  • Helen P. Kavitha “Study of anajesic activity some novel 1-(9’Acridinyl)-5-substituted phenyl tetrazoles”, Indian Journal of Chemical Technology, 9, (361-362), 2002.
  • With S.Malliga, “Effect of Soaking the Wood of Emblica officinalis,on Some Water Parameters”, Journal of   Swamy Bot. 15, (89-90), 1998.

Working Papers

  • With S. Arulmurugan, “Review on Biologically Active Benzimidazole derivatives”: Mini reviews in organic Chemistry.

Academic Experiences

  • Assistant Professor(S. G), SRM University, Ramapuram from Sep 2007 to Jun 2012
  • Lecturer, SRM University, Ramapuram from Aug 2004 to Aug 2007
  • Senior Lecturer, VRS College, Villupuram from Aug 2002 to May 2004
  • Lecturer, VRS College, Villupuram, from Aug 2000 to May 2002
  • Lecturer, ADM College for Women, Nagapattinam from July 94 to April 95

Other Professional Experiences

  • 4 Scholars have been  awarded Ph.D Degree
  • Guiding 3 Ph.D candidates
  • Guided 8 M. Phil and 20 M. Sc projects
  • Principal Investigator for a pilot project funded by SRM University (completed)
  • Co-investigator for a UGC major project (completed)
  • Reviewer for  International Journals
  • Convenor for the National Conference on New Renaissance in Chemical Research, 2011 and 2015.
  • Member Board of Studies –Chemistry,SRM University.
  • Doctoral Committee member in Karunya University
  • Undertaking consultancy work in the department
  • Question paper setter for various universities
  • Convenor for many programmes conducted in the campus
  • Chief Superintendent for SRM University-Ramapuram campus
  • Member in various professional bodies such as MISTE, FICCE and CTA
  • Author of five books in chemistry
  • Executive council member in Association of Chemistry Teachers, Mumbai

Achievement and Award

  • Received Award and cash prize for Research from SRM University from the year 2006-15

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Catalytic carbonyl hydrosilylations via a titanocene borohydride-PMHS reagent system

 spectroscopy, SYNTHESIS  Comments Off on Catalytic carbonyl hydrosilylations via a titanocene borohydride-PMHS reagent system
Jul 142017
 

 

DOI: 10.1039/C7CY01088E, Paper
Godfred D. Fianu, Kyle C. Schipper, Robert A. Flowers II
Catalytic amounts of titanocene(III) borohydride, generated under mild conditions from commercially available titanocene dichloride, in concert with a stoichiometric hydride source is shown to effectively reduce aldehydes and ketones to their respective alcohols in aprotic media.
  • Catalysis Science & Technology

Catalytic carbonyl hydrosilylations viaa titanocene borohydride–PMHS reagent system

 Author affiliations

Abstract

Reduction of a wide range of aldehydes and ketones with catalytic amounts of titanocene borohydride in concert with a stoichiometric poly(methylhydrosiloxane) (PMHS) reductant is reported. Preliminary mechanistic studies demonstrate that the reaction is mediated by a reactive titanocene(III) complex, whose oxidation state remains constant throughout the reaction.

Godfred Fianu

Godfred Fianu

Robert A Flowers

Robert A Flowers

Danser Distinguished Faculty Chair in Chemistry and Deputy Provost for Faculty Affairs
Lehigh University
Bethlehem, United States
Phenyl methanol (2-c)
Phenyl methanol (2-c) was prepared from benzaldehyde (1-c) by the procedure outlined
in GP1. NMR analysis showed 100% conversion in 1 hour. 86% isolated yield of alcohol
product was obtained after complete workup.
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.26 (m,5H), 4.59 (s, 2H), 2.99 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 140.92, 128.56, 127.60, 127.07,77.52, 77.20, 76.88, 65.04.
STR1 STR2

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Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules

 SYNTHESIS, Uncategorized  Comments Off on Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules
Jul 142017
 

 

Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules

Catal. Sci. Technol., 2017, Advance Article
DOI: 10.1039/C7CY01130J, Paper
Kazuto Suzuki, Joshua Kyle Stanfield, Osami Shoji, Sota Yanagisawa, Hiroshi Sugimoto, Yoshitsugu Shiro, Yoshihito Watanabe
The benzylic hydroxylation of non-native substrates was catalysed by cytochrome P450BM3, wherein “decoy molecules” controlled the stereoselectivity of the reactions.
  • Catalysis Science & Technology

Control of stereoselectivity of benzylic hydroxylation catalysed by wild-type cytochrome P450BM3 using decoy molecules

