WO2014102830A1 - Procédé de préparation de ticagrelor et de ses intermédiaires - Google Patents

Procédé de préparation de ticagrelor et de ses intermédiaires Download PDF

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Publication number
WO2014102830A1
WO2014102830A1 PCT/IN2013/000812 IN2013000812W WO2014102830A1 WO 2014102830 A1 WO2014102830 A1 WO 2014102830A1 IN 2013000812 W IN2013000812 W IN 2013000812W WO 2014102830 A1 WO2014102830 A1 WO 2014102830A1
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Prior art keywords
formula
compound
limited
acid
methyl
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PCT/IN2013/000812
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English (en)
Inventor
Vijayavitthal MATHAD VIJAYAVITTHAL THIPPANNACHAR
Navnath NIPHADE NAVNATH CHINTAMAN
Gorakshanath SHINDE GORAKSHANATH BALASAHEB
Santosh PADAKI SANTOSH AMBADAS
Pravin MAHALE PRAVIN KESHAV
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Megafine Pharma (P) Ltd.
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Publication of WO2014102830A1 publication Critical patent/WO2014102830A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a method for the preparation of [1S-(1a, 2a,3 (1S * ,2R*),5p)]-3-[7-[2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-1 ,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)- cyclopentane-1 ,2-diol, ticagrelor of formula (I), and its intermediates thereof.
  • the present invention also relates to a method for the preparation of ticagrelor wherein, the said invention substantially eliminates the impurities formed during the preparation of ticagrelor.
  • Ticagrelor acts as an adenosine uptake inhibitor, platelet aggregation inhibitor, P2Y12 purinoceptor antagonist and a coagulation inhibitor drug, used for the prevention and treatment of thrombosis, angina, ischemic heart diseases, and coronary artery diseases.
  • US6251910 patent discloses a method for preparing derivative of ticagrelor as shown in scheme-1 and the intermediates used for preparation of ticagrelor and its derivatives.
  • US6525060 patent discloses a method for preparing ticagrelor by condensing compound of formula (MA) with, compound of formula (III) in the presence of N, N-diisopropylethylamine in tetrahydrofuran (THF) as solvent to produce compound of formula (IV), followed by reduction in the presence of iron in acetic acid to produce compound of formula (V).
  • THF tetrahydrofuran
  • the compound of formula (V) is reacted with isoamyl nitrile in acetonitrile to produce compound of formula (VI), followed by reaction with ammonia in THF to produce compound of formula (VII), followed by reaction with trifluoromethanesulfonyloxyacetic acid methyl ester in butyl lithium and THF to produce compound of formula (VIII).
  • the obtained compound is further brominated using isoamylnitrile and bromoform to produce compound of formula (IX), followed by condensation with compound of formula (X) in N,N- diisoproylethylamine in methylene dichloride (MDC) as a solvent to produce compound of formula (XI), followed by reaction with DIBAL-H in THF and sodium potassium tartrate to produce compound of formula (XII).
  • MDC methylene dichloride
  • DIBAL-H in THF and sodium potassium tartrate to produce compound of formula (XII).
  • the obtained compound of formula (XII) is deprotected using trifluoroacetic acid in water and ethyl acetate to produce ticagrelor compound of formula (I) as shown in scheme-2.
  • PCT publication number WO01/92263 discloses a method for preparing ticagrelor by condensation of compound of formula (II) with compound of formula (XV) in ethanol and triethylamine to produce compound of formula (XVI), followed by diazotization and ring formation using sodium nitrite in acetic acid to produce compound of formula (XVII).
  • the obtained compound of formula (XVII) is further condensed with compound of formula (X) in acetonitrile in presence of triethylamine to produce compound of formula (XII).
  • the compound of formula (XII) is deprotected with aqueous hydrochloric acid in methanol to furnish ticagrelor compound of formula (I) as shown in scheme-3
  • condensation reaction has to be conducted in autoclave under pressure hence, not production friendly;
  • iv. IMP-1 is formed during the synthesis of compound of formula (I).
  • the present invention proposes an improved process for preparation of ticagrelor and its intermediates thereof; which is economic, efficient, eco- friendly, and eliminates extensive laborious work-up.
  • the primary object of the present invention is to provide an improved process for preparation of ticagrelor of formula (I):
  • Another object of the present invention is to provide improved process for preparation of intermediates of ticagrelor.
  • Yet another object of the present invention is to provide a process for preparation of ticagrelor of formula (I); wherein the said process eliminates laborious workup and extensive purifications. Hence, makes the process simple, easy and user friendly.
