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WO2009082846A1 - Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine - Google Patents

Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine Download PDF

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Publication number
WO2009082846A1
WO2009082846A1 PCT/CN2007/003873 CN2007003873W WO2009082846A1 WO 2009082846 A1 WO2009082846 A1 WO 2009082846A1 CN 2007003873 W CN2007003873 W CN 2007003873W WO 2009082846 A1 WO2009082846 A1 WO 2009082846A1
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WO
WIPO (PCT)
Prior art keywords
deoxy
fluoro
capecitabine
derivative
formula
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2007/003873
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English (en)
Chinese (zh)
Inventor
Jingshan Shen
Xiangrui Jiang
Weiming Chen
Xiujun He
Yang Ou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Topharman Shanghai Co Ltd
Original Assignee
Topharman Shanghai 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 Topharman Shanghai Co Ltd filed Critical Topharman Shanghai Co Ltd
Priority to PCT/CN2007/003873 priority Critical patent/WO2009082846A1/fr
Priority to PCT/CN2008/002123 priority patent/WO2009094847A1/fr
Publication of WO2009082846A1 publication Critical patent/WO2009082846A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicinal chemistry, and more particularly to a capecitabine hydroxy derivative, a process for its preparation and an intermediate in the preparation process, and to a capecitabine hydroxy derivative for the preparation of capecita The use of the coast. Background technique
  • Capecitabine 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.
  • the enzyme associated with capecitabine is higher in tumor tissues than in normal tissues, giving it selective cytotoxicity against tumor cells. Its structural formula is as follows:
  • the currently reported synthesis methods of capecitabine mainly include the following:
  • the last step uses a method of deprotecting the hydroxyl group under strong basic conditions, and this strong alkaline condition causes the occurrence of side reactions, thereby causing Poor controllability of the process, low purity of the crude product and not easy to purify.
  • the present inventors focused on the synthesis of capecitabine, and designed and synthesized a capecitabine hydroxy derivative represented by Formula III during the research process, which provides a suitable protecting group and can be weaker. It is removed by hydrolysis under acidic or basic conditions to obtain capecitabine.
  • the process of this step is highly controllable, the purity of the crude product is high, and no cumbersome purification treatment is required, and the obtained capecitabine can reach the standards of the United States Pharmacopoeia.
  • a capecitabine hydroxyl derivative of the formula III Another object of the present invention is to provide a process for preparing a capecitabine hydroxyl derivative; a further object of the present invention is to provide a use of a capecitabine hydroxyl derivative for the preparation of capecitabine;
  • Still another object of the present invention is to provide two intermediates for preparing a capecitabine hydroxyl derivative, and a process for preparing the intermediate.
  • the present invention provides a capecitabine hydroxy derivative represented by the following formula III:
  • hydrocarbon group having 1 to 4 carbon atoms is selected.
  • Ri is an alkyl group having 1 to 4 carbon atoms, and the alkyl group may be a linear or branched alkyl group, for example, a decyl group, an ethyl group, a propyl group or a butyl group.
  • Base is an alkyl group having 1 to 4 carbon atoms, and the alkyl group may be a linear or branched alkyl group, for example, a decyl group, an ethyl group, a propyl group or a butyl group.
  • the capecitabine hydroxyl derivative of the formula III of the present invention can be produced as follows: Method 1:
  • 5'-deoxy-5-fluoro-uridine is condensed with ortho phthalate HC (OR0 3 to give a 5'-deoxy-5-fluoro-uridine derivative of formula I, Wherein the definition is the same as defined in the above compound of formula III; Then, in an aprotic solvent, the 5'-deoxy-5-fluoro-uridine derivative of the formula I is subjected to two substitution reactions with phosphorus oxychloride, an organic base and aqueous ammonia to obtain 5'- of the general formula II.
  • Deoxy-5-fluoro-cytidine derivative
  • the acylation reagent of IV R ⁇ o" ⁇ is subjected to an acylation reaction to obtain a capecitabine hydroxy derivative of the formula III, wherein R is a leaving group, which is a halogen, a nitrophenoxy group or a butyl group. Diimideoxy.
