- Synthesis and evaluation of 3′-[18F]fluorothymidine-5′-squaryl as a bioisostere of 3′-[18F]fluorothymidine-5′-monophosphate
-
The squaryl moiety has emerged as an important phosphate bioisostere with reportedly greater cell permeability. It has been used in the synthesis of several therapeutic drug molecules including nucleoside and nucleotide analogues but is yet to be evaluated in the context of positron emission tomography (PET) imaging. We have designed, synthesised and evaluated 3′-[18F]fluorothymidine-5′-squaryl ([18F]SqFLT) as a bioisostere to 3′-[18F]fluorothymidine-5′-monophosphate ([18F]FLTMP) for imaging thymidylate kinase (TMPK) activity. The overall radiochemical yield (RCY) was 6.7 ± 2.5% and radiochemical purity (RCP) was >90%. Biological evaluationin vitroshowed low tracer uptake (?1) but significantly discriminated between wildtype HCT116 and CRISPR/Cas9 generated TMPK knockdown HCT116shTMPK?. Evaluation of [18F]SqFLT in HCT116 and HCT116shTMPK?xenograft mouse models showed statistically significant differences in tumour uptake, but lacked an effective tissue retention mechanism, making the radiotracer in its current form unsuitable for PET imaging of proliferation.
- Brickute,Beckley,Allott,Braga,Barnes,Thorley,Aboagye
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p. 12423 - 12433
(2021/04/07)
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- Meteorite-catalyzed intermoleculartrans-glycosylation produces nucleosides under proton beam irradiation
-
Di-glycosylated adenines act as glycosyl donors in the intermoleculartrans-glycosylation of pyrimidine nucleobases under proton beam irradiation conditions. Formamide and chondrite meteorite NWA 1465 increased the yield and the selectivity of the reaction
- Bizzarri, Bruno Mattia,Fanelli, Angelica,Kapralov, Michail,Krasavin, Eugene,Saladino, Raffaele
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p. 19258 - 19264
(2021/06/03)
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- Radiosynthesis of [18F]-labelled pro-nucleotides (ProtIDes)
-
Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of P
- Cavaliere, Alessandra,Probst, Katrin C.,Paisey, Stephen J.,Marshall, Christopher,Dheere, Abdul K.H.,Aigbirhio, Franklin,McGuigan, Christopher,Westwell, Andrew D.
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-
- Synthesis method of beta-thymidine
-
The invention discloses a synthesis method of beta-thymidine. The synthesis method takes trimethylchlorosilane and 5-methyluracil as raw materials to react; in a reaction line process, tetraacetylribose, trifluoromethanesulfonic acid, N,N-dimethylformamide and acetylchloride are introduced; then hydrogenation reaction and hydrolysis reaction are carried out to finally obtain a beta-thymidine finished product and the yield is 89 percent. Compared with an existing synthesis method, the synthesis method of the beta-thymidine has the advantages that the price of raw materials is low, the content of the beta-thymidine in the final product is high, and pollution to the environment in a production process is small; in a synthesis process, the content of generated impurities is less. According to the synthesis method disclosed by the invention, an obtained result is stable and the operation is simple; demands on equipment and preparation environments are not strict so that large-scale popularization is facilitated.
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- METHODS FOR THE TREATMENT OF HEPATITIS B AND HEPATITIS D VIRUS INFECTIONS
-
It is disclosed a method for treating hepatitis B virus infection or hepatitis B virus/hepatits delta virus co-infection, the method comprising administering to a subject in need of such treatment a first pharmaceutically acceptable agent that comprises at least one phosphorothioated nucleic acid polymer and a second pharmaceutically acceptable agent that comprises at least one nucleoside/nucleotide analog HBV polymerase inhibitor.
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- Method for preparing telbivudine
-
The invention relates to a method for preparing telbivudine. The reaction mechanism is as shown in the specification specifically. Compared with a method of the prior art, the method provided by the invention has the advantages that firstly, all raw materials are low in cost and can be easily obtained from the market; secondly, reaction of different steps is normal reaction, and the reaction steps are simple and easy to implement; and thirdly, production requirements can be met by using normal preparation equipment, the production is easy to control, and industrial production can be achieved.
