- One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine
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In Africa around 625-000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment for CM is a combination of amphotericin B and flucytosine, both now WHO Essential Medicines. However, flucytosine is not even registered for use in any African nation due, in part, to its relatively high cost of manufacture and lack of generic manufacturers. Currently, flucytosine is manufactured by an expensive four-step manufacturing process. Here we report a one-step continuous flow process involving the reaction of inexpensive cytosine with fluorine gas using stainless steel tubular laboratory and pilot-scale silicon carbide reactor devices which is readily scaleable to a manufacturing process with a low initial capital expenditure.
- Harsanyi, Antal,Conte, Annelyse,Pichon, Laurent,Rabion, Alain,Grenier, Sandrine,Sandford, Graham
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- 2′,3′-didehydro-2′,3′-dideoxynucleosides are degraded to furfuryl alcohol under acidic conditions
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2′,3′-Didehydro-2′, 3′-dideoxynucleosides are clinically relevant antiviral agents. These nucleosides could be degraded under acidic conditions. Acidic stability studies showed the D4N had the following increasing stability order: D4GA concerted A-1 mechanism has been proposed for the acidic cleavage of D4-nucleosides. The cleavage products were characterized as furfuryl alcohol and the corresponding nucleobase. Furfuryl alcohol is an agent found in many everyday food products. The biological results demonstrated that furfuryl alcohol had neither anti-HIV activity nor cytotoxicity in vitro, suggesting the acid instability of D4-nucleosides is unlikely to have an impact on the toxicity of these nucleoside analogs in humans.
- Shi, Junxing,Ray, Adrian S.,Mathew, Judy S.,Anderson, Karen S.,Chu, Chung K.,Schinazi, Raymond F.
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- 2-CYANO-2-FLUOROETHENOLATE SALTS (CFES): VERSITILE ACTIVE PHARMACEUTICAL INTERMEDIATES
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The present invention relates to new enolate structures with utility as active pharmaceutical intermediates for the preparation of efficacious drugs such as those derived from 5-fluorocytosine (5-FC).
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Paragraph 0011
(2020/08/30)
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- Method for synthesizing 5-fluorocytosine
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The invention discloses a method for synthesizing fluorocytosine, and belongs to the field of nucleoside synthesis in organic chemistry. The method comprises the following reaction steps: with N4-acylprotected cytosine as a raw material and organic carboxylic acid as a solvent, carrying out direct fluorination so as to obtain a one-step intermediate, and carrying out a removal reaction so as to obtain the 5-fluorocytosine. According to the method disclosed by the invention, the raw material cost is reduced, the problem of equipment corrosion caused by a cytosine and hydrogen fluoride processis solved, and meanwhile, the purity of the 5-fluorocytosine obtained by the method can reach 99.9% or above.
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Paragraph 0024-0025; 0027; 0032-0033; 0035-0037; 0039-0041
(2020/01/08)
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- Preparation method of 5-fluorocytosine
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The invention provides a preparation method of 5-fluorocytosine. The method is characterized by including the following steps that 1, an organic solvent, fluoroacetonitrile, ethyl formate and organicbase are added into an autoclave for a heating reaction in a predetermined gaseous environment, then decompressing and cooling are conducted, and first reaction liquid containing an intermediate 1 isobtained; 2, an alcohol solution of hydrogen chloride is added into a reaction still, the first reaction liquid is added for reaction after cooling, a second reaction liquid is obtained after reaction, water is added into the second reaction liquid, the pH value is adjusted to be 6-8, a first organic layer is obtained after standing, and the first organic layer is distilled to obtain an intermediate 2; 3, the intermediate 2 and urea are subjected to an aldimine condensation reaction, and then a crude product of 5-fluorocytosine is obtained. According to the method, the synthesis process is simple, there are a few required reaction steps, the total yield is relatively high, the safety of reaction is high, the production efficiency is improved, and the production cost is reduced.
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Paragraph 0038; 0056-0080; 0082; 0087-0097; 0099; 0104-0115
(2019/10/01)
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- Synthesis of 5-Fluorocytosine Using 2-Cyano-2-fluoroethenolate as a Key Intermediate
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There is an urgent demand for 5-fluorocytosine (5-FC) due to its activity against HIV-induced fungal infections as well as its use as a key intermediate in the synthesis of the clinically highly important anti-HIV drug emtricitabine (FTC). We report a simple, low-cost five steps synthesis of 5-FC starting from chloroacetamide. Overall yields up to 46 % were achieved and the route is devoid of any chromatographic purifications. The previously unknown key intermediate (Z)-2-cyano-2-fluoroethenolate is obtained through a Claisen-type condensation from fluoroacetonitrile. As the direct cyclization with urea only gave poor yields, 5-fluoro-2-methoxypyrimidin-4-amine, 5-fluoro-2-(methylsulfanyl)pyrimidin-4-amine and 5-fluoropyrimidine-2,4-diamine served as synthetic intermediates.
