WO2011048612A2 - Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant - Google Patents

Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant Download PDF

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WO2011048612A2
WO2011048612A2 PCT/IN2010/000671 IN2010000671W WO2011048612A2 WO 2011048612 A2 WO2011048612 A2 WO 2011048612A2 IN 2010000671 W IN2010000671 W IN 2010000671W WO 2011048612 A2 WO2011048612 A2 WO 2011048612A2
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formula
rasagiline
pharmaceutically acceptable
processes
acceptable salt
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PCT/IN2010/000671
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WO2011048612A3 (fr
Inventor
Amit Anant Thanedar
Shekhar Ashok Deshmukh
Sunil Sudhakar Zope
Laxmikant Madhukar Kelkar
Joseph Prabahar Koilpillai
Jitendra Maganbhai Gajera
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Glenmark Generics Limited
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Publication of WO2011048612A2 publication Critical patent/WO2011048612A2/fr
Publication of WO2011048612A3 publication Critical patent/WO2011048612A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present inveni ion relates to processes for the preparation of propargylated aminoindans, compounds of formula I or their pharmaceutically acceptable salts and pharmaceutical compositions thereof.
  • Rasagiline mesyl ate i s an irreversible inhibitor of monoamine oxidase approved for the treatment of idiopathic Parkinson ' s disease.
  • Rasagiline mesylate is chemically described as 5-N-propargyl - ! -( R) aminoindan mesylate and is represented by the structural formula
  • United States Patent No. 5,532,415 (the '41 5 patent) describes optically pure rasagiline and its pharmaceutically acceptable salts thereof.
  • the ' 41 5 patent discloses the preparation of optical ly pure rasagiline by reacting optically pure 1 -aminoindan with propargyl bromide or chloride or propargyl sulfonate ester in the presence of a base and optionally in the presence of a solvent.
  • the ' 41 5 patent also discloses that enantiomerically pure aminoindan deri vat ives can be prepared by the optical resolution of racemic mixtures using any conventional resolution method, like preparative chromatography on a chiral column.
  • United States Patent No. 7,375,249 describes a process for the preparation of optically pure propargyl aminoindans by using optically active ligands and catalysts.
  • the WO ' 055 publication discloses methods for the preparation of indanylamine and aminotetralin deri vatives using, for example, 3-amino-indan-5-ol or 6-methoxy-indan- l - ylamine, as starting materials, including the starting materials for the compounds thereof.
  • some of the said methods produce low yields of the target compounds, due to the formation of signi ficant amount of undesirable by-products, like bisalkylated aminoindans and remai ning of unreacted starting materials as residue which needs additional steps for recovery and purification methods.
  • the present invention provides robust, reproducible, cost effective processes for preparation of propargy lated aminoindans, like rasagiline.
  • the present invention relates to processes for the preparation of propargylated aminoindans or pharmaceutically acceptable salts thereof.
  • the present invention relates to a process for the preparation of a compound of formula I
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, obtained by the processes herein described, having bisalkylated aminoindan or its enantiomer of structural formula
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, obtained by the processes herein described, having bisalkylated aminoindan or its enantiomer of structural formula XII and 1 -indanol of structural formula XIII, in an amount not more than about 0. 1 area %, as measured by HPLC.
  • the present invention relates to pharmaceutical compositions comprising propargylated aminoindans or their pharmaceutically acceptable salts thereof of formula I, obtained by t he processes of present invention, and at least one pharmaceutically acceptable carrier.
  • Fig. 1 is a Particle size di stribution histogram according to Example 4
  • Fig 2 is an X-ray powder diffractogram of rasagiline mesylate according to Example 4.
  • the present invention relates to processes for the preparation of propargylated aminoindans and pharmaceutically acceptable salts thereof.
  • the present invention relates to a process for the preparation of a compound of formula 1
  • Lewis acid i an eleclrophilic compound, that can accept a pair of electrons from an electron-pair donor, form i ng an adduct by the formation of a coordinate covalent bond.
  • Lewis acid include, but are not limited to: Ti-(IV)isopropoxide. aluminium isopropoxide.