- -
-
Paragraph 0052; 0053; 0054
(2016/10/09)
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- Method for preparing high-purity telbivudine compound
-
The invention belongs to the technical field of medicine and provides a method for preparing a high-purity telbivudine compound. The method includes the steps that an LTD-4 compound serves as the raw material and reacts with thymine subjected to silicification protection, and an intermediate, namely an LTD-5 compound, can be obtained; then, through deprotection reaction, the telbivudine compound is obtained after post-processing, wherein MeONa serves as an alkaline reagent of the deprotection reaction, and strong-acidity resin serves as a dealkalization reagent. The method simplifies the production process, the yield of each step is high, and a target product high in purity and yield is obtained. Please see the structural formula in the description.
- -
-
Paragraph 0046; 0047
(2017/01/02)
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- Antiviral activity of various 1-(2′-Deoxy-β- d -lyxofuranosyl), 1-(2′-Fluoro-β- d -xylofuranosyl), 1-(3′-Fluoro-β- d -arabinofuranosyl), and 2′-fluoro-2′,3′-didehydro-2′, 3′-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication
-
Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2′-fluoroxylofuranosyl, 3′- fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro- 2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d- lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d- xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-didehydro-2′- fluorothymidine (48), and 2′,3′-dideoxy-2′,3′-didehydro- 2′-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC50 values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC50 = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC50 of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
- Srivastav, Naveen C.,Shakya, Neeraj,Mak, Michelle,Agrawal, Babita,Tyrrell, D. Lorne,Kumar, Rakesh
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experimental part
p. 7156 - 7166
(2010/12/19)
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- Radiologic Agents for Monitoring Alzheimer's Disease Progression and Evaluating a Response to Therapy and Processes for the Preparation of Such Agents
-
Disclosed are certain cycloSalingenyl pyrimidine nucleoside monophosphates comprising positron emitters or gamma-emitting radiohalides, uses thereof for monitoring Alzheimer's disease progression and evaluating response to therapy and process for their preparation.
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Page/Page column 9-11
(2009/05/28)
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- PROCESS FOR PREPARING L-NUCLEIC ACID DERIVATIVES AND INTERMEDIATES THEREOF
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A novel method has been found to produce 2,2′-anhydro-1-(β-L-arabinofuranosyl)thymine as a novel useful intermediate compound. A novel method has been further found to produce thymidine from 2,2′-anhydro-1-(β-L-arabinofuranosyl)thymine. According to these methods, synthesis of various L-nucleic acid derivatives, synthesis of which has been difficult till now, is possible.
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Page/Page column 5-6
(2009/01/24)
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- Synthesis of L-2′-deoxypentofuranonucleoside derivatives of thymine from D-glucose
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Convergent synthesis of L-2′-deoxypentofuranonucleoside derivatives of thymine was carried out from D-glucose via 6-O-toluoyl-3-deoxy-1,2-O- isopropylidene-β-L-lyxo-hexofuranose as a key intermediate. Copyright Taylor & Francis Group, LLC.
- Sivets, Grigorii G.
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p. 1241 - 1244
(2008/09/19)
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- Method for preparing radiolabeled thymidine having low chromophoric byproducts
-
The invention is a method and related precursor for preparing 18F-FLT. The precursor has a butoxycarbonyl protecting group at the 5′-position that results in low amounts of chromophoric byproducts being formed during deprotection. The method fo
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-
Page/Page column 4
(2008/06/13)
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- 2'-deoxy-L-nucleosides
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This invention provides processes for the preparation of compounds having the structure: wherein X and Y are same or different, and H, OH, OR, SH, SR, NH2, NHR′, or NR′R″Z is H, F, Cl, Br, I, CN, or NH2. R is hydrogen, halogen, lower alkyl of C1-C6 or aralkyl, NO2, NH2, NHR′, NR′R″, OH, OR, SH, SR, CN, CONH2, CSNH2, CO2H, CO2R′, CH2CO2H, CH2CO2R′, CH═CHR, CH2CH═CHR, or C═CR. R′ and R″ are same or different, and lower alkyl of C1-C6. R13 is hydrogen, alkyl, acyl, phosphate (monophosphate, diphosphate, triphosphate, or stabilized phosphate) or silyl; and
- -
-
Page/Page column 37
(2010/02/11)
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- Synthesis of beta-L-2'-deoxy nucleosides
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An improved process for the preparation of 2′-modified nucleosides and 2′-deoxy-nucleosides, such as, β-L-2′-deoxy-thymidine (LdT), is provided. In particular, the improved process is directed to the synthesis of a 2′-deoxynucleoside that may utilize different starting materials but that proceeds via a chloro-sugar intermediate or via a 2,2′-anhydro-1-furanosyl-nucleobase intermediate. Where an 2,2′-anhydro-1-furanosyl base intermediate is utilized, a reducing agent, such as Red-Al, and a sequestering agent, such as 15-crown-5 ether, that cause an intramolecular displacement reaction and formation of the desired nucleoside product in good yields are employed. An alternative process of the present invention utilizes a 2,2′-anhydro-1-furanosyl base intermediate without a sequestering agent to afford 2′-deoxynucleosides in good yields. The compounds made according to the present invention may be used as intermediates in the preparation of other nucleoside analogues, or may be used directly as antiviral and/or antineoplastic agents.
