- Experimental and theoretical study of thymine and cytosine derivatives: The crucial role of weak noncovalent interactions
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In this paper we report the synthesis of N1-hexylthymine (1), N1-hexylcytosine (2), N1-hexylcytosine hydrobromide (3) and [(N1-hexylcytosinium)·(N1-hexylcytosine)] 2·[Cl2Hg(μ-Cl)
- Barcelo-Oliver, Miquel,Baquero, Beatriz A.,Bauza, Antonio,Garcia-Raso, Angel,Terron, Angel,Mata, Ignasi,Molins, Elies,Frontera, Antonio
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Read Online
- A stereoselective method for the direct preparation of 2'-deoxycytidine
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2'-Deoxycytidine is prepared from 2-deoxy-α-D-ribofuranosyl chloride via novel stereoselective glycosylation conditions.
- Kjell, Douglas P.
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Read Online
- Molecular design, chemical synthesis, and evaluation of cytosine-carbohydrate hybrids for selective recognition of a single guanine bulged duplex DNA
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The designed cytosine-carbohydrate hybrid molecule selectively recognized and stabilized the bulged duplex DNA possessing the complementary bulged DNA base, guanine, while the nucleotide base itself did not exhibit any such ability. It was also found that
- Idutsu, Yusuke,Sasaki, Ayaka,Matsumura, Shuichi,Toshima, Kazunobu
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Read Online
- A new route to 2'-C-methylene nucleoside analogs, inhibitors of ribonucleotide reductase
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Glycosyl phenyl sulfone obtained in 4 steps from isosaccharino-lactone was converted into a 2'-C-acetoxymethylfuranoid glycal with SmI2-HMPA. Coupling of this glycal with silylated thymine or cytidine in the presence of Pd(0) led, after deprote
- Pontikis,Wolf,Monneret,Florent
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Read Online
- Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde
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Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1-C11 linear chain and is decora
- Fujino, Haruka,Fukuda, Takumi,Nagatomo, Masanori,Inoue, Masayuki
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supporting information
p. 13227 - 13234
(2020/09/01)
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- Stereoselective N-glycosylation with N4-acyl cytosines and efficient synthesis of gemcitabine
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Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.
- Liu, Tongchao,Tang, Jiadeng,Liang, Jianpeng,Chen, Yabin,Wang, Xiaowen,Shen, Jingkang,Zhao, Dongmei,Xiong, Bing,Cen, Jun-Da,Chen, Yue-Lei
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p. 1203 - 1213
(2019/01/29)
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- A preparation method of lamivudine
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The invention discloses a method for preparation of lamivudine. Refined pure 5 S - (cytosine base - 1 ') - 1, 3 - oxathiolane - 2 - ethoxy carbonyl - (1' R, 2'S, 3' R) - menthyl ester; in the weak base and the solvent removed under the condition of chiral L - menthol to get a product of lamivudine. The material of the invention is cheap, the reagents used in the environmental protection, steps is relatively short, mild reaction conditions, atom utilization rate high, high yield, high chemical purity of the obtained product, reach the medical standard, suitable for large-scale production of lamivudine preparation method.
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Paragraph 0042; 0061-0063
(2019/04/02)
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- HMDS/KI a simple, a cheap and efficient catalyst for the one-pot synthesis of N-functionalized pyrimidines
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The syntheses of N-Alkylpyrimidine derivatives by reacting pyrimidin-2,4-diones with appropriate alkyl halide under microwave irradiation at 400 W were compared to the conventional synthesis route. These methodologies are regioselective and compatible with numerous substrates and furnish the corresponding N-alkylpyrimidines in good yields using a cheap catalyst HMDS/KI in MeCN. A comparison study between these two different modes of heating was investigated.
- Mansouri, Az-Eddine El,Zahouily, Mohamed,Lazrek, Hassan B.
