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WO2018193090A2 - Procédé de préparation d'hémitartrate d'eliglustat et d'intermédiaires de celui-ci - Google Patents

Procédé de préparation d'hémitartrate d'eliglustat et d'intermédiaires de celui-ci Download PDF

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Publication number
WO2018193090A2
WO2018193090A2 PCT/EP2018/060185 EP2018060185W WO2018193090A2 WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2 EP 2018060185 W EP2018060185 W EP 2018060185W WO 2018193090 A2 WO2018193090 A2 WO 2018193090A2
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WIPO (PCT)
Prior art keywords
eliglustat
formula
hemitartrate
suitable solvent
reacting
Prior art date
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PCT/EP2018/060185
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English (en)
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WO2018193090A3 (fr
Inventor
Kanaram Hanumanprasad KUMAWAT
Brijesh Rajendrakumar PATEL
Nilesh Mansukhlal Thumar
Joseph Prabahar UPADHYAY
Joseph Prabahar Koilpillai
Virendrakumar Agarwal
Parva Yogeshchandra Purohit
Arif Badrulhusan Siddiqui
Krushnakant Natvarbhai PATEL
Vipul Veljibhai GONDALIYA
Ankit Ramjibhai BUHA
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Amneal Pharmaceuticals Company Gmbh
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Publication of WO2018193090A2 publication Critical patent/WO2018193090A2/fr
Publication of WO2018193090A3 publication Critical patent/WO2018193090A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present disclosure relates to a novel process for the preparation of eliglustat hemitartrate and intermediates thereof.
  • the present disclosure also relates to stable amorphous form of eliglustat hemitartrate, process for its preparation and pharmaceutical composition thereof.
  • Eliglustat tartrate is chemically described as N-((lR,2R)-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-hydroxy-3-(pyrrolidin-l-yl)propan-2-yl) octanamide (2R,3R)-2,3-dihydroxysuccinate and is marketed as Cerdelga® by Genzyme Corp. for the long term treatment of adult patients with Gaucher disease type 1.
  • Eliglustat hemitartrate has the structure of formula (I).
  • U.S. Patent No. 7,196,205 discloses a process for the preparation of eliglustat as shown in scheme-I.
  • phenyl-a- bromoacetate is reacted with S-(+)-phenyl glycinol to provide (5S)-5-phenylmorpholin-2-one, which is condensed with benzodioxolane-6-carboxaldehyde to provide (lR,3S,5S,8aS)-l,3-bis- (2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][l,4]oxazin-8-one.
  • the resulting cycloadduct compound is reacted with pyrrolidine followed by methanol and aqueous hydrochloric acid solution to provide (2S,3R,l"S)-3-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3- hydroxy-2-(2"-hydroxy-l"-phenyl-ethylamino)-l-pyrrolidin-l-yl-propan-l-one, which is further reduced with lithium aluminum hydride and debenzylated with 20% palladium hydroxide on carbon to yield (lR,2R)-2-amino-l-(2',3'-dihydro-benzo[l,4]dioxin-6'-yl)-3-pyrrolidin-l-yl- propan-l-ol.
  • the final step involves condensation of the resulting product with octanoic acid N- hydroxysuccinimide ester to yield eliglust
  • CN105646442A discloses reaction of (lR,2R)-2-amino- dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-l-ol with boc anhydride followed by benzyl bromide and then de-protection of the boc group to provide (lR,2R)-l-(benzyloxy)-l- (2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-3-(pyrrolidin-l-yl)propan-2-amine. Condensation of the resulting compound with octanoyl chloride yields benzylated eliglustat which is debenzylated by hydrogenation to provide eliglustat.
  • U.S. Patent No. 6,916,802 discloses a process for preparing ceramide-like compounds which involves resolution of isomers by chromatography. However, this process is not suitable for large scale industrial preparations. Therefore, there is a need to develop a simple iterative process for the preparation of eliglustat and its tartrate salt which is economical and applicable on an industrial scale.
  • U.S. Patent Application Publication No. 2013/137743 discloses crystalline form A of eliglustat hemitartrate and a process for preparation thereof.
