WO2010059913A2 - Préparation de rasagiline et de ses sels - Google Patents
Préparation de rasagiline et de ses sels Download PDFInfo
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- WO2010059913A2 WO2010059913A2 PCT/US2009/065279 US2009065279W WO2010059913A2 WO 2010059913 A2 WO2010059913 A2 WO 2010059913A2 US 2009065279 W US2009065279 W US 2009065279W WO 2010059913 A2 WO2010059913 A2 WO 2010059913A2
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- rasagiline
- salt
- rasagiline mesylate
- minutes
- formula
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- NMRXLQWLAGHNGU-UHFFFAOYSA-N C#CCNC(C1)c2ccccc2C1=O Chemical compound C#CCNC(C1)c2ccccc2C1=O NMRXLQWLAGHNGU-UHFFFAOYSA-N 0.000 description 1
- RPAZWTZFMPXUKS-UHFFFAOYSA-N C=CCNC1c2ccccc2CC1 Chemical compound C=CCNC1c2ccccc2CC1 RPAZWTZFMPXUKS-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- aspects of the present application relate to rasagiline, processes for the preparation of rasagiline, and pharmaceutically acceptable salts thereof.
- the drug compound having the adopted name "rasagiline mesylate” has a chemical name (1 R)-N-prop-2-ynyl-2,3-dihydro-1 H-inden-1 -amine methanesulfonate, and can be represented by structural Formula I.
- Rasagiline mesylate is prescribed for the treatment of idiopathic Parkinson's disease.
- U.S. Patent Nos. 3,253,037, 5,457,133, and 5,532,415 pertain to racemic rasagiline, its enantiomer and a mesylate salt.
- Chinese Patent Application No. 1990455 A describes a process for the preparation of rasagiline via reductive amination in the presence of hydrogen gas or borohydride. The process of the Chinese patent application has serious problems, such as a long reaction time (24 hours), and low yields and purity.
- U.S. Patent No. 7,375,249 discloses a process for preparation of rasagiline wherein 1 -indanone is reduced under chiral reducing condition to enantiomerically pure 1 -indanol, followed by activation of the hydroxyl group and its subsequent reaction with propargyl amine.
- U.S. Patent No. 7,491 ,847 discloses a process for isolation of rasagiline from a reaction mixture comprising solvent, primary- aminoindan and tertiary-aminoindan.
- International Application Publication No. WO 2008/076348 A1 discloses crystalline rasagiline free base, a process for its preparation and a pharmaceutical composition comprising crystalline rasagiline free base.
- Rasagiline mesylate It also highlights that the large, irregularly shaped particles arising from salt crystallization can easily decrease content uniformity in formulated products.
- WO 2009/122301 discloses rasagiline mesylate having 90 volume-percent of the particles (D 90 ) with sizes about 600 ⁇ m to about 1500 ⁇ m, and a process for its preparation.
- an active pharmaceutical ingredient such as rasagiline mesylate
- Particle sizes for example, may affect the flowability and mixability of a drug substance.
- pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors include the sizes of crystals, shapes of crystals, water content, residual solvents, and impurities.
- aspects of the present invention provide processes for the preparation of rasagiline and its pharmaceutically acceptable salts, substantially free from chiral and process related impurities, embodiments comprising at least one of the steps: (a) reacting 1 -indanone of Formula Il with propargylamine or its salt, in the presence of a suitable solvent, to afford N-(2-propynyl)-indanyl-imine ("imine intermediate") of Formula III; and
- An aspect of the present invention includes processes for resolution of racemic or an enantiomerically enriched rasagiline to obtain a desired enantiomer, embodiments comprising at least one of the steps: (a) resolving racemic or an enantiomerically enriched rasagiline, in the presence of a suitable chiral resolving agent, to afford a diasteromehc salt;
- the present invention provides particle size distributions of rasagiline mesylate of Formula I, wherein more than about 90% of the particles have sizes less than or equal to about 6 ⁇ m.
- the present invention provides processes for the preparation of uniform particle size distributions of rasagiline mesylate of Formula I, embodiments comprising: a) providing a solution of rasagiline mesylate in isopropyl alcohol; b) combining the solution of a) with an anti-solvent; c) recovering solid rasagiline mesylate from (b); and d) reducing particle sizes of rasagiline mesylate to obtain a D 90 value less than about 6 ⁇ m.
- the present invention provides processes for the preparation of uniform particle size distributions of rasagiline mesylate of Formula I, embodiments comprising: a) slurrying rasagiline mesylate in methyl t-butyl ether; b) recovering solid rasagiline mesylate from a); and c) reducing particle sizes of rasagiline mesylate to obtain a D 90 value less than about 6 ⁇ m.
- substantially pure refers to a compound comprising less than about 5% of other isomers of the same compound, or less than about 3%, or less than about 2%, or less than about 0.5%.
- enantiomerically enriched refers to a mixture that may be racemic or may have a weight ratio greater than about 4:1 to about 1 :4 of rasagiline to another isomer that is an S-isomer analog.
- Percentage values are used herein to denote percent by weight, unless the context indicates otherwise.
- aspects of the present invention include processes for the preparation of rasagiline and its pharmaceutically acceptable salts, substantially free from chiral and process related impurities, embodiments comprising at least one of the steps: (a) reacting 1 -indanone of Formula Il with propargylamine or its salt in the presence of a suitable solvent, to afford N-(2-propynyl)-indanylimine ("imine intermediate") of Formula III; and
- Formula IV Step (a) involves reacting 1 -indanone of Formula Il with propargylamine or its salt in the presence of a suitable solvent, to afford the imine intermediate of Formula III.
- Suitable solvents for use in step (a) include, but are not limited to: alcohols, such as, for example, methanol, ethanol, isopropanol, n-propanol, and the like; hydrocarbons, such as, for example, toluene, xylene, n-heptane, cyclohexane, and the like; mixtures thereof; and combinations thereof with water in various proportions.
- alcohols such as, for example, methanol, ethanol, isopropanol, n-propanol, and the like
- hydrocarbons such as, for example, toluene, xylene, n-heptane, cyclohexane, and the like
- mixtures thereof such as, for example, toluene, xylene, n-heptane, cyclohexane, and the like
- combinations thereof with water in various proportions include, but are not limited to: alcohols, such as, for example,
- Step (a) may be accomplished at temperatures about 10-90 0 C, such as, for example, about 35-40 0 C.