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supporting information
p. 1802 - 1812
(2019/05/15)
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- Synthetic method for lamivudine
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The invention provides a synthetic method for lamivudine. The synthetic method comprises the following steps: cheap easily-available dihaloacetic acid is used as a raw material, the dihaloacetic acidand L-menthol are subjected to condensation, hydrolysis is performed to obtain menthyl glyoxylate, the menthyl glyoxylate and 2,5-dihydroxy-1,4-dithiane are subjected to condensation, halogenation isperformed, the halogenated product and silanized cytosine are subjected to coupling, reduction is performed, the reduced product and salicylic acid are subjected to salt formation to obtain the a salicylate, and finally recrystallization is performed to obtain the optically-pure lamivudine. According to the method provided by the invention, the raw materials used in the whole synthetic process arecheap and easy to obtain, the synthetic process is simple, the synthetic conditions are mild, so that the synthetic costs of the lamivudine are greatly reduced; the raw material utilization rate andreaction selectivity are high, so that the yield of the obtained lamivudine is higher; and at the same time, a chiral substrate is easily removed during the synthesis, three waste (waste water, wastegas and solid waste) generated in the method are less, and the method is suitable for industrialized large-scale production of the lamivudine.
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Paragraph 0028; 0034; 0038
(2019/11/21)
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- Asymmetric synthesis method of lamivudine
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The invention provides an asymmetric synthesis method of lamivudine. The synthesis method comprises: carrying out condensation on L-menthyl chloroformate used as a starting raw material and geminal dihaloethanol, hydrolyzing to obtain an acetaldehyde alcohol optically-active ester, carrying out condensation with 5,5-dihydroxy-1,4-dithiane to obtain trans 5-hydroxy-1,3-oxathiolane-2-methyl optically-active ester, acetylating, coupling with silanized cytosine, and finally removing the chiral auxiliary agent to obtain the product lamivudine. According to the present invention, the raw materials used in the entire synthesis process are cheap and readily available, and have high utilization rate, such that the synthesis cost of lamivudine is substantially reduced; the synthesis process is simple, the synthesis conditions are mild, the yield of the obtained lamivudine is high, the chiral substrate is easily removed during the synthesis, and the generated three-waste pollutants are less; andthe method is suitable for industrial large-scale production of lamivudine.
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Paragraph 0027; 0033
(2019/11/29)
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- PROCESS FOR PRODUCING LAMIVUDINE AND EMTRICITABINE
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This invention provides for flow and batch synthesis processes for the production of Lamivudine and Emtricitabine, including flow and batch synthesis processes wherein at least of the synthesis steps are conducted in a solvent free environment.
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Page/Page column 19; 20; 21
(2018/01/20)
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- Semi-continuous multi-step synthesis of lamivudine
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We report the first continuous flow synthesis of lamivudine, an antiretroviral drug used in the treatment of HIV/AIDS and hepatitis B. The key intermediate (5-acetoxy oxathiolane) was prepared by an integrated two step continuous flow process from l-menthyl glyoxalate hydrate in a single solvent, in 95% overall conversion. For the crucial glycosidation reaction, using pyridinium triflate as the novel catalyst, an improved conversion of 95% was obtained. The overall isolated yield of the desired isomer of lamivudine (40%) was improved in the flow synthesis compared to the batch process.
- Mandala, Devender,Chada, Sravanthi,Watts, Paul
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p. 3444 - 3454
(2017/04/26)
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- Industrial preparation process for key intermediate sulfonated saccharide of Gemcitabine
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The invention relates to a preparation method for a compound represented by a formula (I) shown in the description, i.e., a key intermediate sulfonated saccharide of Gemcitabine. The final product is prepared through subjecting a compound represented by a formula (II) shown in the description to sodium borohydride reduction, hydroxyl protection and resolution. The method is simple in process, high in yield and high in product purity and has no need of harsh reaction conditions, thereby being very suitable for industrial production.
