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WO2012041015A1 - Procédé d'élaboration de composé de nucléoside monophosphate acyclique convenant comme médicament antiviral - Google Patents

Procédé d'élaboration de composé de nucléoside monophosphate acyclique convenant comme médicament antiviral Download PDF

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Publication number
WO2012041015A1
WO2012041015A1 PCT/CN2011/001643 CN2011001643W WO2012041015A1 WO 2012041015 A1 WO2012041015 A1 WO 2012041015A1 CN 2011001643 W CN2011001643 W CN 2011001643W WO 2012041015 A1 WO2012041015 A1 WO 2012041015A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acyclic nucleoside
group
acid
alkane
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/CN2011/001643
Other languages
English (en)
Chinese (zh)
Inventor
李卓荣
刘宗英
易红
李艳萍
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.)
AGENIX BIOPHARMACEUTICAL (SHANGHAI) Co Ltd
Institute of Medicinal Biotechnology of CAMS and PUMC
Original Assignee
AGENIX BIOPHARMACEUTICAL (SHANGHAI) Co Ltd
Institute of Medicinal Biotechnology of CAMS and PUMC
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 AGENIX BIOPHARMACEUTICAL (SHANGHAI) Co Ltd, Institute of Medicinal Biotechnology of CAMS and PUMC filed Critical AGENIX BIOPHARMACEUTICAL (SHANGHAI) Co Ltd
Publication of WO2012041015A1 publication Critical patent/WO2012041015A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a preparation method of a non-cyclic nucleoside antiviral phosphate monoester compound, in particular to a preparation method of adefovir or tenofovir monoester compound.
  • the acyclic nucleoside compounds adefovir and tenofovir have obvious advantages in preventing viral resistance, and they are resistant to cyclic nucleosides.
  • the virus strain is effective, has a low incidence of drug resistance, and is relatively toxic, and can be used to treat patients infected with both HIV-1 and HBV.
  • the phosphate group is negatively charged, the polarity is too strong, and the biofilm permeability is poor, resulting in low bioavailability, making it impossible to be used as a medicine in clinical practice.
  • the patent (CN1810816) introduces a long-chain of a fat-soluble long-chain alkoxyethyl group on a hydroxyl group of a phosphate group in the tenofovir molecule, so that one hydroxyl group of the phosphate group in the molecular structure is esterified, and one is still in a free state.
  • Long-chain alkoxyethyl/propyl monoester derivatives of adefovir and tenofovir The introduction of a long-chain alkoxyethyl/propyl group not only improves the pharmacokinetic properties of the compound, but also allows the free hydroxyl group in the decanoic acid group to be phosphorylated and participate in the viral replication process. It exerts an antiviral effect and thus retains the antiviral activity of tenofovir. That is, the introduction of a fat-soluble long chain improves both the pharmacokinetic properties of the compound and the antiviral activity.
  • the side chain synthesis requires a two-step reaction, and the reaction of synthesizing tenofovir monoester requires stirring at 80 ° C for 6 h, and the post-treatment requires column chromatography separation, Easy to industrialize production.
  • the object of the present invention is to provide a novel preparation method of a non-cyclic nucleoside antiviral phosphate monoester compound, in particular adefovir and tenofovir monoester, which can simplify the operation steps and can Reduce production costs and be suitable for industrial production.
  • the invention provides a method for preparing a non-cyclic nucleoside antiviral phosphate monoester compound, which first prepares a fatty side chain (long-chain alkoxy-ethanol/propanol), and then with an acyclic nucleoside antiviral drug. For example, adefovir or tenofovir react to give the target compound.
  • the substituted alkane is preferably a long-chain alkane of C12-C18 substituted by bromine.
  • the glycol is preferably ethylene glycol or 1,3-propanediol.
  • the aprotic solvent is selected from the group consisting of benzene, diethyl ether, tetrahydrofuran, carbon tetrachloride, dimethyl sulfoxide, hydrazine, hydrazine-dimercaptocarboxamide, hydrazine, hydrazine-dimercaptoacetamide, acetone, acetonitrile, six
  • the mercaptophosphoramide, pyridine or pyrrole is preferably selected from the group consisting of dimercaptosulfoxide, hydrazine, fluorenyl-dimercaptoamide or tetrahydrofuran.
  • the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate, and is preferably sodium hydroxide or potassium hydroxide.
  • the acyclic nucleoside antiviral drug is Adefovir (PMEA) or Tenofovir (PMPA), both of which are commercially available.
  • the dehydrating reagent is diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD), and the molar ratio of the dehydrating reagent to the acyclic nucleoside antiviral drug is 1-5. : 1 , preferably 2-2.5: 1.
  • An embodiment of the present invention is carried out after the step 1), wherein the water is poured into the reaction liquid of the step 1), neutralized with an acid to neutrality, extracted with ethyl acetate, and then saturated with salt. After washing with water, drying, and drying the solvent, it was recrystallized to give Compound II.
  • the acid is selected from hydrochloric acid or sulfuric acid.
  • the solvent in the reaction liquid of the step 2) is evaporated under reduced pressure, and the residue is dissolved in dichlorosilane to wash the dichlorohydrazine.
  • the alkane layer is dried, dried to dryness, and recrystallized to give compound I.
  • the intermediate compound ⁇ (long-chain alkoxy-ethanol/propanol) used in the present invention is easy to prepare, Can industrialize large production;
  • the raw materials used in the invention are easy to obtain and the price is low, and the obtained adefovir and tenofovir monoester have lower cost;
  • R is CH 3 or H
  • X is halogen, ⁇ An alkanesulfonic acid group or a p-toluenesulfonic acid group.