  • Amorphous eliglustat hemitartrate is known from WO2016/001885 and IN201621009771, in which the amorphous eliglustat hemitartrate is obtained by spray drying or by dissolving eliglustat hemitartrate in a solvent or a mixture of solvent, followed by evaporation under reduced pressure to obtain solid residue.
  • the said process is not suitable for industrial application as the residue obtained has a higher amount of residual solvent.
  • the obtained amorphous material is not stable and is hygroscopic in nature, and therefore is not suitable in handling and use for pharmaceutical developments.
  • amorphous eliglustat hemitartrate obtained herein is non-hygroscopic, substantially free from residual solvent, industrially scalable for bulk manufacturing and stable towards polymorphic conversion at ambient conditions.
  • One or more embodiments provide a simple and commercially advantageous process for the preparation of amorphous eliglustat hemitartrate.
  • the present invention provides processes for the preparation of eliglustat or its tartrate salt (I). Also provided are: a stable amorphous form of eliglustat hemitartrate, a process for preparation thereof, a pharmaceutical composition comprising the same, and use of eliglustat hemitartrate for treatment of gaucher disease.
  • a process for preparation of eliglustat or its tartrate salt comprises:
  • a process for preparation of eliglustat or its tartrate salt comprises: (a) reacting racemic eliglustat of formula II)
  • di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII);
  • a process for preparation of racemic eliglustat of formula (VII) comprises:
  • a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
  • eliglustat or its salt is prepared substantially free of impurity eliglustat N-oxide of formula (X)
  • novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl)octan-amide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl)octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation; and
  • a process for preparation of stable amorphous eliglustat hemitartrate comprises:
  • the stable amorphous form of eliglustat hemitartrate is characterized by X-ray powder diffraction as depicted in Fig. 1 and/or Fig. 2.
  • a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • stable amorphous eliglustat hemitartrate is used for treatment of Gaucher disease.
  • Fig. 1 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate obtained after drying at about 50-55° C for about 4-6 hours under reduced pressure.
  • Fig. 2 The X-ray diffraction pattern of stable amorphous eliglustat hemitartrate after 1 month storage at ambient temperature.
  • Lewis acid is used herein to refer to a substance which can accept an unshared electron pair from another molecule.
  • ambient temperature refers to a temperature in the range of about 20° C to about 35° C.
  • Suitable solvent means a single or a combination of two or more solvents.
  • the term "obtaining" means isolating by way of filtration, filtration under vacuum, centrifugation, decantation and the like.
  • the product obtained may be further or additionally dried to achieve the desired moisture values.
  • the product may be dried in a tray drier, dried under vacuum and/or in a fluid bed drier.
  • heartrate salt covers monotartrate and hemitartrate.
  • a process for preparation of eliglustat or its tartrate salt comprises:
  • the resolution solvent may be a solvent or solvent mixture in which the racemic eliglustat and chiral acid are soluble, either completely or partially.
  • Solvents that may be used for salt formation include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like or mixtures thereof.
  • Chiral acids can be used for resolution, which facilitates the synthesis of desired enantiomers with absolute configurational assignment.
  • Suitable chiral acids include any optically enriched chiral acid capable of forming an isolable salt with racemic eliglustat of formula (VIII).
  • Non-limiting examples of chiral acids include one or more of: mandelic acid, malic acid, camphor sulfonic acid, di-p-toluoyl-D-tartaric acid, di-m-toluoyl-D-tartaric acid, and di-benzoyl- D-tartaric acid.
  • di-0,0'-aroyl-D- or L-tartaric acid can be used as a chiral acid to resolve racemic eliglustat of formula (VII). More preferably, the chiral acid is di-p-toluoyl-D- tartaric acid.
  • Suitable bases include any base, either organic or inorganic, which allow release of the eliglustat free base from its salt form. Bases include, but are not limited to, alkali or alkaline earth metal carbonates such as: sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
  • a process for preparation of eliglustat or its tartrate salt comprises the steps of:
  • di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p- toluoyl-D-tartrate salt of formula (VIII); optionally purifying the di-p-toluoyl-D-tartrate salt of formula (VIII)
  • racemic eliglustat of formula (VII) is reacted with di-p-toluoyl-D-tartaric acid in the presence of a suitable solvent to provide di-p-toluoyl-D-tartrate salt of formula (VIII).
  • Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; and halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; or mixtures thereof.
  • Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) may be purified from solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • solvents selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl is
  • eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX).
  • Solvents include, but are not limited to: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform and the like; hydrocarbons such as toluene, xylene and the like; and water; or mixtures thereof.
  • Bases include, but are not limited to: alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate; bicarbonate such as sodium bicarbonate, potassium bicarbonate; and hydroxide such as sodium hydroxide, potassium hydroxide; or mixtures thereof.
  • the reaction may be carried out with dichloromethane, water and potassium carbonate to provide eliglustat free base of formula (IX).
  • Eliglustat free base of formula (IX) may be purified from solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • solvents selected from, but not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; polar aprotic solvents such as dimethylformamide, acetamide and the like; ethers such as tetrahydrofuran, methyl tert. butyl ether and the like; and water; or mixtures thereof.
  • eliglustat free base of formula (IX) is reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate (I).
  • Solvents include, but are not limited to: hydrocarbons such as toluene, xylene and the like; alcohols such methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and water; or mixtures thereof.
  • the reaction may be carried out with toluene, water and L-(+)-tartaric acid to provide eliglustat hemitartrate (I).
  • the reaction may be carried out at a temperature of about 10° C to about 130° C, preferably at about 20° C to about 80° C.
  • the reaction of eliglustat free base of formula (IX) with L-(+)-tartaric acid may be carried out for about 15 min. to about 4 hours, preferably for about 30 min. to about 2 hours.
  • Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture by evaporation, filtration, concentration, precipitation, cooling, centrifugation, decantation or any other suitable technique known in the art.
  • Eliglustat hemitartrate of formula (I) may be isolated from the reaction mixture using solvent.
  • Solvent used for isolation may include, but are not limited to: hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; and water; or mixtures thereof.
  • a process for preparation of racemic eliglustat of formula (VII) comprises:
  • the obtained compound of formula (III) is in situ reacted with an aminating agent and hydrochloric acid to provide 2-amino-l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)ethan-l-one hydrochloride of formula (IV).
  • Aminating agents that may be used include, but are not limited to: hexamine, ammonia and the like.
  • Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; or mixtures thereof.
  • Non-limiting examples of the octanoic acid derivatives include: corresponding octanoyl halide, symmetric or mixed carboxylic anhydride, and the corresponding sulfonyloxy or imidazole derivatives.
  • the reaction can be carried out using condensing agents such as CDI (carbonyldiimidizole), HOBt (1-hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate)), TATU ((0- (7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate)), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), and DCC ( ⁇ , ⁇ '-dicyclohexylcarbodiimide) in
  • Solvents that may be used include, but are not limited to: halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like; hydrocarbon such as toluene, xylene and the like; and ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
  • halogenated hydrocarbons such as dichloromethane, chlorobenzene, chloroform and the like
  • hydrocarbon such as toluene, xylene and the like
  • ethers such as tetrahydrofuran (THF) and diethyl ether; or mixtures thereof.
  • Bases that may be used include, but are not limited to: diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), potassium carbonate, sodium carbonate, and the like.
  • DIPEA diisopropylethylamine
  • TEA triethylamine
  • DEA diethylamine
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • imidazole ⁇ , ⁇ -dimethyl aniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN)
  • DBN diazabicyclo[4.3.0]non-5-ene
  • the acetylation of formula (IV) may be performed
  • compound of formula (VI) is treated with oxalic acid in the presence of a suitable solvent to provide oxalate salt of formula (VI).
  • Solvents that may be used for salt formation include, but are not limited to: alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, or mixtures thereof.
  • Solvents that may be used for reduction include, but are not limited to: alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, and t-butanol, or mixtures thereof.
  • Reduction can be performed by catalytic hydrogenation or with a hydrogenation reducing agent.