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Paragraph 0058; 0059; 0060
(2017/08/28)
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- PROCESS FOR THE PREPARATION OF GEMCITABINE HYDROCHLORIDE
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The present invention relates to an improved as well as an industrially viable process for the preparation of 2'-deoxy-2',2'-difluorocytidine and its pharmaceutical acceptable acid salts thereof in high purity and acceptable yield by using a simple and inexpensive process. The process involves reacting an alpha anomer enriched 2'-deoxy-2',2'-difluorocarbohydrate with silylated nucleobase derivatives via the SN2 displacement of an anomeric sulfonyloxy group in an inert solvent to produce 2',2'-difluoro-2'-deoxycytidine-3',5'-dibenzoate in about a 5:1 β/α anomeric ratio, and a process for selectively isolating β-2',2'-difluoro-2'-deoxycytidine-3',5'- dibenzoate from the 5:1 β/α anomeric mixture. The pure β-2',2'-difluoro-2'- deoxycytidine-3',5'-dibenzoate is then converted to the corresponding nucleoside utilizing ammonium hydroxide in a polar and preferably protic solvent to obtain β- 2'-deoxy-2',2'-difluorocytidine, which is thereafter converted to gemcitabine hydrochloride that is effective against non-small cell lung cancer, pancreatic cancer, bladder cancer and breast cancer. The present invention relates to an improved and convenient method for preparing antineoplastic nucleosides, more particularly, a process for preparing gemcitabine hydrochloride, represented by the formula I below, which exhibits good antitumor activity. (I)
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Page/Page column 17-18
(2016/07/05)
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- A general and enantioselective approach to pentoses: A rapid synthesis of PSI-6130, the nucleoside core of sofosbuvir
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An efficient route towards biologically relevant pentose derivatives is described. The de novo synthetic strategy features an enantioselective α-oxidation reaction enabled by a chiral amine in conjunction with copper(II) catalysis. A subsequent Mukaiyama aldol coupling allows for the incorporation of a wide array of modular two-carbon fragments. Lactone intermediates accessed via this route provide a useful platform for elaboration, as demonstrated by the preparation of a variety of C-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use.
- Peifer, Manuel,Berger, Rapha?lle,Shurtleff, Valerie W.,Conrad, Jay C.,Macmillan, David W. C.
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supporting information
p. 5900 - 5903
(2014/05/20)
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- An efficient large-scale synthesis of gemcitabine employing a crystalline 2, 2-difluoro-α-ribofuranosyl bromide
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An efficient large-scale synthesis of gemcitabine was achieved without chromatography or fractional crystallization. The key steps include stereospecific conversion of a novel β-ribofuranosyl phosphate into a highly crystalline a-ribofuranosyl bromide and coupling of the α-ribofuranosyl bromide and trime- thylsilyl cytosine to produce a β-nucleoside. p-Phenylbenzoyl group was introduced for the protection of one of hydroxy groups in order to enhance the crystallinity of intermediates. Continuous removal of trimethylsilyl bromide, generated during the coupling reaction, by distillation from the reaction medium substantially enhanced the β-selectivity of the crucial coupling reaction.
- Chang, Young-Kil,Lee, Jaeheon,Park, Gha-Seung,Lee, Moonsub,Park, Chul Hyun,Kim, Han Kyong,Lee, Gwansun,Lee, Bo-Young,Baek, Ju Yuel,Kim, Kwan Soo
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experimental part
p. 5687 - 5691
(2010/09/18)
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- Process of Making 2-Deoxy-2,2-Difluoro-D-Ribofuranosyl Nucleosides and Intermediates Therefor
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A compound of formula (A) or salt thereof: wherein each of R1, R2, and R3 independently represents hydrogen, alkyl, aryl, acyl, sulfonyl, or silyl; P represents hydrogen or a hydroxy protective group. This compound may be
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Page/Page column 6-7
(2010/04/23)
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- A PROCESS FOR STEREOSELECTIVE SYNTHESIS OF LAMIVUDINE
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The present invention discloses a process for stereoselective synthesis of Lamivudine comprising the following steps: (a) performing a glycosylation reaction between the compound of formula (I) and cytosine or protected cytosine, and separating the reaction product by recrystallization to obtain the intermediate of formula (II); and (b) deprotecting the intermediate of formula (II) to obtain Lamivudine.
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Page/Page column 8
(2010/04/24)
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- Inactivation of lactobacillus leichmannii ribonucleotide reductase by 2',2'-difluoro2'-deoxycytidine s'-triphosphate: Covalent modification
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Ribonucleotide reductase (RNR) from Lactobacillus leichmannii, a 76 kDa monomer using adenosylcobalamin (AdoCbl) as a cofactor, catalyzes the conversion of nucleoside triphosphates to deoxynucleotides and is rapidly ( 3H]- and [5-3H]F2CTP were synthesized and used independently to inactivate RNR. Sephadex G-50 chromatography of the inactivation mixture revealed that 0.47 equiv of a sugar was covalently bound to RNR and that 0.71 equiv of cytosine was released. Alternatively, analysis of the inactivated RNR by SDS-PAGE without boiling resulted in 33% of RNR migrating as a 110 kDa protein. Inactivation of RNR with a mixture of [1'-3H]F2CTP and [1'-2H]F 2CTP followed by reduction with NaBH4, alkylation with iodoacetamide, trypsin digestion, and HPLC separation of the resulting peptides allowed isolation and identification by MALDI-TOF mass spectrometry (MS) of a 3H/2H-labeled peptide containing C731 and C736 from the C-terminus of RNR accounting for 10% of the labeled protein. The MS analysis also revealed that the two cysteines were cross-linked to a furanone species derived from the sugar of F2CTP. Incubation of [1-3H]F2CTP with C119S-RNR resulted in 0.3 equiv of sugar being covalently bound to the protein, and incubation with NaBH4 subsequent to inactivation resulted in trapping of 2'-fluoro-2'-deoxycytidine. These studies and the ones in the preceding paper (DOI: 10.1021/bi9021318) allow proposal of a mechanism of inactivation of RNR by F2CTP involving multiple reaction pathways. The proposed mechanisms share many common features with F2CDP inactivation of the class I RNRs.