- Dietz, Jule-Philipp,Derstine, Brenden P.,Ferenc, Dorota,Crawford, Evan T.,Arduengo, Anthony J.,Gupton, B. Frank,McQuade, D. Tyler,Opatz, Till
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p. 5519 - 5526
(2019/07/17)
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- Method for synthesizing 5-flucytosine
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The invention discloses a method for synthesizing 5-flucytosine and belongs to the field of organic chemistry. The method comprises the following reaction steps of: adopting fluoroacetonitrile as a raw material, firstly reacting with N,N-dimethyl formamide dimethylacetal to generate 2-fluoro-3-dimethylaminoacrylonitrile, then reacting with urea to obtain an intermediate, and then under the existence of alkali, carrying out cyclization reaction to generate the 5-flucytosine. The method disclosed by the invention has the beneficial effects that the whole process only needs three step reactions,the reaction steps are short, the operation is easy, the use of dangerous chemicals such as fluorine gas and the like is avoided, the total yield reaches not less than 50%, so that the method is suitable for industrial large-scale production.
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Paragraph 0063; 0067
(2018/03/25)
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- Method for fluorinating pyrimidine derivative by using micro-channel reactor
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The invention discloses a method for directly fluorinating a pyrimidine derivative by using a micro-channel reactor. A uracil and/or cytosine and fluorine-containing acid and/or fluorine-containing alcohol mixture used as a raw material reacts with fluorine to prepare corresponding fluorouracil and/or fluorocytosine. The prepared fluorouracil and fluorocytosine have the advantages of high purity, low cost advantage, and safe and easily controlled fluorination process.
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Paragraph 0028-0031; 0047-0051
(2017/06/02)
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- Method for preparing 5-fluorocytosine by adopting micro-channel reactor
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The invention discloses a method for preparing 5-fluorocytosine by adopting a micro-channel reactor. The method comprises the following steps: controlling and injecting cytosine and fluorine dissolved in formic acid into a silicon carbide continuous flow reactor through a flow meter by using a metering pump, wherein a molar ratio of cytosine to fluorine in the raw material is 1:1 to 1:0.77; controlling the temperature to be 5-10 DEG C, wherein the 10wt% cytosine formic acid solution has the flow of 580g/h, and the 10vol% fluorine mixed in nitrogen has the flow of 200g/h; and collecting the yellow reaction mixed solution, adding n-butyl alcohol into the solution, precipitating out the product, and filtering, thereby obtaining the target product 5-fluorocytosine. The method has the advantages of short reaction time, high product selectivity and high raw material conversion rate.
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Paragraph 0036; 0037; 0038; 0039; 0040; 0041; 0042; 0043
(2017/09/26)
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- A 5-fluorocytosine preparation method
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The invention discloses a preparation method of 5-flucytosine. The method comprises the following steps of: 1) cytosine and a halogenating reagent perform halogenating reaction in an organic solvent at 0-80 DEG C to prepare an intermediate (I), 2) the intermediate (I) reacts with an amino protecting agent at 0-120 DEG C to prepare an intermediate (II), and 3) the intermediate (II) and a fluoro reagent perform fluoro reaction in a polar aprotic solvent or hydrogen fluoride at 70-200 DEG C to prepare an intermediate (III), and the intermediate (III) directly performs amino deprotecting reaction, and is separated and purified to prepare 5-flucytosine. According to the method, a process route is reasonable, the product yield is high, the quality is good, the production safety of the fluoro reagent is high, and the method is simple to operate and suitable for industrial production.
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Paragraph 0036
(2017/01/17)
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- Method for 5-fluorocytosine
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A disclosed method for 5-fluorocytosine comprises a reaction shown in the specification, and the method is characterized by comprising the following steps: dissolving a compound shown as a formula IV in an organic solvent, adding triethylamine, dropwise adding phosphorus oxychloride at 40-100 DEG C, after dropwise adding is finished, keeping warm and stirring for reaction for 2-10 h, so as to obtain a compound shown as a formula III; adding the formula III compound into an organic solution of ammonia, and stirring at 40-80 DEG C for reacting for 2-8 h, so as to obtain a compound shown as a formula II; and adding the formula II compound into a hydrogen chloride organic solution, and stirring at 40-80 DEG C for reacting for 3-15 h, so as to obtain a compound shown as a formula I. The method realizes low-cost high-yield large-scale preparation of high-purity 5-fluorocytosine, and possesses substantial industrial value.