  • Yet another object of the present invention is to provide a process for preparation of ticagrelor of formula (I), which is substantially free from impurities, and thereby eliminating the required purification steps and further making the process cost effective and efficient.
  • Yet another object of the present invention is to provide crystalline solid compound of formula (IV), (XVI), (XX), (XXI) and (XXII).
  • Figure 1 illustrates X-ray powder diffraction (XRD) pattern of compound of formula (XVI), prepared according to example 1.
  • FIG. 1 illustrates Infrared spectrum (IR) of compound of formula (XVI), prepared according to example 1.
  • Figure 3 illustrates X-ray powder diffraction (XRD) pattern of ticagrelor compound of formula (I), prepared according to example 4.
  • FIG. 4 illustrates Infrared spectrum (IR) of compound of formula (I), prepared according to example 4.
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising:
  • step (a) reacting compound of formula (XVI) of step (a) using a diazotizing agent in an acid and a solvent to prepare 2-( ⁇ (3a ?,4S,6/?,6aS)-6-[7-chloro-5- (propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl tetrahydro-3aH-cyclopenta[d] [1,3] dioxal-4-yl ⁇ oxy)-1-ethanol compound of formula (XVII);
  • deprotection step (c) of the said process can be carried out insitu or without isolation of intermediate of formula (XII).
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic acids such as tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like.
  • suitable acids such as tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like
  • inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like.
  • the solvent(s) used in step (a), (b), (c) and (d) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether;
  • solvents used in steps (a), (b), (c) and (d) of the present invention may be either same or different.
  • the base used in step (a) and (c) of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ⁇ , ⁇ -dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silan
  • the base used in steps (a) and (c) of the present invention may be either same or different.
  • the catalyst used in step (a) and (c) of the present invention is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 , 8-Diazabicycloundec-7-ene (DBU) or 1 , 5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • the catalyst used in steps (a) and (c) of the present invention may be either same or different.
  • the step (a) is carried out at temperature in the range of 25°C to 150X.
  • the reaction is carried out at temperature in the range of 60°C to 135°C.
  • compound of formula (XVI) may be isolated as crystalline solid.
  • isolation of compound of the formula (XVI) from reaction mass of step (a) comprises the steps of: i. extracting the compound of formula (XVI) from the reaction mass with solvent,
  • step (iv) optionally, purifying the compound of formula (XVI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula, (XVI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like
  • isolation of compound of formula (XVI) from reaction mass of step (a) can also be alternatively performed by:
  • the solvent used for purification of compound of the formula (XVI) includes, but does not limit to esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n-heptane, iso-octane, n- hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso- butanol and the like, ketone such as but not limited to acetone
  • the diazotizing agent used in step (b) for the preparation of compound of formula (XVII) includes but does not limit to resin nitrite, metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like organic nitriles such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like.
  • resin nitrite metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like
  • organic nitriles such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like.
  • the acid used in step (b) may be organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, paratoluene sulphonic acid and the like.
  • the aqueous acid used in step (d) may be either organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, oxalic acid, fumaric acid, maleic acid, paratoluene sulphonic acid and the like or inorganic acid inorganic acid such as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluride in ether and the like.
  • ticagrelor compound of formula (I) may be isolated from the reaction mass to obtain crystalline solid of compound of formula (I)
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (d) comprises the steps of:
  • step (iii) decolorizing the said organic layer of step (ii) with activated charcoal, iv. concentrating the said organic layer of. step (iii) to obtain the residue comprising the compound of formula (I),
  • step (iv) optionally, purifying the compound of formula (I) obtained in step (iv) by:
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane, n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to di-isopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2- methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not limited
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (d) can also be alternatively performed by:
  • the solvent used for purification of ticagrelor compound of formula (I) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic solvent selected from the group consist
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising: a) reacting, 2- ⁇ [(3af?,4S,6 6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[af][1 ,3]-dioxol-4-yl]oxy ⁇ -1-ethanol or salt of formula (II) with 4,6- dichloro-2-(propylthio)pyrimidin-5-nitro of formula (III) in a solvent and base to obtain 2-[((3aR ) 4S,6R,6aS)-6- ⁇ [5-nitro-6-chloro-2-(propylthio)-4- pyrimidinyl]amino ⁇ -2,2-dimethyltetrahydro-3aH-cyclopenta[d
  • deprotection step ( ⁇ ) of the said process can be carried out insitu or without isolation of intermediate of formula (XII).
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like.
  • the solvent(s) used in step (a), (b), (c), (d) and (e) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform; ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl
  • the base used in step (a) and (d) of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ⁇ , ⁇ -dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silan
  • the base used in step (a) and (d) of the present invention may be either same or different.
