WO2005080351A1 - Preparation et application de derives n4-oxycarbonylcytosine - Google Patents

Preparation et application de derives n4-oxycarbonylcytosine Download PDF

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Publication number
WO2005080351A1
WO2005080351A1 PCT/CN2004/000744 CN2004000744W WO2005080351A1 WO 2005080351 A1 WO2005080351 A1 WO 2005080351A1 CN 2004000744 W CN2004000744 W CN 2004000744W WO 2005080351 A1 WO2005080351 A1 WO 2005080351A1
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WO
WIPO (PCT)
Prior art keywords
group
fluorocytosine
general formula
ethynyl
substituted
Prior art date
Application number
PCT/CN2004/000744
Other languages
English (en)
Chinese (zh)
Inventor
Jinliang Li
Baofang He
Lanying Shao
Lei Wang
Original Assignee
Shanghai Desano Pharmaceutical Holding Co., Ltd.
Shanghai Desano Chemical Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Desano Pharmaceutical Holding Co., Ltd., Shanghai Desano Chemical Pharmaceutical Co., Ltd. filed Critical Shanghai Desano Pharmaceutical Holding Co., Ltd.
Publication of WO2005080351A1 publication Critical patent/WO2005080351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical

Definitions

  • N 4 - oxycarbonyl cytosine and derivatives and preparation method TECHNICAL FIELD The present invention belongs to the technical field of pharmaceutical chemistry. Specifically, it relates to N 4 -oxocarbonylcytosine derivative, its preparation method and application. Background technique
  • N 4 -oxycarbonylcytosine derivatives are important raw materials for the preparation of fluorocytosine carbamate anticancer drugs.
  • Capecitabine is the first fluoropyrimidine carbamate antitumor drug. Its chemical name is 5'-deoxy-5-fluoro-N 4 -pentoxycarbonylcytidine, that is: 5-deoxy-5- fluoro-N 4- (pentyloxycarbony) cytidine. Its structural formula is as follows:
  • the invention provides cytosine derivatives of the general formula I:
  • R 2 is halogen atom fluorine or iodine, vinyl, ethynyl or halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl Or aromatic heterocyclyl substituted vinyl, ethynyl.
  • Another object of the present invention is to provide a method for preparing a cytosine derivative of the general formula I, which is prepared by a condensation reaction of the general formula II and the general formula III.
  • R 3 is a halogen atom (such as fluorine, iodine, etc.), a vinyl group, an ethynyl group or a vinyl group, an ethynyl group substituted by a halogen, a fluorenyl group, a cyclofluorenyl group, an arylcycloalkyl group, or an aromatic heterocyclic group.
  • X represents a leaving group
  • R 4 represents a fluorenyl group, a cyclofluorenyl group, an alkenyl group, an arylfluorenyl group, or an aryl group.
  • the condensation reaction of the general formula II and the general formula III can be performed in a solvent such as pyridine, dichloromethane, 1,2-dichloroacetamidine, or water, or in two or more mixed solvents, but Acid acceptors such as triethylamine, pyridine, methylpyridine, alkali metal hydroxides, alkali metal carbonates or phosphates are required.
  • the reaction temperature can be varied within a relatively wide range, generally from 20 ° C to -20V, and preferably at about 0 ° C.
  • Another object of the present invention is to provide a N 4 -oxycarbonylcytosine derivative of the general formula I, which is represented by the general formula N.
  • R 5 is a fluorenyl group, a cycloalkyl group, an alkenyl group, an arylfluorenyl group or an aryl group.
  • N-oxycarbonyl-5-fluorocytosine derivatives (general formula IV) are reacted with 5-deoxy-D-ribofuranosyl compounds (general formula V) to prepare fluorine.
  • Cytosine carbamate antitumor drugs The synthetic method is an effective way to reduce the cost of such drugs and improve the quality.
  • R 6 is a hydrogen atom, an acetyl group or a benzoyl group.
  • Yet another object of the present invention is to provide a method for preparing fluorocytosine carbamate antitumor drug capecitabine using N 4 -pentyloxycarbonyl-5 fluorocytosine as a starting material.
  • the method includes the following steps:
  • N 4 -pentyloxycarbonyl-5-fluorocytosine used as the raw material for the above reaction is obtained by the condensation reaction of 5-fluorocytosine with n-pentyl chloroformate. It is a new compound prepared by the inventors.
  • trimethylsiloxane (OSi (CH 3 ) 3 ) trimethylsiloxane (OSi (CH 3 ) 3 ), hexamethyldisilazane (N [Si (CH 3 ) 3 ] 2 ) or sodium iodide and trimethylchlorosiliconium are heated under reflux in anhydrous acetonitrile, dichloromethane, 1,2-dichloroethane, or toluene.
  • alkyl used in the present invention refers to a straight or branched fluorenyl group having 1 to 19 carbon atoms: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, hexadecyl, heptadecyl, or nonadecyl;
  • Cyclomethyl means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • Alkenyl means an unsubstituted or substituted alkenyl group having 3 to 19 carbon atoms, allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2- Propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptenyl, undecenyl, or 2-phenylvinyl;
  • Alkyl means an unsubstituted or substituted arylfluorenyl, such as benzyl, 1-phenylethyl, methylbenzyl or phenethyl;
  • Aryl means an unsubstituted or substituted aryl, such as phenyl, benzyl, xylyl or ethylphenyl;
  • Vinyl, ethynyl substituted with halogen, fluorenyl, cycloalkyl, arylcyclofluorenyl or arylheterocyclyl means 1-chlorovinyl, 2-bromovinyl, 1-chloro-2-bromo Vinyl, 2-styryl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 3,3-dimethyl-1-butynyl, cyclopentylacetylene Radical, cyclohexylethynyl, phenylethynyl, 3-phenyl-1-propynyl, pyridine-2 -ethynyl or imidazole-2-ethynyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