- Lohman, Gregory J.S.,Stubbe, Joanne
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body text
p. 1404 - 1417
(2011/02/21)
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- Oligonucleotide analogues bearing an acyclonucleoside linked by an internucleotide amide bond
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Oligonucleotide analogues bearing an acyclocytidine linked to thymidine with an amide (3′-O-CH2CO-N-5′) bond were synthesized. Melting curves of duplexes formed by modified oligonucleotides and complementary natural oligomers were obtained and
- Kochetkova,Fillipova,Kolganova,Timofeev,Florentiev
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p. 207 - 214
(2008/09/19)
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- Studies directed toward the development of amide-linked RNA mimics: Synthesis of the monomeric building blocks
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(Chemical Equation Presented) A general approach toward the synthesis of all four monomeric building blocks of the ribonucleoside amino acids 3′-amino-5′-carboxymethyl-3′,5′-dideoxy nucleosides in their protected forms is described that will facilitate the development of amide-linked RNA mimics.
- Chakraborty, Tushar Kanti,Gajula, Praveen Kumar,Koley, Dipankar
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p. 6916 - 6919
(2008/12/22)
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- Method for the Preparation of 2'-Deoxy-2',2'-Difluorocytidine
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This invention relates to an improved method for stereoselectively preparing 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I).
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Page/Page column 6-11
(2008/06/13)
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- METHOD FOR THE PREPARATION OF 2#-DEOXY-2#,2#-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2′-deoxy-2′,2′-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2′-deoxy-2′,2′-difluorocytidine of formula (I).
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Page/Page column 14; 15; 16; 19; 22; 23
(2008/06/13)
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- METHOD FOR THE PREPARATION OF 2'-DEOXY-2',2'-DIFLUOROCYTIDINE
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This invention relates to an improved method for stereoselectively preparing 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I), which comprises the steps of reacting a 1-halo ribofuranose compound of formula (III) with a nucleobase of formula (IV) in a solvent to obtain a nucleoside of formula (II) with removing the silyl halide of formula (V) produced during the reaction; and deprotecting the nucleoside of formula (II) to obtain 2¢¥-deoxy-2¢¥,2¢¥-difluorocytidine of formula (I).
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Page/Page column 15; 16; 17; 18; 21; 24; 25-26
(2008/06/13)
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- STEREOSELECTIVE SYNTHESIS OF β-NUCLEOSIDES
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This invention relates to a process for stereoselectively preparing a nucleoside of the following formula: wherein R3, R4, and B are defined herein. The process includes reacting a furanose compound with a nucleobase in the presence
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Page/Page column 12-13
(2008/06/13)
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- Er(OTf)3 as a valuable catalyst in a short synthesis of 2′,3′-dideoxy pyranosyl nucleosides via Ferrier rearrangement
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Er(OTf)3 is a useful catalyst for the Ferrier rearrangement furnishing 2′,3′-dideoxy pyranosyl nucleosides easily by means of cleaner reaction profiles, short reaction times, mild reaction conditions, good stereoselectivity, and good recoverability of the commercially available catalyst. Georg Thieme Verlag Stuttgart.