  • step (a) is carried out at temperature in the range of 0°C to 50°C.
  • the metal used in step (b) for the preparation of compound of formula (XVI) is a transition metal like iron, palladium, tin, nickel, copper, zinc, silver, platinum and the like.
  • the metal halide used in step (b) for the preparation of compound of formula (XVI) is a transition metal halide like ferric chloride, tin chloride, cupric chloride, and the like.
  • compound of formula (XVI) may be isolated as crystalline solid.
  • isolation of compound of the formula (XVI) from reaction mass of step (b) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XVI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XVI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ether
  • isolation of compound of formula (XVI) from reaction mass of step (b) can also be alternatively performed by:
  • step (i) drying the said compound of formula (XVI) obtained from step (i); iii. crystallizing the said dried compound of formula (XVI) using solvent to obtain purified compound of formula (XVI) as solid.
  • the solvent used for purification of compound of the formula (XVI) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ether
  • the diazotizing agent used in step (c) for the preparation of compound of formula (XVII) includes but does not limit to resin nitrite, metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like organic nitrites such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like.
  • the acid used in step (c) may be organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, paratoluene sulphonic acid and the like.
  • the catalyst used in step (d) for preparation of compound of formula (XII) is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 ,8-Diazabicycloundec-7-ene (DBU) or 1 ,5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • the aqueous acid used in step (e) may be either organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, oxalic acid, fumaric acid, maleic acid, paratoluene sulphonic acid and the like or inorganic acid inorganic acid such as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluride in ether and the like.
  • ticagrelor compound of formula (I) may be as a crystalline solid.
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (e) comprises the steps of:
  • step (iv) optionally, purifying the ticagrelor compound of formula (I) obtained in step (iv) by
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane, n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not limited to esters such as but not limited to ethy
  • the solvent used for purification of ticagrelor compound of formula (I) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isppropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising:
  • R is a good leaving group consisting of halogen (F, CI, Br, I), mesyloxy, tosyloxy, p-nitro phenol, imidazole, diazole, tetrazole, tri- halomethoxy;
  • deprotection step (b) of the said process can be carried out insitu or without isolation of intermediate of formula (XII).
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like.
  • the solvent used in step (a), (b) and (c) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such
  • the solvent, used in step (a), (b) and (c) of the present invention may be either same or different.
  • the base used in step (a) and (b) of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ⁇ , ⁇ -dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silan
  • the base used in step (a) and (b) of the present invention may be either same or different.
  • the step (a) is carried out at temperature in the range of 0°C to 100°C.
  • the catalyst used in step (b) for preparation of compound of formula (XII) is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 ,8-Diazabicycloundec-7-ene (DBU) or 1 ,5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • the aqueous acid used in step (c) may be either organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, oxalic acid, fumaric acid, maleic acid, paratoluene sulphonic acid and the like or inorganic acid inorganic acid such as but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluride in ether and the like.
  • ticagrelor compound of formula (I) may be isolated as crystalline solid.
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (c) comprises the steps of:
  • step (iv) optionally, purifying the ticagrelor compound of formula (I) obtained in step (iv) by
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane, n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not limited to esters such as but not limited to ethy
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (c) can also be alternatively performed by:
  • the solvent used for purification of ticagrelor compound of formula (I) includes, but does not limit to nitriles, ketones, alkylacetates, dimethyfomamide, dimethylsulfoxide, ethers, esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, cyclic ethers, substituted cyclic ethers, dialkylacetamides, ionic liquids, and water or mixtures thereof
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising:
  • the said process can be carried out insitu.
  • compound of formula (XVI), compound of formula (XX) and compound of formula (XXI) may be isolated as crystalline solid.
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like.
  • organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like
  • organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like organic and inorganic acids
  • the solvent used in step (a), (b), (c) and (d) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic
  • step (a), (b), (c) and (d) of the present invention may be either same or different.
  • the base used in step (a) and (d) for of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to N,N-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ⁇ , ⁇ -dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silan
  • the base used in step (a) and (d) for of the present invention may be either same or different.
  • the catalyst used in step (a) and (d) of the present invention is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 , 8-Diazabicycloundec-7-ene (DBU) or 1 , 5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • step (a) and (d) of the present invention may be either same or different.
  • the step (a) is carried out at temperature in the range of 25°C to 150°C.
  • the reaction is carried out at temperature in the range of 60 °C to 135°C
  • compound of formula (XVI) may be as a crystalline solid.