  • Triisopropylsilyl trifluoromethanesulfonate (CFiSChSiiCFhb), Ytterbium trilluoromethanesulfonate (Yb(CF3S03)3) and Stannic chloride (SnCl 4 ) trimethylaluminum or triethylaluminum in toluene, Scandium triflate (SctOTfbX Lanthanide trifluoromethanesullonates (La(OTf)3), Europium triflate (Eu(OTf)3), Copper(II) triflate (Cu(OTf) 2 ), Zinc tri flate ( Zn(OTf) 2 ) Titanium(lII) chloride-aluminum chloride (AlCl 12 Ti 3 ), Titanium(IV)chloride.
  • Tilanium(IV)chloride tetrahydrofuran complex Tin(IV) chloride (SnCl 4 ), Tin(l V) chlori de pentahydrate (Cl 4 Sn ⁇ 5H 2 0 ), Boron trichloride methyl sulfide complex, Boron tri fl uoride acetic acid complex, Boron trifluoride phenol complex, Boron trifluoride phosphoric acid complex, Dicyclohexylboron trifluoromethanesulfonate, Iron(III) bromide, Iron(II l) chl oride hexahydrate.
  • Aluminum bromide Aluminum chloride THF complex, Monlmon l lonile (Al uminum Pi llared Clay).
  • the Lewis acid is Ti-(IV) isopropoxide.
  • the reaction can be carried out in any suitable solvent or combination of solvents, for example, alcohols, such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and the like; halogenaled solvents such as dichloromethane, ethylene dichloride, chloroform and the like; hydrocarbons such as toluene, cyclohexane and the like; esters, such as ethyl acetate, n-propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers, such as tetrahydrofuran.
  • solvents for example, alcohols, such as methanol, ethanol, isopropyl alcohol, tertiary butyl alcohol and the like; halogenaled solvents such as dichloromethane, ethylene dichloride, chloroform and the like; hydrocarbons such as toluene, cyclohexane and the like; est
  • aprotic polar solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like and mixtures thereof.
  • the solvent is ethanol or methanol.
  • the reaction can be carried out at any suitable temperature that allows for facile formation of Lewis acid complex, represented by a compound of formula IV.
  • reaction is carried out at temperatures from at least about 25°C to at least about 35°C, more pre ferably from about at least 25°C to about at least 30°C.
  • the molar equivalents of Lewis acids used based on the weight of the indanone compound of formula 11 is from about 1 : 1 to about 5 : 1 . Preferably the ratio is 1 .2 : 1 .
  • the molar equiv alents of propargyl amine compound of formula III used based on the weight of the indanone compound of formula II is from about 0.5 : 1 to about 2 : 1. Preferably the ratio is 1 : 1 .
  • alkyl includes linear alkyls, branched alkyls, and cycloalkyls. Additionally, the alkyls may be substituted with alkoxy, halo, and like substitutents.
  • alkyl is a C 1 -4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl , iso-butyl , sec-butyl, tert-butyl; cycloalkyl such as cyclopropyl, cyclobutyl, and the like.
  • M represents its mclal moiety and R4 represents the residue of a Lewis acid, b) subjecting the resul tant reaction mixture to reduction.
  • the present invention presents a complex of formula IV, whereupon subjecting thereto said complex to reduction in the presence of an optically inactive reducing agent to form the com und of formula V,
  • R is as defi ned above for formula I.
  • the optical ly inactive reducing agent that can be used is selected from the group consisting of metal hydrides like sodium borohydride, aluminium hydride, lithium aluminium hydride, sodium cvanoborohydride or mixtures thereof.
  • the optically inactive reducing agent is sodium borohydride.
  • the solvent that can be used include, but are not limited to alcohols, such as methanol, ethanol , isopropyi alcohol, tertiary butyl alcohol and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform and the like; hydrocarbons, such as tol uene, cyclohexane and the like; esters, such as ethyl acetate, n- propyl acetate, isopropyi acetate, tertiary butyl acetate and the like; ethers, such as tetrahydrofuran.
