WO2001025236A2 - Procede stereoselectif de preparation d'endo-3-aminoazabicycloalcanes - Google Patents

Procede stereoselectif de preparation d'endo-3-aminoazabicycloalcanes Download PDF

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Publication number
WO2001025236A2
WO2001025236A2 PCT/IB2000/001360 IB0001360W WO0125236A2 WO 2001025236 A2 WO2001025236 A2 WO 2001025236A2 IB 0001360 W IB0001360 W IB 0001360W WO 0125236 A2 WO0125236 A2 WO 0125236A2
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WO
WIPO (PCT)
Prior art keywords
amount
carbon atoms
palladium
solvent
respect
Prior art date
Application number
PCT/IB2000/001360
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English (en)
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WO2001025236A3 (fr
Inventor
Marcello Allegretti
Roberto Curti
Maria Candida Cesta
Luca Nicolini
Original Assignee
Dompe' S.P.A.
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 Dompe' S.P.A. filed Critical Dompe' S.P.A.
Priority to AU73061/00A priority Critical patent/AU7306100A/en
Publication of WO2001025236A2 publication Critical patent/WO2001025236A2/fr
Publication of WO2001025236A3 publication Critical patent/WO2001025236A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Definitions

  • the object of the present invention relates to a stereoselective process for the preparation of endo-3- aminoazabicycloalkanes from azabicycloalkanones, which are intermediates used in the preparation of pharmaceutical compounds .
  • R represents hydrogen, a linear or branched alkyl having 1-6 carbon atoms, an alkyl having 1-3 carbon atoms substituted with a phenyl group, the latter optionally substituted with one or more alkyl radicals having 1-6 carbon atoms and/or with one or more alkoxy radicals having 1-6 carbon atoms and n represents 0 or an integer selected between 1 or 2, by means of reductive amination of azabicycloalkanones
  • R and n have the above-mentioned meanings, said amination being performed in a single step by adding to a hydroalcoholic solution of azabicycloalkanone (II) ammonium formate, at ambient temperature and pressure, in the presence of a suitable catalyst.
  • a suitable catalyst may be represented by a metal in an appropriate form.
  • the alkyl radicals having 1-6 carbon atoms the preferred one is the methyl radical; among the alkoxy radicals having 1-6 carbon atoms the preferred one is the methoxy radical; among the alkyl radicals having 1-3 carbon atoms which are substituted with a phenyl group the preferred one is the benzyl radical and between the integers represented by n, the integer 1 is the preferred one.
  • the endo-3-aminoazabicycloalkanes (I) represent an important element of the structure of widely used pharmaceuticals.
  • their corresponding amides are particularly interesting as receptor antagonists of 5-hydroxytryptamine (5-HT 3 ) : encompassed among them are zatosetron maleate, granisetron and BRL 46470A the syntheses of which are described in United States patents n°4,921,982 and n°4,886,808 and in European patent application n°247266.
  • An endotropylamide namely 7- azaindolylcarboxytropylamide, is an effective antitussive drug described and claimed in the United States patent n°5,750,536 in the name of the Applicant.
  • the process of the present invention for the preparation of endo- 3-aminoazabicycloalkanes (I), as well as providing high total yields and a high stereoselectivity degree has the advantage of being extremely simple and economical.
  • high temperatures or pressures are not used, and neither are reagents requiring particular operations: the desired endo-3- aminoazabicycloalkanes (I) are obtained in single reaction step by adding ammonium formate to a solution, in a hydroalcoholic solvent, of azabicycloalkanones (II), at ambient temperature and pressure and in the presence of a suitable metal acting as a catalyst for the hydrogen transfer.
  • ammonium formate employed in a molar quantity in excess in respect to the substrate to be aminated, surprisingly acts simultaneously as hydrogen transfer and also as nitrogen donor without giving rise to any formation of N-formylamine intermediate, as one would expect in reductive amination according to Leuckart.
  • Suitable catalysts for the process of the invention are those commonly used in the amination processes such as nickel, rhodium, ruthenium, palladium and platinum: platinum in the form of platinum dioxide and the palladium on charcoal are the preferred ones, also because they can easily be recycled.
  • the catalyst after separation of the catalyst by filtration from the reaction medium, it can be reactivate, without appreciable lost of activity and yield, by simply washing it with diluted mineral acids, for example with IN chloridric acid.
  • the so reactivated catalyst may be used, at least, in five consecutive productive cycles.
  • catalyst palladium on charcoal is particularly preferred.
  • Suitable alcohols to be employed in the hydroalcoholic solvent are those which are mixable with water and which contain 1-4 carbon atoms, such as, for example, methanol, ethanol and isopropanol, methanol being particularly preferred.
  • ammonium formate in a weight ratio comprised between 3:1 and 8:1, preferably in a 5:1 weight ratio, in respect to the substrate to be aminated, is added under stirring to an alcoholic solution of azabicycloalkanone (II), prepared using a solvent : solute ratio of 5-20ml:lg, preferably a ratio of 10-12ml:lg.
  • the suspension is gradually diluted with a total amount of demineralized water to represent 5-15% with respect to the amount of alcohol used as solvent (v/v) .
  • the amount of water corresponds to 10% of the total amount of alcoholic solvent.
  • the catalyst consisting of Pd/C
  • a weight ratio between palladium and substrate to be aminated of 5-15:100, preferably 8-12:100, and more preferably of about 10:100.
  • the reaction mixture is maintained under stirring at temperature and pressure ambient for a period of time varying from 8-10 hours up to 24-30 hours.
  • the catalyst is separated, the solvent is removed and from the residue, taken up with alcohol, separate the crystals of endo-3-aminoazabicycloalkane (I) by adding an excess of an aqueous solution of a mineral or organic acid.
  • Aqueous solutions of mineral acids are those of pharmaceutically acceptable mineral acids such as, sulphuric, chloridric, phosphoric and nitric acid.
  • Aqueous solutions of organic acids are those of pharmaceutically acceptable carboxylic acids which are characterized by a high solubility in alcohol such, for example, benzoic acid.
  • Rrt l
  • Rrt 1.03
  • Rrt 1.15 ⁇ -tropylamine* or endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane; ⁇ -tropylamine** or eso-3-amino-8- methyl-8-azabicyclo [3.2.1] octane; tropinone*** or 8- methyl-8-azabicyclo [3.2.1] octan-3-one.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé stéréosélectif permettant, en une seule étape, de préparer des endo-3-aminoazabicycloalcanes à partir d'azabicycloalcanones par amination réductrice.
PCT/IB2000/001360 1999-10-01 2000-09-26 Procede stereoselectif de preparation d'endo-3-aminoazabicycloalcanes WO2001025236A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU73061/00A AU7306100A (en) 1999-10-01 2000-09-26 A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI99A002048 1999-10-01
IT1999MI002048A IT1313660B1 (it) 1999-10-01 1999-10-01 Procedimento stereoselettivo per la preparazione di endo-3-amminoazabicicloalcani.

