- Method for synthesizing cladribine through nitration-chlorination method
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The invention discloses a novel method for synthesizing cladribine through a nitration-chlorination method. According to the method, cheap 6-chloropurine and 1-chloro-2,3,5-tris-O-p-chlorobenzoyl-D-ribose are taken as raw materials, sodium hydride is taken as alkali, acetonitrile is taken as reaction solvent, and a beta isomer is obtained through a high-selectivity reaction; the obtained beta isomer does not need to remove protecting groups, the beta isomer reacts with trifluoromethanesulfonic anhydride after being separated, and nitryl is introduced at the second position; the nitryl is transformed into chlorine atoms in an ethanol solution of NH4Cl; two steps of reactions of protecting group removal and chlorine atom ammonolysis are completed in a methanol solution saturated by ammonia gas, and then the cladribine is obtained through four steps at the total yield of 78%. The method has the advantages that the raw materials are low in cost and easy to obtain, the technology is simple and convenient, the total yield is higher, the cost is low, amplification is easy, expensive reagents and poisonous and harmful heavy metal catalysts are prevented from being used, and when the reaction scale is expanded to the 100-g scale, the yield is not decreased obviously. A novel synthesizing path is supplied to synthesizing of the cladribine, and the potential application prospect is achieved.
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Paragraph 0015; 0017
(2016/10/08)
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- SNAr iodination of 6-chloropurine nucleosides: Aromatic finkelstein reactions at temperatures below -40°C1
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(Equation Presented) Mesitoyl or toluoyl esters of inosine and 2′-deoxyinosine were deoxychlorinated at C6 to give the crystalline 6-chloropurine nucleoside derivatives, which underwent quantitative conversion to the 6-iodo analogues with Nal/TFA/butanone
- Liu, Jiangqiong,Janeba, Zlatko,Robins, Morris J.
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p. 2917 - 2919
(2007/10/03)
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- Synthesis of 6-substituted purine N7-(2-deoxy-β-D-ribonucleosides) via anion glycosylation and anomerization during the N7/N9-glycosyl transfer
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The synthesis of the 7-(2-deoxy-β-D-erythro-pentofuranosyl)adenine (1b) as well as the corresponding hypoxanthine- and purine nucleosides 3 and 4 is described employing the stereoselective nucleobase anion glycosylation. The N7/N9-is
- Seela,Winter
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p. 129 - 142
(2007/10/02)
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- Pentenyl Ribosides: New Reagents for Purine Nucleoside Synthesis
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Protected pent-4-enyl ribosides and deoxyribosides were synthesized as reagents for the preparation of nucleosides and deoxynucleosides.Reaction of pent-4-enyl 2',3',5'-tri-O-benzoyl-D-erythro-pentofuranoside with five nucleobases in the presence of N-iod
- Chapeau, Marie-Christine,Marnett, Lawrence J.
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p. 7258 - 7262
(2007/10/02)
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- FACILE STEREOSPECIFIC SYNTHESIS OF α-ANOMERIC 2'-DEOXYNUCLEOSIDES
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The coupling reaction of activated nucleobases, such as the sodium salts of N-benzoyladenine and 6-chloropurine and 2,4-bis-O-trimethylsilylthymine, with 1-α-chloro-2-deoxy-3,5-di-O-p-toluoylribofuranose (1) in a mixture of acetonitrile and tetrahydrofuran leads to the stereospecific formation of α-anomeric 2'-deoxynucleosides with satisfactory yields.The ratio of the distribution between the resulted α- and β-stereoisomers was about 3:1 in each case.The method is simple and applicable to the preparation of both purine and pyrimidine α-2'-deoxynucleosides.
- Shinozuka, Kazuo,Hirota, Yoshiki,Morita, Tsutomu,Sawai, Hiroaki
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p. 2117 - 2121
(2007/10/02)
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- Synthesis and duplex stability of oligonucleotides containing adenine-guanine analogues
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The nucleosides N6-methoxy-2'-deoxyadenosine (dZ) and 2-amino-9-(2-deoxy-β-ribofuranosyl)-6-methoxyaminopurine (dK) have been synthesised and converted into 5'-O-dimethoxytrityl 3'-(2-cyanoethyl N,N-diisopropylphosphoramidites). These monomers have been used in machine DNA synthesis to give a set of heptadecanucleotides containing up to three analogue nucleotides. The melting transitions (T(m) show that the 17-mer duplexes containing Z·T and Z·C base-pairs have closely similar stabilities, as have those containing K·T and K·C pairs. They are less stable than the corresponding fully complementary duplexes, but more stable than those containing mismatched pairs. This, in the case of dZ, is in accord with the amino-imino tautomeric ratio of ~1:4 observed for the nucleoside in methyl sulfoxide. The application of oligomers containing such 'degenerate' bases in oligonucleotide probes and primers is discussed. The nucleosides N6-methoxy-2′-deoxyadenosine (dZ) and 2-amino-9-(2-deoxy-β-ribofuranosyl)-6-methoxyaminopurine (dK) have been synthesised and converted into 5′-O-dimethoxytrityl 3′-(2-cyanoethyl N,N-diisopropylphosphoramidites). These monomers have been used in machine DNA synthesis to give a set of heptadecanucleotides containing up to three analogue nucleotides. The melting transitions (Tm) show that the 17-mer duplexes containing Z·T and Z·C base-pairs have closely similar stabilities, as have those containing K·T and K·C pairs. They are less stable than the corresponding fully complementary duplexes, but more stable than those containing mismatched pairs. This, in the case of dZ, is in accord with the amino-imino tautomeric ratio of approximately 1:4 observed for the nucleoside in methyl sulfoxide. The application of oligomers containing such 'degenerate' bases in oligonucleotide probes and primers is discussed.