  • alcohols such as methanol, ethanol , isopropyi alcohol, tertiary butyl alcohol and the like
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like
  • hydrocarbons such as tol uene, cyclohexane and the like
  • esters such as e
  • the sol vent is methanol or ethanol.
  • the chiral resolving agent is selected from the group consisting of ⁇ S-(+) mandelic acid, R-(-) mandelic acid, L-(-r)tartaric acid, D-(-)tartaric acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyi-L-tartaric acid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (-t-)-Dipara-toluoyl-D-tartaric acid, (+)-Dipara-toluoyl-D-tartaric acid monohydrate.
  • the chiral acid used is L-(+) tartaric acid.
  • the reactions are carried out at temperatures from about at least 25°C to about at least 100°C. Preferably: from about 80°C to about 85°C.
  • the time period for the reaction to complete can range from about at least 30 minutes to about at least 5 hours. Preferably, from about at least 30 minutes to about at least 1 hour.
  • the reactions can be carried out in the presence or absence of base and solvents.
  • the present invention presents a process for the preparation of propargylated aminoindans of form a I com rising reducti of complex of formula IV
  • optical ly active reducing agents that can be used include, but are not limited to L- selectride, 2,2'-dihydroxy- l .1 '-binaphthyl-lithium aluminum hydride (BINAL-H),
  • DIBAL Diisobutylaluminium hydride
  • (+)-B-Chlorodiiso-2-ethylapopinocampheylborane (+)-B-Fluorodiiso-2-elhylapopinocampheylborane
  • (+)-B-Bromodiiso-2-ethylapopino- campheyl-borane bis( 10-mcthylisopinocampheyl)chloroborane and the like or mixtures thereof.
  • the chiral ligands that can be used is selected from the group consisting of [(R) HexaPHEMP RuCl 2 (R,R )-DACH], [(R)-HexaPHEMP RuCl 2 (R.R)-DPEN], [(R)-PhanePhos RuCl 2 (S.S)-DACH], [(S)- PhancPhos RuCl; (R.R)-DPEN], [(S)-MeO-Xylyl-PhanePhos RuCl 2 (R.R)-DPEN], [(R)-MeO-Xyl- I-PhanePhos RuCl 2 (S.S)-DACH], [(S)-SynPhos RuCl 2 (S,S)- DPEN], [(S)-Xy lyl-BI NAP RuCl 2 (S,S)-DPEN], [(S)-F-Phenyl-PhanePhos RuCl 2 (R,R
  • An optical ly active reducing agent or chiral ligand is used to attain enantiomeric selectivity and to afford the desired enantiomer in higher yield and purity.
  • uivalcnts of optically active reducing agents or chiral ligand relative to the weight of the complex of formula IV taken is from about 1 : 1 to about 5 : 1 .
  • the ratio is 2: 1 .
  • the solvents' that can be used include, but are not limited to alcohols, such as methanol, ethanol . i sopropyl alcohol, tertiary butyl alcohol and the like; halogenated solvents, such as dichloromethane, ethylene dichloride, chloroform and the like: hydrocarbons , such as tol uene, cyclohexane and the like; esters, such as ethyl acetate, n- propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers, such as tetrahydrofuran. l ,4-dio ⁇ ane.
  • alcohols such as methanol, ethanol . i sopropyl alcohol, tertiary butyl alcohol and the like
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like: hydrocarbons , such as tol uene
  • diisopropyl ether and the like aprotic polar solvents, such as dimethyl formamkie, di methyl sulfoxide, dimethyl acetamide and the like and mixtures thereof.
  • aprotic polar solvents such as dimethyl formamkie, di methyl sulfoxide, dimethyl acetamide and the like and mixtures thereof.
  • methanol or ethanol aprotic polar solvent
  • ethanol ethanol
  • the reactions are carried out at temperatures from about -25°C to about 35°C. Preferably, from about 25°C to about 30°C.
  • the time period for tine reaction to complete can range from about 30 minutes to about 5 hours. Preferably from about 30 minutes to 1 hour.
  • optical ly pure is intended to mean optical purity over about 90%, preferably over 95%, and more preferably over 99%. expressed as the percent enantiomeric excess.
