WO2014059956A1 - Procédé de production de l'intermédiaire clé pour la synthèse de lapatinib - Google Patents

Procédé de production de l'intermédiaire clé pour la synthèse de lapatinib Download PDF

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Publication number
WO2014059956A1
WO2014059956A1 PCT/CZ2013/000132 CZ2013000132W WO2014059956A1 WO 2014059956 A1 WO2014059956 A1 WO 2014059956A1 CZ 2013000132 W CZ2013000132 W CZ 2013000132W WO 2014059956 A1 WO2014059956 A1 WO 2014059956A1
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WO
WIPO (PCT)
Prior art keywords
formula
mmol
boronate
cyclic
boronic acid
Prior art date
Application number
PCT/CZ2013/000132
Other languages
English (en)
Inventor
Stanislav Radl
Martin STEFKO
Josef Cerny
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2014059956A1 publication Critical patent/WO2014059956A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids

Definitions

  • lapatinib aldehyde which is frequently referred to as lapatinib aldehyde and which is used as the key intermediate in the production of lapatinib of formula II.
  • This drug belongs to the drug group called protein kinase inhibitors and has been approved for treatment of metastatic breast tumours under the name TYKERB.
  • the invention provides an improved process of producing lapatinib aldehyde of formula I
  • R 1 , R 2 , R 3 and R 4 is H, or a C1-C4 (un)branched alkyl and wherein X is either a bond, or CR 5 R 6 , wherein R 5 and R 6 is H, or a C1-C4 (un)branched alkyl.
  • the coupling is carried out at the boiling temperature of the solvent or mixture used, or at a temperature close to the boiling point, e.g., in the range of from 68°C to 78°C.
  • the amount of the respective boronic acid is often important for the course of the Suzuki coupling.
  • reactions that are sensitive to the ratio of the coupling components the fact that boronic acids are not completely stable and tend to form the corresponding dehydrated substances, including cyclic boroxines, represents a problem. Even though some of such derivatives are also able to provide products of Suzuki couplings, the exact ratio of the boron component to the halogenated component cannot be easily established.
  • One of the possibilities of ensuring an exact ratio of the boron component to the halogenated component consists in using stable cyclic boronates of the general formula VII
  • R 1 , R 2 , R 3 and R 4 is H, or a C1-C4 (un)branched alkyl and wherein X is either a bond, or CR 5 R 6 , wherein R 5 and R 6 is H, or a C1-C4 (un)branched alkyl,
  • Another aspect of this invention provides new cyclic boronates of formulae Vila, Vllb and Vile,
  • X CR 5 R 6 , wherein R 5
  • R 4 H
  • X CH 2 , which are especially suitable as stable cyclic boronates for use in the Suzuki coupling.
  • lapatinib aldehyde of formula I preferably isolated in the form of a salt with p-toluenesulfonic acid (PTSA), also in a sufficient purity for further pharmaceutical use.
  • PTSA p-toluenesulfonic acid
  • the aldehyde of formula I can be converted to lapatinib of formula II and/or its salts by commonly known methods such as, e.g., described in EP1 294 715.
  • A/,A/-diisopropylethylamine (0.13 ml, 0.73 mmol, 1.15 equiv.) and ethanol (4.8 ml) were added to a mixture of the boronic acid VI (120 mg, 0.86 mmol, 1.35 equiv.), Ill (322 mg, 0.64 mmol, 1 equiv.), 10 % Pd/C (8.8 mg, 0.008 mmol, 1.3 mol. %) and the resulting suspension was refluxed for 3 hours. After cooling to the room temperature the yellow suspension was filtered through kieselguhr and washed with methanol (4 X 3 ml).
  • Triethylamine (0.2 ml) was added to a mixture of the boronic acid VI (104 mg, 0.74 mmol, 1.5 equiv.), Ill (250 mg, 0.49 mmol) and 10 % Pd/C (13 mg, 0.012 mmol, 2.5 mol. %), DME (4 ml) and methanol (2 ml) and the resulting substance was stirred at the temperature of 50°C for 14 hours. After working, 184 mg (78%) of a yellow powdery substance was obtained containing 91% of the title compound I and 8% of the unreacted input substance III according to HPLC.
  • Acetic acid 0.5 ml, 8.44 mmol, 4 equiv.
  • A/-ethyldiisopropylamine (1.47 ml, 8.44 mmol, 4 equiv.) were added dropwise to a suspension of the aldehyde I (1 g, 2.11 mmol) and 2-(methylsulfonyl)ethaneamine hydrochloride (0.54 g, 3.37 mmol, 1.6 equiv.) in THF (10 ml) at the room temperature.
  • reaction mixture was stirred at 40°C for 1 h, cooled to 20°C, a solution of NaBH(OAc) 3 (0.9 g, 4.25 mmol, 2 equiv.) in THF (4.2 ml) was added and the resulting mixture was stirred at 20°C for 3 h. Then, a 1.25M solution of NaOH (16 ml) was added dropwise, the mixture was stirred at 20°C for 30 min, the product was extracted to ethyl acetate (3 x 8 ml), the organic layer was dried over MgS0 4 , filtered and evaporated at a reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention porte sur un procédé de production du composé de formule I, consistant à coupler le dérivé iodé de formule III avec des dérivés de l'acide boronique, le couplage étant catalysé par des catalyseurs au Pd appropriés dans un solvant, les dérivés de l'acide boronique étant des boronates cycliques représentés par la formule générale VII, dans laquelle R1, R2, R3 et R4 représentent chacun H ou un groupe alkyle en C1-C4 ramifié ou non ramifié et X représente soit une liaison soit CR5R6, R5 et R6 représentant chacun H ou un groupe alkyle en C1-C4 ramifié ou non ramifié. L'invention porte également dans d'autres aspects sur des boronates cycliques et sur l'utilisation du composé de formule I.
PCT/CZ2013/000132 2012-10-17 2013-10-17 Procédé de production de l'intermédiaire clé pour la synthèse de lapatinib WO2014059956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2012-712 2012-10-17
CZ2012-712A CZ2012712A3 (cs) 2012-10-17 2012-10-17 Nový způsob výroby klíčového intermediátu výroby lapatinibu

