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WO2014155389A2 - Procédé de préparation de ticagrelor - Google Patents

Procédé de préparation de ticagrelor Download PDF

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Publication number
WO2014155389A2
WO2014155389A2 PCT/IN2014/000165 IN2014000165W WO2014155389A2 WO 2014155389 A2 WO2014155389 A2 WO 2014155389A2 IN 2014000165 W IN2014000165 W IN 2014000165W WO 2014155389 A2 WO2014155389 A2 WO 2014155389A2
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WO
WIPO (PCT)
Prior art keywords
compound
formula
ticagrelor
acid
give
Prior art date
Application number
PCT/IN2014/000165
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English (en)
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WO2014155389A3 (fr
Inventor
Navin G. BHATT
Samir Naik
Ajay Kumar Sharma
Mahendra CHORAGHE
Shekhar Bhaskar Bhirud
Original Assignee
Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
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Application filed by Glenmark Pharmaceuticals Limited; Glenmark Generics Limited filed Critical Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
Publication of WO2014155389A2 publication Critical patent/WO2014155389A2/fr
Publication of WO2014155389A3 publication Critical patent/WO2014155389A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of ticagrelor and pharmaceutically acceptable salts thereof.
  • Ticagrelor also known as (15,2S,3 ⁇ ,5 ⁇ -3-[7- ⁇ [(l ?,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopentane-l,2-diol, is represented by the structure of formula I.
  • Ticagrelor is a P2Y 12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome. Ticagrelor is marketed under the brand name BRILINTA® in the United States (approved in July 201 1) and under the brand name BRILIQUE® and POSSIA® in Europe (approved in December 2010).
  • United States Patent No. 6525060 discloses ticagrelor and its salts.
  • the object of the present invention is to provide a process for the preparation of ticagrelor via novel intermediate compounds.
  • the present invention provides process for the preparation of ticagrelor, a compound of formula I,
  • the present invention provides a compound of formula VI or a salt thereof.
  • the present invention provides use of compound of formula III, IV, V, VI or VII or its salt thereof in the preparation of ticagrelor or salt thereof.
  • the present invention provides use of compound of formula II in the preparation of ticagrelor or salt thereof.
  • the present invention provides a process for the purification of ticagrelor, the process comprising:
  • Figure 1 is a characteristic XRPD of ticagrelor in amorphous form as obtained in Example 1 1.
  • the present invention provides process for the preparation of ticagrelor, a compound of formula I,
  • room temperature means a temperature of about 25°C to about 30°C.
  • the reaction may be carried out in the presence of a suitable base.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n
  • the reaction may be carried out in the presence of a suitable solvent.
  • suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof.
  • the solvent selected is tetrahydrofuran.
  • the salts of the compound of formula VI may be prepared by reacting the compound of formula VI with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid.
  • acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • a suitable reducing agent includes, but is not limited to sodium dithionite, zinc/acetic acid, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof.
  • the solvent selected is acetic acid, methanol.
  • the salts of the compound of formula V may be prepared by reacting the compound of formula V with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid.
  • the acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the reaction may be carried out in the presence of alkali metal nitrite such as sodium nitrite, potassium nitrite and the like; alkaline earth metal nitrite such as calcium nitrite and the like.
  • alkali metal nitrite such as sodium nitrite, potassium nitrite and the like
  • alkaline earth metal nitrite such as calcium nitrite and the like.
  • sodium nitrite is used.
  • the reaction may be carried out in the presence of an acid.
  • a suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid.
  • the acid selected is acetic acid.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1 -butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; hydrocarbons such as toluene, xylene and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof.
  • the solvent selected is acetic acid-water mixture.
  • the present invention provides a process for the preparation of the compound of formula I wherein the product of step (c) is not isolated.
  • the reaction may be carried out in the presence of a suitable base.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n
  • the reaction may be carried out in the presence of a suitable solvent.
  • suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof.
  • the solvent selected is dimethyl formamide, tetrahydrofuran.
  • a suitable deprotecting reagent is selected from an acid or a base.
  • a suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid.
  • the acid selected is hydrochloric acid.
  • a suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, , caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetate
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof.
  • the solvent selected is tetrahydrofuran, methanol, methanol-water mixture.
  • the acetylating agent includes, but is not limited to acetyl chloride, acetic anhydride.
  • the reaction may be carried out in the presence of a suitable base.
  • the suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n