  • solvent and “resolution”, as used herein, are intended to encompass the complete or partial separation of the two optical enantiomers.
  • the compounds of formula (II) and (III) may be prepared by processes known in the an. Suitably, one or more sequential steps are carried out. without isolating intermediate compounds.
  • i he present invention provides propargylated aminoindans of interest are rasagiline represented by the formula VIII, the process for preparing is depicted in the scheme below.
  • the present invention provides ladostigil represented by formula IX or a pharmaceutical l y acceptable salt thereof.
  • the R-isomer of formula VIII is commonly known as rasagihne, which is herein rasagih ne or R -i asagiline.
  • the present invention provides the mother liquor obtained in resolution of compound of formula V to compound of formula I, for example, or the mother liquor from recrystallizations. when optionally carried out, are rich with (S)-rasagiline; whereupon said ( S)-rasagiline present in one or more of these liquors, or the pooled liquors, may be converted into racemic rasagi hne for reuse in a process according to the present invention substantially as herein before described.
  • one or more mother liquors obtained from a process as described above, or from a pooled mother l iquors may be treated with a base to remove any residual chiral acid and to thereby afford the free base enriched in (S)-rasagiline.
  • the free base can then be converted to the racemate. typically by reflux in a suitable solvent for several hours, optionally in the presence of a suitable acid, as for example in hydrochloric acid (HC1) or a base, as for example, sod ium hydroxide (NaOH), and the resultant racemate can then be recycled for use in a process according to the present invention substantially as herein before described.
  • a suitable acid as for example in hydrochloric acid (HC1)
  • a base as for example, sod ium hydroxide (NaOH
  • the processes known for the synthesis of propargylated aminoindans typically involve chromatographic separation of enantiomers, the use of toxic chemicals and flammable materials, like propargyl halides and propargyl sulfonate esters, including the use of expensi ve chiral precatalysts and ligands, which may render the processes to be expensi ve, non-ecofriendly, thus making said processes unsuitable on a commercial scale.
  • the comparative example signifies that there is a need for reliable processes, which are suitable for industrial production, to produce indanylamine derivatives in high yields as intermediates, to prepare aminoindan derivatives and specifically compounds of Formula I.
  • the processes of the present invention require a few steps, thus making the processes applicable on an industrial scale.
  • the compounds produced by the processes of the current invention are sui table for use as pharmaceuticals, or as starting materials or as intermediates in the production of a variety of pharmaceuticals.
  • the present invention provides processes which are not only simple without employing environmentally aggressive chemicals, but more significantly, provide the least formation of undesirable bisalkylated by-products, whi le concomi tantly producing final products in high yield and purity of rasagiline or pharmaceutilcally salts thereof.
  • the present invention provides that the crystalline diastereomeric salt can be filtered and the free base liberated by basifying the salt with a suitable basifying agent.
  • Said agents include, but are not limited to ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or mixtures thereof.
  • potassium carbonate sol ution or ammonia Preferably, potassium carbonate sol ution or ammonia.
  • the mother liquid can be recovered after filtering and be further treated in order to recover the enantiomer which was not previously removed by precipitation.
  • the . treatment may comprise e.g. cooling the mother liquid and recovering the resulting crystall ine d iastereomeric salt.
  • the product obtained by the above described method contains about 90 wt% of the desired enantiomer of formula ( I).
  • the purity of the product can be increased to about 96 wt% by recrystal l ization using suitable solvents. Methanol is the preferred recrystallization sol vent.
  • the product which is enriched in (-)enantiomer is recrystallized by adding the product to methanol solvent, refluxing the mixture and filtering precipitate. The fi ltrate is concentrated, if necessary, and cooled in order to crystallize the (R)-enantiomer of formula ( I ). This allows recovering the substantially pure (-) enantiomer of formula (I) from the mother solution by crystallization.
  • the preci pitation is carried out with cooling, decreasing the amount of the solvent and/or by adding an ant isol vcnl .
  • the free base obtained may be optionally purified by recrystallization or slurrying in suitable solvents.
