- Preparation method of fludarabine antitumor drug intermediate
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The invention relates to the field of preparation of fludarabine antitumor drug intermediates, and discloses a preparation method of a fludarabine antitumor drug intermediate. The method comprises the following steps: (1) mixing pyridine and triethylamine, adding a compound 1 and trifluoroacetic anhydride, reacting for 3-4 hours, and carrying out aftertreatment to obtain a compound 2; (2) mixing dichloromethane, dichloroethane and tetrahydrofuran, adding tetrabutylammonium nitrate and trifluoroacetic anhydride, adding the compound 2, reacting for 6-7 hours, and carrying out aftertreatment to obtain a compound 3; (3) mixing the compound 3, NaF, KF, tetrabutylammonium fluoride and DMF, reacting at 40-50 DEG C for 3-3.5 hours, and carrying out aftertreatment to obtain a compound 4; and (4) adding a compound 4 into methanol/water of KOH and LiOH, reacting for 2-3 hours, and carrying out post-treatment to obtain a compound 5, namely 2-fluorine-6-aminopurine. According to the method, the total yield of the fludarabine antitumor drug intermediate is increased.
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Paragraph 0045; 0046; 0054-0055; 0056; 0064-0065; 0066
(2021/04/17)
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- Development of a Commercial Manufacturing Route to 2-Fluoroadenine, the Key Unnatural Nucleobase of Islatravir
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We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and pre-exposure prophylaxis (PrEP) against HIV infection. The fragment, the unnatural nucleobase 2-fluoroadenine, is incorporated into MK-8591 via a biocatalytic aldol-glycosylation cascade, which imposes stringent requirements for its synthesis and isolation. Presented herein is the development work leading to a practical, scalable route from guanine, featuring a dual fluorination approach to a novel 9-THP-2,6-difluoropurine intermediate that enables a mild, highly selective, direct amination. This one-pot fluorination/amination sequence utilizes a direct isolation to deliver high purity 9-THP-2-fluoroadenine, which features ideal properties with respect to reactivity, solubility, and crystallinity. An acid-catalyzed liberation of 2-fluoroadenine in aqueous buffer delivers the appropriate purity profile to facilitate the enzymatic cascade to access MK-8591.
- Hong, Cynthia M.,Xu, Yingju,Chung, John Y. L.,Schultz, Danielle M.,Weisel, Mark,Varsolona, Richard J.,Zhong, Yong-Li,Purohit, Akasha K.,He, Cyndi Q.,Gauthier, Donald R.,Humphrey, Guy R.,Maloney, Kevin M.,Lévesque, Fran?ois,Wang, Zhixun,Whittaker, Aaron M.,Sirota, Eric,McMullen, Jonathan P.
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supporting information
p. 395 - 404
(2021/05/03)
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- PROCESS FOR THE PREPARATION OF 2-FLUOROADENINE
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The present invention provides processes for the preparation of 2-fluoroadenine, as well as certain intermediates useful in the preparation of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (EFdA): EFdA.
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Page/Page column 16
(2021/01/23)
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- Thermodynamic Reaction Control of Nucleoside Phosphorolysis
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Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
- Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
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supporting information
p. 867 - 876
(2020/01/24)
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- One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation
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We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity of the reaction and the heat removal, which were critical for the development of the process. Our goal was to improve the yield and purity of this pharmaceutical intermediate (2-fluoroadenine) and develop a more robust process.
- Salehi Marzijarani, Nastaran,Snead, David R.,McMullen, Jonathan P.,Lévesque, Fran?ois,Weisel, Mark,Varsolona, Richard J.,Lam, Yu-Hong,Liu, Zhijian,Naber, John R.