Abstract

The hydroxylation of non-native substrates catalysed by wild-type P450BM3 is reported, wherein “decoy molecules”, i.e., native substrate mimics, controlled the stereoselectivity of hydroxylation reactions. We employed decoy molecules with diverse structures, resulting in either a significant improvement in enantioselectivity or clear inversion of stereoselectivity in the benzylic hydroxylation of alkylbenzenes and cycloalkylbenzenes. For example, supplementation of wild-type P450BM3 with 5-cyclohexylvaleric acid-L-phenylalanine (5CHVA-Phe) and Z-proline-L-phenylalanine yielded 53% (R) ee and 56% (S) ee for indane hydroxylation, respectively, although 16% (S) ee was still observed in the absence of any additives. Moreover, we performed a successful crystal structure analysis of 5CHVA-L-tryptophan-bound P450BM3 at 2.00 Å, which suggests that the changes in selectivity observed were caused by conformational changes in the enzyme induced by binding of the decoy molecules.

M2 Kazuto Suzuki \ suzuki.kazuto*c.mbox.nagoya-u.ac.jp

Yoshihito Watanabe yoshi*nucc.cc.nagoya-u.ac.jp

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2,2,5,5-Tetramethyltetrahydrofuran (TMTHF): a non-polar, non-peroxide forming ether replacement for hazardous hydrocarbon solvents

 SYNTHESIS  Comments Off on 2,2,5,5-Tetramethyltetrahydrofuran (TMTHF): a non-polar, non-peroxide forming ether replacement for hazardous hydrocarbon solvents
Jul 132017
 

 

2,2,5,5-Tetramethyltetrahydrofuran (TMTHF): a non-polar, non-peroxide forming ether replacement for hazardous hydrocarbon solvents

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01392B, Paper
Fergal Byrne, Bart Forier, Greet Bossaert, Charly Hoebers, Thomas J. Farmer, James H. Clark, Andrew J. Hunt
An inherently non-peroxide forming ether solvent, 2,2,5,5-tetramethyltetrahydrofuran (2,2,5,5-tetramethyloxolane), has been synthesized from readily available and potentially renewable feedstocks, and its solvation properties have been tested

2,2,5,5-Tetramethyltetrahydrofuran (TMTHF): a non-polar, non-peroxide forming ether replacement for hazardous hydrocarbon solvents

 

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC01392B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Abstract

An inherently non-peroxide forming ether solvent, 2,2,5,5-tetramethyltetrahydrofuran (2,2,5,5-tetramethyloxolane), has been synthesized from readily available and potentially renewable feedstocks, and its solvation properties have been tested. Unlike traditional ethers, its absence of a proton at the alpha-position to the oxygen of the ether eliminates the potential to form hazardous peroxides. Additionally, this unusual structure leads to lower basicity compared with many traditional ethers, due to the concealment of the ethereal oxygen by four bulky methyl groups at the alpha-position. As such, this molecule exhibits similar solvent properties to common hydrocarbon solvents, particularly toluene. Its solvent properties have been proved by testing its performance in Fischer esterification, amidation and Grignard reactions. TMTHF’s differences from traditional ethers is further demonstrated by its ability to produce high molecular weight radical-initiated polymers for use as pressure-sensitive adhesives.

STR1

[TMTHF].

1H NMR (400 MHz, CDCl3): δ 1.81 (s, 4H), 1.21 (s, 12H);

13C NMR (400 MHz, CDCl3): δ 29.75, 38.75, 80.75;

IR 2968, 2930, 2968, 1458, 1377, 1366, 1310, 1265, 1205, 1144, 991, 984, 885, 849, 767 cm−1;

m/z (%): (ESI–MS) 128 (40) [M+ ]

STR1

 

Fergal Byrne

Fergal Byrne

PHD Researcher at Green Chemistry Centre of Excellence

University of York

York, United Kingdom

University of York

Green Chemistry Centre of Excellence, University of York, York YO10 5DD, UK 

 

Andrew Hunt

Andrew Hunt

Catalysis, Environmental Chemistry, Green Chemistry

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NMR predict

[TMTHF].

1H NMR (400 MHz, CDCl3): δ 1.81 (s, 4H), 1.21 (s, 12H);

STR1 STR2

13C NMR (400 MHz, CDCl3): δ 29.75, 38.75, 80.75;

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Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

 FLOW CHEMISTRY, flow synthesis  Comments Off on Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
Jun 052017
 

 

 

Abstract Image

The first continuous flow synthesis of C8–C16 alkane fuel precursors from biobased platform molecules is reported. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) was found to be a recyclable and highly efficient organic base catalyst for the aldol condensation of furfural with carbonyl compounds, and the selectivity of mono- or difuryl product can be easily regulated by adjusting the molar ratio of substrates. By means of flow technique, a shorter reaction time, satisfactory output, and continuous preparation are achieved under the present procedure, representing a significant advance over the corresponding batch reaction conditions.

