- Multinuclear NMR measurements and DFT calculations for capecitabine tautomeric form assignment in a solution
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The molecular structure of capecitabine (a widely applied prodrug of 5-fluorouracil) was studied by multinuclear NMR measurements and DFT quantum mechanical calculations. One or two tautomeric forms in a solution were detected depending on the solvent used. In the organic solvents, a mixture of two forms of capecitabine was observed: carbamate and imine tautomers. In the aqueous solution, only the carbamate form was found. The methylation of capecitabine yields mainly two products in different proportions: N3-methylcapecitabine and N7-methylcapecitabine. The protonation of capecitabine in organic solvents with perchloric acid occurs at the N3 nitrogen atom. DFT calculations strongly support the results coming from the analysis of the NMR spectra.
- Cmoch, Piotr,Krzeczyński, Piotr,Le?, Andrzej
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Read Online
- Preparation of capecitabine intermediate
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The invention belongs to the field of medicine synthesis, and provides a preparation method of capecitabine intermediate, in particular to a compound of the formula I II in the presence of a ketone solvent and an organic base.
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Paragraph 0021-0024
(2021/09/01)
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- Cytidine derivative and method for preparing capecitabine medicines through derivative
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The invention discloses a 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as shown in a general formula (I) and a preparation method of the derivative, and a method for preparing a N4-deoxycarbonyl cytidine derivative and antitumor medicines namely capecitabine by using the general formula (I) as a raw material, wherein the structure of the general formula (I) is as shown in the description. The 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as the raw material of a reaction is used as a glycosyl donor and can be activated under the condition of Lewis acid trimethylsilyl trifluoromethanesulfonate and N-lodosuccinimide in catalysis quantity, so that Lewis acid in traditional use equivalent or excessive quantity is avoided, and a reaction system is mild, free from occurrence of other side reactions and efficient.
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Paragraph 0074-0077
(2020/05/14)
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- A capecitabine synthetic method
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The invention belongs to the technical field of medicine preparation and relates to a synthetic method of capecitabine. The method comprises the following steps: 1) condensation reaction: reacting 2', 3'-bi-O-acetyl-5'-deoxy-5-fluoro-cytidine with halo n-amyl formate in the presence of an acid applying agent and a dimethylamino-pyridine catalyst to prepare N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine; and 2) hydrolysis reaction: carrying out hydrolysis reaction on N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine in the presence of an inorganic base to prepare the final product capecitabine. Compared with the prior art, the method provided by the invention has the advantages that by taking the inorganic base as the acid applying agent, use of a lot of organic bases is avoided and therefore the yield is improved, the production cost lowered, the environmental pollution is reduced, the physical health of the worker is ensured, and industrial production is facilitated.
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Paragraph 0018; 0019; 0020; 0022; 0025; 0028
(2018/06/21)
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- A capecitabine key intermediate synthesis method
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The invention discloses a synthetic method for capecitabine key intermediate 2`,3`-O-diacetylpyridine-5`-deoxygenation-5-fluorine-N4-[(pentyloxy) carbonyl] cytidine. The synthetic method for the capecitabine key intermediate comprises the following steps that 1, 5- fluorocytosine, an acid-binding agent, chloroform, water and phase transfer catalyst are mixed, pentyl chloroformate is added dropwise under stirring, and the chloroform solution of (5-fluorine-2-oxo-1,2-dihydropyrimidine-4-base) amylcarbamate is obtained; 2, 1,2,3-three-O-acetyl-5-deoxygenation-6- ribofuranose is added into the chloroform solution obtained in the step 1, lewis acid is added dropwise, the reaction is performed for 2-10 hours after adding, and the capecitabine key intermediate is obtained after post-processing. The synthetic method is simple and convenient in operation, a silicane protective agent and intermediate product purification are not needed, the high yield of finished products is achieved, the proportion of alpha isomer in the products is effectively controlled, and compared with literature data, the purity of the obtained products is greatly improved.