  • a catalytic hydrogenation reducing agent may include: noble metal catalyst such as Pd, Pt, Rh and Ru supported on carbon, or using a complex of such metal such as palladium, palladium-carbon, palladium hydroxide-carbon, platinum oxide, copper chromite, palladium acetate, platinum- carbon, palladium-alumina, and Raney nickel.
  • a hydrogenation reducing agent may include: sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite; tetra lower alkyl ammonium borohydrides such as tetra methyl ammonium borohydride, tetra ethyl ammonium borohydride, tetra-n-butyl ammonium borohydride, tetra-n-butyl ammonium cyanoborohydride, sodium cyanoborohydride, lithium cyanoborohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride and diborane.
  • sulfite compounds such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, ammonium sulfite, ammonium sulfite monohydrate, or ammonium bisulfite
  • eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is directly converted to eliglustat hemitartrate of formula (I) without isolating the eliglustat free base of formula (IX).
  • eliglustat free base of formula (IX) is not isolated but rather converted in situ to the eliglustat hemitartrate of formula (I).
  • Eliglustat di-p-toluoyl-D-tartrate salt of formula (VIII) is reacted with a suitable base in the presence of a solvent to provide eliglustat free base of formula (IX), which was in situ reacted with L-(+)-tartaric acid in the presence of a suitable solvent to provide eliglustat tartrate, preferably eliglustat hemitartrate of formula (I).
  • the undesired isomer of eliglustat can be recovered from the mother liquors of the resolution step by oxidation, followed by epimerization and reduction to provide racemic eliglustat, which can be recycled for further resolution.
  • a process for recycling racemic eliglustat of formula (VII) or its salt comprises:
  • the mother liquor obtained after the isolation of the desired eliglustat di-p-toluoyl-D- tartrate salt of formula (VIII) may be oxidized by oxidizing agent such as potassium dichromate, potassium permanganate, hydrogen peroxide, sodium hypochlorite, sodium hypobromite, chromium trioxide in dilute sulfuric acid, mixture of potassium dichromate and dilute sulfuric acid, Jones oxidation, Swern oxidation, Baeyer-Villiger oxidation, Oppenauer oxidation, and Pinnick oxidation, or mixtures thereof.
  • Oxidation may be carried out in the presence of a solvent such as: ketone, ether, and a halogenated hydrocarbon, or mixtures thereof.
  • the obtained compound of formula (VI) may be epimerized in the presence or absence of base. Reduction of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI) or its oxalate salt may carried out as described above.
  • eliglustat or its salt is prepared having a relatively low content of one or more organic impurities compared to known organic impurities in the art.
  • a content of eliglustat N-oxide impurity of formula (X) can be controlled to a minimum level by in situ reacting the eliglustat base of formula (IX) with tartaric acid and thereby obtaining eliglustat hemitartrate salt substantially free from eli lustat N-oxide impurity of formula (X)
  • novel intermediates N-(2-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-oxoethyl) octanamide of formula (V); N-(l-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l-yl)propan-2-yl)octanamide of formula (VI); oxalate salt of N-(l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l-oxo-3-(pyrrolidin-l- yl)propan-2-yl) octanamide of formula (VI); and di-p-toluoyl-D-tartrate salt of eliglustat of formula (VIII), and their pharmaceutically acceptable solvates and hydrates thereof; processes for their preparation;
  • amorphous eliglustat hemitartrate is non-hygroscopic and does not convert into crystalline form at ambient temperature. Also, amorphous eliglustat hemitartrate, as described herein, is stable against thermal degradation during drying at elevated temperature.
  • the amorphous eliglustat hemitartrate is non-hygroscopic.
  • the change in the total weight of amorphous eliglustat hemitartrate was found to be about 0.02 weight percent.
  • the amorphous eliglustat hemitartrate may be characterized by such non- hygroscopicity upon exposure to an atmosphere of about 36% humidity for a period of 20 hours. This non-hygroscopic nature of the amorphous eliglustat hemitartrate renders it exceptionally suitable for use in preparing pharmaceutical compositions.