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Paragraph 0041; 0042; 0043
(2016/11/17)
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- A cytosine fluorinated synthetic 5-fluorocytosine method
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The invention discloses a method for fluoridating and synthesizing 5-flucytosine by cytosine, which comprises the following steps: 1)under inert gas protection, adding cytosine in anhydrous hydrogen fluoride, introducing fluorine containing gas for a fluorination reaction under -5--20 DEG C, and 2)after reacting for 3-5 hours, distilling and concentrating the reaction solution, adding water for dissolving, adding alkali to adjust the pH value of the reaction solution, and separating to obtain the 5-flucytosine by cytosine. The method has the advantages of short synthesis route and good technology selectivity, no organic solvent is used during the production process, and the synthesized 5-flucytosine by cytosine has the advantages of high purity and high synthesis yield.
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Paragraph 0042-0043
(2017/04/11)
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- PROCESS FOR PRODUCING FLUOROCYTOSINE AND FLUOROCYTOSINE DERIVATIVES
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The present invention relates to a method of manufacturing a fluorocytosine based compound of Formula I. (I) The invention also relates to a compound obtained by such a method, a pharmaceutical drug substance and a method for its manufacture, a pharmaceutical composition, and also various uses in therapy of the compounds, pharmaceutical drug substances, and pharmaceutical compositions of the invention.
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Paragraph 00251
(2016/03/22)
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- Preparation of thionucleosides
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The invention relates to the preparation of homochiral thiolactones which have application in the synthesis of 3?- and 4?- thionucleosides. Substituents on the thiolactone can be used to influence the configuration of the C-1? position in the final nucleoside. Configuration at the C-4? position is controlled by use of the appropriate homochiral glycidol as starting material in the synthesis of the thiolactone. This process also offers the possibility of introducing substituents diastereoselectively in the C-2? and C-3? positions.
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- Glorination of Pyrimidines. Part 2. Mechanistic Aspects of the Reaction of Acetyl Hypofluorite with Uracil and Cytosine Derivatives
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The reaction of acetyl hypofluorite (AcOF) with uracil, cytosine, and some N-1-substituted derivatives dissolved in either acetic acid or water has been investigated.Analysis by radio-h.p.l.c., using (18)f as a tracer, and by (1)H n.m.r. revealed that a substituent at N-1 of uracil has a remarkable effect on the stability of the intermediate 6-acetoxy-5-fluoro-5,6-dihydrouracils.In addition, it was found that these cytosine adducts rapidly deaminate in water yielding their corresponding uracil analogues.
- Visser, W. M. Gerard,Herder, E. Renella,Kanter, Frans J. J. de,Herscheid D. M. Jacobus
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p. 1203 - 1208
(2007/10/02)
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- Process for the preparation of 5-fluorocytosine
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5-fluorocytosine is prepared by reacting 2,5-difluoro-4-chloro-pyrimidine with a proton acid in the presence of water to yield 2-hydroxy-4-chloro-5-fluoropyrimidine and reacting the 2-hydroxy-4-chloro-5-fluoropyrimidine with ammonia to yield 5-fluoro-cytosine.
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- Mechanism and Stereochemistry of the luorination of Uracil and Cytosine Using Fluorine and Acetyl Hypofluorite
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The products of the reaction of CH3COOF and F2 with uracil and cytosine dissolved in acetic acid and water were studied by using 18F as a tracer.Apart from 5-fluorouracil (2) and the 5,5-difluoro adducts 5a and 5b, the 1H NMR spectra of the crude reaction mixture showed the presence of two geometric isomers of both 5- fluoro-6-acetoxy-5,6-dihydrouracil (3a, 4a) and 5-fluoro-6-hydroxy-5,6-dihydrouracil (3b, 4b).In the fluorination of cytosine, corresponding products were observed with the exception of the acetoxy adducts.For both reagents and for both substrates a radical-cation mechanism is proposed.The observed conversions of the acetoxy adducts of uracil are explained by an acylimine (iii) as an intermediary.
- Visser, Gerard W. M.,Boele, Saskia,Halteren, Bert W. v.,Knops, Gertrudis H. J. N.,Herscheid, Jacobus D. M.,et al.
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p. 1466 - 1471
(2007/10/02)
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- Nucleoside process
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Process for producing 1-halo-2-deoxy-2-fluoroarabinofuranoside derivatives bearing protective ester groups from 1,3,5-tri-O-acylribofuranose; the 1-halo compounds are intermediates in the synthesis of therapeutically active nucleosidic compounds.
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- UBER SYNTHESEN VON DIFLUORAMINOPYRIMIDINEN
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The synthese of difluoroaminopyrimidines are reported.By direct fluorination of amino derivatives the corresponding difluoroamino-compounds and other fluorinated products are formed.In the case of the alkylation of difluoroamine by protonated pyrimidines the formation of difluoroamino-compounds is discussed.
- Meinert, H.,Gross, U.,Rudiger, St.
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p. 355 - 362
(2007/10/02)
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