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-
Page/Page column 35; 36
(2010/02/11)
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- Regioselective enzymatic acylation of β-L-2′-deoxynucleosides: Application in resolution of β-D/L-2′-deoxynucleosides
-
(Chemical Equation Presented) A practical synthesis of β-L-3′- and β-L-5′-O-levulinyl-2′-deoxynucleosides has been described for the first time through enzymatic acylation and/or hydrolysis processes. It is noteworthy that the different behavior exhibited by Pseudomonas cepacia lipase in the acylation of D- and L-nucleosides allows the parallel kinetic resolution of D/L-nucleosides.
- Garcia, Javier,Fernandez, Susana,Ferrero, Miguel,Sanghvi, Yogesh S.,Gotor, Vicente
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p. 3759 - 3762
(2007/10/03)
-
- Synthesis and Antiviral Activity of Novel Fluorinated 2′,3′ -Dideoxynucleosides
-
A series of 5-(trifluoroethoxymethyl)-2′,3′-dideoxyuridines and 5-[bis(trifluormethoxy)-methyl]-2′,3′-dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn- and anti conformations for these 5-(2,2,2-trifluoroethoxymethyl)- and 5-[bis(2,2,2-trifluoroethoxy)-methyl]-derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti-HIV-1 and anti-HIV-2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.
- Kumar, Piyush,Ohkura, Kazue,Balzarini, Jan,De Clercq, Erik,Seki, Koh-Ichi,Wiebe, Leonard I.
-
-
- Methods of manufacture of 2'-deoxy-beta-L-nucleosides
-
The present invention relates to the synthesis of 2′-deoxy-β-L-thymidine, 2′-deoxy-β-L-uridine and 2′-deoxy-β-L-cytidine, and their derivatives, such as the 3′-O-acyl or 3′,5′-O-diacyl prodrugs, including the 3′-O-L-aminoacyl and 3′,5′-O-L-diaminoacyl prodrugs, and particularly the 3′-O-L-valinyl and 3′,5′-O-L-divalinyl prodrugs.
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Page/Page column 23
(2008/06/13)
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- Process for preparing beta-L-2'deoxy-thymidine
-
The present invention relates to a new, essentially four-step process for preparing beta-L-2′-deoxy-thymidine starting from L-arabinose. The process according to the invention is particularly important for mass production of beta-L-2′-deoxy-thymidine.
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-
-
- L-NUCLEIC ACID DERIVATIVES AND PROCESSES FOR THE SYNTHESIS THEREOF
-
A novel method has been found to produce 2,2'-anhydro-1-(β-L-arabinofuranosyl)thymine as a novel useful intermediate compound. A novel method has been further found to produce thymidine from 2,2'-anhydro-1-(β-L-arabinofuranosyl)thymine. A novel method has been further found to L-2'-deoxyribose derivatives as a useful synthetic intermediate through L-2,2'-anhydro-5,6-dihydrocyclouridine derivative. According to these methods, synthesis of various L-nucleic acid derivatives, synthesis of which has been difficult till now.
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Page/Page column 19
(2008/06/13)
-
- Selective cleavage of O-(dimethoxytrityl) protecting group with sodium periodate
-
Sodium periodate in aqueous organic solvents selectively removes, under mild reaction conditions, the O-(dimethoxytrityl) protecting group. Selectivity of the cleavage was studied using the nucleoside derivatives protected by various types of groups commonly used in nucleoside and nucleotide chemistry.
- Rejman, Dominik,Kralikova, Sarka,Tocik, Zdenek,Liboska, Radek,Rosenberg, Ivan
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p. 502 - 508
(2007/10/03)
-
- A facile method for deprotection of trityl ethers using column chromatography
-
A mild, efficient and inexpensive detritylation method is reported that uses trifluoroacetic acid on a silica gel column to obtain pure, detritylated compounds in one-step. This method is applicable to acid stable as well as acid sensitive compounds with only slight alterations in the procedure. Nineteen examples are given.
