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WO2008144980A1 - Procédé de préparation et intermédiaires de la capécitabine - Google Patents

Procédé de préparation et intermédiaires de la capécitabine Download PDF

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Publication number
WO2008144980A1
WO2008144980A1 PCT/CN2007/070051 CN2007070051W WO2008144980A1 WO 2008144980 A1 WO2008144980 A1 WO 2008144980A1 CN 2007070051 W CN2007070051 W CN 2007070051W WO 2008144980 A1 WO2008144980 A1 WO 2008144980A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
deoxyfluorocytidine
derivative
preparation
reaction
Prior art date
Application number
PCT/CN2007/070051
Other languages
English (en)
Chinese (zh)
Inventor
Xiangrui Jiang
Yang Ou
Jingshan Shen
Original Assignee
Topharman Shanghai Co., Ltd.
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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 Topharman Shanghai Co., Ltd., Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences filed Critical Topharman Shanghai Co., Ltd.
Priority to CN200780052717.9A priority Critical patent/CN101657462B/zh
Priority to PCT/CN2007/070051 priority patent/WO2008144980A1/fr
Publication of WO2008144980A1 publication Critical patent/WO2008144980A1/fr

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Classifications

    • 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
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical

Definitions

  • the invention relates to a process for preparing capecitabine and an intermediate thereof. Background technique
  • Capec i tabine is a prodrug of 5-fluorouracil that has a selective effect on tumor cells and can be used as an oral cytotoxic agent.
  • Capecitabine itself is not cytotoxic, but can be converted to cytotoxic 5-fluorouracil in three steps by the action of enzymes in the body. Enzymes associated with the metabolism of capecitabine are higher in tumor tissues than in normal tissues, giving them selective cytotoxicity against tumor cells. Its
  • the structure is as follows: .
  • the currently reported synthesis methods of capecitabine mainly include the following:
  • the present invention provides a novel capecitabine synthesis route for preparing capecitabine from deoxy fluorouridine.
  • the present invention provides a compound, a deoxyfluorouridine derivative, as shown in formula (I):
  • ⁇ is selected from a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom and containing 1 to 8 a linear or branched alkyl group of a carbon atom, a benzene ring or a substituted benzene ring.
  • the present invention also provides a process for preparing a deoxyfluorouridine derivative of the formula (I), which comprises a condensation reaction of deoxyfluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a formula (I).
  • Oxyfluorouridine derivatives are also provided.
  • the present invention provides a compound, a deoxyfluorocytidine derivative, as shown in formula (II):
  • ⁇ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.
  • the present invention also provides a method for preparing a deoxyfluorocytidine derivative represented by the formula (II), which is obtained by reacting a deoxyfluorouridine derivative represented by the formula (I) with phosphorus oxychloride, an organic alkali or ammonia water.
  • (II) Deoxyfluorocytidine derivative shown.
  • the present invention provides a deoxyfluorocytidine derivative, as shown by the formula (in):
  • ⁇ may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring; and R 2 may be selected from a hydrogen atom, an alkyl group, a benzene ring or a substituted benzene ring.
  • the present invention also provides a process for preparing a deoxyfluorocytidine derivative represented by the formula (in), which comprises reacting a deoxyfluorocytidine derivative represented by the formula (II) with a compound represented by the formula (IV) to obtain a formula ( III) Deoxyfluorocytidine derivative as shown.
  • the present invention also provides a process for the preparation of capecitabine which is obtained by deamination of a hydroxy protecting group under acidic conditions with a deoxyfluorocytidine derivative of the formula (in) to give capecitabine.
  • the deoxyfluorocytidine derivative represented by the formula (III) is reacted with a compound represented by the formula (IV) by a deoxyfluorocytidine derivative represented by the formula (II) to obtain a deoxyfluoride cell represented by the formula (III). Glycoside derivatives.
  • the deoxyfluorocytidine derivative represented by the formula (II) is reacted with a phosphorus fluorouridine derivative represented by the formula (I), phosphorus oxychloride, an organic alkali or ammonia water to obtain a deoxyfluoride represented by the formula (II). Cytidine derivatives.