  • the stable amorphous eliglustat hemitartrate refers to an amorphous form of eliglustat hemitartrate that remains stable towards conversion to crystalline form at ambient temperature for a period of at least 1 month, showing no change in polymorphic form by X-ray powder diffraction when placed at a temperature of 25 ⁇ 2° C at a relative humidity of 60 +5% for 1 month, or at a temperature of 5 ⁇ 2° C for 1 month.
  • the stable amorphous eliglustat hemitartrate is substantially free of residual solvent, wherein the term “substantially free of residual solvent” refers to the stable amorphous form of eliglustat hemitartrate having less than 5000 ppm of residual solvent.
  • a process for preparation of stable amorphous eliglustat hemitartrate comprises:
  • the starting material to be used for the preparation of stable amorphous eliglustat hemitartrate can be obtained by a method known to a person of ordinary skill in the art including, for example, the method described in WO 2016/001885 and/or US Publication No. 2013/0137743, which are incorporated herein by reference.
  • the suspension of eliglustat hemitartarate can be obtained by known methods that include direct use of a reaction mixture containing eliglustat hemitartarate that is obtained in the course of its synthesis, or suspension of eliglustat hemitartarate in suitable solvent or mixture of solvents.
  • the suspension of eliglustat hemitartrate may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in suitable solvent.
  • suitable solvent may include, but is not limited to,: hydrocarbons such as toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol and the like; ketones such as acetone, butanone, 2-pentanone, 3- pentanone, methyl butyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobuty
  • solvent is removed to obtain a residue.
  • the suspension of eliglustat hemitartrate in solvent may be distilled until partial removal of solvent by distillation under vacuum.
  • Suitable techniques that can be used for the removal of solvent include but not limited to: evaporation, simple evaporation, decantation, and rotational drying, or any other suitable technique known in the art.
  • the solvent may be removed, optionally under reduced pressures, at temperature less than about 150° C, less than about 100° C, less than about 75° C, less than about 50° C, or any other suitable temperature.
  • eliglustat hemitartrate is suspended in toluene under reflux conditions and the water contained in it is removed by azeotropic distillation.
  • the solvents of (b) include but are not limited to a group of solvents in which eliglustat hemitartrate is insoluble or poorly soluble or partially soluble.
  • the solvents may include, but are not limited to: ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol and the like; and hydrocarbons such as toluene, xylene, hexane, cyclohexane, heptane and the like; or mixtures thereof.
  • Embodiments of the process may further comprise dissolving the obtained eliglustat hemitartrate in solvent and removing the solvent to obtain a residue.
  • the residue is treated with suitable solvent to obtain an amorphous form of eliglustat hemitartrate.
  • an amorphous form of eliglustat hemitartrate is obtained.
  • the isolation may be effected by removing the solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to filtration, decantation or any other suitable technique known in the art.
  • suitable techniques which can be used for obtaining an amorphous form of eliglustat hemitartrate include, but not limited to, filtration under vacuum, evaporation, decantation or any other suitable technique known in the art.
  • the obtained amorphous eliglustat hemitartrate from (c) may be collected by using techniques such as by scraping or by shaking the container or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford an amorphous form of eliglustat hemitartrate. Drying can be carried out under reduced pressure, vacuum tray drying or air drying. Drying can be carried out for any desired times until the required product quality is achieved.
  • the obtained eliglustat hemitartrate may be dried under vacuum at about 50° C to 70° C for 6-12 hours to obtain the amorphous form substantially free from residual solvent.
  • the obtained amorphous eliglustat hemitartrate is stable under ordinary stability conditions at least for 1 month and does not change to crystalline form.
  • the stable amorphous form of eliglustat hemitartrate is characterized by the X-ray powder diffraction substantially as depicted in Fig. 1 and/or Fig. 2.
  • a pharmaceutical composition comprises the stable amorphous form of eliglustat hemitartrate together with one or more pharmaceutically acceptable carriers or excipients.
  • compositions containing stable amorphous eliglustat hemitartrate may be prepared by using excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
  • excipients such as diluents, binders, wetting agents, disintegrating agents, surface active agents and lubricants.