- Procopio, Antonio,Dalpozzo, Renato,De Nino, Antonio,Nardi, Monica,Oliverio, Manuela,Russo, Beatrice
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p. 2608 - 2612
(2008/02/04)
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- Nucleosides and nucleotides. Part 212: Practical large-scale synthesis of 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd), a potent antitumor nucleoside. Isobutyryloxy group as an efficient anomeric leaving group in the Vorbrüggen glycosylation reaction
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A practical synthetic route to the antitumor nucleoside, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, 1) from 1,2-O-isopropylidene-D-xylofuranose (3) has been developed. Since most of the compounds were obtained as crystals, the target ECyd was prepared without any chromatographic purification in 31% overall yield from compound 3. The isobutyryloxy group was found to be an effective leaving group at the anomeric position of the 3-β-C-ethynyl glycosyl donors in the key Vorbru?ggen glycosylation reaction. Using a similar procedure without chromatographic purification, the uracil congener EUrd [1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil (2), which also has a potent antitumor effect, was synthesized from 3 in 39% overall yield.
- Nomura, Makoto,Sato, Tsutomu,Washinosu, Masato,Tanaka, Motoaki,Asao, Tetsuji,Shuto, Satoshi,Matsuda, Akira
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p. 1279 - 1288
(2007/10/03)
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- A convenient method for the synthesis of N-vinyl derivatives of nucleobases
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Trimethylsilyl trifluoromethanesulfonate (TMSOTf) reveals, one more time, its enormous flexibility as Lewis acid catalyst, transforming the well known, but drastic, exchange of the acetyl group of vinyl acetate with pyrimidine and purine derivatives in a very gentle and quick method to obtain a whole set of vinyl nucleobases.
- Dalpozzo, Renato,De Nino, Antonio,Maiuolo, Loredana,Procopio, Antonio,Romeo, Roberto,Sindona, Giovanni
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p. 172 - 174
(2007/10/03)
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- L-pyranosyl nucleosides
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This invention relates to α and β-L-pyranosyl nucleosides of Formula (I), wherein the nucleoside substitution on the pyranosyl carbohydrate molecule comprises a substituted or unsubstituted purine (adenine or guanine) or pyrimidine (cytosine, uracil, thym
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- A Completely Diastereoselective Electrophilic Fluorination of a Chiral, Noncarbohydrate Sugar Ring Precursor: Application to the Synthesis of Several Novel 2′-Fluoronucleosides
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A new and completely diastereoselective method for the introduction of fluorine into a noncarbohydrate sugar ring precursor has been developed. The use of N-fluorodibenzenesulfonimide (5) for the electrophilic fluorination of chiral lactone 4, which is derived from L-glutamic acid, yields the key intermediate 6. This is transformed into an anomeric acetate 8 and is used for the synthesis of a number of novel α-2′-fluoronucleosides. Since glutamic acid is used as the synthetic starting material, the L enantiomer may also be synthesized simply by using D-glutamic acid. The incorporation of fluorine into the 2′ position of the nucleoside provides several advantages including acid stability of the anomeric bond and general resistance to oxidative metabolism. Further, fluorine is a close mimic of hydroxyl groups in size and polarity and in its ability to act as a hydrogen bond acceptor. This may aid in the recognition of these nucleosides by the enzymes involved in nucleoside activation.
- Jeffrey McAtee,Schinazi, Raymond F.,Liotta, Dennis C.
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p. 2161 - 2167
(2007/10/03)
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- An efficient and highly stereoselective synthesis of nucleoside derivatives from furanoid 1,2-diols
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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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- Synthesis of dihydroisoxazole nucleoside and nucleotide analogs
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The dihydroisoxazole nucleosides as well as their phosphonate derivatives were efficiently prepared via 1,3-dipolar cycloaddition reactions of nitrile oxides with corresponding vinyl nucleoside bases for antiviral studies.
- Gi, Hung-Jang,Xiang, Yuejun,Schinazi, Raymond F.,Zhao, Kang
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- A convenient one-pot synthesis of acyclonucleosides
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Bis(trimethylsilyl)pyrimidine bases were treated directly with 1,3-dioxolane (or 2-methyl-1,3-dioxolane), chlorotrimethylsilane and a metal iodide, such as KI or NaI, in acetonitrile at room temperature to afford acyclopyrimidine derivatives, including 2-thiopyrimidine derivatives, in good yields. Introduction of an acyclic chain into 2-thiopyrimidine bases, however, necessitated the use of 2 eq of the reagents.