- Pathak, Ashish K.,Pathak, Vibha,Seitz, Lainne E.,Tiwari, Kamal N.,Akhtar, Mohammad S.,Reynolds, Robert C
-
p. 7755 - 7757
(2007/10/03)
-
- Synthesis and enzymatic digestion of an RNA nonamer in both enantiomeric forms
-
The D- and L-RNA nonamers of the sequence r(GCUUCGGC)T have been synthesised for X-ray crystallographic purposes. In vitro digestion of the unnatural optical antipode by snake venom phosphodiesterase I takes place at an approximately 1800-fold slower rate than that of the natural D-nonamer. The digestion experiments showed - to our knowledge for the first time - that L-RNA can indeed be cleaved enzymatically when phosphodiesterase I from snake venom is used - as opposed to a number of cellular ribonucleases - which sheds an interesting light on the evolution and possibly structure/function relationship of venom versus cellular degradation enzymes. The broad substrate specificity of this enzyme could be taken advantage of to study and further optimise the resistance towards biodegradation of therapeutic L-RNA aptamers. (C) 2000 Elsevier Science Ltd.
- Moyroud, Elisabeth,Biala, Ewa,Strazewski, Peter
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p. 1475 - 1484
(2007/10/03)
-
- L-ribonucileosides for racemic RNA
-
Two L-ribosyl donors were synthesised from L-xylose, then submitted to a glycosidation reaction according to Vorbruggen's conditions to furnish L- ribonucleosides in high yield.
- Moyroud,Botta,Strazewski
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p. 693 - 695
(2007/10/03)
-
- Stereocontrolled synthesis of β-2'-deoxypyrimidine nucleosides via intramolecular glycosylations
-
A pyrimidine moiety was tethered at the 3'-β-position of D-threo-furanosides. By carefully controlling the reaction conditions, pyrimidine bases can be delivered to the anomeric center to give of β-pyrimidine nucleosides in good yield and with complete stereocontrol.
- Xia, Xiaoyang,Wang, Jianying,Hager, Michael W.,Sisti, Nicholas,Liotta, Dennis C.
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p. 1111 - 1114
(2007/10/03)
-
- An efficient and highly stereoselective synthesis of nucleoside derivatives from furanoid 1,2-diols
-
Reaction between suitably protected furanoid glycals 1b-4b, readily obtained from furanoid 1,2-diols (1a-4a), and different silylated pyrimidine bases, gave the corresponding 3',5'- and 3',5',6'-O-protected 2'-deoxy-2'-iodo-β-D-xylo-pentofuranosyl 5-10 and β-D-gluco-hexofuranosyl 11 nucleosides, respectively. Compound 5 has been transformed into its 2'-deoxy 12 and 2',3'-anhydro 14 derivatives. The high stereoselectivity of the reaction is discussed.
- Robles, Rafael,Rodriguez, Concepcion,Izquierdo, Isidoro,Plaza, Maria T.,Mota, Antonio
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p. 2959 - 2965
(2007/10/03)
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- SELENIUM-CONTROLLED STEREOSELECTIVE SYNTHESIS OF 2'-DEOXYNUCLEOSIDES FROM GLYCALS. A FORMAL SYNTHESIS OF AZT
-
2'-Deoxynucleosides have been stereoselectively synthesized starting from glycals, using phenylselenyl reagents.Key Words: 2'-Deoxynucleosides, stereoselective glycosylation, glycals.
- El-Laghdach, Anas,Diaz, Yolanda,Castillon, Sergio
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p. 2821 - 2822
(2007/10/02)
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- Enzymatic acylation and alkoxycarbonylation of α-, xylo-, anhydro-, and arabino-nucleosides
-
5'-O-acyl and 5'-O-alkoxycarbonyl derivatives of α-, anhydro-, xylo- and arabinonucleosides could be obtained through a lipase-mediated reaction with SP 435 lipase (from Candida antarctica) by using acetoxime butyrate or butyric anhydride, together with benzyloxycarbonyl-O-acetoxine as acylating agents. Alkoxycarbonylation gave poorer yields than acylation and other lipases tested gave non-selective reaction or not reaction at all.