- Propargylamine used in (a) may be in the form of the free base or an acid addition salt.
- step (a) may employ propagylamine hydrochloride.
- the imine intermediate of Formula III may be isolated in the form of an acid addition salt and further purified by recrystallization, to achieve the desired purity.
- Step (b) involves reduction of the imine intermediate Formula III with a suitable reducing agent under suitable reaction conditions, to afford racemic rasagiline of Formula IV.
- Suitable reducing agents include, but are not limited to: metal catalysts, such as, for example, Raney nickel, palladium on carbon, and platinum dioxide; lithium aluminium hydride; sodium borohydhde (NaBH 4 ); sodium cyanoborohydride (NaBH 4 CN); NaBH 4 in acidic conditions; and sodium bis(2- methoxyethoxy)aluminum hydride (e.g., VITRIDE®).
- metal catalysts such as, for example, Raney nickel, palladium on carbon, and platinum dioxide
- lithium aluminium hydride such as, for example, Raney nickel, palladium on carbon, and platinum dioxide
- lithium aluminium hydride such as, for example, Raney nickel, palladium on carbon, and platinum dioxide
- lithium aluminium hydride such as, for example, Raney nickel, palladium on carbon, and platinum dioxide
- lithium aluminium hydride such as, for example, Raney nickel, palladium on carbon, and platinum dioxide
- lithium aluminium hydride such as
- Suitable solvents that can be used in this step include, but are not limited to: alcohols, such as, for example, Ci-C 4 alcohols; halogenated solvents, such as, for example, Ci-C ⁇ straight chain branched or aromatic halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and the like; hydrocarbons, such as, for example, toluene, xylene, cyclohexane, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; aprotic solvents, such as, for example, dimethylsulphoxide (DMSO), N,N-dimethylformamide (DMF), N 1 N- dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), and the like; mixtures thereof; and combinations thereof with water in various proportions
- Step (b) may be conducted at temperatures about 10-75 0 C, or about 20- 40 0 C.
- steps (a) and (b) can be carried out in a single vessel, by generation of the imine and its subsequent in situ reduction with a suitable reducing agent.
- steps (a) and (b) can be carried out stereoselective ⁇ to obtain an enantiomerically enriched or substantially enantiomerically pure R- propargylaminoindan.
- the product compound can be separated from the reaction mixture by adjusting the pH to values above about 8 with a base, followed by extraction of the compound into a suitable water immiscible organic solvent.
- suitable solvents that can be used for extraction of the compound include, but are not limited to: C3-C6 ketones, such as, for example, ethyl methyl ketone and diethyl ketone; halogenated hydrocarbons, such as, for example, dichloromethane, ethylene dichloride, chloroform, and carbon tetrachloride; esters, such as, for example, ethyl acetate, isopropyl acetate, t-butyl acetate; mixtures thereof; and combinations thereof with water in various proportions.
- racemic rasagiline free base can optionally be subjected to diastereomeric salt formation in the same flask by reaction of racemic rasagiline free base with a suitable chiral resolving agent, to form its diastereomeric salt.
- racemic rasagiline may be converted to an acid addition salt and further purified by recrystallization to achieve the desired purity.
- Embodiments of the present invention include processes for resolution of racemic or enantiomerically enriched rasagiline to obtain a desired enantiomer of rasagiline, comprising at least one of the steps:
- step (b) optionally, obtaining the free base of an enantiomer from its corresponding diastereomeric salt obtained in step (a); and (c) reacting the free base obtained in step (b) or diastereomeric salt of step
- Resolution step (a) involves resolving racemic or enantiomerically enriched rasagiline in the presence of a suitable chiral resolving agent to afford a diastereomeric salt.
- Suitable chiral resolving agents include, but are not limited to: a tartaric acid, such as L-(+)-tartaric acid and (-)-di-p-toluoyltartahc acid ("DPTTA"); a mandelic acid, such as D-(-)-mandelic acid; a camphorsulphonic acid, such as (-)-camphor-I O-sulphonic acid; (S)-6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid (S-naproxen); (S)-(+)-ibuprofen (dexibuprofen); and the like.
- DPTTA di-p-toluoyltartahc acid
- Suitable organic solvents for resolution step (a) include, but are not limited to: alcohols, such as, for example, methanol, ethanol, isopropanol, n-butanol, and the like; ketones, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; halogenated hydrocarbons, such as, for example, dichloromethane, ethylene dichlohde, chloroform, and the like; aprotic solvents, such as, for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dinnethylace
- the chiral resolving agent may be combined with the solution of racemic rasagiline at temperatures about 20-120 0 C, or about 60-70 0 C.
- the reaction mass may be maintained at temperatures lower than the reaction temperature, such as, for example, below about 25°C, for periods of time as desired for a more complete formation of the product.
- temperatures lower than the reaction temperature such as, for example, below about 25°C, for periods of time as desired for a more complete formation of the product.
- a person skilled in the art can readily determine the exact cooling temperatures and times required for complete formation.
- the diastereomeric salt of rasagiline may be separated from the final mixture by any techniques, including decantation, filtration by gravity or suction, centrifugation, and the like, optionally drying the solid using conventional means of drying.
- the diastereomeric salt of rasagiline obtained in resolution step (a) typically comprises less than about 10%, or less than about 5%, or less than about 1 %, or less than about 0.05%, of the isomeric impurity.
- Resolution step (b) involves optionally obtaining a free base of an enantiomer from its corresponding diastereomeric salt obtained in step (a), by treatment with a suitable base
- Suitable solvents that can be used to dissolve a diasteromeric salt include, but are not limited to: alcohols, such as, for example, Ci-C 4 alcohols; C 2 -C 6 ketones, such as, for example, acetone, ethyl methyl ketone, and diethyl ketone; halogenated solvents, such as, for example, Ci-C ⁇ straight chain branched or aromatic halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and the like; hydrocarbons, such as, for example, toluene, xylene, cyclohexane, and the like; esters, such as, for example, ethyl acetate, isopropyl acetate, t-butyl acetate, and the like; nitriles, such as, for example, acetonitrile,
- Suitable bases include, but are not limited to: inorganic bases such as hydroxides, alkoxides and carbonates; organic bases such as pyridine, lutidine, triethylamine, 4-dimethylaminopyridine (DMAP), dicyclohexylamine, diisopropylethylamine, and the like.