- Ubasawa,Takashima,Sekiya
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p. 142 - 143
(2007/10/02)
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- An efficient synthesis of 2-[(4-amino-1,2-dihydro-2-oxo-1- pyrimidinyl)methoxy]-1,3-propanediyl-di-L-valinate an anti-cytomegalovirus agent
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An efficient synthesis for large scale preparation of the titled compound, a prodrug for the anti-HCMV agent 1-[2-hydroxy-1- (hydroxymethyl)ethoxy)methyl]cytosine, 9, has been developed. The product of each step is easily purified by either distillation o
- Ghali,Johnston,Beauchamp,Naseree,Scott,Flanagan,Rodriguez
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p. 1591 - 1600
(2007/10/02)
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- Photocatalysed Addition of Alcohols to 5-Substituted 2,5-Dihydrofuran-2-ones: Novel Synthesis of (3'R)-2',3'-Dideoxy-3'-hydroxymethyl Nucleosides
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Methanol and propan-2-ol add in a regiospecific and higly stereocontrolled fashion to 5-substituted 2,5-dihydrofuran-2-ones (butenolides) under irradiation.The photoadducts with methanol have been converted into a number of (3'R)-2',3'-dideoxy-3'-hydroxymethyl nucleosides.
- Mann, John,Weymouth-Wilson, Alexander C.
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p. 3141 - 3148
(2007/10/02)
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- Synthetic approaches to novel cis and trans dideoxynucleosides of the apiose family
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Stereoselective synthesis of the complete family of optically active dideoxygenated nucleosides of the apiose family have been developed. The chiral aldodiol system 7, a key intermediate in this synthesis, was prepared from the prochiral molecule 6, through the action of the lipase from Candida cylindracia. Approaches to novel enantiomeric and diastereoisomeric dideoxynucleosides containing the tetrahydrofuranethanol moiety have also been discovered. A key intermediate in this approach was the optically active trans-allyllactone 61, prepared from L-glutamic acid, and its isomerization product, the corresponding cis-allylbutyrolactone 62. The methodologies developed have generality and allow synthetic access to a wide variety of new nucleosides.
- Sells, Todd B.,Nair, Vasu
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p. 117 - 138
(2007/10/02)
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- Synthesis of 2',3'-Dideoxy-3'-C-(hydroxymethyl)-4'-thionucleosides as Potential Inhibitors of HIV
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The synthesis of 2',3'-dideoxy-3'-C-(hydroxymethyl)-4'-thionucleosides is described.For the synthesis of the carbohydrate part, the configuration of the secondary hydroxyl group in (2S,3R)-1-O-(p-bromobenzyl)-3-(2'-propenyl)-1,2,4-butanetriol (1) was inve
- Branalt, Jonas,Kvarnstroem, Ingemar,Niklasson, Gunilla,Svensson, Stefan C. T.,Classon, Bjoern,Samuelsson, Bertil
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p. 1783 - 1788
(2007/10/02)
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- COMPOUNDS SIMILAR TO ACYCLOVIR. VII. SYNTHESIS AND ANTIVIRAL ACTIVITIES OF (R/S)-5-HYDROXY-4-HYDROXYMETHYL-3-OXAPENT-2-YL DERIVATIVES OF NUCLEIC BASES
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5-Hydroxy-4-hydroxymethyl-3-oxapent-2-yl derivatives of uracil, thymine, cytosine, adenine, guanine, and 1,2,4-triazole-4-carboxamide have been synthesized with the use of 1,3-diacetoxy-2-(1-acetoxyethoxy)propane and 1,3-dichloro-2-(1-chloroethoxy)propane as alkylating agents. 9-(5-Hydroxy-4-hydroxymethyl-3-oxapent-2-yl)guanine has shown pronounced antiviral activity in relation to herpes virus type 1 (chemitherapeutic index 32).
- Smirnov, I. P,Tsilevich, T. L.,Kochetkova, S. V.,Vladyko, G. V.,Korobchenko, L. V.,et al.
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- Chemistry and anti-HIV properties of 2'-fluoro-2',3'- dideoxyarabinofuranosylpyrimidines
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The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'- dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compound is as potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after >24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
- Siddiqui,Driscoll,Marquez,Roth,Shirasaka,Mitsuya,Barchi Jr.,Kelley
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p. 2195 - 2201
(2007/10/02)
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- STEREOSELECTIVITIES IN THE COUPLING REACTION BETWEEN SILYLATED PYRIMIDINE BASES AND 1-HALO-2,3-DIDEOXYRIBOSE
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Coupling reactions between 1-chloro-2,3-dideoxyribose and silylated pyrimidines have been examined from the point of stereoselectivity.When the reaction was carried out in chloroform, the selectivity was in the anomeric ratio of α:β = 4:6.On the other hand, the presence of tertiary amine raises the selectivity to α:β = 3:7.