  • Recrystallization involves providing a solution of crude R-rasagiline in a suitable solvent and then crystal lizing the solid from the solution.
  • Suitable solvents in which R-rasagiline can be dissolved for purification include, but are not limited to. C 1 -C 5 ketones, such as acetone, ethyl methyl ketone, butanone and the like; alcohols, such as et hanol, methanol, and isopropanol; ethers, such as such as tetrahydrofuran, 1.4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
  • the solvent i acetone or ethyl acetate.
  • the concentration of the R-rasagiline in a solvent or mixture of solvents can range from about 40% to greater than about 80%.
  • the solution can be prepared at an elevated temperature if desired to achieve a higher solute concentration. Any temperature is acceptable for the dissol ution as long as a clear solution of the R-rasagiline is obtained and is not detrimental to the drug substance chemically or physically.
  • the solution may be brought down to a lower temperature for further processing if required or an elevated temperature may be used. A higher temperature for dissolution will allow the precipitation from solutions with higher concentrations of R-rasagiline.
  • the product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35°C to about 70°C. The drying can be carried out for any desired time periods to achieve the desired product purity.
  • the process of the present invention may further comprise the conversion of aproduct into a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include, but are not limited to. the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide. esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sul fate salts.
  • the present invention additionally comprises products as pharmaceutically acceptable salts. Preferably, mesylate or tartrate.
  • the present invention provides the process of preparing the pharmaceutically acceptable salt of R-rasagiline comprising reacting a pharmaceutically acceptable acid with R-rasagiline in solution.
  • the acid is dissolved in a solvent before adding it to the solution of R- rasagiline free base.
  • the solvent used for the dissolution of R-rasagiline and the acid may be the same, or different solvents may be used .
  • Suitable solvents in which the acid addition salt of R-rasagiline can be prepared include, but are not limited to C 1 -C 5 ketones, such as acetone, ethyl methyl ketone, butanone and the like; alcohols, such as ethanol, methanol, and isopropanol; ethers, such as tetrahydrofuran, 1 ,4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
  • the mesylate of R-rasagiline is prepared from R - rasagiline and methanesulfonic acid in acetone.
  • the present invention provides a process for preparing R- rasagiline mesylate having a particle size distribution wherein 90% of particles (D90) have particle size greater than 1 500 ⁇ , comprising reacting R -rasagiline with methanesulfonic acid in methyl ethyl ketone.
  • D90 is in the range of about 1500 ⁇ to about
  • Particle size d istri bution means the cumulative volume size distribution of equivalent spherical diameters. The methodology and protocols for particle size distribution of R- rasagiline Mesylate by laser diffraction are described below:
  • Sample Preparation About 1 50mg of sample in beaker. Add 3-4 drops of silicon oil. Make a paste. Add 25ml of silicon oil and stir to mix well. Sonicate for 60 seconds.
  • the acid addition salt obtained can be purified further by recrystallization or slurrying in suitable sol vents.
  • suitable solvents in which the acid addition salt of R-rasagiline can be dissolved for purification include, but are not limited to C 1 -C 5 ketones, such as acetone, ethyl methyl ketone, butanone and the lik e; alcohols, such as ethanol, methanol, and isopropanol; ethers, such as tetrahydroluran. 1 .4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
  • acetone or water Preferably, acetone or water.
  • the product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35°C to about 90°C. The drying can be carried out for any desired time until the required product purity is achieved.
  • the present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I, having purity greater than about 98.5% as determined by chiral HPI .C.
  • the present invention provides propargylated aminoindans or a pharmaceutical ly acceptable salt thereof of formula I, having purity greater than about 99% as determined by chiral HP I.C.
  • the present invention provides propargylated aminoindans or a pharmaceutical ly acceptable sal t thereof of formula I, having less than about 0. 1 5 area % of (S)-isomer impurity as determined by chiral HPLC.
  • the present invention provides propargylated aminoindans or a pharmaceutically acceptable salt thereof of formula I, having less than about 0.1 area% of ( S)-isomer impurity as determined by chiral HPLC.
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof having purity of about at least 98 area %, as determined by chiral HPLC.
