EP2142539A2 - Verfahren zur herstellung von epothilonderivaten durch selektive katalytische epoxidierung - Google Patents

Verfahren zur herstellung von epothilonderivaten durch selektive katalytische epoxidierung

Info

Publication number
EP2142539A2
EP2142539A2 EP08734992A EP08734992A EP2142539A2 EP 2142539 A2 EP2142539 A2 EP 2142539A2 EP 08734992 A EP08734992 A EP 08734992A EP 08734992 A EP08734992 A EP 08734992A EP 2142539 A2 EP2142539 A2 EP 2142539A2
Authority
EP
European Patent Office
Prior art keywords
formula
solvent
pyridine
substituted
mol
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.)
Withdrawn
Application number
EP08734992A
Other languages
German (de)
English (en)
French (fr)
Inventor
Johannes Platzek
Orlin Petrov
Stephan Pruehs
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.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Schering Pharma AG
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 Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2142539A2 publication Critical patent/EP2142539A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings

Definitions

  • the invention relates to the subject matter characterized in the claims, that is to say a novel selective epoxidation process for the preparation of the epothilone derivative of the formula I.
  • the process according to the invention provides the target compound of the formula I in high chemical and diastereomeric purity, very good yields and allows the preparation on a large scale.
  • Epothilone A H
  • Epothilones are members of a class of promising antitumor agents that have been tested as potent against a range of cancer lineages.
  • An overview of the syntheses is z. B. by J. Mulzer in Monatsh. Chem. 2000, 131, 205-238. These agents have the same biological mechanism of action as paclitaxel and other taxanes (for paclitaxel see D.G.I. Scientific, Chem. Commun. 2001, 867-880).
  • a whole range of synthetically modified epothilone derivatives have been prepared, including those which carry an aromatic or a heteroaromatic grouping in the 1 position instead of the methylthiazolemethylvinyl side chains.
  • Epothilone derivatives with annulated aromatic heterocycles in the 1-position are known in the patent literature, e.g. from Schering AG, WO 00/66589 and Novartis WO 2000/037473. Since these compounds are very potent anti-tumor agents, it is of great interest to have an economical and efficient synthesis of this structural class in their hands.
  • Epoxidation of the exo-double bond leads in an immediate subsequent reaction to the below-mentioned undesired impurities (IMa + MIb).
  • impurities can be formed from the product of formula I (by overoxidation) or even from the alkene II:
  • the beta-isomer (Ia) Due to the moderate selectivity of the described epoxidation methods in addition to the target compound I, the beta-isomer (Ia) is present in the reaction mixture, from which also in analog The corresponding impurities arise. The separation of all these by-products is cumbersome and is done by a difficult, expensive and cost intensive chromatography.
  • Epothilone B a / B 10: 1
  • the present invention solves this problem and describes a novel process for the preparation of this Epothilonderivates of formula I starting from the well-known Dialken of formula II
  • MTO methyltrioxorhenium
  • substituted pyridines in particular with 4-cyanopyhdin.
  • the compound of the formula (I) is obtained from the dialken of the formula II,
  • dl (i) by reaction in an aprotic solvent, in particular a chlorinated hydrocarbon, preferably dichloromethane or mixtures thereof with low-boiling alkanes, trifluorotoluene or toluene
  • aprotic solvent in particular a chlorinated hydrocarbon, preferably dichloromethane or mixtures thereof with low-boiling alkanes, trifluorotoluene or toluene
  • Solvent in concentrations of 5 times means: 1 g of dialken in 5 ml of solvent) to 50 times (1 g of dialene in 50 ml of solvent), preferably 5-20 times, more preferably 10 times, using 6 to 36 mol% , preferably 10-25 mol%, particularly preferably 18 mol% of a substituted pyridine, preferably of an electron-poor substituted pyridine, more preferably 4-CN-pyridine, and 1-7 mol% of methyltrioxorhenium, preferably 1-5 mol%, particularly preferably 3 mol %, and
  • chlorinated hydrocarbons or mixtures thereof with low-boiling alkanes or toluene or trifluorotoluene as solvent
  • One aspect of the invention is the method described above when the preferred conditions
  • Another embodiment of the invention is the method described above, when all particularly preferred conditions are combined, and if no particularly preferred range is given, the preferred range is to be combined:
  • a particular embodiment of the invention is a process for the preparation of the compound of the formula (I),
  • the process is carried out exactly under the conditions of Example 1.
  • An embodiment of the invention is one of the methods as described above, wherein the reaction temperature is -60 0 C to -20 0 C.
  • the reaction takes place at temperatures of -55 to -35 ° C.
  • Another embodiment is the process as described in claim 1 wherein the reaction times are between 20-120 hours