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Paragraph 0033; 0035; 0036; 0038; 0039; 0041
(2018/11/03)
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- Synthesis method of capecitabine intermediate
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The invention provides a synthesis method of a capecitabine intermediate. The synthesis method comprises the following steps of performing a reaction on 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, carbonyldiimidazole and n-pentanol at a low temperature to produce 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(n-pentyloxycarbonyl) cytidine. By the synthesis method, the reaction yield is increased, and the yield is higher than or equal to 91%. By the synthesis method, the step is simple, the operation is convenient, few byproducts are produced, and industrial production is facilitated.
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Paragraph 0024-0026
(2018/06/15)
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- Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine
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The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine; the method comprises: reacting a compound of formula IV as a raw material with n-amyl chloroformate under the action of K3PO4 to obtain the compound of formula V, 2',3'-bis-O-acetyl-5'-deoxy-5-fluorine-N4-[(pentyloxy)carbonyl]cytidine. The invention also provides application of the method in the preparation of capecitabine. The preparation method has the advantages that reaction yield can be significantly increased, product purity is high, reaction conditions are mild, the use of pyridine is avoided, pyridine residue in the product is avoided, and the method is suitable for industrial production of medicine.
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Paragraph 0010; 0022; 0039; 0040; 0041; 0042; 0043-0060
(2017/08/28)
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- Safe and Alternate Process for the Reductions of Methanesulfonates: Application in the Synthesis of 1,2,3-Triacetyl-5-deoxy-d-ribofuranoside
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Diethylene glycol dimethyl ether, diglyme, and 1,2-bis(2-methoxyethoxy)ethane, triglyme, are found to be suitable and safe alternate solvents to DMSO for the reduction of methanesulfonate in sodium borohydride. Addition of anhydrous lithium chloride led to the complete reduction of methanesulfonate esters to the corresponding alkanes in the presence of sodium borohydride in these solvents (diglyme and triglyme). This protocol is useful in the preparation of 1,2,3-triacetyl-5-deoxy-d-ribofuranoside, 7, a key intermediate of Capecitabine, 1, on the commercial scale.
- Mekala, Nagaraju,Moturu, Murthy V.R.K.,Dammalapati, Rao V.L.N.,Parimi, Atchuta R.
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p. 609 - 614
(2016/04/04)
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- Capecitabine and wherein the intermediate preparation method
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The invention discloses a preparation method of capecitabine. The method comprises the following steps: based on D-ribose serving as a starting raw material, carrying out hydroxyl protection, 5-site tosylation, iodine substitution, hypophosphorous acid deiodination and acetylation so as to obtain the key intermediate 12,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose; carrying out glycosylation on the key intermediate and 5-fluorocytosine; and finally, carrying out N-4 site acylation and deprotection so as to obtain the capecitabine. In the method, a metal catalyst dose not need to be used for participating in reaction, the reaction condition is mild, and the yield is high, thus the method is economical and effective as well as suitable for industrial production on a large scale.
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Paragraph 0062; 0063; 0064
(2017/02/09)
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- The capecitabine industrial preparation method
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The invention optimizes the synthesis process of capecitabine bulk drug, especially improves the purification method of capecitabine. The method involved in the invention is suitable for industrial production, remarkably reduces the quantity and limit of related impurities in the capecitabine bulk drug, and improves the quality of the capecitabine bulk drug.
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Paragraph 0012; 0036; 0037
(2017/01/23)
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- Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach
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Capecitabine is a 5′-deoxynucleoside endowed with antitumoral activity. We planned a new approach to its synthesis: a cross linked enzyme aggregate subtilisin (Alcalase CLEA)-catalyzed alcoholysis allowed the selective deprotection of primary acetyl ester of the N1-(2′,3′,5′-tri-O-acetyl-β-d-ribofuranosyl)-5-fluoro-N4-(n-pentyloxycarbonyl)cytosine affording the corresponding 5′-hydroxyderivative; the 5′-alcohol was transformed into the methyl group of capecitabine after a careful investigation about the best reducing agent and reaction conditions.