  • the reaction may be carried out in the presence of a suitable solvent.
  • suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ' ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof.
  • the solvent selected is dichloromethane.
  • the deprotection reaction may be carried out by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst.
  • the compound of formula VIII is deprotected to give the compound of formula VII by catalytic hydrogenation using palladium on carbon catalyst.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof.
  • the solvent selected is methanol.
  • the compound of formula VII may be purified by preparing its salt.
  • the salts of the compound of formula VII may be prepared by reacting the compound of formula VII with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid.
  • acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the acid is tartaric acid.
  • the present invention provides a compound of formula VI or a salt thereof.
  • the present invention provides use of compound of formula III, IV, V, VI or its salt thereof in the preparation of ticagrelor or salt thereof.
  • the present invention provides a compound of formula II.
  • the present invention provides use of compound of formula II in the preparation of ticagrelor or salt thereof.
  • the present invention provides a process for the preparation of ticagrelor, a compound of formula I, and pharmaceutically acceptable salts thereof, the process comprising treating a compound of formula II with a deprotecting reagent.
  • a suitable deprotecting reagent is selected from an acid or a base. 1
  • a suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid.
  • the acid selected is hydrochloric acid.
  • a suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium ' methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetate
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof.
  • the solvent selected is tetrahydrofuran, methanol-water mixture.
  • the compound of formula II is obtained by deprotecting the compound of formula III to give the compound of formula II.
  • the deprotection reaction may be carried out in the presence of an acid.
  • a suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid.
  • the acid selected is hydrochloric acid.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol ai d the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof.
  • the solvent selected is methanol-water mixture.
  • the present invention provides a process for the preparation of ticagrelor, a compound of formula I, and pharmaceutically acceptable salts thereof, the process comprising treating a c tecting reagent.
  • R ⁇ and R 2 are protecting groups selected from the group consisting of Cj. 6 alkyl, C 3-8 cycloalkyl, trialkylsilyl, acyl, or Rj and R 2 together with the atoms to which they are attached form an alkylidene ring such as methylidene or isopropylidene ring, or Rj and R 2 can form an alkoxymethylidene ring such as ethoxymethylidene.
  • C 1-6 alkyl includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl.
  • C 3-8 cycloalkyl includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • titaniumkylsilyl includes groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldimethylsilyl.
  • acyl includes groups such as acetyl, optionally substituted benzoyl, pivaloyl.
  • optionally substituted benzoyl means benzoyl which is optionally substituted with halo or nitro group wherein halo includes CI, Br, I.
  • a suitable deprotecting reagent is selected from an acid or a base.
  • a suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid.
  • a suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide;
  • the present invention provides a process for the preparation' of ticagrelor or salt thereof, the process comprising:
  • a suitable deprotecting reagent includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert- butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof.
  • the solvent selected is tetrahydrofuran.
  • a suitable deprotecting reagent includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid.
  • the deprotecting reagent selected is hydrochloric acid.
  • the reaction may be carried out in the presence of a suitable solvent.
  • the suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as tetrahydrofuran, ' dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof.
  • the solvent selected is methanol.
  • the present invention provides a process for the purification of ticagrelor, the process comprising: (a) dissolving tigacrelor in aromatic hydrocarbons, or a mixture of aromatic hydrocarbons with ketones or esters to form a solution,
  • the aromatic hydrocarbons used for dissolving ticagrelor include, but are not limited to toluene, xylene, chlorobenzene and the like; ketones include, but are not limited to acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters include, but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like.
  • ticagrelor is dissolved in toluene to form a solution.
  • ticagrelor is dissolved in toluene-methyl isobutyl ketone mixture to form a solution.
  • ticagrelor is dissolved in toluene-isopropyl acetate mixture to form a solution.
  • Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • ticagrelor is obtained in a purity of at least 99%, as determined by high performance liquid chromatography.
  • ticagrelor obtained is substantially free of compound of formula XII.
  • the term "substantially free” means the compound of formula XII is less than 0.10% w/w with respect to ticagrelor, as determined by high performance liquid chromatography (HPLC).
  • ticagrelor obtained is substantially free of one or more of compounds of formula XII, A or B.