- Brown,Lin
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p. 129 - 139
(2007/10/02)
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- A convenient synthesis of 2'-deoxy-6-thioguanosine, ara-guanine, ara-6-thioguanine and certain related purine nucleosides by the stereospecific sodium salt glycosylation procedure [1]
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A simple and high-yield synthesis of biologically significant 2'-deoxy-6-thioguanosine, ara-6-thioguanine and araG has been accomplished employing the stereospecific sodium salt glycosylation method. Glycosylation of the sodium salt of 6-chloro- and 2-amino-6-chloropurine (1 and 2, respectively) with 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranose gave the corresponding N-9 substituted nucleosides as major products with the β-anomeric configuration (4 and 5, respectively) along with a minor amount of the N-7 positional isomers (6 and 7). Treatment of 4 with hydrogen sulfide in methanol containing sodium methoxide gave 2'-deoxy-6-thioinosine in 93% yield. Similarly, 5 was transformed into 2'-deoxy-6-thioguanosine (β-TGdR, 11) in 71% yield. Reaction of the sodium salt of 2 with 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose gave N-7 and N-9 glycosylated products 13 and 9, respectively. Debenzylation of 9 with boron trichloride at -78° gave the versatile intermediate 2-amino-6-chloro-9-β-D-arabinofuranosylpurine 62% yield. Direct treatment of 14 with sodium hydrosulfide furnished ara-6-thioguanine. Alkaline hydrolysis of 14 readily gave 9-β-D-arabinofuranosylguanine (araG, 17), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded araG 5'-monophosphate.
- Hanna,Ramasamy,Robins,Revankar
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p. 1899 - 1903
(2007/10/02)
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- Method for the production of 2'-deoxyadenosine compounds
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A method that is direct and stereospecific is provided for the production of 2'-deoxyadenosine derivatives and related analogs. The method comprises glycosylation of the sodium salt of 2,6-dichloropurine or 6-chloropurine and ammonolysis of the glycosylat
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- ACIDIC HYDROLYSIS OF 6-SUBSTITUTED 9-(2-DEOXY-β-D-ERYTHRO-PENTOFURANOSYL)PURINES AND THEIR 9-(1-ALKOXYETHYL) COUNTERPARTS: KINETICS AND MECHANISM.
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The rate constants for the hydrolysis of several 6-substituted 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines and 9-(1-alkoxyethyl)purines have been measured at different concentrations of oxonium ion.The effects that varying the polar nature of the alkoxy group exerts on the hydrolysis of unsubstituted 9-(1-alkoxyethyl)purines are interpreted to indicate that the reaction proceeds by a rate-limiting departure of the protonated base moiety with a concomitant formation of an alkoxyethyl oxocarbenium ion.The same mechanism is applied to the hydrolysis of 9-(2-deoxy-β-D-erythro-pentofuranosyl)purines by comparing the influences that 6-substituents have on the reactivity of these compounds and their 9-(1-alkoxyethyl) counterparts.No sign of anomerisation was detected, when the hydrolysis of 2'-deoxyadenosine was followed by 1H NMR spectroscopy.
- Oivanen, Mikko,Loennberg, Harri,Zhou, Xiao-xiong,Chattopadhyaya, Jyoti
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p. 1133 - 1140
(2007/10/02)
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- Synthesis of 2'-Deoxytubercidin, 2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel Direct Stereospecific Sodium Salt Glycosylation Procedure
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A general and stereospecific synthesis has been developed for the direct preparation of 2'-deoxy-β-D-ribofuranosylpurine analogues including 2'-deoxyadenosine derivatives.The reaction of the sodium salt of 4-chloropyrrolopyrimidine (4) or 2,4-dichloropyrrolopyrimidine (1) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose (25) provided the corresponding N-1,2'-deoxy-β-D-ribofuranosyl blocked derivatives (5 and 2) which, on ammonolysis, gave 2'-deoxytubercidin (6) and 2-chloro-2'-deoxytubercidin (3), respectively, in good yield.This glycosylation also readily proceeds in the presence of a 2-methylthio group.Application of this glycosylation procedure to 4,6-dichloroimidazopyridine (10), 6-chloropurine (16), 2,6-dichloropurine (13), and 4-chloropyrazolopyrimidine (19) gave 2-chloro-2'-deoxy-3-deazaadenosine (12), 2-'-deoxyadenosine (18), 2-chloro-2'-deoxyadenosine (15), and 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazolopyrimidine (21), respectively.Similarly, glycosylation and ammonolysis of 4,6-dichloro-1H-pyrrolopyridine (22) gave 4,6-dichloro-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolopyridine (24).This stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl moiety appears to be due to a Walden inversion at the C-1 carbon of 25.
- Kazimierczuk, Zygmunt,Cottam, Howard B.,Revankar, Ganapathi R.,Robins, Roland K.
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p. 6379 - 6382
(2007/10/02)
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