La présente invention porte sur un nouveau dérivé N4-oxycarbonylcytidine et sur sa préparation. Cette invention concerne également un nouveau dérivé N4-oxycarbonylcytidine représenté par la formule générale (I) ainsi qu'un procédé de préparation de fluorocytidine amino formiate utilisé dans un agent thérapeutique antitumoral tel que la capécitabine, lequel procédé utilise une N4-pentyloxycarbonyl-5-fluorocytidine comme substance de départ.
PCT/CN2004/000744 2004-02-23 2004-07-05 Preparation et application de derives n4-oxycarbonylcytosine WO2005080351A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2004100164722A CN100383128C (zh) 2004-02-23 2004-02-23 N4－氧羰基胞嘧啶衍生物及制备方法与应用
CN200410016472.2 2004-02-23

Publications (1)

Publication Number Publication Date
WO2005080351A1 true WO2005080351A1 (fr) 2005-09-01

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Application Number Title Priority Date Filing Date
PCT/CN2004/000744 WO2005080351A1 (fr) 2004-02-23 2004-07-05 Preparation et application de derives n4-oxycarbonylcytosine

Country Status (3)

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CN (1) CN100383128C (fr)
AR (1) AR046077A1 (fr)
WO (1) WO2005080351A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008131062A2 (fr) 2007-04-20 2008-10-30 Dr. Reddy's Laboratories Ltd. Procédé pour la préparation de capécitabine
WO2009071726A1 (fr) * 2007-12-06 2009-06-11 Coll Farma S.L. Procédé de préparation de capécitabine et produits intermédiaires pouvant être utilisés dans ce procédé
WO2010047866A2 (fr) 2008-08-01 2010-04-29 Dow Agrosciences Llc Utilisation de 5-fluorocytosine en tant que fongicide
WO2010061402A3 (fr) * 2008-11-25 2012-05-10 Vishwanath Kannan Procede ameliore de preparation de la capecitabine
CN102558262A (zh) * 2010-12-23 2012-07-11 天津泰普药品科技发展有限公司 一种高纯度卡培他滨的制备方法
CN103772453A (zh) * 2014-03-04 2014-05-07 大连大学 β-榄香烯取代乙基全乙酰化糖配合物、β-榄香烯取代乙基糖配合物、制备方法及用途
CN104926901A (zh) * 2015-06-15 2015-09-23 广安凯特医药化工有限公司 一种卡培他滨关键中间体的合成方法
CN105566419A (zh) * 2015-12-28 2016-05-11 上海金和生物技术有限公司 卡培他滨的制备方法
CN111072734A (zh) * 2019-12-11 2020-04-28 中国科学院昆明植物研究所 一种尿嘧啶核苷衍生物及该衍生物制备去氧氟尿苷药物的方法