  • Various modes of administration of the pharmaceutical compositions of the invention may be selected depending on the therapeutic purpose for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injection preparations.
  • stable amorphous eliglustat hemitartrate is for treatment of Gaucher disease.
  • the pharmaceutical compositions containing stable amorphous eliglustat hemitartrate disclosed herein can be used for treatment of Gaucher disease.
  • HPLC purity of eliglustat hemitartrate was determined using a symmetry CI 8 (250* 4.6mm, 5 ⁇ ) column with a flow rate of 1.2 ml/min; column oven temperature: 40° C; sample tray temperature: ambient; detector: UV at 275nm; injection volume: 20 ⁇ 1; runtime: 65 min.
  • the synthetic reaction scheme for eliglustat hemitartrate is as shown in Scheme-Ill.
  • Eliglustate hemitartrate Eliglustat
  • the reaction mixture was allowed to warm at 25-35° C and then water (700 ml) and dichloromethane (700 ml) were added to the reaction mixture.
  • the pH of the reaction mixture was adjusted to 8.0-10.0 with 20% potassium carbonate solution.
  • the reaction mixture was stirred for 30 min. and then the layers were separated.
  • the organic layer was washed with water (200 ml), distilled out under vacuum and then azeotroped with methanol (100 ml).
  • the obtained crude product (VII) was dissolved in methanol (700 ml), and then a solution of di-p-tolyl-D-tartaric acid (74.5 g) in methanol (300 ml) was added at 50-60° C.
  • the reaction mixture was stirred at 50-60° C for 1 h. Then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). Suck dry and mixed the obtained wet cake with methanol (750 ml). The reaction mixture was heated to reflux for 1 h, then the reaction mixture was cooled at 25-35° C and stirred for 2 h. The solid was filtered and washed with methanol (50 ml X 2). The solid was dried at 25-35° C for 2 h and then at 55-65° C for 8 h to give the title product (43.32 g).
  • Cyclohexane (40 ml) was added to the obtained residue and stirred for 30 min. The cyclohexane was distilled out under vacuum and then the residue degassed under vacuum to remove traces of solvent. Cyclohexane (200 ml) was added to the obtained residue and stirred for 1 h at 45-55° C. The reaction mixture was cooled to 25-35° C and stirred for 1 h. The solid was filtered and washed with cyclohexane (20ml X 2). The solid was dried at 25-35° C for 2 h and then at 45-55° C for 4 h to give the title product (19.5 g).
  • the organic layer was filtered through a Hyflo bed and washed with toluene.
  • a solution of L-(+) tartaric acid (9.4 g) in water (200 ml) was added to the obtained toluene layer at 25-35°C and stirred for 30 min.
  • the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (50 ml).
  • the aqueous layer was distilled out under vacuum below 60° C to provide residue. Water (75 ml) was added to the residue at 35-45°C and stirred to provide a clear solution.
  • the obtained solution was dried in a vacuum tray dryer at 35-45°C for 2 h and then at 45-55° C for 12 h.
  • the obtained product was further dried in a vacuum tray dryer at 45-55°C until the water content was not more than 1.0 %w/w to give the title product (49.89 g).
  • the layers were separated and the organic layer was washed with dilute aqueous ammonia solution (-2% w/v) (50 ml) followed by water (50 ml X 3).
  • the organic layer was filtered through a Hyflo bed and washed with toluene (25 ml).
  • a solution of L-(+) tartaric acid (2.37 g) in water (50 ml) was added to the obtained toluene layer at 25-35° C and stirred for 30 min.
  • the layers were separated, and the aqueous layer (containing product)was filtered to remove particulate matter and washed with water (7 ml).
  • the aqueous layer was distilled out under vacuum below 60° C to provide residue.
  • Residual solvent content (toluene): 0.01wt%.
  • the obtained amorphous eliglustat hemitartrate was kept in an open air having about 36% humidity for 20 h to evaluate any change in the water content and thus its hygroscopicity.