  • reaction times are 40 to 80 hours.
  • the amount of methyltrioxorhenium is 1-5 mol%, the amount based on the dialkene.
  • Another embodiment is one of the methods described above, wherein the concentrations of the compound of the formula II are from 1 g in 5 ml of solvent to 1 g in 50 ml of solvent.
  • Another embodiment is one of the methods described above wherein the dialken is present in concentrations of 1 g in 5 ml of solvent to 1 g in 20 ml of solvent
  • dichloromethane instead of dichloromethane, other solvents, such as 1, 2 dichloroethane, chloroform and their mixtures with pentane, hexane, heptane, cyclohexane or other low-boiling alkanes in different ratios, and aromatic solvents (arylalkanes) such as. Toluene, trifluorotoluene can be used. Dichloromethane can also be used in mixtures with the abovementioned alkanes and arylalkanes.
  • Low-boiling alkanes are straight-chain and branched alkanes and cycloalkanes having boiling points of about 35 ° C to 100 0 C to understand.
  • the solvent is selected from the group of dichloromethane, 1, 2-dichloroethane, chloroform, and mixtures thereof with pentane, hexane, heptane, cyclohexane, toluene or trifluorotoluene, or toluene or trifluorotoluene alone
  • the solvent is selected from the group of the mixtures of dichloromethane with pentane, hexane, heptane, cyclohexane, toluene, or trifluorotoluene.
  • the solvent is selected from the group of dichloromethane and mixtures of dichloromethane with pentane, hexane, heptane, cyclohexane, toluene, or trifluorotoluene.
  • 2- or 4-substituted electron-deficient pyridine derivatives are substituted with CN, Br, Cl, F, CF 3 , SO 2 (C 1 -C 4) alkyl, SO 2 NH 2 , SO 2 N [(C 1 - C 4 ) alkyl] 2 , COOH, COO (C 1 -C 4 ) alkyl, in particular with CN, Cl, F, SO 2 CH 3 , COOH, COO (C r C 4 ) alkyl substituted pyridines used.
  • 4-substituted electron-deficient pyridine derivatives are substituted with CN, Br, Cl, F, CF 3 , SO 2 -dC 1 alkyl, SO 2 NH 2 , SO 2 N [(CrC 4 ) alkyl] 2 , COOH, COO ( Ci-C 4 ) alkyl, in particular with CN 1 Cl, F, SO 2 CH 3 , COOH, COO (C 1 -C 4 ) alkyl substituted pyridines used.
  • 2- and 4-CN-pyridine are particularly preferred.
  • C 1 -C 4 -A ⁇ yI means straight-chain or branched, for example methyl, ethyl, propyl, isopropyl.
  • the amount of substituted pyridine is 10-20 mol%, the amount being based on the dialkene.
  • aqueous hydrogen peroxide solution is used.
  • An embodiment of the invention therefore relates to a process as defined in claim 1, wherein UHP is used as epoxidizing agent.
  • the chromatographic purification can be dispensed with and the crude product can be used directly in the final crystallization.
  • another object of the invention is a method as described in claim 1, to which directly after crystallization followed by workup.
  • the rhenium content of a compound of the formula I thus prepared is 7 7 ppm (LOD * : 7 ppm) (* level of detection, method: ICP-OES). Whether amounts less than 7ppm can be detected depends on the amount of epothilone derivative provided for the measurement. The larger the amount of epothilone derivative, the sooner a content of less than 7 ppm rhenium is detectable.
  • Another aspect of the invention is also a product of the process according to the invention which still contains rhenium.
  • One aspect of the invention is the product of formula I containing more than 0.0004 ppm rhenium.
  • the final product contains> 0.0004 ppm to 7 ppm rhenium.
  • the final product contains> 0.0004 ppm to 1 ppm rhenium.
  • One aspect of the invention is the product of formula I containing rhenium in the range of 0.01 ppm to 30 ppm.
  • Another aspect of the invention is the product of formula I containing rhenium in the range of 0.1 ppm to 30 ppm.
  • the reaction product contains 1 ppm up to 30 ppm rhenium.
  • the final product contains ⁇ 7 ppm to 30 ppm rhenium.
  • the final product contains from 0.01 ppm to 7 ppm rhenium.
  • the final product contains from 0.01 ppm to 1 ppm of rhenium.
  • the new process allows the compound of formula (I) to be prepared in high diastereoselectivity and yield and purity.
  • the method is easy to handle and allows up-scaling in the multi-kg range. It has the great advantage, in addition to the methods described in the prior art, that no precious substance is lost by attacking the exo double bond. Therefore, this method is classified as a very practical and economically valuable method.
  • the following examples serve to explain the subject matter of the invention in more detail without wishing to restrict it to the following:
  • Rhenium content 7 ppm (LOD: 7 ppm)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP08734992A 2007-03-30 2008-03-27 Verfahren zur herstellung von epothilonderivaten durch selektive katalytische epoxidierung Withdrawn EP2142539A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007016046A DE102007016046A1 (de) 2007-03-30 2007-03-30 Verfahren zur Herstellung von Epothilonderivaten durch selektive katalytische Epoxidierung
PCT/EP2008/002652 WO2008119563A2 (de) 2007-03-30 2008-03-27 Verfahren zur herstellung von epothilonderivaten durch selektive katalytische epoxidierung