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof having purity of about at least 99 area %, as determined by chiral HPLC.
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, having bisalkylated aminoindan or its enantiomer of structural
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof of. having bisalkylated aminoindan or its enantiomer of structural formula XII and 1 -indanol of structural formula XIII, in an amount not more than about 0.1 area %, as measured by HPLC .
  • the present invention provides rasagiline or a pharmaceutically acceptable salt thereof, obtained by the processes herein described, having less than about 0. 1 5 area % of any individual impurity and 0.5 area % or less of total impurities as measured by chiral HPLC.
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising propargylaled aminoindans or their pharmaceutically acceptable salts thereof, obtained by the processes of the present invention, and at least one pharmaceutically acceptable carrier.
  • the present i nven tion provides propargylated aminoindans or a pharmaceutically acceptable salt thereo f of formula I, obtained by the processes described herein are substantially crystal line or amorphous or mixtures thereof.
  • the present inv ention provides rasagiline or any of the pharmaceutically acceptable salts prepared in accordance with the present invention, contains less than about 0.5%, of the corresponding impuri ties as characterized by chiral HPLC .
  • the chromatogram is obtained from a mixture comprising the desired compound and one or more of the said impurities, preferably less than about 0. 1 %.
  • the percentage here refers to weight percent obtained from the area % of the peaks representing the impurities.
  • R-rasagiline and salts thereof also arc substantial ly free of other process-related impurities.
  • the process of the present invention advantageously provides R-rasagiline or its pharmaceutically acceptable salts in relatively high purity, of greater than about 98 % and preferably greater than aboul 99% as determined by chiral HPLC.
  • the R-rasagi line or i ts pharmaceutically acceptable salts obtained by the processes of the present invention has residual organic solvent less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. Pharmacopoeia: the. recommended amount is less than 5000 ppm for ethanol, isopropanol, methanol, ethyl acetate and acetone; less than 800ppm for toluene, dichloromethane, dimethyl formamide and di i sopropyl ether.
  • the amount is less than about 3000 ppm residual organic so l vent , more preferably less than about 2000 ppm residual organic solvent, most preferably, less than about 1000 ppm.
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising propargylated aminoindans or their pharmaceutically acceptable salts thereof obtained by the processes of present invention and at least one pharmaceutically acceptable carrier as an activ e ingredient, in association with a pharmaceutically acceptable carrier,
  • the pharmaceutical composition comprising R-rasagiline or its pharmaceutically acceptable salts prepared by the processes of present invention may be formulated for oral administration to treat depression, Attention Deficit Disorder (ADD), Attention Deficit and Hyperactivity Di sorder ( A DHD ). Tourett's Syndrome, Alzheimer's Disease and other dementias.
  • D90 particle size of the unformulated rasagiline or pharmaceutically acceptable salts thei eof used as starting material in preparing a pharmaceutical composition generally is less than 300 microns, preferably less than about 200 microns, more preferably less than 100 microns, still more preferably less than about 50 microns. Any mil li ng, grinding micronizing or other particle size reduction method known in the art can be used to bring the solid state rasagiline or its pharmaceutically acceptable salt thereof into any desi red particle size range as set forth above.
  • compositions of the present invention can be administered to humans and animals in such dosage forms as oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), intracistemal , intravaginal, intraperitoneal, local (powders, ointments or drops), ophthalmic, transdermal, or sublingual forms or as a buccal or nasal spray.
  • Oral dosage forms include, but are not limited to, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs, tablets, capsules (including soft gel capsules), ovules, solutions, and the like which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications.
  • R-rasagiline or its pharmaceutically acceptable salt thereof prepared by the process as described herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.
  • the most preferred route o f administration of the rasagiline or its pharmaceutically acceptable salts thereof of the present in vention is oral.
  • the active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles.
  • Suitable pharmaceutical composition of the invention may be in coated or uncoated form as desired.
  • compositions may have few or many components depending upon the tableting method used, t he release rate desired and other factors.
  • the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cell ulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cel lulose. hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and - other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calci um diphosphate and other diluents known to one of ordinary skill in the art.