- Moris,Gotor
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p. 10089 - 10098
(2007/10/02)
-
- Ionization of purine nucleosides and nucleotides and their components by 193-nm laser photolysis in aqueous solution: Model studies for oxidative damage of DNA 1
-
The effect of 20-ns pulses of 193-nm laser light on aqueous solutions of purine bases, (2′-deoxy)nucleosides, and (2′-deoxy)nucleotides was investigated, and monophotonic ionization was observed. Although (deoxy)ribose and (deoxy)ribose phosphates are also ionized by 193-nm light, the photoionization of the (deoxy)nucleosides and -tides takes place predominantly (90%) at the purine moiety, due to the much higher extinction coefficients at 193 nm of the bases as compared to the (deoxy)ribose phosphates. The quantum yields of photoionization (φPl) of the purines are in the range 0.01 to 0.08, based on φ(Cl-) at 193 nm of 0.46. As shown by comparison with data obtained from pulse radiolysis, the ionized purines, i.e., the radical cations, deprotonate in neutral solution, yielding neutral radicals. The radical cation of 1-methylguanosine, produced by photoionization in oxygen-saturated aqueous solution, deprotonates with the rate constant 3.5 × 105 s-1. In the absence of oxygen, the hydrated electrons resulting from the photoionization react with the untransformed purine derivatives to yield the corresponding radical anions. As these are rapidly protonated by water (as concluded from pulse radiolysis), the photoionization in deaerated neutral solution results in two different neutral radicals: a deprotonated radical cation and a protonated radical anion.
- Candeias,Steenken
-
p. 699 - 704
(2007/10/02)
-
- Preparation of 3'-azido-3'-deoxy-thymidine (AZT) from D-xylose.
-
A synthetic route to 3'-azido-3'-deoxy-thymidine (AZT) starting from readily available D-xylose is described.In order to perform complete stereocontrol during the coupling step we decided to prepare the D-xylofuranose synthon 6a bearing a participating group at C-2 and non base-labile protective groups at C-3 and C-5.Thus, further selective deprotection at C-2' of the resulting nucleoside, followed by deoxygenation is straightforward and affords (2'-deoxy-β-D-threo-pentofuranosyl)-thymine 11, a precursor close to AZT.
- Benhaddou, R.,Czernecki, S.,Valery, J. M.,Bellosta, V.
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p. 108 - 111
(2007/10/02)
-
- New synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides.
-
The 3'-iodonucleoside 4 and the 3'-O-methylsulfonylthymidine 9 have been synthesized by condensation of silylated uracils 2 with methyl 5-O-tert-butyldiphensilyl-2,3-dideoxy-3-iodo-D-threo-pentofuran oside (3) and methyl 5-O-tert-butyldiphenylsilyl-2-deoxy-3-methylsulfonyl-D-erythro- pentofuranoside (8), respectively. The nucleoside 4 and 9 produced the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 5 in an elimination reaction on treatment with sodium methoxide. The compounds 5b showed no antiviral activity against HIV-1.
- Abdel-Megied,Hansen,Pedersen,Nielsen
-
p. 1060 - 1063
(2007/10/02)
-
- Chemical process
-
This invention relates to a new synthetic process for the manufacture of zidovudine from the starting material D-xylose involving: i) Conversion of D-xylose to a 1-(β-D-xylofuranosyl)thymine derivative; ii) 2?-Deoxygenation of the thymine derivative; and iii) 3?-Azidation of the 2?-deoxy compound.
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-
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- 1-(3,5-Di-0-benzoyl-2-deoxy-beta-D-threo-pentofuranosyl)thymine and the method of producing the same
-
The invention concerns drug manufacturing inter-mediates. It solves the problem of a new, economically more advantageous intermediate for the synthetic production of an antiviral and describes the method of its preparation. The invention relates to the new compound, 1-(3,5-di-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)thymine suitable for manufacturing 3?-azido-2?,3?-dideoxythymidine. The method of producing the said compound according to the invention starts from D-xylose which is specifically protected and converted successively into 1-(3,5-di-O--benzoyl-β-D-xylofuranosyl)thymine, its 2?-chloro-2?-deoxy derivative and finally into the claimed compound by reduction with tri-n-butyltin hydride.
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-
-
- Nucleic acid related compounds. 53. Synthesis and biological evaluation of 2'-deoxy-&β-threo-pentofuranosyl nucleosides. "Reversion to starting alcohol" in Barton-type reductions of thionocarbonates
-
Treatment of selectively 3',5'-protected β-D-xylofuranosyl nucleosides (4) with phenyl chlorothionocarbonate and DMAP followed by hydrogenolysis of the resulting (2'-O-phenoxythiocarbonyl) phenyl thionocarbonate esters (6) with tributylstannane/AIBN, and
- Robins, Morris J.,Madej, Danuta,Hansske, Fritz,Wilson, John S.,Gosselin, Gilles,et al.
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p. 1258 - 1262
(2007/10/02)
-