WO2013080218A1 - Nouveaux intermédiaires et procédé de préparation de lapatinib et de ses sels pharmaceutiquement acceptables - Google Patents

Nouveaux intermédiaires et procédé de préparation de lapatinib et de ses sels pharmaceutiquement acceptables Download PDF

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Publication number
WO2013080218A1
WO2013080218A1 PCT/IN2012/000753 IN2012000753W WO2013080218A1 WO 2013080218 A1 WO2013080218 A1 WO 2013080218A1 IN 2012000753 W IN2012000753 W IN 2012000753W WO 2013080218 A1 WO2013080218 A1 WO 2013080218A1
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WIPO (PCT)
Prior art keywords
formula
chloro
compound
organic solvent
furan
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PCT/IN2012/000753
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English (en)
Inventor
Saswata Lahiri
Nitin Gupta
Hemant Kumar Singh
Vishal Handa
Sunil Sanghani
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Fresenius Kabi Oncology Ltd.
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Publication date
Application filed by Fresenius Kabi Oncology Ltd. filed Critical Fresenius Kabi Oncology Ltd.
Publication of WO2013080218A1 publication Critical patent/WO2013080218A1/fr

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    • 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

Definitions

  • the present invention relates to a process for the synthesis of Lapatinib comprising novel intermediates and its pharmaceutically acceptable salts thereof.
  • the compound of the Formula-(l) reacts with 5-(l,3-dioxolan-2-yl)-2-(tributylstannyl)furan to get the compound of Formula-(2) which on deprotection with HC1, removes the 1,3- dioxolan-2-yl protecting group and liberates 5-(4- ⁇ 3-chloro-4-(3-fluoro- benzyloxy)anilino ⁇ -6- quinazolinyl)-furan-2-carbaldehyde of Formula-(3).
  • Lapatinib ditosylate has been prepared by reacting the tosylate salt of 5-(4-[3- chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde of Formula (3) with 2-(methylsulfonyl)ethylamine in the presence of base (diisopropyl- ethylamine) followed by reduction with sodium triacetoxyborohydride to obtain Lapatinib base which is converted to Lapatinib ditosylate anhydrate by adding para- toulenesulfonic acid. Conversion to Lapatinib ditosylate monohydrate is carried out using THF/H 2 0. Intercon vers ion to the anhydrate of the ditosylate salt and back to monohydrate is carried out with methanol and water respectively.
  • WO201 1039759 filed by Natco Pharma also describes a process for the preparation of Lapatinib from 2-amino benzonitrile, as given in scheme-Ill.
  • 2- aminobenzonitrile (6) is reacted with iodine monochloride in acetic acid medium to form compound of Formula (7) which is recrystallized from mixture of hexane and toluene.
  • the compound of Formula (1) is reacted with N,N-dimethylformamide dimethy
  • the compound of Formula (7) is then coupled with compound of Formula (8) in presence of acid catalyst such as trifluoroacetic acid, formic acid or acetic acid to form compound of Formula (3).
  • acid catalyst such as trifluoroacetic acid, formic acid or acetic acid
  • the compound of Formula (3) is the subjected to Suzuki coupling with 5-formyl-2-furyl boronic acid in ethereal solvent in the presence of catalyst selected from palladium (II) acetate, palladium (II) chloride, and palladium on carbon to form aldehyde compound of Formula (4).
  • the compound of Formula (4) is reacted with 2-methanesulphonyl ethylamine or its salt to produce imine compound of Formula (VI) which is reduced with sodium borohydride to form Lapatinib base (II).
  • the crude Lapatinib base is purified by crystallization from organic solvents.
  • the purified Lapatinib base is converted into Lapatinib ditosylate anhydrous by treating Lapatinib base in organic solvent with /7-toluenesulfonic acid monohydrate which is then recrystallized from aqueous alcohol to produce pharmaceutically acceptable Lapatinib ditosylate monohydrate.
  • the process is depicted in Scheme-Ill.
  • Lapatinib (II) WO2010017387 filed by Teva relates to Lapatinib intermediates and process for the preparation of Lapatinib base and Lapatinib ditosylate.
  • the application relates to highly pure intermediate of Formula (2), 3-chloro-4-(3-fluorobenzyloxy)aniline which is prepared by reducing a compound of Formula (1), 3-chloro-4-(3- fluorobenzyloxy)nitrobenzene, with iron and ammonium chloride system in the presence of a C1 -C4 alcohol and water at refluxing temperature.
  • the application also relates to highly pure intermediate of Formula (3), N-[3-chloro-4-(3-fluorobenzyloxy)- phenyl]-6-iodoquinazolin-4-amine, which is prepared in one-pot process from compound of Formula (1 ) by reduction using iron and ammonium chloride system in presence of C1 -C4 alcohol and water.
  • the compound of Formula (3) is reacted with 5- formyl-2-furanboronic acid in the presence of a palladium catalyst and a base in a polar organic solvent to obtain Lapatinib aldehyde base, compound of Formula (4).
  • Lapatinib aldehyde base is combined with /?
  • Lapatinib aldehyde base or its salt is combined with methylsulfonylethylamine or its hydrochloride salt, acetic acid, an inorganic base in an organic solvent and a reducing agent (sodium triacetoxyborohydride) to form Lapatinib base.
  • Lapatinib base is further purified by using organic solvents.
  • Lapatinib base obtained is further converted to Lapatinib ditosylate. The process is depicted in scheme-IV.
  • Palladium catalyst palladium (II) acetate, palladium (II) chloride and palladium tetrakistriphenylphosphine
  • Reducing agent alkali borohydride or alkali cyanoborohydride
  • Inorganic base alkali carbonates, alkali bicarbonates, alkali phosphates and alkali acetate
  • Reducing agent sodium rriacetoxyborohydride
  • Second aspect of the present Invention provides intermediate compound of Formula (la)
  • Third aspect of the invention provides a process for preparing a compound of Formula (la) comprising reacting 2-chloro-4-(6-iodoquinazolin-4-ylamino)-phenol (III)