  • sui table d i luents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol , aery late polymers and copolymers, as well as pectin, dextrin and gelatin.
  • excipients contemplated by the present invention include binders, such as acacia gum, pregelalinizcd starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate. crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives: pharmaceutical ly acceptable dyes and glidants such as silicon dioxide.
  • binders such as acacia gum, pregelalinizcd starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes
  • disintegrants such as sodium starch glycolate. crospovidone, low-substituted hydroxypropyl cellulose and others
  • lubricants like magnesium and calcium stearate and sodium stearyl fumarate
  • Capsule dosages wil l contain the solid composition within a capsule which may be coated with gelatin .
  • Tablets and powders may also be coated with an enteric coating.
  • the enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmeihyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcell ulose. a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
  • a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
  • 1 -Indanone (50g. 0.38 mol ), titanium(lV ) isopropoxide ( 128.9g, 0.45 mol) and) propargyl amine (20.8g. 0.38 mol) were taken in absolute ethanol ( 500 ml) and the reaction mixture was stirred at about 25-30°C for 8h to obtain the titanium complex. Thereafter, this titanium complex is reduced by adding sodium borohydride (21 .45g, 0.56 mol) at about 25- 30°C. The reaction mixture was further stirred at about 25-30°C for about 8 h. The reaction mass was quenched by addi ng in a mixture of aqueous ammonia solution ( 100ml) and ethyl acetate.
  • the precipi tated inorganic solid was filtered.
  • the organic layer was separated.
  • the organic layer was extracted with 16% w/w aqueous hydrochloric acid.
  • the aqueous extract was ' basified to pl l 7.5-8.0 with aqueous ammonia solution and extracted with cyclohexane.
  • the cylcohexane extract was concentrated at about 40-45°C to obtain the rasagiline base as oily residue. Purity by H PLC: 98%.
  • EXAMPLE 2 PREPARATION OF R-( + )-RASAGILINE TARTRATE.
  • Rasagiline base as prepared in example l ( 85 g, 0.49 mol) and L(+)-Tartaric acid ( 1 12 g, 0.77 mol) were taken in isopropanol ( 1020 ml) and the reaction mixture was stirred at reflux temperalui c for aboul 30 minutes. Thereafter, the reaction mass was gradually cooled to about 25-30°C and stirred for about 1 .0 hr.
  • the precipitated R-(+)-Rasagiline tartrate salts was filtered, washed w i th isopropanol (85ml) and dried at about 50-55°C to obtain 36 gm of crude R-(+)-RasaIgiline tartrate.
  • EXAMPLE 3 PREPARATION OF R-(+)-RASAGILINE MESYLATE.
  • R-(+) Rasagi l ine tartrate 20.0g, 0.081 mol
  • DM water 200 ml
  • the pH of the solution was adj usted to about 8.5-9 by adding aqueous ammonia solution.
  • the solution was extracted with cyclohexane and the organic layer was concentrated at about 40- 45°C to obtain a oily residue (9 gm)(assay by HPLC 97.35%).
  • R-(+) Rasagiline tartrate ( 1 50 g , 0.3047 mole) was dissolved in DM water ( 1 .5 Ltr) and the pH of the solution was adjusted to about 9- 10 using 25% aqueous ammonia solution (96ml). Thereafter the reaction mass was stirred for 1 5min and aqueous layer extracted with cyclohexane. The organi c layer was distilled under reduced pressure at about about 40-45°C to obtain R-Rasagiline base as oily product 100 g.
  • R-rasagiline base oil 100 g was dissolved in methylethylketone ( 3.0 Ltr) and thereafter reaction mass was stirred for about 1 5 minutes.
  • methane sulphonic acid (67.36 g, 0.700 mole) was added to reaction mass at about 25-30°C in about 1 0 min and the reaction mass was stirred for about 1 0- 15 min.
  • the reaction mass was heated to about 70-75°C.
  • dimineralized water ( 74ml) was added to reaction mass at temperature of about 70-75 C.
  • the reaction mass was heated at reflux temp for about 15 min.
  • the heating and stirring were stopped and reaction mass was allowed to cool to about 20-25°C.