  • deoxyfluorouridine derivative of the formula (I) is subjected to a condensation reaction of deoxy fluorouridine with an aldehyde or a ketone in the presence of an acidic catalyst to obtain a deoxyfluorouridine derivative of the formula (I).
  • the specific steps of the above method are as follows:
  • the condensation reaction of deoxy fluorouridine with different aldehydes or ketones gives the deoxyfluorouridine derivative of formula (I), and then reacts with phosphorus oxychloride, organic alkali, and ammonia to obtain formula (II).
  • the deoxyfluorocytidine derivative is acylated with an acylating reagent of the formula (IV) to obtain a deoxyfluorocytidine derivative of the formula (III), and finally the hydroxy protecting group is removed under acidic conditions. Capecitabine.
  • the condensation reaction of deoxy fluorouridine with an aldehyde or a ketone may be carried out in a mixed solvent of toluene, benzene, acetone, tetrahydrofuran, dichloromethane or dichloroethane of an acidic catalyst or any ratio thereof. get on.
  • the acidic catalyst may be selected from the group consisting of p-toluenesulfonic acid, zinc chloride, and tin chloride.
  • the reaction temperature can be varied within a wide range, generally -2 ⁇ rC - 120 ° C, preferably 80 ° C - 120 ° C, and the molar ratio of deoxy fluorouridine to aldehyde or ketone is 1: 1-1: 2.
  • the reaction of the deoxyfluorouridine derivative of the formula (I) with phosphorus oxychloride, an organic base, and aqueous ammonia can be carried out in a mixed solvent of acetonitrile or another water-miscible aprotic solvent.
  • the reaction temperature is -io°c -
  • the deoxyfluorocytidine derivative represented by the formula (II) and the acylating reagent represented by the formula (IV) can be carried out in an acetonitrile or other aprotic solvent to which a basic catalyst is added.
  • the basic catalyst can be
  • the inorganic base or organic base may be specifically selected from the group consisting of potassium carbonate, triethylamine, and pyridine.
  • the reaction temperature is -io°c-
  • the molar ratio of the deoxyfluorocytidine derivative represented by the formula (II) to the acylating reagent represented by the formula (IV) is 1:1.1-1:3, preferably 1:1.1-1:2.
  • the deprotected group of the deoxyfluorocytidine derivative represented by the formula (III) is obtained by reacting capecitabine, and can be carried out in an aqueous solution of a protic acid, or in an alcohol solution of a protic acid or an ether solution. It can also be carried out in a solution of an aprotic acid. It is preferably carried out in an alcohol solution of a protic acid.
  • the method uses the deoxy fluorouridine determined by the configuration as a raw material, and after three steps of reaction, capecitabine is obtained, and the synthetic route is short, and the formation of stereoisomers is avoided. It has been proved by experiments that the yield of the method is high, the process is easy to control, and the product quality is stable. Specific implementation method:
  • the invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention.
  • the technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
  • Example 12 6.0 g of Ila was dissolved in 40 ml of acetonitrile, 6.78 g (26.8 mmol) of nitrophenyl n-pentyl carbonate and 3.7 g (26.8 ol) of potassium carbonate were added, and the mixture was stirred at room temperature for 24 hours, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed twice with 1N EtOAc EtOAc (EtOAc)EtOAc. The step yield was 62%.
  • the capecitabine was obtained in the same manner as in Example 17 using IIIb, IIIc or Illd as the starting materials, respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le procédé de préparation ainsi que des intermédiaires de la capécitabine. La présente invention concerne une nouvelle voie de synthèse de la capécitabine, dans laquelle de la doxifluridine est utilisée en tant que produit de départ et la capécitabine est obtenue à travers trois étapes de réaction. La présente invention concerne également les intermédiaires utilisés dans ladite voie de synthèse. La voie de synthèse est courte, ce qui permet d'éviter la production de stéréoisomères. Le procédé est caractérisé par un rendement élevé, le processus technique est facile à contoler et la qualité des produits est stable.
PCT/CN2007/070051 2007-05-25 2007-05-25 Procédé de préparation et intermédiaires de la capécitabine WO2008144980A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN200780052717.9A CN101657462B (zh) 2007-05-25 2007-05-25 卡培他滨的制备方法及其中间体
PCT/CN2007/070051 WO2008144980A1 (fr) 2007-05-25 2007-05-25 Procédé de préparation et intermédiaires de la capécitabine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/070051 WO2008144980A1 (fr) 2007-05-25 2007-05-25 Procédé de préparation et intermédiaires de la capécitabine

Publications (1)

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WO2008144980A1 true WO2008144980A1 (fr) 2008-12-04