Publications (1)

Publication Number Publication Date
EP2142539A2 true EP2142539A2 (de) 2010-01-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP08734992A Withdrawn EP2142539A2 (de) 2007-03-30 2008-03-27 Verfahren zur herstellung von epothilonderivaten durch selektive katalytische epoxidierung

Country Status (13)

Country Link
US (2) US20080242868A1 (enExample)
EP (1) EP2142539A2 (enExample)
JP (1) JP2010523481A (enExample)
KR (1) KR20090125259A (enExample)
CN (1) CN101652362B (enExample)
AR (1) AR066692A1 (enExample)
CA (1) CA2681806A1 (enExample)
CL (1) CL2008000901A1 (enExample)
DE (1) DE102007016046A1 (enExample)
PA (1) PA8773901A1 (enExample)
TW (1) TW200902538A (enExample)
UY (1) UY30985A1 (enExample)
WO (1) WO2008119563A2 (enExample)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114539143A (zh) * 2022-01-28 2022-05-27 安徽瑞邦生物科技有限公司 一种4-氰基吡啶的纯化方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69910831T2 (de) * 1998-12-22 2004-07-15 Novartis Ag Epothilonderivate und ihre verwendung als antitumormittel
AR023792A1 (es) 1999-04-30 2002-09-04 Bayer Schering Pharma Ag Derivados 6-alquenilo- y 6-alquinilo-epotilona, los procedimientos para prepararlos y su empleo en productos farmaceuticos
EP1340498A1 (en) * 2002-03-01 2003-09-03 Schering Aktiengesellschaft Use of epothilones in the treatment of brain diseases associated with proliferative processes
GB0405898D0 (en) * 2004-03-16 2004-04-21 Novartis Ag Organic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008119563A2 *

Also Published As

Publication number Publication date
WO2008119563A2 (de) 2008-10-09
JP2010523481A (ja) 2010-07-15
WO2008119563A3 (de) 2009-02-12
CL2008000901A1 (es) 2008-10-17
UY30985A1 (es) 2008-10-31
DE102007016046A1 (de) 2008-10-23
CN101652362B (zh) 2012-10-10
US8314248B2 (en) 2012-11-20
AR066692A1 (es) 2009-09-09
US20080242868A1 (en) 2008-10-02
CA2681806A1 (en) 2008-10-09
KR20090125259A (ko) 2009-12-04
TW200902538A (en) 2009-01-16
CN101652362A (zh) 2010-02-17
US20120077984A1 (en) 2012-03-29
PA8773901A1 (es) 2008-11-19

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