Publications (1)

Publication Number Publication Date
WO2014059956A1 true WO2014059956A1 (fr) 2014-04-24

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2013/000132 WO2014059956A1 (fr) 2012-10-17 2013-10-17 Procédé de production de l'intermédiaire clé pour la synthèse de lapatinib

Country Status (2)

Country Link
CZ (1) CZ2012712A3 (fr)
WO (1) WO2014059956A1 (fr)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999035146A1 (fr) 1998-01-12 1999-07-15 Glaxo Group Limited Composes heteroaromatiques bicycliques agissant comme inhibiteurs de la tyrosine kinase
WO2002002552A1 (fr) 2000-06-30 2002-01-10 Glaxo Group Limited Composes ditosylates de quinazoline
EP1403271A1 (fr) 2002-09-25 2004-03-31 Degussa AG Préparation de l'acide 5-formyl-3-furylboronique
WO2005046678A1 (fr) 2003-11-07 2005-05-26 Smithkline Beecham (Cork) Limited Methode de traitement du cancer
US20060131762A1 (en) 2002-08-31 2006-06-22 Andreas Meudt Method for metal-organic production of organic intermediate products by means of aryl lithium-bases
WO2006066267A2 (fr) 2004-12-17 2006-06-22 Smithkline Beecham (Cork) Limited Technique de traitement de cancer
DE102006050717A1 (de) 2005-10-24 2007-04-26 Chemetall Gmbh Verfahren zur Herstellung funktionalisierter Fünfringheterocyclen und deren Verwendung
EP1792902A1 (fr) 2000-06-30 2007-06-06 Glaxo Group Limited Procédés pour la préparation de 5-(6-quinazolinyl)-furane-2-carbaldéhydes
WO2008024439A2 (fr) 2006-08-22 2008-02-28 Concert Pharmaceuticals Inc. Dérivés de 4-aminoquinazoline et leurs procédés d'utilisation
WO2009042613A1 (fr) 2007-09-24 2009-04-02 Tragara Pharmaceuticals, Inc. Polythérapie pour le traitement de cancer au moyen d'inhibiteurs de la cox-2 et d'inhibiteurs doubles de l'egfr [erbb1] et de l'her-2 [erbb2]
WO2010017387A2 (fr) * 2008-08-06 2010-02-11 Teva Pharmaceutical Industries Ltd. Intermédiaires de lapatinib
WO2011039759A1 (fr) * 2009-09-29 2011-04-07 Natco Pharma Limited Nouveau procédé de préparation de lapatinib et de ses sels pharmaceutiquement acceptables

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999035146A1 (fr) 1998-01-12 1999-07-15 Glaxo Group Limited Composes heteroaromatiques bicycliques agissant comme inhibiteurs de la tyrosine kinase
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO2002002552A1 (fr) 2000-06-30 2002-01-10 Glaxo Group Limited Composes ditosylates de quinazoline
EP1294715A1 (fr) 2000-06-30 2003-03-26 Glaxo Group Limited Composes ditosylates de quinazoline
EP1792902A1 (fr) 2000-06-30 2007-06-06 Glaxo Group Limited Procédés pour la préparation de 5-(6-quinazolinyl)-furane-2-carbaldéhydes
US20060131762A1 (en) 2002-08-31 2006-06-22 Andreas Meudt Method for metal-organic production of organic intermediate products by means of aryl lithium-bases
EP1403271A1 (fr) 2002-09-25 2004-03-31 Degussa AG Préparation de l'acide 5-formyl-3-furylboronique
WO2005046678A1 (fr) 2003-11-07 2005-05-26 Smithkline Beecham (Cork) Limited Methode de traitement du cancer
WO2006066267A2 (fr) 2004-12-17 2006-06-22 Smithkline Beecham (Cork) Limited Technique de traitement de cancer
DE102006050717A1 (de) 2005-10-24 2007-04-26 Chemetall Gmbh Verfahren zur Herstellung funktionalisierter Fünfringheterocyclen und deren Verwendung
WO2008024439A2 (fr) 2006-08-22 2008-02-28 Concert Pharmaceuticals Inc. Dérivés de 4-aminoquinazoline et leurs procédés d'utilisation
WO2009042613A1 (fr) 2007-09-24 2009-04-02 Tragara Pharmaceuticals, Inc. Polythérapie pour le traitement de cancer au moyen d'inhibiteurs de la cox-2 et d'inhibiteurs doubles de l'egfr [erbb1] et de l'her-2 [erbb2]
US20110306572A1 (en) 2007-09-24 2011-12-15 Tragara Pharmaceuticals, Inc COMBINATION THERAPY FOR THE TREATMENT OF CANCER USING COX-2 INHIBITORS AND DUAL InHIBITORS OF EGFR [ErbB1] AND HER-2 [ErbB2]
WO2010017387A2 (fr) * 2008-08-06 2010-02-11 Teva Pharmaceutical Industries Ltd. Intermédiaires de lapatinib
WO2011039759A1 (fr) * 2009-09-29 2011-04-07 Natco Pharma Limited Nouveau procédé de préparation de lapatinib et de ses sels pharmaceutiquement acceptables

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