  • isolation of compound of the formula (XVI) from reaction mass of step (a) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XVI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XVI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like;
  • isolation of compound of formula (XVI) from reaction mass of step (a) can also be alternatively performed by:
  • step (i) drying the said compound of formula (XVI) obtained from step (i); iii. crystallizing the said dried compound of formula (XVI) using solvent to obtain purified compound of formula (XVI) as solid.
  • the solvent used for purification of compound of the formula (XVI) includes, but does not limit to esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n-heptane, iso-octane, n- hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso- butanol and the like, ketone such as but not limited to acetone
  • Deprotection of compound of formula (XVI) is carried out using acid in solvent; wherein the acid may be organic or inorganic acid and the solvent used for deprotection is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, ⁇ chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl
  • the step (b) is carried out at temperature in the range of 25°C to 50°C.
  • compound of formula (XX) may be isolated as a crystalline solid.
  • isolation of compound of the formula (XX) from reaction mass of step (b) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XX) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XX) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like;
  • isolation of compound of formula (XX) from reaction mass of step (b) can also be alternatively performed by:
  • the solvent used for purification of compound of the formula (XX) includes, but does not limit to esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n-heptane, iso-octane, n- hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso- butanol and the like, ketone such as but not limited to acetone
  • the diazotizing agent used in step (c) for the preparation of compound of formula (XXI) includes but does not limit to resin nitrite, metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like organic nitriles such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like.
  • resin nitrite metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like
  • organic nitriles such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like.
  • the acid used in step (c) may be organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, paratoluene sulphonic acid and the like.
  • compound of formula (XXI) may be isolated as crystalline solid.
  • isolation of compound of the formula (XXI) from reaction mass of step (c) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XXI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XXI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like
  • the solvent used for purification of compound of the formula (XXI) includes, but does not limit to esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n-heptane, iso-octane, n- hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso- butanol and the like, ketone such as but not limited to acetane,
  • ticagrelor compound of formula (I) may be as a crystalline solid.
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (d) comprises the steps of: i. extracting the ticagrelor compound of formula (I) from the reaction mass with solvent,
  • step (iv) optionally, purifying the ticagrelor compound of formula (I) obtained . in step (iv) by
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane, n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to di-isopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2- methyl tetrahydrofuran, and the like,* alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not
  • the solvent used for purification of ticagrelor compound of formula (I) includes, but does not limit to nitriles, ketones, alkylacetates, dimethyfomamide, dimethylsulfoxide, ethers, esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, cyclic ethers, substituted cyclic ethers, dialkylacetamides, ionic liquids, halogenated aliphatic hydrocarbons and water or mixtures thereof.
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising:
  • the said process can be carried out insitu.
  • compound of formula (IV), compound of formula (XX), compound of formula (XXI) and compound of formula (XXII) may be isolated as crystalline solid.
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like.
  • the solvent used in step (a), (b), (c), (d) and (e) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformannides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether;
  • step (a), (b), (c), (d) and (e) of the present invention may be either same or different.
  • the base used in step (a) and (e) of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, ⁇ , ⁇ -dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal si
  • the base used in step (a) and (e) of the present invention may be either same or different.
  • the step (a) is carried out at temperature in the range of 0°C to 50°C.
  • isolation of compound of the formula (IV) from reaction mass of step (a) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (IV) obtained in step (iv) by: a. crystallization using solvent to obtain solid, or
  • the solvent used for extraction of the compound of formula (IV) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers
  • the solid obtained may be crystalline solid of compound of formula (IV).
  • isolation of compound of formula (IV) from reaction mass of step (a) can also be alternatively performed by:
  • step (i) drying the said compound of formula (IV) obtained from step (i); iii. crystallizing the said dried compound of formula (IV) using solvent to obtain purified compound of formula (IV) as solid.
  • the solvent used for purification of compound of the formula (IV) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers
  • Compound of formula (IV) obtained in step (a) is deprotected using acid in solvent to obtain compound of formula (XXII); wherein the acid may be organic or inorganic acid and the solvent used for deprotection is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isoprop
  • the step (b) may be carried out at temperature 25°C to 50°C.
  • isolation of compound of the formula (XXII) from reaction mass of step (b) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XXII) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XXII) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons ⁇ selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and
  • the solid obtained is crystalline compound of formula (XXII).
  • isolation of compound of formula (XXII) from reaction mass of step (b) can also be alternatively performed by:
  • the solvent used for purification of compound of the formula (XXII) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic solvent selected from the group
  • the metal used in step (c) for the preparation of compound of formula (XX) is a transition metal like Iron, palladium, Tin, nickel, copper, zinc, silver, platinum and the like.