Continuous Microflow Synthesis of Fuel Precursors from Platform Molecules Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

Tao Shen, Jingjing Tang, Chenglun Tang, Jinglan Wu, Linfeng Wang, Chenjie Zhu*§ , and Hanjie Ying§
College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, China
National Engineering Technique Research Center for Biotechnology, Nanjing 211816, China
§Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing 211816, China
State Key Laboratory of Motor Vehicle Biofuel Technology, Nanyang 473000, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00141

 

*E-mail: zhucj@njtech.edu.cn. Phone/Fax: +86 25 58139389.
1-(furan-2-yl)-2-methylpent-1-en-3-one
1a
3-pentanone (100 mmol, 8.6 g) and furfural (100 mmol, 9.6 g) were diluted with MeOH-H2O to 40 mL in stream 1, catalyst TBD (10 mmol, 1.39 g) were diluted with MeOH-H2O (v/v = 1/1) to 40 mL in stream 2, the two streams was purged in a 0.2 mL/min speed into slit plate mixer and at the 353 K passed tubing reactor. Finally, the product was extracted with EtOAc and water, the obtained organic layer was evaporated and purified by silica gel flash chromatography (25:1 hexane-EtOAc) to provide the analytically pure product for further characterization, the aqueous phase was collected and reused.According to the general procedure afforded 14.92 g (91%) of product 1a, isolated as pale yellow oil;
1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 1.4 Hz, 1H), 7.29 (s, 1H), 6.71 (d, J = 3.5 Hz, 1H), 6.52 (dd, J = 3.4, 1.8 Hz, 1H), 2.71 (q, J = 7.3 Hz, 2H), 2.05 (s, 3H), 1.04 (t, J = 7.3 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 203.5, 153.0, 145.8, 133.8, 126.8, 116.6, 113.3, 31.1, 13.2, 9.2.
STR1 STR2 str3
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Guest blogger, Dr Pravin Patil, Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles

 Uncategorized  Comments Off on Guest blogger, Dr Pravin Patil, Synthesis of Extended Oxazoles III: Reactions of 2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles
Jun 042017
 

University of Louisville

Chemistry building and Shumaker building

Department of Chemistry, University of Louisville

Synthesis of Extended Oxazoles III: Reactions of  2-(Phenylsulfonyl)methyl-4,5-Diaryloxazoles

Pravin C. Patil and Frederick A. Luzzio*

Department of Chemistry, University of Louisville, 2320South Brook Street, Louisville, Kentucky 40292 

Faluzz01@louisville.edu

*Corresponding Author: Email: faluzz01@louisville.edu

J Org. Chem.201681(21), pp 10521–10526.

Publication Date (Web): July 21, 2016 (Note)

DOI: 10.1021/acs.joc.6b01280

Image result for Frederick A. Luzzio

Frederick A. Luzzio

Professor, Organic Chemistry: Organic and Medicinal Chemistry

str0

STR2

str0

STR2

Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq. 1) and 18 (Table 2). To a solution of the alkylated 2-(sulfonylethyl)-4,5-diphenyloxazole 5 (0.12 mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15 mL), was added an excess of food-grade aluminum foil (2.32 mmol, 20 equiv) with vigorous stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux until the metal disappeared. The reaction mixture was then allowed to cool to room temperature and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate was concentrated to a crude residue which was submitted to gravity-column chromatography on silica gel to provide 2-methyl-4,5-diphenyloxazole 4 (96%) or 2-ethyl-4,5-diphenyloxazole 18 (97%).

General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones 5-17. To a stirred solution of an alkylated 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole (0.12 mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol, 15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant crude residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate) to afford the pure products 1827 listed in Table 2.

 

Typical Procedure for Aluminum/HgCl2-Mediated Desulfonylation for Synthesis of 4 (Eq. 1) and 18 (Table 2). To a solution of the alkylated 2-(sulfonylethyl)-4,5-diphenyloxazole 5 (0.12 mmol, 1.0 equiv) and crystals of mercuric chloride (0.034 mmol, 0.3 equiv), in methanol (15 mL), was added an excess of food-grade aluminum foil (2.32 mmol, 20 equiv) with vigorous stirring under a nitrogen atmosphere. The resulting heterogeneous mixture was heated at reflux until the metal disappeared. The reaction mixture was then allowed to cool to room temperature and filtered through a Celite bed followed by washing with methanol (2 x 15mL). The filtrate was concentrated to a crude residue which was submitted to gravity-column chromatography on silica gel to provide 2-methyl-4,5-diphenyloxazole 4 (96%) or 2-ethyl-4,5-diphenyloxazole 18 (97%).