  • the present invention provides ticagrelor wherein the compound of formula XII is present to an extent of less than 0.10% w/w relative to the amount of ticagrelor, obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
  • Apparatus A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
  • the retention time of ticagrelor is about 35.0 minutes under these conditions.
  • Relative retention time for compound of formula XII is about is about 1.24 with respect to ticagrelor.
  • ticagrelor is obtained in a chiral purity of at least 99.9%, as determined by high performance liquid chromatography.
  • the present invention provides pure amorphous ticagrelor and a process thereof.
  • the present invention provides amorphous form of ticagrelor having an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.
  • XRPD X-ray powder diffraction
  • the present invention provides a process for the preparation of ticagrelor i amorphous form, comprising the steps of: (a) dissolving ticagrelor in a solvent to form a solution,
  • a suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform and the like; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; or mixtures thereof.
  • the solvent selected is dichloromethane, dichloromethane-methanol mixture.
  • ticagrelor is dissolved in dichloromethane at about 40°C to form a solution.
  • Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
  • solvent was removed by concentrating the solution under vacuum to give amorphous ticagrelor.
  • the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
  • the solvate of ticagrelor includes solvate with water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, or dimethyl sulfoxide.
  • the solvent used for dissolution of the solvate of ticagrelor includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert- butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform
  • Stirring may be continued for any desired time period to achieve a complete dissolution of the compound.
  • the stirring time may range from about 30 minutes to about 3 hours, or longer.
  • the solution may be optionally treated with charcoal and filtered to get a particle-free solution.
  • Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.
  • the solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
  • solvent was removed by concentrating the solution under vacuum to give amorphous ticagrelor.
  • the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
  • the salt of ticagrelor includes salt with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.
  • the solvent used for dissolution of the salt of ticagrelor includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert- butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the
  • Stirring may be continued for any desired time period to achieve a complete dissolution of the compound.
  • the stirring time may range from about 30 minutes to about 3 hours, or longer.
  • the solution may be optionally treated with charcoal and filtered to get a particle-free solution.
  • Removal of solvent may be accomplished as discussed supra.
  • the isolated ticagrelor may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.
  • reaction mixture was further stirred for about lh to about 2h at about 0°C to about 5°C. After completion of reaction, water added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with 20% sodium chloride solution, concentrated and degassed to give the title compound.
  • the reaction mixture was stirred for about 30min to about lh at about 15°C to about 20°C.
  • Water (20mL) and toluene (20mL) was added to the reaction mixture.
  • the reaction mixture was stirred for about 5min and the two layers were separated.
  • the organic layer was washed with water.
  • the organic layer was cooled to about 10°C and a mixture of acetic acid (2mL) and water (lOmL) was added to it.
  • Sodium nitrite (0.45g) dissolved in water (5mL) was slowly added to the reaction mixture in about lOmin to about 15min maintaining the temperature at about below 20°C.
  • water was added to the reaction mixture and the pH was adjusted to about 7 to about 8 by adding sodium carbonate.
  • the two layers were separated and the organic layer was washed with water, concentrated and degassed to give 0.7g of the title compound.
  • reaction mixture was concentrated. Water (lOmL) and ethyl acetate (lOmL) was added to the reaction mixture and the pH was adjusted to about 7 to about 8 by adding sodium bicarbonate. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound.
  • reaction mixture was concentrated. Water (lOmL) and ethyl acetate (lOmL) was added to the reaction mixture and the pH was adjusted to about 7 to about 8 by adding sodium bicarbonate. The two layers were separated and the/ organic layer was washed with water, concentrated and
  • tartrate salt of 2- ⁇ [(3ai?,4S,67?,6aS)-6-amino-2,2-dimethyl- hexahydrocyclopenta[d][l,3] dioxol-4-yl]oxy ⁇ ethyl acetate tartrate salt of compound of formula VII (lg) and sodium bicarbonate (0.52g) in water (lOmL) was stirred for about 30min to about lh.
  • compound of formula X (0.82g) in tetrahydrofuran (lOmL) was added the above reaction mixture in about 30min to about lh.
  • reaction mixture was stirred for about lh to about 2h and concentrated to give an oily residue.
  • Ethyl acetate and water was added to the above residue.
  • the reaction mixture was stirred and the two layers were separated. The organic layer was washed with water, concentrated and degassed to give the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compounds Of Unknown Constitution (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé de préparation de ticagrelor et de ses sels pharmaceutiquement acceptables.
PCT/IN2014/000165 2013-03-25 2014-03-14 Procédé de préparation de ticagrelor WO2014155389A2 (fr)