- inorganic bases such as hydroxides, alkoxides and carbonates
- organic bases such as pyridine, lutidine, triethylamine, 4-dimethylaminopyridine (DMAP), dicyclohexylamine, diisopropylethylamine, and the like.
- DMAP 4-dimethylaminopyridine
- a specific example of a useful base is sodium hydroxide.
- Suitable temperatures for conducting resolution step (b) are about 10- 75°C, or about 20 ⁇ 0 0 C.
- Step (c) involves reacting the rasagiline free base obtained in step (b) with a pharmaceutically acceptable acid, to afford a rasagiline salt.
- Suitable solvents that can be used to dissolve the rasagiline free base include, but are not limited to: alcohols, such as, for example, Ci-C 4 alcohols; C 2 - C ⁇ ketones, such as, for example, acetone, ethyl methyl ketone, and diethyl ketone; halogenated solvents, such as, for example, Ci-C ⁇ straight chain branched or aromatic halogenated hydrocarbons, e.g., dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and the like; hydrocarbons, such as, for example, toluene, xylene, cyclohexane, and the like; esters, such as, for example, ethyl acetate, isopropyl acetate, t-butyl acetate, and the like; nitriles, such as, for example, acetonithle,
- the present invention includes rasagiline of Formula I, substantially free from N,N-di-(2-propynyl)-indanylamine of Formula V.
- the present invention includes rasagiline of Formula I substantially free from N-allyl indanylamine of Formula Vl.
- the present invention includes rasagiline of Formula I substantially free from N-propylindanylamine of Formula VII.
- the present invention includes rasagiline or its salts substantially free from 3-propynyl-amino-1-indanone of Formula VIII or its salts. In embodiments, this impurity will be present in amounts less than about 0.05 weight percent.
- the presence of impurities in rasagiline mesylate may pose a problem for pharmaceutical product formulation, in that impurities often affect the safety and shelf life of a formulation.
- the present invention provides a method for ameliorating the effect of an impurity present in formulations of rasagiline Mesylate by reducing the amount of the impurities during synthesis.
- the purity of product can be increased by recrystallization or slurrying of racemic Rasagiline or diastereomehc salt or any other salt of rasagiline in suitable solvents by processes known in the art.
- the suitable crystallization techniques include, but are not limited to: concentrating, cooling, stirring, or shaking, a solution containing the compound or by adding anti-solvent, adding seed crystals, evaporation, flash evaporation and the like.
- An anti-solvent as used herein refers to a solvent in which salt of rasagiline is less soluble or poorly soluble.
- the solvents that can be employed for crystallization include, but are not limited to lower alkanols, such as methanol, ethanol, isopropyl alcohol, esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate, ethers such as 1 ,4-dioxane and tetrahydrofuran, nithles such as acetonitrile, and mixtures thereof.
- lower alkanols such as methanol, ethanol, isopropyl alcohol
- esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate
- ethers such as 1 ,4-dioxane and tetrahydrofuran
- nithles such as acetonitrile
- the pharmaceutically acceptable acid addition salts or diastereomehc salts have potential to serve as intermediates in the purification of free base or preparation of other, for example, pharmaceutically acceptable acid addition salts.
- the rasagiline salt is substantially free from impurities.
- the rasagiline salt is of high purity, such as at least about 99%, 99.5%, or 99.9%, by weight pure.
- the level of impurities may be less than about 1 %, 0.5%, or 0.1 %, by weight, as determined using high performance liquid chromatography (HPLC). Rasagiline and its impurities can be analyzed by HPLC using a ZORBAX
- Detector UV detector. Injection volume: 10 ⁇ L.
- Buffer Dissolve 1 .36 grams of potassium dihydrogen phosphate and 2.44 grams of decane-1 -sulfonic acid sodium salt in 1 L of water and add 1 mL of triethylamine. Adjust the pH to 2.0 with 10% v/v phosphoric acid.
- Eluent A degassed mixture of buffer, acetonitrile and methanol in a volume ratio of 80:19:1
- Eluent B degassed mixture of buffer and acetonitrile in a volume ratio of 20:80.
- the present invention provides rasagiline mesylate of Formula I having a particle size distribution, wherein more than about 90% of the total particles have sizes less than 6 ⁇ m.
- Dio, D 5 O, and D 90 values are useful for indicating a particle size distribution.
- D 90 refers to 90 volume percent of the particles having a size smaller than the specified value.
- D 10 refers to 10 volume percent of the particles having a size smaller than the specified value.
- D 50 refers to 50 volume percent of the particles having a size smaller than the specified value.
- Methods for determining Di 0 , D 50 and D 90 include laser diffraction, such as using Malvern equipment (from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom).
- the present invention provides processes for the preparation of rasagiline mesylate of Formula I having desired particle size distributions, which comprise the steps: a) providing a solution of rasagiline mesylate in an aqueous organic solvent or organic solvent; b) combining the solution of step a) with an anti-solvent; c) recovering solid rasagiline mesylate; and d) reducing particle sizes of rasagiline mesylate to obtain D 90 values less than about 6 ⁇ m.
- Step a) involves providing a solution of rasagiline mesylate in a solvent, such as isopropyl alcohol.
- the solution of rasagiline mesylate may be obtained by dissolving rasagiline mesylate in a solvent, such as isopropyl alcohol.
- a solvent such as isopropyl alcohol.
- the rasagiline mesylate solution may be obtained directly from a reaction in which rasagiline mesylate is formed.
- Suitable solvents for step a) include, but are not limited to: alcohols, such as, for example, methanol, ethanol, isopropanol, n-butanol, and the like; ketones, such as, for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, and the like; nitriles, such as, for example, acetonithle, propionithle, and the like; mixtures thereof; and combinations thereof with water in various proportions.
- alcohols such as, for example, methanol, ethanol, isopropanol, n-butanol, and the like
- ketones such as, for example, acetone, ethyl methyl ketone, methyl isobutyl
- Temperatures for dissolution can range from about 25°C to about 100 0 C.
- the time period can be as long as required for a complete dissolution. Any other temperatures also are acceptable, as long as the stability of rasagiline mesylate is not compromised and a clear solution is obtained. Suitable temperatures can be about 50-90 0 C, or about 70-80°C.
- the solution can optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization.
