- Preparation method of capecitabine key intermediate
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The invention discloses a preparation method of a capecitabine key intermediate. According to the method, 2', 3', 5'-tri-0-acetyl-5-fluorocytidine servers as an initial raw material, selectively deacetylating through di-tert-butyl chlorotin hydroxide, and reducing through triethyl silane and trifluoroacetic acid to obtain a target product. The method has the advantages of cheap and easily available raw materials, short synthesis steps, simple operation, high product purity and high yield, and is especially suitable for industrial production.
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Paragraph 0018; 0033; 0036-0037; 0038; 0041-0042
(2021/06/02)
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- AMPHIPHILE PRODRUGS
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Amphiphilic prodrugs of general formula A-X are disclosed, wherein A is a biologically active agent or may be metabolised to a biologically active agent; and X is selected from the group consisting of R, or up to three R moieties attached to a linker, Y1, Y2 or Y3, wherein R is selected from a group consisting of alkyl, alkenyl, alkynyl, branched alkyl, branched alkenyl, branched alkynyl, substituted alkyl, substituted alkenyl and substituted alkynyl groups and their analogues; Y1 is a linker group which covalently attached to an R group at one site and is attached to A at a further independent site; Y2 is a linker group which is covalently attached to two R groups at two independent sites and is attached to A at a further independent site; and Y3 is a linker group which is covalently attached to three R groups at three independent sites and is attached to A at a further independent site. Self-assembly of the amphiphilic prodrugs into reverse lyotropic phases, particularly hexagonal, cubic and sponge, is disclosed. In preferred embodiments A is dopamine or a 5-fluorouracil prodrug.
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Paragraph 0142; 0151; 0152
(2019/06/12)
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- Method for preparing capecitabine intermediate shown I
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The invention discloses a method for preparing a Capecitabine intermediate represented by formula I. The method comprises the following reaction route shown in the description, wherein in the reaction a, 5-fluorocytosine reacts with hexamethyldisilazane to produce a compound represented by a formula III; in the reaction b, the compound represented by the formula III reacts with a compound represented by a formula II to produce the Capecitabine intermediate represented by the formula I; and in the general formula, R is H or a hydroxyl protecting group. According to the method, the high-yield preparation of the high-purity Capecitabine intermediate represented by the formula I is realized through strictly controlling the dropwise adding temperature and dropwise adding rate of Lewis acid, so that the subsequent preparation of high-purity Capecitabine is facilitated, and the requirements on industrialization of Capecitabine are met; and the method has a significant practical value.
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Paragraph 0038-0049
(2019/08/21)
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- Preparation method and product of capecitabine intermediate
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The invention relates to a preparation method of a capecitabine intermediate. The capecitabine intermediate is 2',3'-di-O-acetyl-5'-deoxy-5-fuluro-D-cytidine, and the method comprises the following steps: 5-fluorocytosine is placed in a solvent, 1,2,3-tri-O-acetyl-5-deoxyribose is added, and Lewis acid is added with stirring for a catalytic reaction; sodium bicarbonate and water are added to a reaction liquid obtained after reaction completion for quenching, then separation and crystallization are performed, and the capecitabine intermediate is prepared. In the preparation method, 5-fluorocytosine does not need silylation protection and is subjected to glycosylation with 1,2,3-tri-O-acetyl-5-deoxyribose directly, so that reaction steps are reduced, and reaction time is shortened; energy consumption is reduced, production efficiency is increased, produced waste is reduced, and resources are saved; the obtained capecitabine intermediate is high in purity, alpha isomers are few or even cannot be detected, and optical purity of the product can reach 99.8% or higher.
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Paragraph 0037-0046
(2018/09/13)
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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 0020; 0061; 0062
(2017/08/28)
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- Effective synthesis of nucleosides utilizing O-acetyl-glycosyl chlorides as glycosyl donors in the absence of catalyst: Mechanism revision and application to silyl-hilbert-johnson reaction
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An effective synthesis of nucleosides using glycosyl chlorides as glycosyl donors in the absence of Lewis acid has been developed. Glycosyl chlorides have been shown to be pivotal intermediates in the classical silyl-Hilbert-Johnson reaction. A possible mechanism that differs from the currently accepted mechanism advanced by Vorbrueggen has been proposed and verified by experiments. In practice, this catalyst-free method provides easy access to Capecitabine in high yield.