 

General procedure for Magnesium/HgCl2-Mediated Desulfonylation of Alkylated Sulfones 5-17. To a stirred solution of an alkylated 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole (0.12 mmol, 1.0 equiv. from Table 1) in methanol (5 mL) was added magnesium turnings (1.73 mmol, 15 equiv) and crystals of mercuric chloride (0.012 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at room temperature (2 h) while monitoring the reaction progress by TLC. After the reaction was complete, the reaction mixture was filtered through a Celite bed followed by washing with methanol (2 x 10 mL). The filtrate was concentrated and the resultant crude residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate) to afford the pure products 1827 listed in Table 2.

str0 STR2

Typical procedure: Synthesis of Oxaprozin

Ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate (28). To a prechilled solution of 2-(phenylsulfonyl)methyl-4,5-diphenyloxazole 3 (100 mg, 0.27 mmol) in dry THF (15 mL) was added potassium tert-butoxide (33 mg, 0.29 mmol) under a nitrogen atmosphere. The resulting yellow solution was stirred (5°C) for 30 min. To the reaction mixture was slowly added ethyl bromoacetate (49 mg, 32.4 μL, 0.29 mmol) and stirring was continued (16 h) at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was quenched with cold water (20 mL) and extracted with dichloromethane (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude oily residue. The residue was submitted to gravity-column chromatography on silica gel (hexane/ethyl acetate, 4:1) afford pure ethyl 3-(4,5-diphenyloxazol-2-yl)-3-(phenylsulfonyl)propanoate 28 as off-white solid ( 88 mg, 72%).

Ethyl 3-(4,5-diphenyloxazol-2-yl)acrylate (29). To a cooled (5°C) solution of sulfonyloxazole ester 28 (225 mg, 0.49 mmol) in dry THF was added potassium tert-butoxide (60.2 mg, 0.54 mmol) under nitrogen and the reaction mixture was then stirred at 5-10°C (2 h) while monitoring by TLC. After completion of the reaction, the reaction mixture was extracted with dichloromethane (2 x 25 mL) followed by washing the extracts with water and brine then drying over anhydrous Na2SO4. Removal of the drying agent and concentration of the filtrate gave a crude residue which was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide unsaturated oxazole ester 29 as a colorless oil (100 mg, 65%).

Ethyl 3-(4,5-diphenyloxazol-2-yl)propanoate (30).17 The unsaturated oxazole ester 30 (160 mg, 0.50 mmol) was dissolved in methanol (25 mL) then 10% Pd/C (16 mg, 10% wt/wt) was added at room temperature. The reaction mixture was purged with nitrogen while stirring followed by the addition of hydrogen gas (balloon) and then stirring was continued (16 h) under an atmosphere of hydrogen. Upon completion of reaction, the reaction mixture was filtered through a bed of Celite while washing with methanol (2 x 30 mL). The combined filtrates were concentrated and the crude residue was submitted to gravity-column chromatography (hexane/ethyl acetate, 4:1) to afford 30 as an off-white solid (129 mg, 80%).

Methyl 3-(4,5-diphenyloxazol-2-yl)propanoate (31).13  To a clear solution of sulfonyloxazole ester 28 (80 mg, 0.173 mmol) in methanol (10 mL) was added magnesium turnings (63 mg, 2.60 mmol) followed by solid mercuric chloride (4.7 mg, 0.017 mmol) at room temperature. The resulting reaction mixture was stirred (2 h) while monitoring the reaction progress by TLC. After completion of the reaction, the heterogeneous mixture was then filtered through a Celite bed followed by washing with methanol (2 x 15 mL). The methanolic filtrates were combined and concentrated to afford a crude residue. The residue was submitted to gravity-column chromatography (hexane/ethylacetate, 4:1) to provide ester 31 as an off-white solid (52 mg, 97%).

3-(4,5-Diphenyloxazol-2-yl)propanoic acid (Oxaprozin) (32).13 Ethyl ester 30 (128 mg, 0.39 mmol) or methyl ester 31 (65 mg, 0.21 mmol) and 20% aquous NaOH solution (3 mL) was stirred overnight at room temperature. Upon completion of reaction as indicated by TLC, the reaction mixture was slowly acidified to pH 3-4 using conc. HCl (3 mL) at room temperature and stirring was continued (3 h). After the neutralization was complete the reaction mixture was diluted with cold water (15 mL) and extracted with dichloromethane (2 x 15 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to give a white solid residue. The residue was submitted to gravity-column chromatography (chloroform/methanol, 9:1) to afford pure Oxaprozin 32 as white solid (80 mg, 68%, from the ethyl ester 30) or (60 mg, 97%, from the methyl ester 31).

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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.