  • the change in the total weight of amorphous eliglustat hemitartrate found 0.02%, indicating a low degree of hygroscopicity.
  • Residual solvent content (toluene): 0.01wt%.

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Abstract

L'invention concerne un procédé de préparation d'hémitartrate d'eliglustat et d'intermédiaires de celui-ci. Elle concerne également des compositions pharmaceutiques stables à forme amorphe d'hémitartrate d'eliglustat comprenant la forme amorphe d'hémitartrate d'eliglustat, ainsi que leurs utilisations.
PCT/EP2018/060185 2017-04-21 2018-04-20 Procédé de préparation d'hémitartrate d'eliglustat et d'intermédiaires de celui-ci WO2018193090A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110759885A (zh) * 2018-07-27 2020-02-07 中国医学科学院药物研究所 制备光活依格鲁特的方法
CN110878079A (zh) * 2018-12-31 2020-03-13 北京启慧生物医药有限公司 一种高纯度依利格鲁司他的制备方法
US10888547B2 (en) 2009-11-27 2021-01-12 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
EP3941917A4 (fr) * 2019-03-22 2022-12-21 Piramal Pharma Limited Procédé amélioré pour la préparation d'éliglustat et de son intermédiaire
CN118284600A (zh) * 2021-11-12 2024-07-02 曙方(上海)医药科技有限公司 依利格鲁司他可药用盐及其晶型

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6916802B2 (en) 2002-04-29 2005-07-12 Genzyme Corporation Amino ceramide-like compounds and therapeutic methods of use
US7196205B2 (en) 2001-07-16 2007-03-27 The Regents Of The University Of Michigan Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US20130137743A1 (en) 2009-11-27 2013-05-30 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
WO2016001885A2 (fr) 2014-07-03 2016-01-07 Dr. Reddy’S Laboratories Limited Forme amorphe d'hémitartrate d'eliglustat
CN105646442A (zh) 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 一种依利格鲁司他的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE407133T1 (de) * 2003-05-13 2008-09-15 Hoffmann La Roche 2-imidazo-benzothiazole als adenosin-rezeptor liganden
FR2864628B1 (fr) * 2003-12-30 2006-02-17 Commissariat Energie Atomique Systeme de detection de rayonnements a comptage d'impulsions a double remise a zero

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7196205B2 (en) 2001-07-16 2007-03-27 The Regents Of The University Of Michigan Synthesis of UDP-glucose: N-acylsphingosine glucosyltransferase inhibitors
US6916802B2 (en) 2002-04-29 2005-07-12 Genzyme Corporation Amino ceramide-like compounds and therapeutic methods of use
US20130137743A1 (en) 2009-11-27 2013-05-30 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
WO2016001885A2 (fr) 2014-07-03 2016-01-07 Dr. Reddy’S Laboratories Limited Forme amorphe d'hémitartrate d'eliglustat
CN105646442A (zh) 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 一种依利格鲁司他的制备方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10888547B2 (en) 2009-11-27 2021-01-12 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
US11458119B2 (en) 2009-11-27 2022-10-04 Genzyme Corporation Amorphous and a crystalline form of genz 112638 hemitartrate as inhibitor of glucosylceramide synthase
CN110759885A (zh) * 2018-07-27 2020-02-07 中国医学科学院药物研究所 制备光活依格鲁特的方法
CN110759885B (zh) * 2018-07-27 2021-10-22 中国医学科学院药物研究所 制备光活依格鲁特的方法
CN110878079A (zh) * 2018-12-31 2020-03-13 北京启慧生物医药有限公司 一种高纯度依利格鲁司他的制备方法
EP3941917A4 (fr) * 2019-03-22 2022-12-21 Piramal Pharma Limited Procédé amélioré pour la préparation d'éliglustat et de son intermédiaire
US12398114B2 (en) 2019-03-22 2025-08-26 Piramal Pharma Limited Process for the preparation of ELIGLUSTAT and its intermediate
CN118284600A (zh) * 2021-11-12 2024-07-02 曙方(上海)医药科技有限公司 依利格鲁司他可药用盐及其晶型

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