Applications Claiming Priority (2)

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IN1111/MUM/2013 2013-03-25
IN1111MU2013 IN2013MU01111A (fr) 2013-03-25 2014-03-14

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WO2014155389A2 true WO2014155389A2 (fr) 2014-10-02
WO2014155389A3 WO2014155389A3 (fr) 2015-01-15

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IN (1) IN2013MU01111A (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801583A (zh) * 2014-12-31 2016-07-27 徐州万邦金桥制药有限公司 一种替格瑞洛的纯化方法
CN109633063A (zh) * 2018-12-26 2019-04-16 哈尔滨医科大学 一种人血浆中替格瑞洛及其活性代谢产物浓度的检测方法
CN110642862A (zh) * 2019-10-29 2020-01-03 株洲千金药业股份有限公司 一种替格瑞洛乙酯化杂质的制备方法
CN112394109A (zh) * 2019-08-12 2021-02-23 武汉武药科技有限公司 替格瑞洛中杂质的检测方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI229674B (en) * 1998-12-04 2005-03-21 Astra Pharma Prod Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses
GB0013407D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
WO2012138981A2 (fr) * 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. Nouveaux intermédiaires et procédés pour la préparation du ticagrelor
CN102731467B (zh) * 2011-04-15 2015-12-16 博瑞生物医药（苏州）股份有限公司 替卡格雷的中间体及制备替卡格雷的方法
CN102603751A (zh) * 2012-02-24 2012-07-25 中国药科大学 三唑并(4,5-d)嘧啶衍生物及其制备方法与在制药中的用途
CN102875537A (zh) * 2012-09-10 2013-01-16 常州制药厂有限公司 一种新的抗血栓药物的制备方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105801583A (zh) * 2014-12-31 2016-07-27 徐州万邦金桥制药有限公司 一种替格瑞洛的纯化方法
CN109633063A (zh) * 2018-12-26 2019-04-16 哈尔滨医科大学 一种人血浆中替格瑞洛及其活性代谢产物浓度的检测方法
CN112394109A (zh) * 2019-08-12 2021-02-23 武汉武药科技有限公司 替格瑞洛中杂质的检测方法
CN110642862A (zh) * 2019-10-29 2020-01-03 株洲千金药业股份有限公司 一种替格瑞洛乙酯化杂质的制备方法
CN110642862B (zh) * 2019-10-29 2021-01-26 株洲千金药业股份有限公司 一种替格瑞洛乙酯化杂质的制备方法

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Publication number Publication date
IN2013MU01111A (fr) 2015-05-01
WO2014155389A3 (fr) 2015-01-15

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