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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to an improved process for the preparation of a 2- (ethoxymethyl) -tropanderivates by reacting a 2- (hydroxymethyl) - tropane derivative with ethyl bromide in the presence of a base and a phase transfer catalyst.
• 2- (ethoxymethyl) tropane derivatives are valuable pharmaceutical agents for the treatment of various central nervous disorders, such as e.g. Parkinsonism or Alzheimer's disease.
• the present invention is therefore based on the object to provide a method which makes it possible to produce 2- (ethoxymethyl) -tropanderivate in good yields on a large scale and thereby avoid the disadvantages associated with known from the prior art methods disadvantages.
• R 1 is hydrogen or C ⁇ -6 alkyl, especially methyl; and R 2 is phenyl optionally mono- or polysubstituted by halogen, trifluoromethyl or cyano, in particular 3,4-dichlorophenyl; in good yields and on an industrial scale by reacting a 2- (hydroxymethyl) -tropanderivates the
• R 1 and R 2 have the meaning given for formula (I), can be prepared with ethyl bromide in the presence of a base, a phase transfer catalyst, and optionally a diluent.
• the invention thus provides an improved process for the preparation of a 2- (ethoxymethyl) -tropanderivates of formula (I) or a pharmaceutically acceptable salt thereof, wherein a 2- (hydroxymethyl) -tropanderivate of formula (II) with ethyl bromide in the presence of Base, a phase transfer catalyst, and optionally a diluent, and then optionally treated with an acid.
• alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in particular powdered potassium hydroxide
• B using as phase transfer catalyst (PTK) a tetraalkylammonium or tetraalkylphosphonium salt, the respective alkyl groups being the same or different, for example salts of tetraoctylammonium, methyltrioctylammonium, tetramethylammonium, tetraethylammonium, tetrahexylammonium aliquot 175 (tributylmethylammonium) or aliquat 336 (methyltrioctylammonium) used.
• PTK phase transfer catalyst
• the PTK is preferably a tetraalkylammonium halide, a tetraalkylammonium sulfate, a tetraalkylammonium hydrogensulfate, a tetraalkylammonium nitrate or a tetraalkylammonium phosphate, in particular a tetraalkylammonium hydrogensulfate, very particularly preferably tetra-n-butylammonium hydrogensulfate.
• alkyl as used above and below with respect to the phase transfer catalyst comprises straight-chain and branched alkyl groups having 1 to 8, preferably 2 to 6, in particular 4, carbon atoms -., z '-propyl, ⁇ -butyl, 2-butyl, tert-butyl, n-pentyl, called, 2-pentyl, neo-pentyl, rc-hexyl and 2-Hexylgrappe very particularly preferably is the n-butyl group.
• the diluent is an aromatic hydrocarbon, preferably benzene, toluene or xylene, in particular toluene, or an optionally halogenated aliphatic hydrocarbon, preferably cyclohexane, methylcyclohexane, dichloromethane, chloroform, carbon tetrachloride or dichloroethane, especially dichloromethane or an ether, preferably tetrahydrofuran (THF ), Diethyl ether, diisopropyl ether, tert-butyl methyl ether (TBME) or 1,2-dimethoxyethane (DME), especially 1,2-dimethoxyethane;
• THF tetrahydrofuran
• DME 1,2-dimethoxyethane
• the resulting acid addition salts are, for example, hydrochlorides, hydrobromides, phosphates, nitrates, perchlorates, sulphates, citrates, lactates, tartrates, maleates, fumarates, mandelates, benzoates, ascorbates, cinnamates, benzenesulphonates, methanesulphonates, stearates, succinates, glutamates, glycollates, Toluene-p-sulphonates, formats, malonates, naphthalenes-2-sulphonates, salicylates and acetates. Particularly preferred are the citrates.
• Such salts are prepared according to well-known methods of preparation.
• ethyl bromide optionally dissolved in 1,2-dimethoxyethane
• 30 to 25 300 preferably stirred for about 45 to 180 minutes at a temperature between 40 and 80 ° C.

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• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2004
  • 2004-01-31 DE DE102004004965A patent/DE102004004965B4/de not_active Expired - Fee Related
• 2005
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  • 2005-01-20 JP JP2006550028A patent/JP2007519660A/ja active Pending
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