Publications (2)

Publication Number Publication Date
WO2001025236A2 true WO2001025236A2 (fr) 2001-04-12
WO2001025236A3 WO2001025236A3 (fr) 2002-01-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2000/001360 WO2001025236A2 (fr) 1999-10-01 2000-09-26 Procede stereoselectif de preparation d'endo-3-aminoazabicycloalcanes

Country Status (3)

Country Link
AU (1) AU7306100A (fr)
IT (1) IT1313660B1 (fr)
WO (1) WO2001025236A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351704B2 (en) 2004-02-18 2008-04-01 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US7396933B2 (en) 2004-11-05 2008-07-08 Theravance, Inc. Quinolinone-carboxamide compounds
US7399862B2 (en) 2004-11-05 2008-07-15 Theravance, Inc. 5-HT4 receptor agonist compounds
US7419989B2 (en) 2004-12-22 2008-09-02 Theravance, Inc. Indazole-carboxamide compounds
US7446114B2 (en) 2005-03-02 2008-11-04 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
US7671198B2 (en) 2006-02-16 2010-03-02 Theravance, Inc. Process for preparing intermediates to 5-HT4 receptor agonist compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081054A2 (fr) * 1978-12-30 1983-06-15 Beecham Group Plc Dérivés azabicyclo alkylés
US5625065A (en) * 1994-06-27 1997-04-29 Eli Lilly And Company Stereoselective process for making endo-tropanamine and like compounds
US5856489A (en) * 1994-07-23 1999-01-05 Smithkline Beecham P.L.C. Process for the production of aminoazobicycloalkanes from oximes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081054A2 (fr) * 1978-12-30 1983-06-15 Beecham Group Plc Dérivés azabicyclo alkylés
US5625065A (en) * 1994-06-27 1997-04-29 Eli Lilly And Company Stereoselective process for making endo-tropanamine and like compounds
US5856489A (en) * 1994-07-23 1999-01-05 Smithkline Beecham P.L.C. Process for the production of aminoazobicycloalkanes from oximes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A. LUKASIEWICZ: "The Mechanism of the Leuckart-Wallach Reaction and of the Reduction of Schiff Bases by Formic Acid" TETRAHEDRON , vol. 19, 1963, pages 1789-1799, XP002171306 *
MCGILL J M ET AL: "Hydride Reagents for Stereoselective Reductive Amination. An Improved Preparation of 3-Endo-Tropanamine" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 37, no. 23, 3 June 1996 (1996-06-03), pages 3977-3980, XP004029275 ISSN: 0040-4039 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7674908B2 (en) 2004-02-18 2010-03-09 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US7351704B2 (en) 2004-02-18 2008-04-01 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US8044045B2 (en) 2004-02-18 2011-10-25 Theravance, Inc. Indazole-carboxamide compounds as 5-HT4 receptor agonists
US7396933B2 (en) 2004-11-05 2008-07-08 Theravance, Inc. Quinolinone-carboxamide compounds
US7399862B2 (en) 2004-11-05 2008-07-15 Theravance, Inc. 5-HT4 receptor agonist compounds
US7498442B2 (en) 2004-11-05 2009-03-03 Theravance, Inc. Quinolinone-carboxamide compounds
US7534889B2 (en) 2004-11-05 2009-05-19 Theravance, Inc. 5-HT4 receptor agonist compounds
US7419989B2 (en) 2004-12-22 2008-09-02 Theravance, Inc. Indazole-carboxamide compounds
US7786136B2 (en) 2004-12-22 2010-08-31 Theravance, Inc. Indazole-carboxamide compounds
US8003664B2 (en) 2004-12-22 2011-08-23 Theravance, Inc. Indazole-carboxamide compounds
US7875629B2 (en) 2005-03-02 2011-01-25 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
US7446114B2 (en) 2005-03-02 2008-11-04 Theravance, Inc. Quinolinone compounds as 5-HT4 receptor agonists
US7671198B2 (en) 2006-02-16 2010-03-02 Theravance, Inc. Process for preparing intermediates to 5-HT4 receptor agonist compounds

Also Published As

Publication number Publication date
ITMI992048A0 (it) 1999-10-01
ITMI992048A1 (it) 2001-04-01
AU7306100A (en) 2001-05-10
IT1313660B1 (it) 2002-09-09
WO2001025236A3 (fr) 2002-01-17

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