- Step b) involves combining the solution of step a) with an anti-solvent.
- the rasagiline salt solution of step a) can be combined with a suitable anti- solvent.
- suitable anti-solvents used in this step include, but are not limited to, ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1 ,4-dioxane, and the like.
- Suitable temperatures of an anti-solvent for combining with a rasagiline salt range from about -10 0 C to about 10 0 C.
- the anti-solvent is used in an amount about 2 to about 50 times the volume of the solution.
- the mixture may be stirred for solid formation at temperatures such as, for example, below about 5°C to about 25°C, for periods of time as required for complete solid formation.
- temperatures such as, for example, below about 5°C to about 25°C
- time as required for complete solid formation.
- Step c) involves recovering rasagiline mesylate from step b).
- the methods by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature can be any of techniques such as decantation, filtration by gravity or suction, centrifugation, and the like.
- the isolated crystals may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the isolated crystals may be washed with a solvent to wash out the mother liquor.
- the wet cake obtained may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 30 0 C to about 90°C, with or without applying vacuum. The drying can be carried out for any desired times until the desired product purity is achieved.
- Step d) involves reducing particle sizes of rasagiline mesylate salt of step c) to obtain D 90 values less than about 6 ⁇ m.
- the obtained rasagiline mesylate obtained from step c) may have agglomerates or have poor content uniformity.
- the uniformity of the particles can be increased by reducing the particle sizes. Suitable techniques that can be used to reduce the particle sizes include grinding, milling, micronizing, pulverizing, etc. The injecting and milling pressure for micronisation varies with batch size.
- steps a) and b) can be replaced by a single step of slurrying, wherein rasagiline mesylate is mixed with a suitable liquid, such as methyl-t-butyl ether or another anti-solvent, followed by its recovery and micron ization.
- a suitable liquid such as methyl-t-butyl ether or another anti-solvent
- Rasagiline mesylate according to embodiments of the present invention has particle size distributions where: Di 0 is less than about 1 ⁇ m, or less than about 3 ⁇ m; D 5 o is less than about 5 ⁇ m, or less than about 3 ⁇ m; and D 90 is less than about 6 ⁇ m. There is no specific lower limit for any of the D values. It has been observed that rasagiline mesylate of such small particle sizes is susceptible to agglomerate formation when exposed to the atmosphere. Thus, the exposure of rasagiline mesylate to the atmosphere may lead to deviation of the drug product from content uniformity requirements as a result of agglomeration. In order to enhance the uniformity in particle size, rasagiline mesylate obtained after micronization has been packaged under an inert atmosphere, such that the agglomerate formation is reduced.
- a packaging and storage process for stabilizing the micronised material comprises placing micronised rasagiline mesylate in a sealed container under an inert atmosphere, such as a nitrogen atmosphere.
- the present invention includes rasagiline mesylate formulated as: solid oral dosage forms, such as, for example, powders, granules, pellets, tablets, capsules; liquid oral dosage forms, such as, for example, syrups, suspensions, dispersions, emulsions; and injectable preparations, such as, for example, solutions, dispersions, freeze dried compositions
- Immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations.
- Modified release compositions may comprise hydrophilic and/or hydrophobic release rate controlling substances to form matrix and/or reservoir systems.
- the compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, or by extrusion and spheronization.
- Compositions may be either uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated.
- Pharmaceutical compositions of rasagiline comprise one or more pharmaceutically acceptable excipients.
- compositions include, but are not limited to: diluents, such as, for example starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, thcalcium phosphate, mannitol, sorbitol, sugar, and the like; binders, such as, for example acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants, such as, for example starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodiums, colloidal silicon dioxides, and the like; lubricants, such as, for example stearic acid, magnesium stearate, zinc stearate, and the like; glidants, such as, for example colloidal silicon dioxides
- compositions include, but not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
- the mass is heated to 25-35°C and stirred for about 6 hours, then the reaction is quenched by adding 5000 ml_ of water and the mass is extracted with ethyl acetate (2*1000 ml_). The organic layer is washed with water (2*1000 ml_) and distilled completely under vacuum to afford a residue. To the residue, ethyl acetate (2000 ml_) is added and cooled to about 5°C.
- Racemic rasagiline hydrochloride salt (170 g) is dissolved in water (100 ml_), pH is adjusted to 11 by adding caustic lye solution (50 ml_, 40% aq. sodium hydroxide), and the mass is extracted with ethyl acetate (2*850 ml_). The organic layer is separated, washed with water (2*425 ml_), and distilled completely under vacuum to afford 135 g of the title compound.
- EXAMPLE 2 PREPARATION OF RACEMIC RASAGILINE HYDROCHLORIDE.
- N-(2-propynyl)-indanylimine hydrochloride (1.5 g) is placed into a round bottom flask containing methanol (5 mL), cooled to about 0-10 0 C, and stirred for about 15 minutes.
- Sodium borohydride (0.13 g) is added to the solution and stirred for about 25-35°C until completion of the reaction.
- Water (20 mL) is added to the mixture and the reaction is quenched by adding acetic acid (2 mL) and stirring for about 10 minutes.
- the pH is adjusted to 12 by addition of caustic lye solution (0.9 mL).
- the mass is extracted with ethyl acetate (2*20 mL).
- the organic layer is distilled completely under vacuum.
- EXAMPLE 3 PREPARATION OF PROPARGYLAMINE HYDROCHLORIDE.
- Propargylamine 200 g is charged into a round bottom flask containing ethyl acetate (1500 mL) and stirred for about 10 minutes.
- the solution is cooled to 0-5 0 C, pH is adjusted to 2-5 by addition of hydrogen chloride in isopropanol (18%, 1405 mL), and the mixture is stirred for solid formation.
- the solid is filtered and washed with ethyl acetate (400 mL), and then suction dried for about 30 minutes.
- the obtained solid is dried at 70 0 C for 6-7 hours to afford 300 g of the title compound.
- aqueous layer pH is adjusted to 11 -13 by addition of caustic lye (5 mL) and extracted with ethyl acetate (2 ⁇ 30 mL). The organic layer is separated, washed with water (2 ⁇ 30 mL), and is distilled completely under vaccum to afford 5.8 g of the title compound as a residue (89.6% yield).
- EXAMPLE 5 PREPARATION OF N-(2-PROPYNYL)-INDANYLAMINE.