  • Fifth aspect of the invention provides a process for preparing a compound of Formula (lb) comprising treating compound of Formula (la) with >-toluenesulfonic acid.
  • Seventh aspect of the invention provides a process for preparing a compound of Formula (Ic) comprising reacting compound of Formula (la)
  • Suitable base may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
  • metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate
  • metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate
  • metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri C I- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; N,N-dimethylaniline; pyridine; hydrazines and pyrrolidine.
  • the ambient temperature employed is in the range of 20-60°C and more preferably from about 45 to 50°C.
  • Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.
  • alcohols such as methanol, ethanol and isopropanol
  • nitriles such as acetonitrile
  • 5-(4-(3-chloro-4-hydroxyphenylamino)quinazolin-6-yl)furan-2-carbaldehyde of Formula (la) may be converted to its. salt (lb) by treating it with an acid.
  • acid include inorganic acids resulting in forming salts such as but not limited to hydrohalides (e.g.hydrochloride and hydrobromide), sulfate, nitrate, phosphate, diphosphate, carbonate, bicarbonate, and the like; and organic monocarboxyhc or dicarboxylic acids resulting in forming salts such as, for example, acetate, propanoate, hydroxyacetate, 2-hydroxypropanoate, 2-oxopropanoate, lactate, pyruvate, oxalate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, ethariesulfonate, benzoate, 2-hydroxybenzoate
  • a p-toluenesulfonate salt of 5-(4-(3- chloro-4-hydroxyphenylamino)quinazolin-6-yl)furan-2-carbaldehyde of Formula (la) may be prepared by using /?-toluenesulfonic acid.
  • the base used for the reaction of 5-(4-(3-chloro-4- hydroxyphenylamino)quinazolin-6-yl)furan-2-carbaldehyde of Formula (la) or Formula (lb) with 2-(Methylsulfonyl)ethanamine or its salts may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
  • metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate
  • metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate
  • metal hydroxide such as
  • the base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri CI- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; N,N-dimethylaniline; pyridine; hydrazines and pyrrolidine.
  • C1-C4 alkyl ammonia mono, di or tri CI- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; N,N-dimethylaniline; pyridine; hydrazines and pyrrolidine.
  • Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.
  • alcohols such as methanol, ethanol and isopropanol
  • nitriles such as acetonitrile
  • the base used for the reaction of 2-chloro-4-(6-(5-((2- (methylsulfonyl)ethylimino) methyl)furan-2-yl) quinazolin-4-ylamino)phenol of Formula (Ic) with 3-Fluorobenzylbromide may be selected from the group comprising of metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate; metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate and metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and magnesium hydroxide.
  • metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate and magnesium carbonate
  • metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, barium bicarbonate, calcium bicarbonate and magnesium bicarbonate
  • metal hydroxide such
  • the base may also be selected from the group comprising of C1-C4 alkyl ammonia; mono, di or tri C I- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C 1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; ⁇ , ⁇ -dimethylaniline; pyridine; hydrazines and pyrrolidine.
  • C1-C4 alkyl ammonia mono, di or tri C I- C4 alkyl amine such as triethyl amine, diisipropropyl ethyl amine; mono, di or tri hydroxy C 1-C4 alkyl amine; morpholine; thiomorpholine; piperidine; ⁇ , ⁇ -dimethylaniline; pyridine; hydrazines and pyrrolidine.
  • Organic solvent may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.
  • alcohols such as methanol, ethanol and isopropanol
  • nitriles such as acetonitrile
  • the ambient temperature employed is in the range of 20-40°C and more preferably from about 20 to 25°C.
  • the organic solvent used for the reduction of compound of Formula (VI) in presence of a sodium triacetoxy borohydride may be selected from the group comprising of water; alcohols, such as methanol, ethanol and isopropanol; nitriles, such as acetonitrile; chlorinated hydrocarbons, such as methylene chloride, ethylenedichloride; dipolar aprotic solvents, such as dimethylsulfoxide, dimethyacetamide and dimethylformamide; esters, such as ethyl acetate and isopropyl acetate; cyclic ethers, such as dioxane and tetrahydrofuran; ketone such as acetone, diisobutyl ketone, cyclohexanone, methylcyclohexanone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone or mixtures thereof.
  • alcohols such as methanol, ethanol
  • Lapatinib of Formula (II) may be converted to its Ditosylate salt (Ila) by treating it with ⁇ ?-toluenesulfonic acid.
  • the solid obtained was filtered and dried under vacuum at 65-70°C till constant weight.

Abstract

La présente invention concerne de nouveaux intermédiaires et procédés pour la synthèse du Lapatinib et de ses sels pharmaceutiquement acceptables.
PCT/IN2012/000753 2011-11-28 2012-11-19 Nouveaux intermédiaires et procédé de préparation de lapatinib et de ses sels pharmaceutiquement acceptables WO2013080218A1 (fr)

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IN3406/DEL/2011 2011-11-28
IN3406DE2011 2011-11-28

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Citations (4)

* 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
US7157466B2 (en) 2000-06-30 2007-01-02 Smithkline Beecham (Cork) Limited Quinazoline ditosylate salt compounds
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 (5)

* 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
US7157466B2 (en) 2000-06-30 2007-01-02 Smithkline Beecham (Cork) Limited Quinazoline ditosylate salt compounds
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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