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CN (1) CN101657462B (fr)
WO (1) WO2008144980A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN101845070A (zh) * 2010-05-25 2010-09-29 郑州大学 抗肿瘤药物卡培他滨的合成方法
WO2011067588A1 (fr) 2009-12-04 2011-06-09 Generics [Uk] Limited Esters sulfinyle cycliques de cytidine
WO2011104540A1 (fr) 2010-02-24 2011-09-01 Generics [Uk] Limited Procédé en une étape pour la préparation de la capécitabine
CN103113441A (zh) * 2013-03-13 2013-05-22 上海龙翔生物医药开发有限公司 一种制备卡培他滨的方法
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
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
CN106699825A (zh) * 2016-12-01 2017-05-24 齐鲁天和惠世制药有限公司 一种以卡培他滨废水提取物制备卡培他滨的方法
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
WO2019143860A1 (fr) * 2018-01-19 2019-07-25 Nucorion Pharmaceuticals, Inc. Composés de 5-fluorouracile
US10435429B2 (en) 2017-10-03 2019-10-08 Nucorion Pharmaceuticals, Inc. 5-fluorouridine monophosphate cyclic triester compounds
EP3950673A1 (fr) 2014-04-30 2022-02-09 Inspirna, Inc. Inhibiteurs de transport de créatine et leurs utilisations
US11427550B2 (en) 2018-01-19 2022-08-30 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
US11566041B2 (en) 2020-04-21 2023-01-31 Ligand Pharmaceuticals, Inc. Nucleotide prodrug compounds
US12110311B2 (en) 2019-07-17 2024-10-08 Nucorion Pharmaceuticals, Inc. Cyclic deoxyribonucleotide compounds
US12110308B2 (en) 2018-01-10 2024-10-08 Nucorion Pharmaceuticals, Inc. Phosphor(n)amidatacetal and phosph(on)atalcetal compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114644666A (zh) * 2020-12-18 2022-06-21 上海特化医药科技有限公司 5’-核苷前药的制备方法及中间体

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US6310039B1 (en) * 1996-09-11 2001-10-30 Felix Kratz Antineoplastic conjugates of transferrin, albumin and polyethylene glycol
CN1935828A (zh) * 2006-10-31 2007-03-28 浙江海正药业股份有限公司 一种含氟嘧啶类化合物烷氧羰酰化的方法

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
WO2011067588A1 (fr) 2009-12-04 2011-06-09 Generics [Uk] Limited Esters sulfinyle cycliques de cytidine
WO2011104540A1 (fr) 2010-02-24 2011-09-01 Generics [Uk] Limited Procédé en une étape pour la préparation de la capécitabine
CN101845070A (zh) * 2010-05-25 2010-09-29 郑州大学 抗肿瘤药物卡培他滨的合成方法
CN101845070B (zh) * 2010-05-25 2012-05-16 郑州大学 抗肿瘤药物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
CN103113441A (zh) * 2013-03-13 2013-05-22 上海龙翔生物医药开发有限公司 一种制备卡培他滨的方法
EP3950673A1 (fr) 2014-04-30 2022-02-09 Inspirna, Inc. Inhibiteurs de transport de créatine et leurs utilisations
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
CN106699825A (zh) * 2016-12-01 2017-05-24 齐鲁天和惠世制药有限公司 一种以卡培他滨废水提取物制备卡培他滨的方法
US10435429B2 (en) 2017-10-03 2019-10-08 Nucorion Pharmaceuticals, Inc. 5-fluorouridine monophosphate cyclic triester compounds
US12110308B2 (en) 2018-01-10 2024-10-08 Nucorion Pharmaceuticals, Inc. Phosphor(n)amidatacetal and phosph(on)atalcetal compounds
WO2019143860A1 (fr) * 2018-01-19 2019-07-25 Nucorion Pharmaceuticals, Inc. Composés de 5-fluorouracile
US11427550B2 (en) 2018-01-19 2022-08-30 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
US12110311B2 (en) 2019-07-17 2024-10-08 Nucorion Pharmaceuticals, Inc. Cyclic deoxyribonucleotide compounds
US11566041B2 (en) 2020-04-21 2023-01-31 Ligand Pharmaceuticals, Inc. Nucleotide prodrug compounds

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Publication number Publication date
CN101657462B (zh) 2013-06-05
CN101657462A (zh) 2010-02-24

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