    Prof K. G. Akamanchi

    ICT Mumbai

    SEE…………

    About

    The long term goals of our research are focused at the interface of chemistry and biology. We are interested in solving problems in biomedicine using the techniques and application of synthetic organic, medicinal and natural products chemistry. Toward our goals in biomedicine we concentrate our efforts in the following three areas of organic chemistry: (1) the development of new methods and strategy which are applicable to the synthesis of biologically active compounds; (2) the total synthesis of a wide range of complex molecules including natural products, pharmaceutical leads and their analogues; and (3) the isolation and discovery of biologically active compounds from natural sources. Within our objectives in item 1 (above), we have had a long-term collaboration with the Clinical Pharmacology Section of the National Cancer Institute in which we have synthesized metabolites and analogues of thalidomide, a small-molecule immunomodulator and angiogenesis inhibitor. The derivatives and analogues of thalidomide were stereospecifically synthesized in order to ascertain the mode of action and the molecular target of this small molecule. Ultimately, the synthetic studies are leading to analogues of thalidomide which are more potent, but which have less undesirable side effects than the parent compound. In the neurosciences area we have completed an enantioselective synthesis of both optical isomers of a key intermediate in preparing the histrionicotoxins, a group of compounds which are isolated for the neurotoxic Amazon “poison dart” frogs. One of our present natural products projects  (under item 3,above) entails the isolation, neurotoxicity assays and synthesis of a series of naturally-occurring compounds called acetogenins from the North American paw paw tree Asimina triloba. The isolation, purification and structural confirmation of the natural products has been conducted in collaboration with the Neurosciences Department within the University of Louisville School of Medicine. In the area of anti-infectives (under 1), we are designing and synthesizing an array of nitrogen and nitrogen/oxygen heterocyclic scaffolds bearing acetylenic and azido groups for use in the so-called “click reaction.” The multiply-connected scaffolds have proven to be effective for inhibiting micro-organisms working in tandem to produce biofilms necessary for their establishment and survival.

    Education

    1976   B.S.   Vanderbilt University
    1979   M.S.  Tufts University
    1982   Ph.D. Tufts University
    1982-1985  Postdoctoral Fellow, Harvard University

    Current Service

    Executive Committee/Treasurer, International Society of Heterocyclic Chemistry HETCHEM@louisville.edu

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    Tegafur

     Uncategorized  Comments Off on Tegafur
    Jun 012017
     

    Skeletal formula of tegafur

    Tegafur

    CAS 17902-23-7

    2,​4(1H,​3H)​-​Pyrimidinedione, 5-​fluoro-​1-​(tetrahydro-​2-​furanyl)​-
    Molecular Weight,200.17, MF C8 H9 F N2 O3
    172-173 °C

    Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, 29(11), PG 3181-90

    Uracil, 5-fluoro-1-(tetrahydro-2-furyl)-
    Utefos
    Venoterpine
    WY1559000
    YR0450000
    5-fluoro-1-tetrahydrofuran-2-ylpyrimidine-2,4(1H,3H)-dione
    Carzonal
    N1-(2′-Furanidyl)-5-fluorouracil
    • Synonyms:Ftorafur
    • ATC:L01BC03
    • EINECS:241-846-2
    • LD50:800 mg/kg (M, i.v.); 775 mg/kg (M, p.o.);
      685 mg/kg (R, i.v.); 930 mg/kg (R, p.o.);
      34 mg/kg (dog, p.o.)

    Derivatives, monosodium salt

    • Formula:C8H8FN2NaO3
    • MW:222.15 g/mol
    • CAS-RN:28721-46-2

    Tegafur (INN, BAN, USAN) is a chemotherapeutic prodrug of 5-flourouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.[1]

    Medical uses

    As a prodrug to 5-FU it is used in the treatment of the following cancers:[2]

    It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).[2]

    Image result for tegafur

    Adverse effects

    The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.[2] Central neurotoxicity is more common with tegafur than with fluorouracil.[2]

    Image result for tegafur

    Pharmacogenetics

    The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.[4][5] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.[4][5]

    Mechanism of action

    It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor.[2]

    Pharmacokinetics

    It is metabolised to 5-FU by CYP2A6.[6][7]

    Interactive pathway map

    Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

    FluoropyrimidineActivity_WP1601

    go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article

    The interactive pathway map can be edited at WikiPathways: “FluoropyrimidineActivity_WP1601”.