  • the reaction mass was maintained at temperature of about 20-25°C for about 12-14 hours.
  • the reaction mass was filtered to obtain wet rasagiline mesylate salt which was dried under vacuum tray dryer at about 55-60°C, to obtain
  • X- ray powder diffraction (XRD) pattern with characteristic peaks at about
  • X- ray powder diffraction (XRD) pattern with characteristic peaks at about

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Abstract

L'invention concerne l'élaboration d'un composé de formule (I), dans laquelle R1 = H ou correspond à la formule (b) et R2 est alkyle C1-C4, R3 = H ou alkyle C1-C4, et cette élaboration consiste à : a) faire réagir une dérivé indanone ou un sel correspondant de formule (II) avec propargyl amine ou un sel correspondant de formule (III) en présence d'un acide de Lewis; et b) soumettre le mélange de réaction résultant à une réduction
PCT/IN2010/000671 2009-10-14 2010-10-08 Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant WO2011048612A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011092717A2 (fr) * 2010-02-01 2011-08-04 Alkem Laboratories Ltd. Mésylate de rasagiline ayant une grande taille des particules et procédé pour sa préparation
CN103864646B (zh) * 2014-02-21 2016-08-24 常州市第四制药厂有限公司 甲磺酸雷沙吉兰的杂质制备及分析方法
CN110776429A (zh) * 2018-07-30 2020-02-11 齐鲁制药有限公司 一种雷沙吉兰消旋中间体的改进制备方法

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US5786390A (en) * 1990-01-03 1998-07-28 Teva Pharmaceutical Industries Ltd. Pharmaceutical compositions of the R-enantiomer of N-propargyl -1-aminoindan
CN1990455A (zh) * 2005-12-29 2007-07-04 北京德众万全医药科技有限公司 一种简单、新颖的茚衍生物的制备方法
CN101062897A (zh) * 2006-04-25 2007-10-31 重庆医药工业研究院有限责任公司 一种制备2，3－二氢－1h－茚－1－胺及其衍生物的改进方法
CN101260048A (zh) * 2008-04-15 2008-09-10 苏州凯达生物医药技术有限公司 雷沙吉兰的制备方法
WO2010059913A2 (fr) * 2008-11-20 2010-05-27 Dr. Reddy's Laboratories Ltd. Préparation de rasagiline et de ses sels

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786390A (en) * 1990-01-03 1998-07-28 Teva Pharmaceutical Industries Ltd. Pharmaceutical compositions of the R-enantiomer of N-propargyl -1-aminoindan
CN1990455A (zh) * 2005-12-29 2007-07-04 北京德众万全医药科技有限公司 一种简单、新颖的茚衍生物的制备方法
CN101062897A (zh) * 2006-04-25 2007-10-31 重庆医药工业研究院有限责任公司 一种制备2，3－二氢－1h－茚－1－胺及其衍生物的改进方法
CN101260048A (zh) * 2008-04-15 2008-09-10 苏州凯达生物医药技术有限公司 雷沙吉兰的制备方法
WO2010059913A2 (fr) * 2008-11-20 2010-05-27 Dr. Reddy's Laboratories Ltd. Préparation de rasagiline et de ses sels

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011092717A2 (fr) * 2010-02-01 2011-08-04 Alkem Laboratories Ltd. Mésylate de rasagiline ayant une grande taille des particules et procédé pour sa préparation
WO2011092717A3 (fr) * 2010-02-01 2011-10-13 Alkem Laboratories Ltd. Mésylate de rasagiline ayant une grande taille des particules et procédé pour sa préparation
CN103864646B (zh) * 2014-02-21 2016-08-24 常州市第四制药厂有限公司 甲磺酸雷沙吉兰的杂质制备及分析方法
CN110776429A (zh) * 2018-07-30 2020-02-11 齐鲁制药有限公司 一种雷沙吉兰消旋中间体的改进制备方法
CN110776429B (zh) * 2018-07-30 2022-12-02 齐鲁制药有限公司 一种雷沙吉兰消旋中间体的改进制备方法

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