AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
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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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

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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.

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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

    Links

    Gordon Research Conferences on Natural Products 2009

    The Natural Products Gordon Conference. 1951-2011

    International Society of Heterocyclic Chemistry

    Organic Links

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    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

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    1H NMR

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    IR

     

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    13C NMR

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    RAMAN

     

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    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

    Image result for presentation animation

     

    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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    Dnyaneshwar B. Gophane, Guest blogger, Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids Dnyaneshwar B. Gophane Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids

     breakthrough designation  Comments Off on Dnyaneshwar B. Gophane, Guest blogger, Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids Dnyaneshwar B. Gophane Hydrogen-bonding controlled rigidity of an isoindoline-derived nitroxide spin label for nucleic acids
    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

    str6

     

    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.

     str5

    Scheme 2. Improved synthesis of diamino isoindoline 6.

    str4

    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.


     STR1

    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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    Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinal Chemistry Letters, Elsevier Publications.

     INDIA  Comments Off on Dr. D. Srinivasa Reddy has been appointed as an editor of Bioorganic & Medicinal Chemistry Letters, Elsevier Publications.
    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
     

    Image for unlabelled figure

    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]

      str2

      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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