  • 5'-deoxy-5-fluoro-cytidine is reacted with orthoformate HC (OR0 3 in the presence of an acidic catalyst to give a 5'-deoxy-5-fluoro-cytidine derivative of the general formula II, Wherein the definition is the same as defined in the above compound of formula III;
  • a pecitabine hydroxy derivative of the formula III is obtained wherein R is a leaving group and is a halogen, nitrophenoxy or succinimideoxy group.
  • the condensation reaction of 5'-deoxy-5-fluoro-uridine with orthoformate HC OR ⁇ can be carried out in an aprotic solvent such as toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane. It is also possible to carry out the above two or more mixed solvents; the acidic catalyst, for example, p-benzoic acid, zinc chloride, tin chloride or boron trifluoride; the reaction temperature can be varied within a wide range, generally -20. C ⁇ 120. C, preferably -20. C ⁇ 80.
  • the molar ratio of C; 5'-deoxy-5-fluoro-uridine to orthoformate ⁇ ) 3 is from 1:1 to 1:10, and preferably from 1:1 to 1:3.
  • the two-substitution reaction of the 5'-deoxy-5-fluoro-uridine derivative of the formula I with phosphorus oxychloride, an organic base and aqueous ammonia can be carried out in one or more aprotic solvents, A non-substance such as acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dihydrazinamide or a mixture thereof; the reaction temperature is -10. C ⁇ 30 °C, preferably -5.020.
  • the acylation reaction of the acylating reagent, wherein the acylating reagent of the formula IV is preferably the following three:
  • the acylation reaction can be carried out in one or more aprotic solvents such as dichlorosilane, acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dimethyl hydrazide or mixtures thereof;
  • aprotic solvents such as dichlorosilane, acetonitrile, tetrahydrofuran, acetone, hydrazine, hydrazine-dimethyl hydrazide or mixtures thereof;
  • the reaction is usually carried out in the presence of a basic catalyst such as an inorganic base such as potassium carbonate, triethylamine or pyridine or a compound; the reaction temperature is -10. C ⁇ 50 °C, preferably at 0.
  • the molar ratio of the 5'-deoxy-5-fluoro-cytidine derivative of the general formula II to the acylating reagent of the formula IV is 1:1 to 1:3, preferably 1: U ⁇ 1 :2.
  • 5'-deoxy-5-fluoro-cytidine and orthoformate HC OR0 3 condensation reaction can be carried out in aprotic solvents such as toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane
  • aprotic solvents such as toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane
  • the acidic catalyst for example, p-toluenesulfonic acid, zinc chloride, tin chloride or boron trifluoride
  • the reaction temperature may be Change in a larger range, generally -20 ° C ⁇ 120 ° C, preferably -20 ° C ⁇ 80 ° C
  • 5 '-deoxy-5-fluoro-cytidine and orthophthalate HC OR ⁇ molar ratio 1:1 ⁇ 1:10, excellent 1:1
  • the same acylation step in the first method is followed.
  • the capecitabine hydroxy steroid of the general formula III is obtained.
  • the capecitabine hydroxy derivative of the formula III provided by the present invention can be used for the preparation of capecitabine, that is, the capecitabine hydroxy steroid of the formula III is deprotected by a hydrolysis reaction to obtain capecitabine.
  • the hydrolysis reaction can be carried out in a protic solvent (for example: methanol, ethanol, propanol), an aprotic solvent (for example: tetrahydrofuran, acetonitrile, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, acetone) or water. It is also possible to carry out in the above two or more mixed solvents.
  • a protic solvent for example: methanol, ethanol, propanol
  • an aprotic solvent for example: tetrahydrofuran, acetonitrile, dimethyl sulfoxide, hydrazine, hydrazine-dimethylformamide, acetone
  • the reaction is usually carried out in the presence of an acidic catalyst (for example, hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, etc.) (control pH value is 1 to 6)
  • an alkaline reagent for example, sodium hydrogencarbonate, sodium carbonate, carbonic acid
  • Potassium, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc. adjust the pH value to 7 to 11 to promote the reaction to completion.
  • the reaction condition is mild, the operation is easy, the yield is high, the quality of the obtained crude product is stable, and the purity is obtained. high.
  • the reaction conditions required for the preparation of capecitabine in the compound III deprotection group are mild, and the controllability of the reaction process is high, and the obtained crude product purity meets the requirements of the United States Pharmacopoeia, and can be industrially scaled up.
  • capecitabine was obtained in a two-step yield of 69%.