- Liang, Chengyuan,Ju, Weihui,Ding, Shunjun,Sun, Han,Mao, Gennian
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supporting information
(2017/01/24)
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- 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine synthesis method
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The present invention discloses a 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine synthesis method, which comprises: (1) suspending 5-fluorocytosine in anhydrous toluene, adding hexamethyldisilazane, and carrying out a heating reflux reaction; (2) carrying out pressure reducing concentration on the solution obtained in the step (1) at a temperature of less than or equal to 60 DEG C to achieve a dry state, adding 5-triacetyl deoxyribose and anhydrous 1,2-dichloroethane to the remaining substance, adding anhydrous tin tetrachloride and an anhydrous 1,2-dichloroethane solution in a dropwise manner at a temperature of -5 DEG C, and carrying out a reaction at a temperature of 0 DEG C after completing the adding; (3) adding a sodium bicarbonate solution to the solution obtained in the step (2), stirring for a certain time at a room temperature, filtering, washing with a 5% sodium bicarbonate solution, drying with anhydrous sodium sulfate, and concentrating to achieve a dry state; and (4) purifying the remaining substance obtained in the step (3) with a silica gel chromatography column so as to obtain the crystal 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, wherein the solution obtained in the step (2) is slowly added to the -5 DEG C sodium bicarbonate aqueous solution in a dropwise manner in the step (3). The method of the present invention has characteristics of less operation and low loss.
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Paragraph 0008
(2016/12/01)
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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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- 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; 0031-0033
(2017/01/23)
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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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- 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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- NOVEL SYNTHESIS OF 5-DEOXY-5'-FLUOROCYTIDINE COMPOUNDS
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This invention relates to a process of synthesizing a β-nucleoside compound of formula (I): wherein R1 is alkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl. The process includes reacting a compound of formula (II): with a compound of formula (III): wherein R1 is as defined above and X is chloride, bromide, iodide, methanesulfonate, triflate, p-toluenesulfonate, trifluoroacetate, 4-nitrophenoxy, or N-succinimidyloxy, in a solvent and in the presence of a base.
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Paragraph 0028; 0029
(2013/07/25)
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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
(2011/02/18)
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- HYDROXAMIC ACID DERIVATIVES
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The disclosure includes hydroxamic compounds of Formula I: (I) wherein P, Z, and m are defined herein. Also disclosed is a method for treating a neoplastic disease or an immune disease with these compounds.
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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 23
(2010/06/20)
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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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- 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 4-5
(2009/01/20)
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- BIOREDUCTIVELY-ACTIVATED PRODRUGS
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The present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt thereof, Formula: (1); wherein: R1 is a substituted aryl or heteroaryl group bearing at least one nitro or azido group or is an optionally substituted benzoquinone, optionally substituted naphthoquinone or optionally substituted fused heterocycloquinone; R2 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, aryl or heteroaryl; and R3 is selected such that R3NH2 represents a cytotoxic nucleoside analogue or an ester or phosphate ester prodrug of a cytotoxic nucleoside analogue, with the proviso that if R1 is an aryl group then R2 is not H.
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Page/Page column 25
(2010/10/20)
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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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- N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds, compositions and methods of using same
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The invention relates to N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives which are useful as an agent for treating tumors, pharmaceutical compositions including the same, a method of treating tumors and a method of preparing N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine derivatives for treating tumors. Compounds of formula (I), STR1 wherein R1 is a saturated or unsaturated, straight or branched hydrocarbon radical wherein the number of carbon atoms in the longest straight chain of this hydrocarbon radical ranges from three to seven, or is a radical of the formula --(CH2)n--Y wherein Y is a cyclohexyl radical, a C1 -C4 alkoxy radical or a phenyl radical and wherein when Y is a cyclohexyl radical n is an integer from 0 to 4, and when Y is C1 -C4 alkoxy radical or a phenyl radical n is an integer from 2 to 4, and R2 is a hydrogen atom or a radical easily hydrolyzable under physiological conditions, or a hydrate or solvate thereof. Compounds of formula (I) are useful in the treatment of tumors.
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- Process for producing N4 -acyl-5'-deoxy-5-fluorocytidine compounds
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A novel process for producing derivatives of the anti-tumor agent N4 -acyl-5'-deoxy-5-fluorocytidine using the novel 5'-deoxy-5-fluoro-N4, 2'-0,3'-0-triacylcytidine derivatives as intermediates is provided. 5-Deoxy-1,2,3-tri-0-acyl-β-D-ribofuranoside is reacted with 5-fluorocytosine to produce 5'-deoxy-2',3'-di-0-acyl-5-fluorocytidine, followed by acylation, to produce the novel intermediate 5'-deoxy-5-flouro-N4,2'-0,3'-0-triacylcytidine. The acyl radicals of this intermediate are selectively de-0-acylated to obtain N4 -acyl-5'-deoxy-5-fluorocytidine derivatives. From fluorocytosine, N4 -acyl-5'-deoxy-5-fluorocytidine derivatives can be obtained through few steps in high yield, an in satisfactory purity.
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