    Image result for tegafur

    Image result for tegafur SYNTHESIS

     

     

    Image result for tegafur SYNTHESIS

     

    MASS SPECTRUM

    STR2

    1H NMR

    str3 str4

    IR

     

    str5

     

    13C NMR

    STR2 str3

    RAMAN

     

    str4

     

    STR2 str3

    Synthesis

    Image result for tegafur SYNTHESIS

    Substances Referenced in Synthesis Path

    CAS-RN Formula Chemical Name CAS Index Name
    58138-78-6 C10H19FN2O2Si2 1,3-bis(trimethylsilyl)fluorouracil 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-1,3-bis(trimethylsilyl)-
    13369-70-5 C4H7ClO 2-chlorotetrahydrofuran Furan, 2-chlorotetrahydro-
    1191-99-7 C4H6O 2,3-dihydrofuran Furan, 2,3-dihydro-
    51-21-8 C4H3FN2O2 5-fluorouracil 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-

    Image result for tegafur SYNTHESIS

    Image result for tegafur

    ChemSpider 2D Image | Tegafur | C8H9FN2O3

     

    SYN1

    STR1

    CN 106397416

    SYN 2

    STR2

     

    Advanced Synthesis & Catalysis, 356(16), 3325-3330; 2014

    PATENTS

    CN 106397416

    CN 104513230

    CN 103159746

    PATENT

    CN 102285972

    tegafur is a derivative of 5-fluorouracil, and in 1967, Hiller of the former Soviet Union synthesized tegafur (SA Hiller, RA Zhuk, M. Yu. Lidak, et al. Substituted Uracil [ P, British Patent, 1168391 (1969)). In 1974, it was listed in Japan. China was successfully developed by Shandong Jinan Pharmaceutical Factory in 1979. Its present origin is Shanghai and Shandong provinces and cities. The anti-cancer effect of tegafur is similar to that of 5-fluorouracil and is activated in vivo by 5-fluorouracil through liver activation. Unlike 5-fluorouracil, tegafur is fat-soluble, has good oral absorption, maintains high concentrations in the blood for a long time and easily passes through the blood-brain barrier. Clinical and animal experiments show that tegafur on gastrointestinal cancer, breast cancer is better, the role of rectal cancer than 5-fluorouracil good, less toxic than 5-fluorouracil. Teflon has a chemotherapy index of 2-fold for 5-fluorouracil and only 1 / 4-1 / 7 of toxicity. So the addition of fluoride is widely used in cancer patients with chemotherapy.

    [0003] The first synthesis of tegafur is Hiller ([SA Hiller, RA Zhuk, Μ. Yu. Lidak, et al. Substituted Uracil [P], British Patent, 1168391 (1969)]. 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-Fu, 1) and 2-chlorotetrahydrofuran (Thf-Cl), and it is reported that this synthesis must be carried out at low temperature (- 20 to -40 ° C), because Thf-Cl is unstable, and excess Thf-Cl results in a decomposition reaction, thereby reducing the yield of Thf-Fu.

    [0004] Earl and Townsend also prepared 1_ (tetrahydro-2-furyl) uracil using Thf-Cl and 2,4-bis (trimethylsilyl) uracil, and then using trifluoromethyl fluorite to product Fluorination. Mitsugi Yasurnoto reacts with the Friedel-Crafts catalyst in the presence of 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-U, 1) 2-acetoxytetrahydrofuran (Thf-OAc, 2) (Kazu Kigasawa et al., 2-tert-Butoxy), & lt; RTI ID = 0.0 & gt;, & lt; / RTI & gt; (K. Kigasawa, M. Hiiragi, K. ffakisaka, et al. J. Heterocyclic Chem. 1977, 14: 473-475) was reacted with 5-Fu at 155-160 ° C. Reported in the literature for the fluoride production route there are the following questions: 1, high energy consumption. In the traditional synthesis method, in order to obtain the product, the second step of the reaction needs to continue heating at 160 ° C for 5-6 hours, high energy consumption; 2, difficult to produce, low yield: 5-fluorouracil as a solid powder The reaction needs to be carried out at a high temperature (160 ° C), which requires the use of a high boiling solvent N, N-dimethylformamide (DMF). But it is difficult to completely remove the fluoride from the addition of fluoride, because DMF can form hydrogen bonds with the fluoride molecules, difficult to separate from each other; 3, in order to unreacted 5-fluorouracil and tegafur separation and recycling , The use of carcinogenic solvent chloroform as a extractant in the conventional method to separate 5-fluorouracil and tegafur. However, the main role of chloroform on the central nervous system, with anesthesia, the heart, liver, kidney damage; the environment is also harmful to the water can cause pollution. Therefore, the use of volatile solvent chloroform, even if the necessary measures to reduce its volatilization, will still cause harm to human health and the environment; 4, low yield. Since both NI and N-3 in the 5-fluorouracil molecule react with 2-tert-butoxytetrahydrofuran, the addition of tegafur is also the addition of 1,3-bis (tetrahydro-2-furyl) -5 – Fluorouracil. Therefore, the improvement of the traditional production process of tegafur is a significant and imminent task.

    Example 1 (for example, the best reaction conditions):

    Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 10. 0 mg CuCl2, microwave irradiation 250W at 25 ° C reaction 0. 6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), and microwave irradiation at 400 ° C for 100 ° C. After distilling off the low boiling solvent, the oil was obtained. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give 1.34349 g of product. Melting point: 160-165 ° C. The yield was 75%.