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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)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un dérivé hydroxyle de la capécitabine comme représenté par la structure suivante, sur ses procédés de préparation et sur des intermédiaires dans les procédés et sur l'utilisation de l'hydrolyse dudit dérivé hydroxyle de la capécitabine pour obtenir la capécitabine. Le dérivé hydroxyle de la capécitabine fournit le groupe protecteur correct qui peut être retiré par hydrolyse pour obtenir la capécitabine dans des conditions acides ou basiques plus faibles. Le procédé de l'étape de réaction est bien contrôlé, la pureté du produit brut est élevée et la capécitabine résultante satisfait à la norme de la pharmacopée américaine sans purification compliquée.
PCT/CN2007/003873 2007-12-28 2007-12-28 Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine Ceased WO2009082846A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2007/003873 WO2009082846A1 (fr) 2007-12-28 2007-12-28 Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine
PCT/CN2008/002123 WO2009094847A1 (fr) 2007-12-28 2008-12-29 Dérivé hydroxyle de capécitabine, procédés de préparation et d' utilisation de la capécitabine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2007/003873 WO2009082846A1 (fr) 2007-12-28 2007-12-28 Dérivé hydroxyle de la capécitabine, ses procédés de préparation et ses utilisations pour préparer la capécitabine

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WO2009082846A1 true WO2009082846A1 (fr) 2009-07-09

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
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
US12110308B2 (en) 2018-01-10 2024-10-08 Nucorion Pharmaceuticals, Inc. Phosphor(n)amidatacetal and phosph(on)atalcetal compounds
US12110311B2 (en) 2019-07-17 2024-10-08 Nucorion Pharmaceuticals, Inc. Cyclic deoxyribonucleotide compounds

Citations (4)

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CN1126726A (zh) * 1994-08-26 1996-07-17 霍夫曼-拉罗奇有限公司 又一种制备n4-酰基-5′-脱氧-5-氟胞苷衍生物的方法
CN1201037A (zh) * 1997-06-02 1998-12-09 霍夫曼-拉罗奇有限公司 5’－脱氧胞苷衍生物
CN1660819A (zh) * 2004-02-23 2005-08-31 上海迪赛诺医药发展有限公司 N4－氧羰基胞嘧啶衍生物及制备方法与应用
CN1896089A (zh) * 2005-07-15 2007-01-17 上海奥锐特国际贸易有限公司 合成n4－酰基－5＇－脱氧－5－氟胞苷衍生物的方法

Patent Citations (4)

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CN1126726A (zh) * 1994-08-26 1996-07-17 霍夫曼-拉罗奇有限公司 又一种制备n4-酰基-5′-脱氧-5-氟胞苷衍生物的方法
CN1201037A (zh) * 1997-06-02 1998-12-09 霍夫曼-拉罗奇有限公司 5’－脱氧胞苷衍生物
CN1660819A (zh) * 2004-02-23 2005-08-31 上海迪赛诺医药发展有限公司 N4－氧羰基胞嘧啶衍生物及制备方法与应用
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Title
YU J. ET AL.: "Improved Synthesis of Anticancer Drug Capecitabine.", CHINESE JOURNAL OF MEDICINAL CHEMISTRY, vol. 15, no. 3, June 2005 (2005-06-01), pages 173 - 176, XP008156583 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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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