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supporting information
p. 1522 - 1528
(2019/07/10)
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- The Method For Adenine Derivative
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The present invention provides a method for manufacturing 2-fluoroadenine, comprising: a first step of amidating 6-chloro-2-fluoropurine (CFP) compound to synthesize a first intermediate product, which is N-(2-fluoropurin-6-yl)triphenylphosphine amide represented by chemical formula 2; a second step of acidifying the first intermediate product to synthesize a second intermediate product, which is 2-flouroadenine hydrochloride (2-FA HCl) represented by chemical formula 3; and a third step of neutralizing the second intermediate product to synthesize 2-fluorodadenine (2-FA) represented by chemical formula 4.COPYRIGHT KIPO 2019
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Paragraph 0144-0161
(2019/03/05)
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- The Method For Adenine Derivative
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The purpose of the present invention is to provide a method for manufacturing adenine derivatives with high purity which can be easily manufactured. Provided is a method for manufacturing adenine derivatives to manufacture 2-fluoroadenine represented by chemical formula 3 by reacting 6-azido-2-fluoropurine compounds represented by chemical formula 1 with triphenylphosphine represented by chemical formula 2 in the presence of a solvent of tetrahydrofuran (THF) and hydrogenchloride (HCl).COPYRIGHT KIPO 2018
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Paragraph 0054; 0072-0078
(2018/04/11)
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- A 2 - fluoro adenine synthesis method (by machine translation)
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The invention discloses a 2 - fluoro adenine synthesis method. Cheap 6 - chloropurine as raw materials, to the 9 bit NH to tetrahydropyranyl protection, then and trifluoromethanesulfonic anhydride reaction, in 2 introduces nitro, then and NH4 F reaction, nitro into atomic fluorine will at the same time, getting rid of the tetrahydro-pyranyl, finally being ammonia saturated methanol solution, the 6 position chlorine atom is converted into amino, to obtain 2 - fluoro adenine, total yield of 58%. The method easily obtained and cheap materials, to avoid the use of expensive and harmful toxic reagent, avoid the use of dangerous and corrosivity of the operation steps, and the reaction scale expanded to 200 g of the scale, the yield is not obviously dropped. The invention application for 2 - fluoro adenine synthesis provides a new synthetic pathway, has potential application prospect. (by machine translation)
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Paragraph 0019; 0027; 0028
(2017/10/13)
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- Process for the preparation of 2-fluoroadenine
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The invention relates to a process for the preparation of 2-fluoroadenine with a purity of at least 98% (HPLC Area) characterised in that this very high purity degree of at least 98% (HPLC Area) is obtained directly on the crude product after washing and filtration, without recrystallization and/or any further purification steps.
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Page/Page column 4
(2009/07/10)
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- PROCESS FOR THE PREPARATION OF 2-FLUOROADENINE
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A process for the preparation of 2-fluoroadenine with a purity of at least 98% (HPLC Area) is presented. Such very high purity degree of at least 98% (HPLC Area) is obtained directly on the crude product after washing and filtration, without recrystallization and/or any further purification steps.
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Page/Page column 2
(2009/07/10)
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- PURINE NUCLEOSIDE ANALOGS
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The present invention is directed to purine nucleoside analogs of the general Formula (I), or tautomers thereof, physiologically acceptable salts, solvents and physiologically functional derivatives thereof, and pharmaceutical compositions comprising such compounds, salts and derivatives, which are useful as anti-bacterial and anti-protozoan agents. The invention is also directed to methods for treating a bacterial or protozoan infection in a mammal and use of the compounds for inhibiting the growth of a bacteria or protozoa.
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Page/Page column 26-27
(2008/06/13)
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- Gene therapy of cancer: activation of nucleoside prodrugs with e. colipurine nucleoside phosphorylase
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During the last few years, many gene therapy strategies have been developed for various disease targets. The development of anticancer gene therapy strategies to selectively generate cytotoxic nucleoside or nucleotide analogs is an attractive goal. One such approach involves the delivery of herpes simplex virus thymidine kinase followed by the acyclic nucleoside analog ganciclovir. We have developed another gene therapy methodology for the treatment of cancer that has several significant attributes. Specifically, our approach involves the delivery of E. coli purine nucleoside phosphorylase, followed by treatment with a relatively non-toxic nucleoside prodrug that is cleaved by the enzyme to a toxic compound. .This presentation describes the concept, details our search for suitable prodrugs, and summarizes the current biological data. Copyright
- Secrist III, John A.
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p. 745 - 757
(2007/10/03)
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- 6-azido-2-fluoropurine, useful in the synthesis of nucleosides
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This invention pertains to novel methods of synthesizing fludarabine, fludarabine phosphate and related nucleoside pharmacologic agents utilizing 6-azido-2-fluoropurine as a novel intermediate. In particular this invention pertains to a synthesis of fludarabine where the relatively low yield fluorination step is done before the costly coupling step.
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