- the pH of the aqueous layer is adjusted to 11-13 by adding caustic lye (5.4 mL) and the layer is extracted with ethyl acetate (2*25 mL). The organic layer is washed with water (2*25 mL) and distilled completely under vacuum below 60 0 C, to afford 5.8 g of the title compound as a residue.
- the pH of the aqueous layer is adjusted to 11-13 by adding caustic lye (1.9 mL) and it is extracted with ethyl acetate (2*5 mL). The organic layer is washed with water (2*5 mL) and distilled completely under vacuum to afford 2.2 g of the title compound as a residue.
- EXAMPLE 7 PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE.
- Racemic rasagiline free base (2 g) is charged into a round-bottom flask containing 2-butanol (20 mL) and stirred for about 5 minutes.
- DPTTA (2.257g) is added to the solution, heated to 60 0 C, and maintained for about 45 minutes.
- the solution is cooled to room temperature and stirred for solid formation.
- the solid is filtered, washed with 2-butanol (4 mL), and suction dried for about 30 minutes to afford the title compound (1.1 g).
- EXAMPLE 8 PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE. Racemic rasagiline free base (2 g) is charged into a round-bottom flask containing acetone (20 mL) and stirred for about 5 minutes. DPTTA (4.7 g) is added to the solution, heated to 60°C, and maintained for about 45 minutes. The solution is cooled to room temperature and stirred for solid formation. The solid is filtered, washed with acetone (4.7 mL), and suction dried for about 30 minutes to afford the title compound (1.9 g).
- EXAMPLE 9 PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE.
- Racemic rasagiline free base (2 g) is charged into a round-bottom flask containing ethyl acetate (20 mL) and stirred for about 5 minutes.
- DPTTA (1.35 g) is added to the solution, heated to 40 0 C, and maintained for about 45 minutes.
- the solution is cooled to room temperature and stirred for solid formation.
- the solid is filtered, washed with ethyl acetate (4 mL), and suction dried for about 30 minutes to afford the title compound (1.3 g).
- EXAMPLE 10 PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE. Racemic rasagiline free base (2 g) is charged into a round-bottom flask containing isopropanol (60 mL) and stirred for about 5 minutes. DPTTA (4.51 g) is added to the solution, heated to 40 0 C, and maintained for about 45 minutes. The solution is cooled to room temperature and stirred for solid formation. The solid is filtered, washed with isopropanol (10 mL), and suction dried for about 30 minutes to afford the title compound (1.3 g).
- EXAMPLE 11 PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE. Racemic rasagiline free base (5 g) is charged into a round-bottom flask containing isopropanol (50 mL) and stirred for about 5 minutes. L-(+)-tartaric acid (1.315 g) is added to the solution, heated to 60°C, and maintained for about 45-60 minutes. The solution is cooled to 25-30 0 C and stirred for solid formation. The solid is filtered, washed with isopropanol (10 mL), and suction dried for about 30 minutes. The obtained solid is dried at 60°C to afford the title compound (3.3 g). Purity by chiral HPLC: 94.80% R-isomer. EXAMPLE 12: PREPARATION OF DIASTEREOMERIC SALT OF RASAGILINE.
- Racemic rasagiline free base (100 g) is charged into a round bottom flask containing a mixture of isopropyl alcohol (500 ml) and methanol (700 ml) and stirred for about 5 minutes.
- L-(+)-tartaric acid (26.3 g) is added to the solution, heated to 60 0 C, and maintained for about 45 minutes, followed by cooling to 25- 30 0 C and stirring for solid formation.
- the solid is filtered, washed with isopropyl alcohol (100 mL) and suction dried for about 30 minutes. The solid is dried at 70°C to afford the title compound (49 g).
- EXAMPLE 13 PREPARATION OF RASAGILINE MESYLATE.
- a rasagiline tartrate salt (5 g) is charged into a round-bottom flask containing isopropanol (50 mL) and stirred for about 5 minutes.
- Methanesulfonic acid (2 g) is added to the solution, heated to reflux, and maintained for about 45 minutes.
- the solution is cooled to 10 0 C and stirred for solid formation.
- the solid is filtered, washed with isopropanol (10 mL), and dried under vaccum at 60°C to afford the title compound (2.8 g).
- EXAMPLE 14 PREPARATION OF RASAGILINE MESYLATE.
- a rasagiline tartrate salt (25 g) is charged into a round-bottom flask containing acetone (375 mL) and stirred for about 5 minutes.
- Methanesulfonic acid (11.22 g) is added to the solution, heated to reflux, and maintained for about 45 minutes.
- the solution is cooled to 25-30°C and stirred for solid formation.
- the solid is filtered, washed with acetone (50 mL), and dried under vaccum at 60 0 C to afford the title compound (19 g).
- EXAMPLE 15 CONVERSION OF (S)-N-(2-PROPYNYL)-INDANYLAMINE DIASTEROMERIC SALT INTO A RACEMIC MIXTURE OF RASAGILINE.
- EXAMPLE 16 PREPARATION OF RASAGILINE TARTRATE.
- Rasagiline tartrate (30 g) is charged into a round bottom flask containing methanol (450 ml_). The mixture is heated to reflux for dissolution and stirred for 25-30 minutes, followed by addition of isopropyl alcohol (150 ml_) at 55-65°C. The mixture is stirred at the same temperature for 25-30 minutes, followed by cooling to 25-35°C and stirring for 45-60 minutes. The solid obtained is filtered, washed with isopropyl alcohol (60 ml_) and dried at 60-70 0 C to afford the title compound in 76.6% yield.
- EXAMPLE 18 PREPARATION OF RASAGILINE TARTRATE.
- Rasagiline tartrate (10 g) is charged into a round bottom flask containing methanol (150 mL). The mixture is heated to reflux for dissolution and stirred for 45-60 minutes at reflux followed by cooling to 25-30 0 C. The mixture is stirred at this temperature for 45-60 minutes. The solid obtained is filtered, washed with methanol (10 mL) and dried below 60°C to afford the title compound.
