Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
  • C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
  • C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings

Definitions

• the invention relates to a method of producing Cinacalcet of formula I, chemically N-[(1R)-1- (naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propane-l -amine, and its pharmaceutically acceptable salts, for instance hydrochloride.
• Cinacalcet in the form of its hydrochloride is being sold under the trademark Mimpara. It has been approved for therapy of secondary hyperparathyreosis in dialysed patients with kidney disease and also in therapy of hypercalcemia in patients with parathyroid cancer.
• US patent 6,011 ,068 discloses a group of arylalkylamines, in which Cinacalcet and generally its pharmaceutically acceptable salts are also included.
• US patent 6,21 1 ,244 specifically describes Cinacalcet.
• This patent also shows possible synthesis of substances with structure analogous to that of Cinacalcet using reductive amination consisting in coupling the respective aromatic aldehyde or ketone with a suitable arylamine, followed by reduction with a hydride agent.
• the amine can also be coupled with a nitrile in presence of diisobutyl aluminium hydride, which leads to preparation of the respective imine, which is again reduced. This process is described in US patent 5,504,253.
• Cinacalcet described in Drugs of the Future 2002, 27(9), 831-836, comprises reaction of (R)-(l -naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]- propionaldehyde in the presence of titanium tetraisopropoxide to form the respective imine, which is finally reduced by cyanoborohydride in ethanol (see Scheme 1).
• Patent application WO 2008/035212 discloses an alternative procedure of preparing 3-[3-(trifluoromethyl)phenyl]propionaldehyde by oxidation of the respective alcohol with the radical agent TEMPO.
• Cinacalcet Another possibility of preparing Cinacalcet mentioned in US patent 7,250,533 consists in conversion of the alcoholic group of 3-[3-(trifluoromethyl)phenyl]propanol to a well leaving group and subsequent N-alkylation of (R)-(l-naphthyl)ethylamine, as depicted in the following Scheme 2.
• Scheme 3 :
• This invention provides a new efficient procedure of producing Cinacalcet of formula I
• This invention provides a new efficient procedure of producing Cinacalcet of formula I
• catalysts based on a transition metal such as, for instance, Fe, Cu, Au, Pd, Ru, Rh, Re, Ir.
• the catalyst is used in an amount of 0.4 to 5 mol % based on the starting substance.
• the alkylation is performed in an inert organic solvent, such as, for instance, aromatic hydrocarbons, in particular toluene.
• the reaction is carried out in the temperature interval of 80 to 130 °C, preferably at temperatures of 100 to 1 10 °C.
• the respective salt is prepared without isolating the base.
• the Cinacalcet salt is prepared, which directly crystallizes from the reaction mixture or a suitable co-solvent is added before the crystallization.
• the alkylation is carried out in toluene in the presence of a catalyst, which is [dichloro(pentamethylcyclopentadienyl)iridium(III) dimer], at temperature of 100 to 1 10°C.
• a catalyst which is [dichloro(pentamethylcyclopentadienyl)iridium(III) dimer]
• the reaction mixture is then diluted with a co-solvent, which is ethyl acetate, and hydrogen chloride in an organic solvent, for instance in ether, is added to the reaction mixture.
• the respective hydrochloride is isolated from the reaction mixture in the yield of 75 % and HPLC purity higher than 99.5 %. If necessary, the product can be crystallized, for instance from ethyl acetate.
• the new method of producing Cinacalcet and its salts is a one-step one; unlike in the prior procedures, the alkylation does not require conversion of the poorly reactive hydroxyl group to another better leaving group and allows obtaining Cinacalcet and its salts in a high yield and in a purity suitable for pharmaceutical use.

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Publications (1)

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• 2011
  • 2011-11-25 CZ CZ20110770A patent/CZ2011770A3/cs not_active IP Right Cessation
• 2012
  • 2012-11-21 CN CN201280057515.4A patent/CN103958456B/zh active Active
  • 2012-11-21 WO PCT/CZ2012/000119 patent/WO2013075679A1/en active Application Filing
  • 2012-11-21 IN IN1319KON2014 patent/IN2014KN01319A/en unknown
  • 2012-11-21 HU HU1400341A patent/HUP1400341A3/hu unknown
  • 2012-11-21 BR BR112014012434A patent/BR112014012434A2/pt not_active IP Right Cessation
• 2014
  • 2014-05-18 IL IL232678A patent/IL232678A/en active IP Right Grant

Patent Citations (7)

Non-Patent Citations (4)

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