- Kawakami, Hiroshi,Ebata, Takashi,Koseki, Koshi,Matsumoto, Katsuya,Matsushita, Hajime,et al.
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p. 2041 - 2054
(2007/10/02)
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- Synthesis of the Dideoxynucleosides ddC and CNT from Glutamic Acid, Ribonolactone, and Pyrimidine Bases
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2,3-Dideoxyribose in suitably protected form was prepared from glutamic acid and coupled with silylated cytosine to give a mixture of the α-and β-anomers of 2',3'-dideoxycitidine.The anomer ratio depended on the Lewis acid used in the coupling, with EtAlCl2 favoring the β-anomer ddC, a potent anti-HIV drug.Conjugate addition of cyanide to a 4-butenolide prepared from D-ribonolactone gave a mixture of (racemic) α- and β-3-cyanobutyrolactones.Both isomers were reduced to lactols and coupled with thymine to give α/β-anomer pairs.The α-cyano lactone, the struct ure of which was established by X-ray crystallography, afforded an authentic sample of the putative (but in fact inactive) anti-HIV substance known in AIDS research as CNT.
- Okabe, Masami,Sun, Ruen-Chu,Tam, Steve Y.-K.,Todaro, Louis J.,Coffen, David L.
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p. 4780 - 4786
(2007/10/02)
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- SYNTHESIS OF 1-(3-HALOTETRAHYDRO-2-FURYL) DERIVATIVES OF URACIL, 5-SUBSTITUTED URACILS, AND CYTOSINE
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The cis and trans isomers of 1-(3-halotetrahydro-2-furyl) derivatives of uracil, 5-substituted uracils, and cytosine were obtained by alkylation of 2,4-bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine with 2,3-dihalotetrahydrofurans . 2,3'-Anhydro compounds are also formed in the alkylation of 5-halouracil derivatives.The physicochemical properties of the compounds obtained and the antineoplastic activities of the 5-fluorouracil derivatives were studied.
- Kaulinya, L. T.,Lidak, M. Yu.
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- Synthesis of the mirror image of the RNA fragment D-CAAGG: A model compound to study interactions between oligonucleotides of opposite handedness
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The pentamer L-CAAGG was prepared starting from properly protected β-L-ribonucleosides via a phosphotriester approach.The identity and chiral purity of the pentamer were established by 1H NMR and CD spectroscopy, respectively.
- Visser, G. M.,van Westrenen, J.,van Boeckel, C. A. A.,van Boom, J. H.
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p. 528 - 537
(2007/10/02)
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- Synthesis and Biological Effects of Acyclic Pyrimidine Nucleoside Analogues
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A series of nucleoside analogues has been prepared, wherein the cyclic carbohydrate moiety is replaced by aliphatic side chains attached to cytosine, thymine, uracil, and 5-fluorouracil.The 1- derivatives of these heterocycles were synthesized by reacting the silylated bases with 2-(chloromethoxy)ethyl benzoate, followed by removal of the protecting groups with methanolic ammonia.The hydroxy group of a number of these derivatives was subsequently replaced by an azido, amino, or carbamoyloxy moiety.The 1-(2-oxo-3-butyl) and 1-(2-oxo-3-nonyl)derivatives of cytosine were also prepared, their synthesis being accomplished by condensation of the silylated heterocycle with the appropriate α-halo ketone.At 10-4 M concentrations, the newly prepared compounds were inactive against leukemia L-1210 cells in culture.However, a number of the agents inhibited the in vitro growth of Escherichia coli K-12, the most potent among these, 1--5-fluorouracil, being active at an IC50 of 1.2 μM.This compound was equally active in preventing the growth of a 5-fluorouracil resistant strain of E. coli.Some of the analogues were also found the selectively interfere with herpes simplex virus replication in vitro.None of the cytosine derivatives tested served as either substrates or inhibitors of human liver citosine nucleoside deaminase.
- Schroeder, Alan C.,Hughes, Robert G.,Bloch, Alexander
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p. 1078 - 1083
(2007/10/02)
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