- Ciceri, Samuele,Ciuffreda, Pierangela,Grisenti, Paride,Ferraboschi, Patrizia
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p. 5909 - 5913
(2015/11/02)
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- Synthesis and biological activity evaluation of cytidine-5′-deoxy-5- fluoro-N-[(alkoxy/aryloxy)] carbonyl-cyclic 2′,3′-carbonates
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Capecitabine, an oral prodrug of 5-FU was developed to improve the tumor selectivity and tolerability. To enhance the efficacy of capacitabine, a series of 5′-deoxy-5-fluorocytidine derivatives 5a-e were synthesized. In the present study, we investigated antitumor activity of 5′-deoxy-5- fluorocytidine derivatives both in vivo and in vitro methods. Title compounds were non-mutagenic to Salmonella typhimurium tester strain in Ames test. Compounds 5d and 5e are potent to inhibit the proliferation of NCI-69, PZ-HPV-7, MCF-7 and HeLa cells in MTT assay. In particular, 5d and 5e showed potent antitumor activities against L1210 leukemia cell line. Collectively, these findings suggest that 5d and 5e are more potent anti-cancer compounds than capecitabine.
- Jhansi Rani,Raghavendra,Kishore,Nanda Kumar,Hema Kumar,Jagadeeswarareddy
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experimental part
p. 690 - 696
(2012/09/08)
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- Rapid continuous synthesis of 5′-deoxyribonucleosides in flow via Br?nsted acid catalyzed glycosylation
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A general, green, and efficient Br?nsted acid-catalyzed glycosylation serves as a key step in the one-flow, multistep syntheses of several important 5′-deoxyribonucleoside pharmaceuticals.
- Shen, Bo,Jamison, Timothy F.
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supporting information; experimental part
p. 3348 - 3351
(2012/08/08)
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- Process for Producing Fluorocytidine Derivatives
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A process for making a capecitabine or its derivative comprising (a) reacting a compound of the formula (II): wherein each of R1 and R2 independently represents a hydroxyl protecting group, with an acylating agent of formula (III): X—C(═O)—R3, wherein X is an acyl activating group in an organic solvent to produce an acylated compound; (b) deprotecting the acylated compound to obtain the compound of formula (I); and (c) purifying the compound of formula (I) with a solvent.
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Page/Page column 3; 5-6
(2011/02/18)
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- PREPARATION OF CAPECITABINE
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The present invention relates to substantially pure capecitabine and processes for the preparation thereof.
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Page/Page column 9; 24
(2010/06/20)
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- METHOD FOR THE PREPARATION OF CAPECITABINE AND INTERMEDIATES USED IN SAID METHOD
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A process to obtain capecitabine compound and its pharmaceutically acceptable derivatives is hereby disclosed. Likewise, novel intermediates to be used in the preparation of capecitabine compound and its pharmaceutically acceptable derivatives are also disclosed. The procedure comprises the stage of causing a reaction of N4-(n-pentyloxycarbonyl))-5- fluorocytosine with (1,2,3-tri-O-acetyl-5-deoxy- α,β-D-ribofuranose.
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Page/Page column 9
(2010/11/03)
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Described herein are compositions and methods for using these compositions in the treatment of cancer, tumors, and tumor-related disorders in a subject.
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Page/Page column 56
(2009/05/29)
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- Process for the preparation of capecitabine
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The present application relates to an improved process for the preparation of capecitabine.
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Page/Page column 8
(2009/09/05)
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- PROCESS FOR PREPARING CAPECITABINE
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There is provided processes for the preparation of capecitabine and intermediates thereof.
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Page/Page column 37
(2008/12/08)
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- PROCESSES RELATED TO MAKING CAPECITABINE
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An intermediate (2) useful in making capecitabine can be formed without the use, or presence, of a silylation agent.
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Page/Page column 1; 4
(2009/01/20)
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- The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, Capecitabine
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To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys. Copyright (C) 2000 Elsevier Science Ltd.
- Shimma, Nobuo,Umeda, Isao,Arasaki, Motohiro,Murasaki, Chikako,Masubuchi, Kazunao,Kohchi, Yasunori,Miwa, Masanori,Ura, Masako,Sawada, Noriaki,Tahara, Hitoshi,Kuruma, Isamu,Horii, Ikuo,Ishitsuka, Hideo
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p. 1697 - 1706
(2007/10/03)
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