- EXAMPLE 19 PREPARATION OF RASAGILINE TARTRATE. Rasagiline free base (8.0 g), L-(+)-tartahc acid (2.10 g), methanol (56 mL) and isopropyl alcohol (40 mL) are placed in a flask and the mixture is stirred for 5- 15 minutes. The mixture is heated to reflux and maintained for 60-90 minutes under constant stirring. The mixture is then cooled to 25-35°C and stirred for 60- 90 minutes. The solid obtained is filtered under vacuum, washed with isopropyl alcohol (8 mL), and dried for 6-8 hours at 60-70 0 C to afford the title compound. HPLC purity is 99.94%
- EXAMPLE 20 PREPARATION OF RASAGILINE MESYLATE.
- Rasagiline tartrate (200 g), is charged into a round bottom flask containing water and stirred to produce a solution, and pH is adjusted to 1 1 .98 with aqueous sodium hydroxide solution under constant stirring.
- Rasagiline free base is extracted from the aqueous solution using two lots of ethyl acetate (930 mL and 1000 mL). The combined organic layer is washed with two lots of water (1070 mL and 1090 mL), followed by distillation under vacuum below 70 0 C.
- EXAMPLE 21 PREPARATION OF RASAGILINE MESYLATE.
- Rasagiline tartrate (730 g) is charged into a reactor containing water (14.6 L) and stirred to dissolve, and pH is adjusted to 11 -12 with aqueous sodium hydroxide solution under constant stirring.
- Rasagiline free base is extracted from the aqueous solution using two lots of ethyl acetate (2*5.11 L).
- the combined organic layer is washed with water (3.65 L), followed by distillation of the organic layer under vacuum below 70 0 C.
- isopropyl alcohol (10.95 L) is added, followed by addition of methanesulfonic acid (340 g) over 15 minutes. The mixture is stirred until solid separates, then is maintained under reflux for dissolution and stirred for 60-90 minutes.
- the mixture is allowed to cool to 25- 35°C and stirred for 60-90 minutes, and then solid is separated by centhfugation and washed with isopropyl alcohol (730 mL). The solid is spin dried, then dried under vacuum at 60-70 0 C for about 8 hours to give rasagiline mesylate in 42% yield.
- Rasagiline tartrate 120 g is charged into a reactor containing acetone (1800 mL) and stirred for about 5 minutes. Methanesulfonic acid (48.1 g) is added to the mixture and dissolved, then the mixture is heated to reflux and maintained for about 45-60 minutes. The solution is cooled to 25-35°C and stirred for 30-45 minutes for solid formation. The solid is filtered, washed with acetone (240 ml_), and dried under vaccum at 60 0 C to a constant weight. The dry solid is mixed with acetone (94 ml_) in a flask, heated to reflux, and maintained for about 45-60 minutes. The mixture is cooled to room temperature and stirred for 45-60 minutes.
- the solid obtained is filtered, washed with acetone (189 ml_), and dried at 55- 60 0 C to a constant weight.
- the dry compound is combined with isopropyl alcohol (400 ml_) in a flask and heated to reflux for dissolution, then maintained for 20-30 minutes. The mixture is cooled to 25-35°C for solid formation.
- Acetone (800 ml_) is added to the mixture at 25-35°C and stirred for 45-60 minutes.
- the solid obtained is filtered under vacuum, washed with acetone (160 ml_), and dried at 55-60 0 C to afford the title compound in 60.4% yield. Purity: 99.91 %.
- Rasagiline tartrate (10 g) is charged into a reactor containing isopropyl alcohol (10 mL). Methanesulfonic acid (4.0 g) is added and dissolved, then the mixture is heated to reflux and maintained for about 60 minutes. The solution is cooled to 0-5°C and stirred for 30 minutes for solid formation. The solid is filtered, washed with isopropyl alcohol (10 mL), and dried at below 80 0 C to afford the title compound in 65% yield. Purity: 99.90%.
- EXAMPLE 24 PREPARATION OF RASAGILINE MESYLATE. Rasagiline mesylate (1.0 g) is charged into a flask containing methanol (4 mL). The solvent is distilled under vacuum below 20°C. A vacuum is applied after distillation for about 2-3 hours.
- EXAMPLE 25 PREPARATION OF RASAGILINE MESYLATE. Rasagiline mesylate (1.0 g) is charged into a flask containing water (5 mL).
- Rasagiline tartrate (3 kg) is charged into a reactor containing water (60 L) and stirred to produce a solution, and pH is adjusted to 11 -12.5 with aqueous sodium hydroxide solution under constant stirring at 25-35°C.
- Rasagiline free base is extracted from the aqueous solution with ethyl acetate (2*21 L).
- the combined organic layer is washed with water (2*21 L), followed by distillation of the organic layer under vacuum below 55°C.
- isopropyl alcohol (6 L) is added followed by distillation under vacuum below 60 0 C.
- Isopropyl alcohol (20 L) is added to the residue, followed by addition of methanesulfonic acid (1.35 Kg) at 25-35°C under a nitrogen atmosphere over 15 minutes.
- the mixture is stirred at 65-75°C for dissolution and maintained for 10-30 minutes.
- the mixture is allowed to cool to 25-35°C and maintained for 45-60 minutes under a nitrogen atmosphere, and then solid is centhfuged and washed with isopropyl alcohol (6 L). The solid is spin dried, then dried under vacuum at 60-65 0 C for about 8 hours to give rasagiline mesylate in 57% yield.
- HPLC purity 99.5%.
- EXAMPLE 27 PREPARATION OF RASAGILINE MESYLATE HAVING D 90 BELOW 6 ⁇ m.
- Rasagiline mesylate (10 g) is charged into a dry round-bottom flask containing isopropyl alcohol (100 mL), heated to 75°C, and stirred to produce a clear solution.
- the solution is filtered hot to remove particles and the filtrate is poured into chilled methyl t-butyl ether (500 mL) at 2°C, then stirred for solid formation for about 5-10 minutes.
- the solid is filtered and suction dried for about 5-20 minutes.
- the solid is dried under vacuum at 50-60 0 C for about 4 hours.
- the dry solid is sifted through a 40 mesh sieve to get uniform particle sizes.
- EXAMPLE 28 PREPARATION OF RASAGILINE MESYLATE HAVING D 90 BELOW 6 ⁇ m.
- Rasagiline mesylate (5 g) is charged into a dry round bottom flask containing isopropyl alcohol (50 mL), heated to 75°C and stirred to produce a clear solution. The solution is filtered hot to remove particles and subsequently poured into chilled methyl t-butyl ether (240 mL) at 2°C and stirred for solid formation for about 5-10 minutes. The solid is filtered and suction dried for about 5-20 minutes. The solid is dried under vacuum at 50-60 0 C for about 4 hours. The dry solid (3.4 g) is sifted through an 80 mesh sieve to get uniform particle sizes.