    [0011] Example 2

    Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 3.8 g (100 mmol) of ethanol were added to a single-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 5mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), microwave irradiation 400W, reaction temperature 60 ° C under the reaction pool. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give the product 0. 46 g. Melting point: 160-165 ° C. The yield was 15%.

    [0012] Example 3

    Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 20mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1301: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give the product 1.81 g. Melting point: 160-165 ° C. The yield was 61%.

    [0013] Example 4

    Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran and 19 g (500 mmol) of ethanol were added to a single-necked flask. To this was added 20 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give product U6g. Melting point: 160-165 ° C. The yield was 43%.

    [0014] Example 5

    Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 9.5 g (250 mmol) of ethanol were added to a single-necked flask. To this was added 30 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 6001, reaction temperature 1001: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give 1.15 g of product. Melting point: 160-165 ° C. The yield was 38%.

    [0015] Example 6

    Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 25 ml of tetrahydrofuran (THF). And then weighed 15mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 5001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give product 2.10 g. Melting point: 160-165 ° C. The yield was 70%.

     

    Paper

    A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

    Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions

    Aleksandra Zasada, Ewa Mironiuk-Puchalska, and Mariola Koszytkowska-Stawińska* 

    Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland

    Org. Process Res. Dev., Article ASAP

    DOI: 10.1021/acs.oprd.7b00103

    *E-mail: mkoszyt@ch.pw.edu.pl.

    http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00103

    http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00103/suppl_file/op7b00103_si_001.pdf

    Tegafur, a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967. The compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.

    The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, a rapid breakdown of the released 5-FUra in the gastrointestinal tract is avoided.(6) In injectable form, tegafur provoked serious side effects, such as nausea, vomiting, or central nervous system disturbances.

    The first generation of oral formulation of tegafur , UFT) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding the USA.

    S-1 is the next generation of oral formulation of tegafur.(7) It is a combination of tegafur, gimeracil, and oteracil in a fixed molar ratio of 1:0.4:1, respectively.

    Gimeracil inhibits the enzyme responsible for the degradation of 5-FUra. Oteracil prevents the activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well-tolerated, but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent. Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea, and Singapore for the treatment of patients with gastric cancer.

    In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin. Currently, S-1 has not been approved by the FDA in the United States.

    There is a great interest in further examination of S-1 as an anticancer chemotherapeutic. Currently, 23 clinical trials with S-1 has been registered in National Institutes of Health (NIH). Combinations of S-1 and other anticancer agents have been employed in a majority of these trials.

    5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Tegafur)

    δH 1.89–2.10 (m, 3H), 2.38–2.45 (m, 1H), 3.97–4.01 (q-like m, 1H), 4.20–4.24 (dq-like m), 5.97–5.98 (m, 1H), 7.41 (d, 3JHF 6.1), 9.21 (bs, 1H, NH).

    δC 23.82, 32.90, 70.26, 87.58, 123.63 (d, 2JCF 33.89), 140.33 (d, 1JCF 237.20) 148.66, 156.9 (d, 2JCF 26.81).

    HRMS m/z calcd for C8H10N2O3F [M – H]+ 201.0670, found 201.0669.

    Elemental analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for 3(C8H9N2O3F)·H2O: C%, 46.61; H%, 4.73; N%, 13.59.

    PATENT CITATIONS
    Cited Patent Filing date Publication date Applicant Title
    CN85108855A * Nov 6, 1985 Sep 24, 1986 Central Chemical Research Institute Preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
    GB1168391A * Title not available
    JPS5452085A * Title not available
    JPS5455581A * Title not available
    JPS5459288A * Title not available
    JPS52118479A * Title not available
    JPS54103880A * Title not available
    US4256885 * Dec 10, 1976 Mar 17, 1981 Mitsui Toatsu Kagaku Kabushiki Kaisha Process for the preparation of 1- (2-tetrahydrofuryl) -5-fluorouracil
    US5075446 * Oct 12, 1990 Dec 24, 1991 Korea Advanced Institute Of Science & Technology Synthesis of tetrahydro-2-furylated pyrimidine derivatives
    NON-PATENT CITATIONS
    Reference
    1 * KAZUO KIGASAWA, et al .: ” Studies on the Synthesis of Chemotherapeutics. Synthetic of 1- (2-Tetrahydrofuryl) -5-fluorouracil [Ftorafur] (Studies on the Syntheses of Heterocyclic Compound. Part 703) “, “J. HETEROCCLIC CHEM ., Vol. 14, 31 May 1977 (1977-05-31), pages 473 – 475

    References

    1

    Matt P, van Zwieten-Boot B, Calvo Rojas G, Ter Hofstede H, Garcia-Carbonero R, Camarero J, Abadie E, Pignatti F (October 2011). “The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP).” (PDF). The Oncologist. 16 (10): 1451–1457. doi:10.1634/theoncologist.2011-0224. PMC 3228070Freely accessible. PMID 21963999.