Landscapes

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

Abstract

La présente invention concerne un procédé d'élaboration d'un composé de nucléoside monophosphate acyclique convenant comme médicament antiviral. Ce procédé consiste à prendre, comme produit de départ, un médicament antiviral à base de nucléoside acyclique tel que l'adéfovir ou le ténofovir, et à le faire réagir avec un alcoxy-éthanol ou un alcoxy-propanol à longue chaîne aliphatique de façon à obtenir le composé attendu. La présente invention, qui vient à bout des inconvénients de l'état actuel de la technique, permet, non seulement d'augmenter la qualité de l'adéfovir monophosphate ou du ténofovir monophosphate, mais aussi de réduire les coûts de production, tout en présentant les avantages d'être commode à mettre en œuvre et de se prêter facilement à la production industrielle.
PCT/CN2011/001643 2010-09-28 2011-09-28 Procédé d'élaboration de composé de nucléoside monophosphate acyclique convenant comme médicament antiviral Ceased WO2012041015A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010294901.8A CN102417521B (zh) 2010-09-28 2010-09-28 一种非环核苷类抗病毒药物磷酸单酯化合物的制备方法
CN201010294901.8 2010-09-28

Publications (1)

Publication Number Publication Date
WO2012041015A1 true WO2012041015A1 (fr) 2012-04-05

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Application Number Title Priority Date Filing Date
PCT/CN2011/001643 Ceased WO2012041015A1 (fr) 2010-09-28 2011-09-28 Procédé d'élaboration de composé de nucléoside monophosphate acyclique convenant comme médicament antiviral

Country Status (2)

Country Link
CN (1) CN102417521B (fr)
WO (1) WO2012041015A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786549B (zh) * 2012-08-13 2013-07-03 洛阳聚慧投资股份有限公司 一组具有抑制hiv-1病毒复制活性的替诺福韦双酯化合物、制备方法及其药物用途
CN103242366B (zh) * 2012-08-13 2014-08-20 洛阳聚慧投资股份有限公司 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用
CN103845345A (zh) * 2012-12-03 2014-06-11 中国人民解放军军事医学科学院毒物药物研究所 肝炎治疗药物
CN110577555A (zh) * 2018-06-08 2019-12-17 欣凯医药化工中间体（上海）有限公司 一种无定形的替诺福韦十八烷氧乙酯的制备方法及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087788A2 (fr) * 2004-03-04 2005-09-22 The Regents Of The University Of California Elaboration de phorphonates-esters nucleosidiques
CN1810816A (zh) * 2006-03-07 2006-08-02 中国医学科学院医药生物技术研究所 一组具有抑制hiv－1/hbv病毒复制活性的替诺福韦单酯化合物
WO2006110656A2 (fr) * 2005-04-08 2006-10-19 Chimerix, Inc. Composes, compositions et methodes de traitement d'infections virales et autres troubles medicaux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2533248T3 (es) * 2005-05-06 2015-04-08 Novartis Ag Inmunógenos para vacunas contra Meningitidis A

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005087788A2 (fr) * 2004-03-04 2005-09-22 The Regents Of The University Of California Elaboration de phorphonates-esters nucleosidiques
WO2006110656A2 (fr) * 2005-04-08 2006-10-19 Chimerix, Inc. Composes, compositions et methodes de traitement d'infections virales et autres troubles medicaux
CN1810816A (zh) * 2006-03-07 2006-08-02 中国医学科学院医药生物技术研究所 一组具有抑制hiv－1/hbv病毒复制活性的替诺福韦单酯化合物

Also Published As

Publication number Publication date
CN102417521A (zh) 2012-04-18
CN102417521B (zh) 2014-05-07
HK1169121A1 (en) 2013-01-18

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