- EXAMPLE 29 PREPARATION OF RESAGILINE MESYLATE WITH REDUCED PARTICLE SIZES BY RECRYSTALLIZATION.
- Rasagiline tartrate 120 g is charged into a round bottom flask containing acetone (1800 mL) and stirred, followed by addition of methanesulfonic acid (48.1 g). The mixture is heated to reflux and maintained for 45-60 minutes, followed by cooling to 25-35°C with constant stirring for 30-45 minutes. The formed solid is filtered, washed with acetone (240 mL), dried by suction, and dried at 55-60 0 C to a constant weight. The dry solid is placed into another flask containing acetone (940 mL) and the mixture is heated to reflux and maintained for 45-60 minutes, followed by cooling to room temperature and continuous stirring for another 45-60 minutes.
- the formed solid is filtered under vacuum and washed with acetone (189 mL), followed by suction drying and drying at 55-60 0 C to a constant weight.
- the dry compound is charged into a flask containing isopropyl alcohol (400 mL) and refluxed for 20-30 minutes. The mixture is allowed to cool to 25-35°C, followed by addition of acetone (800 mL) at 25-35°C. The mixture is stirred for 45-60 minutes and formed solid is filtered under vacuum, washed with acetone (160 mL), suction dried, and dried at 55-60 0 C to a constant weight, giving the product in 60.4% yield.
- EXAMPLE 30 PREPARATION OF RESAGILINE MESYLATE WITH REDUCED PARTICLE SIZES BY SLURRYING.
- Rasagiline tartrate (1 kg) is charged into a reactor containing water (20 L) and stirred at 25-35°C to produce a solution, and pH is adjusted to 11 -12.5 with 40% aqueous sodium hydroxide solution (0.62 L) under constant stirring at 25- 35°C.
- Rasagiline free base is extracted from the aqueous solution with ethyl acetate (2*7 L).
- the combined organic layer is washed with water (5 L), followed by distillation of the organic layer under vacuum below 70 0 C.
- isopropyl alcohol (15 L) is added followed by addition of methanesulfonic acid (0.47 Kg) at 25-35°C. The mixture is stirred at reflux for dissolution and maintained for 60-90 minutes.
- the mixture is allowed to cool to 25-35°C and maintained for 60-90 minutes under a nitrogen atmosphere, and then formed solid is centrifuged and washed with isopropyl alcohol (1 L).
- the solid is spin dried, then dried under vacuum at 60-65 0 C for about 8 hours to give rasagiline mesylate in 50.6 % yield.
- EXAMPLE 32 PREPARATION OF RESAGILINE MESYLATE WITH REDUCED PARTICLE SIZES BY SLURRYING.
- EXAMPLE 33 AGGLOMERATION OF MICRONIZED RASAGILINE MESYLATE DURING STORAGE.
- the samples are analyzed for particle size distribution on the 5 th and 18 th days. The particle size distribution of the sample packaged with a nitrogen atmosphere is substantially unchanged during the experiment, as shown below.
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La présente invention porte sur des procédés de préparation de mésylate de rasagiline. L'invention porte également sur un mésylate de rasagiline dont 90 pour cent en volume des particules (D90) ont des dimensions inférieures à environ 6 µm. L'invention porte également sur des procédés de préparation de celui-ci.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP09828275A EP2358658A4 (fr) | 2008-11-20 | 2009-11-20 | Préparation de rasagiline et de ses sels |
US13/112,146 US20110218360A1 (en) | 2008-11-20 | 2011-05-20 | Preparation of rasagiline and salts thereof |
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IN2882/CHE/2008 | 2008-11-20 | ||
IN2882CH2008 | 2008-11-20 | ||
US14399609P | 2009-01-12 | 2009-01-12 | |
US61/143,996 | 2009-01-12 | ||
IN1650/CHE/2009 | 2009-07-13 | ||
IN1650CH2009 | 2009-07-13 |
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US13/112,146 Continuation US20110218360A1 (en) | 2008-11-20 | 2011-05-20 | Preparation of rasagiline and salts thereof |
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US (1) | US20110218360A1 (fr) |
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2011009873A2 (fr) * | 2009-07-20 | 2011-01-27 | Medichem, S.A. | Nouvelle forme d'un dérivé de mésylate d'aminoindane |
WO2011048612A2 (fr) * | 2009-10-14 | 2011-04-28 | Glenmark Generics Limited | Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant |
US20110218361A1 (en) * | 2010-03-04 | 2011-09-08 | Everlight Usa, Inc. | Method for producing compound for preparation of anti-parkinson's disease drug |
EP2364967A2 (fr) | 2009-11-26 | 2011-09-14 | USV Limited | Procédé pour la préparation de rasagiline et de ses sels |
CN102464589A (zh) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | 雷沙吉兰、其甲磺酸盐及其中间体的制备方法 |
CN102476998A (zh) * | 2010-11-25 | 2012-05-30 | 台湾永光化学工业股份有限公司 | 抗帕金森氏症药物制备用化合物的制造方法 |
EP2515891A1 (fr) | 2009-12-22 | 2012-10-31 | Teva Pharmaceutical Industries Ltd. | 3-céto-n-propargyl-1-aminoindane |
WO2013054346A2 (fr) * | 2011-07-15 | 2013-04-18 | Alkem Laboratories Limited | Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants |
EP2610239A1 (fr) | 2012-01-02 | 2013-07-03 | Dr. Reddy's Laboratories Ltd. | Préparation de rasagiline hémitartrate |
EP2764862A1 (fr) | 2013-02-06 | 2014-08-13 | Galenicum Health S.L. | Comprimés à libération immédiate de l'hémitartrate de rasagiline |
EP2796130A2 (fr) | 2013-02-06 | 2014-10-29 | Galenicum Health S.L. | Comprimés à libération immédiate comprenant de l'hémitartrate de rasagiline |