    1. (1) Hirose, Takashi; Oncology Reports 2010, V24(2), P529-536 
    2. (2) Fujita, Ken-ichi; Cancer Science 2008, V99(5), P1049-1054 
    3. (3) Tahara, Makoto; Cancer Science 2011, V102(2), P419-424 
    4. (4) Chu, Quincy Siu-Chung; Clinical Cancer Research 2004, V10(15), P4913-4921 
    5. (5) Tominaga, Kazunari; Oncology 2004, V66(5), P358-364 
    6. (6) Peters, Godefridus J.; Clinical Cancer Research 2004, V10(12, Pt. 1), P4072-4076 
    7. (7) Kim, Woo Young; Cancer Science 2007, V98(10), P1604-1608 
    8.  Hillers, Solomon; Puti Sinteza i Izyskaniya Protivoopukholevykh Preparatov 1970, VNo. 3, P109-12 
    9.  Grishko, V. A.; Trudy Kazakhskogo Nauchno-Issledovatel’skogo Instituta Onkologii i Radiologii 1977, V12, P110-14 
    10. Ootsu, Koichiro; Takeda Kenkyushoho 1978, V37(3-4), P267-77 
    11.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
    12. Yabuuchi, Youichi; Oyo Yakuri 1971, V5(4), P569-84 
    13.  Germane, S.; Eksperimental’naya i Klinicheskaya Farmakoterapiya 1970, (1), P85-92 
    14.  JP 56046814 A 1981

    MORE

    1. AIST: Integrated Spectral Database System of Organic Compounds. (Data were obtained from the National Institute of Advanced Industrial Science and Technology (Japan))
    2.  ACD-A: Sigma-Aldrich (Spectral data were obtained from Advanced Chemistry Development, Inc.)
    3. Nomura, Hiroaki; Chemical & Pharmaceutical Bulletin 1979, V27(4), P899-906 
    4. Sakurai, Kuniyoshi; Chemical & Pharmaceutical Bulletin 1978, V26(11), P3565-6 
    5. Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, V29(11), P3181-90
    6. Lukevics, E.; Zhurnal Obshchei Khimii 1981, V51(4), P827-34 
    7.  Needham, F.; Powder Diffraction 2006, V21(3), P245-247 
      1. Nomura, Hiroaki; Chemical & Pharmaceutical Bulletin 1979, V27(4), P899-906 
      2. Sakurai, Kuniyoshi; Chemical & Pharmaceutical Bulletin 1978, V26(11), P3565-6 
      3.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
      4.  Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, V29(11), P3181-90 
      5.  “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)
      6.  Lukevics, E.; Zhurnal Obshchei Khimii 1981, V51(4), P827-34 
      7.  Lukevics, E.; Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija 1982, (3), P317-20 
      8. Kruse, C. G.; Recueil des Travaux Chimiques des Pays-Bas 1979, V98(6), P371-80 
      9. Lukevics, E.; Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija 1981, (4), P492-3
      10.  Kametani, Tetsuji; Heterocycles 1977, V6(5), P529-33
      11.  Kametani, Tetsuji; Journal of Heterocyclic Chemistry 1977, V14(3), P473-5 
      12. Hillers, S.; GB 1168391 1969 

     

    Tegafur
    Skeletal formula of tegafur
    Ball-and-stick model of the tegafur molecule
    Clinical data
    AHFS/Drugs.com International Drug Names
    Pregnancy
    category
    • AU: D
    Routes of
    administration
    Oral
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    Pharmacokinetic data
    Biological half-life 3.9-11 hours
    Identifiers
    Synonyms 5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    KEGG
    ChEMBL
    ECHA InfoCard 100.038.027
    Chemical and physical data
    Formula C8H9FN2O3
    Molar mass 200.16 g/mol
    3D model (Jmol)

    ///////////TEGAFUR

    FC1=CN(C2CCCO2)C(=O)NC1=O

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    KemInnTek Laboratories, helps you synthesize in mg to multi-kg scale.

     regulatory, SYNTHESIS, Uncategorized  Comments Off on KemInnTek Laboratories, helps you synthesize in mg to multi-kg scale.
    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

    logo
    Visit

    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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    Dnyaneshwar Gopane, Guest blogger, Novel diarylheptanoids as inhibitors of TNF-α production

     Uncategorized  Comments Off on Dnyaneshwar Gopane, Guest blogger, Novel diarylheptanoids as inhibitors of TNF-α production
    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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