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101469008B (zh) * 2007-12-29 2013-08-07 上海特化医药科技有限公司 卡培他滨羟基衍生物、其制备方法和用于制备卡培他滨
WO2009094847A1 (fr) * 2007-12-28 2009-08-06 Topharman Shanghai Co., Ltd. Dérivé hydroxyle de capécitabine, procédés de préparation et d' utilisation de la capécitabine
WO2009082844A1 (fr) * 2007-12-28 2009-07-09 Topharman Shanghai Co., Ltd Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine
WO2009082846A1 (fr) * 2007-12-28 2009-07-09 Topharman Shanghai Co., Ltd. Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine
EP2210895A1 (fr) * 2009-01-27 2010-07-28 F. Hoffmann-La Roche AG Procédé pour la récupération de béta-Acétylfuranoside
CN101987857A (zh) * 2009-08-07 2011-03-23 合肥华方医药科技有限公司 一种抗肿瘤药物卡培他滨及其中间体的合成方法
CN101830953A (zh) * 2010-05-26 2010-09-15 南京亚东启天药业有限公司 一种卡培他滨及其中间体的制备方法
CN101928314A (zh) * 2010-08-27 2010-12-29 广东肇庆星湖生物科技股份有限公司 一种卡培他滨的制备方法
CN102924548B (zh) * 2012-11-30 2015-05-20 安润医药科技（苏州）有限公司 卡培他滨的合成方法
CN103897005B (zh) * 2012-12-27 2017-07-28 鲁南制药集团股份有限公司 一种连续操作合成卡培他滨的方法
CN103333119A (zh) * 2013-05-28 2013-10-02 中国药科大学 1,2-二氢-6-甲基-4-取代氨基-5-嘧啶羧酸类化合物及其制备方法和用途
CN104478975A (zh) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 一种卡培他滨的合成方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008131062A2 (fr) 2007-04-20 2008-10-30 Dr. Reddy's Laboratories Ltd. Procédé pour la préparation de capécitabine
WO2009071726A1 (fr) * 2007-12-06 2009-06-11 Coll Farma S.L. Procédé de préparation de capécitabine et produits intermédiaires pouvant être utilisés dans ce procédé
WO2010047866A2 (fr) 2008-08-01 2010-04-29 Dow Agrosciences Llc Utilisation de 5-fluorocytosine en tant que fongicide
EP2647287A1 (fr) 2008-08-01 2013-10-09 Dow AgroSciences LLC Utilisation de 5-fluorocytosine et ses dérivés en tant que fongicides
WO2010061402A3 (fr) * 2008-11-25 2012-05-10 Vishwanath Kannan Procede ameliore de preparation de la capecitabine
CN102558262A (zh) * 2010-12-23 2012-07-11 天津泰普药品科技发展有限公司 一种高纯度卡培他滨的制备方法
CN103772453A (zh) * 2014-03-04 2014-05-07 大连大学 β-榄香烯取代乙基全乙酰化糖配合物、β-榄香烯取代乙基糖配合物、制备方法及用途
CN104926901A (zh) * 2015-06-15 2015-09-23 广安凯特医药化工有限公司 一种卡培他滨关键中间体的合成方法
CN104926901B (zh) * 2015-06-15 2018-04-20 广安凯特制药有限公司 一种卡培他滨关键中间体的合成方法
CN105566419A (zh) * 2015-12-28 2016-05-11 上海金和生物技术有限公司 卡培他滨的制备方法
CN111072734A (zh) * 2019-12-11 2020-04-28 中国科学院昆明植物研究所 一种尿嘧啶核苷衍生物及该衍生物制备去氧氟尿苷药物的方法
CN111072734B (zh) * 2019-12-11 2023-04-07 中国科学院昆明植物研究所 一种尿嘧啶核苷衍生物及该衍生物制备去氧氟尿苷药物的方法

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CN1660819A (zh) 2005-08-31
CN100383128C (zh) 2008-04-23
AR046077A1 (es) 2005-11-23

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