US10370329B2 (en) * | 2015-04-27 | 2019-08-06 | Mylan Laboratories Limited | Process for the enantiomeric resolution of apremilast intermediates |
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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 |
CN114933288B (zh) * | 2022-04-28 | 2023-05-19 | 四川轻化工大学 | 一种高纯磷酸二氢钾及其制备方法 |
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US3253037A (en) | 1962-06-19 | 1966-05-24 | Ciba Geigy Corp | N-2-alkynyl-amino-benzocylo-alkanes |
IL92952A (en) | 1990-01-03 | 1994-06-24 | Teva Pharma | R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them |
US6403588B1 (en) * | 2000-04-27 | 2002-06-11 | Yamanouchi Pharmaceutical Co., Ltd. | Imidazopyridine derivatives |
US20050197365A1 (en) * | 2004-02-27 | 2005-09-08 | Jeffrey Sterling | Diamino thiazoloindan derivatives and their use |
WO2005097773A1 (fr) * | 2004-04-07 | 2005-10-20 | Applied Research Systems Ars Holding N.V. | Derives de 1,1'-(1,2-ethynediyle)bis-benzene inhibiteurs de ptp 1-b |
CA2588293C (fr) * | 2004-11-24 | 2013-07-02 | Teva Pharmaceutical Industries Ltd. | Compositions de rasagiline delitantes oralement |
JP2008531546A (ja) * | 2005-02-22 | 2008-08-14 | テバ ファーマシューティカル インダストリーズ リミティド | エナンチオマー性インダニルアミン誘導体の合成のための改良されたプロセス |
BRPI0608209A2 (pt) * | 2005-02-23 | 2010-11-09 | Teva Pharma | mistura de partìculas, composição sólida, método para tratamento de um paciente com mal de parkinson, processo para preparação de uma composição, e, composição farmacêutica sólida |
WO2007061717A2 (fr) * | 2005-11-17 | 2007-05-31 | Teva Pharmaceutical Industries, Ltd. | Procedes de separation d’amino-indanes propargyles |
CN1990455B (zh) | 2005-12-29 | 2011-06-08 | 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 |
EP1892233A1 (fr) * | 2006-08-18 | 2008-02-27 | Ratiopharm GmbH | De nouveaux sels de la substance active rasagiline |
ZA200903903B (en) * | 2006-12-14 | 2010-08-25 | Teva Pharma | Crystalline solid rasagiline base |
CN101486655A (zh) | 2008-01-17 | 2009-07-22 | 美德(江西)生物科技有限公司 | 甲磺酸雷沙吉兰晶形及其制备方法 |
WO2009118657A2 (fr) * | 2008-03-28 | 2009-10-01 | Medichem, S.A. | Forme polymorphe d'un dérivé de mésylate d'amino-indane |
US20110117200A1 (en) * | 2008-03-31 | 2011-05-19 | Actavis Group Ptc Ehf | Rasagiline mesylate particles and process for the preparation thereof |
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2009
- 2009-11-20 EP EP09828275A patent/EP2358658A4/fr not_active Withdrawn
- 2009-11-20 EP EP13167359.2A patent/EP2657221A1/fr not_active Withdrawn
- 2009-11-20 WO PCT/US2009/065279 patent/WO2010059913A2/fr active Application Filing
-
2011
- 2011-05-20 US US13/112,146 patent/US20110218360A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of EP2358658A2 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2011009873A3 (fr) * | 2009-07-20 | 2011-05-05 | Medichem, S.A. | Nouvelle forme d'un dérivé de mésylate d'aminoindane |
WO2011009873A2 (fr) * | 2009-07-20 | 2011-01-27 | Medichem, S.A. | Nouvelle forme d'un dérivé de mésylate d'aminoindane |
WO2011048612A2 (fr) * | 2009-10-14 | 2011-04-28 | Glenmark Generics Limited | Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant |
WO2011048612A3 (fr) * | 2009-10-14 | 2011-08-11 | Glenmark Generics Limited | Procédé d'élaboration d'aminoindanes propargylés y compris un sel pharmaceutiquement acceptable correspondant |
EP2364967A2 (fr) | 2009-11-26 | 2011-09-14 | USV Limited | Procédé pour la préparation de rasagiline et de ses sels |
EP2515891A1 (fr) | 2009-12-22 | 2012-10-31 | Teva Pharmaceutical Industries Ltd. | 3-céto-n-propargyl-1-aminoindane |
EP2939669A1 (fr) * | 2009-12-22 | 2015-11-04 | Teva Pharmaceutical Industries, Ltd. | 3-céto-n-propargyl-1-aminoindane |
US20110218361A1 (en) * | 2010-03-04 | 2011-09-08 | Everlight Usa, Inc. | Method for producing compound for preparation of anti-parkinson's disease drug |
CN102464589A (zh) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | 雷沙吉兰、其甲磺酸盐及其中间体的制备方法 |
CN102476998A (zh) * | 2010-11-25 | 2012-05-30 | 台湾永光化学工业股份有限公司 | 抗帕金森氏症药物制备用化合物的制造方法 |
WO2013054346A2 (fr) * | 2011-07-15 | 2013-04-18 | Alkem Laboratories Limited | Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants |
WO2013054346A3 (fr) * | 2011-07-15 | 2013-07-04 | Alkem Laboratories Limited | Procédé de préparation de n-propragyl 1-amino indane et de sels pharmaceutiquement acceptables correspondants |
EP2610239A1 (fr) | 2012-01-02 | 2013-07-03 | Dr. Reddy's Laboratories Ltd. | Préparation de rasagiline hémitartrate |
EP2764862A1 (fr) | 2013-02-06 | 2014-08-13 | Galenicum Health S.L. | Comprimés à libération immédiate de l'hémitartrate de rasagiline |
EP2796130A2 (fr) | 2013-02-06 | 2014-10-29 | Galenicum Health S.L. | Comprimés à libération immédiate comprenant de l'hémitartrate de rasagiline |
EP2796130A3 (fr) * | 2013-02-06 | 2015-02-25 | Galenicum Health S.L. | Comprimés à libération immédiate comprenant de l'hémitartrate de rasagiline |
US10370329B2 (en) * | 2015-04-27 | 2019-08-06 | Mylan Laboratories Limited | Process for the enantiomeric resolution of apremilast intermediates |
Also Published As
Publication number | Publication date |
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WO2010059913A3 (fr) | 2010-09-16 |
EP2358658A4 (fr) | 2012-11-14 |
US20110218360A1 (en) | 2011-09-08 |
EP2657221A1 (fr) | 2013-10-30 |
EP2358658A2 (fr) | 2011-08-24 |
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