  • the metal halide used in step (c) for the preparation of compound of formula (XX) is a transition metal halide like ferric chloride, tin chloride, cupric chloride, and the like.
  • isolation of compound of the formula (XX) from reaction mass of step (c) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XX) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XX) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like;
  • the solid obtained is crystalline compound of formula (XX).
  • isolation of compound of formula (XX) from reaction mass of step (c) can also be alternatively performed by:
  • the solvent used for purification of compound of the formula (XX) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ether
  • the diazotizing agent used in step (d) for the preparation of compound of formula (XXI) includes but does not limit to resin nitrite, metal nitrite such as but not limited to sodium nitrite, potassium nitrite, silver nitrite, aluminum nitrite, lithium nitrate, rubidium nitrate, cesium nitrate, and the like organic nitrites such as but not limited to isoamyl nitrite, isopentyl nitrite, methyl nitrite and the like
  • the acid used in step (d) may be organic acid such as but not limited to formic acid, acetic acid, propanoic acid, trifluroacetic acid, perchloric acid, oxalic acid, fumaric acid, maleic acid, paratoluene suiphonic acid and the like.
  • isolation of compound of the formula (XXI) from reaction mass of step (d) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XXI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XXI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1 ,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like
  • the solid obtained is crystalline compound of formula (XXI).
  • isolation of compound of formula (XXI) from reaction mass of step (d) can also be alternatively performed by:
  • the solvent used for purification of compound of the formula (XXI) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic solvent selected from the group consist
  • the catalyst used in step (e) for preparation of compound of formula (I) is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 ,8-Diazabicycloundec-7-ene (DBU) or 1 ,5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • ticagrelor compound of formula (I) may be isolated from the reaction mass to obtain crystalline solid of compound of formula t (l)
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (e) comprises the steps of:
  • step (iv) optionally, purifying the ticagrelor compound of formula (I) obtained in step (iv) by
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, * methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane, n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahedrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not limited to esters such as but not limited to eth
  • the solvent used for purification of ticagrelor compound of formula (I) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic solvent selected from the group consist
  • the present invention provides a process for the preparation of ticagrelor of formula (I) comprising:
  • R is a good leaving group consisting of halogen (F, CI, Br, I), mesyloxy, tosyloxy, p-nitro phenol, imidazole, diazole, tetrazole, tri- halomethoxy;
  • the said process can be carried out insitu.
  • ticagrelor compound of formula (I) may be further purified either by acid-base treatment, or solvent crystallization, or converting into its acid addition salts.
  • the acid addition salts of ticagrelor of formula (I) can be prepared by treating the same with suitable acids; wherein the said acid includes organic and inorganic acids such as but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic carboxylic acid like tartaric acid, fumaric acid, acetic acid, succinic acid, maleic acid, formic acid, oxalic acid and the like.
  • the solvent used in step (a), (b) and (c) of the present invention is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers such
  • step (a), (b) and (c) of the present invention may be either same or different.
  • the base used in step (a) and (c) of the present invention may be organic or inorganic base; preferably organic bases such as but not limited primary amines such as but not limited to methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, 2-amino ethanol and the like; secondary amines such as but not limited to ⁇ , ⁇ -diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, pyrrole methylethanolamine, and the like; tertiary amines like triethylamine, ⁇ , ⁇ -dimethly aniline, n,n-diisopropyl ethyl amine, trimethyl amine, pyridine, pyrimidine, N,N-dimethylethyl amine and the like; tetraalkylammonium and phosphonium hydroxides; Metal alkoxides and amides; metal silano
  • the base used in step (a) and (c) of the present invention may be either same or different.
  • the step (a) is carried out at temperature in the range of 0°C to 100°C.
  • Compound of formula (XVII) obtained in step (a) is deprotected using acid in solvent to prepare compound of formula (XXI); wherein the acid may be organic or inorganic acid and the solvent used for deprotection is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-iso
  • isolation of compound of the formula (XXI) from reaction mass of step (b) comprises the steps of:
  • step (iv) optionally, purifying the compound of formula (XXI) obtained in step (iv) by:
  • the solvent used for extraction of the compound of formula (XXI) comprises of esters selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene, halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride, ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic ethers selected from tetrahydrofuran, 1,4-dioxane and the like; substituted cyclic ethers selected from 2-methyl tetrahydrofuran and the like; alcohol
  • the solid obtained is crystalline compound of formula (XXI).
  • isolation of compound of formula (XXI) from reaction mass of step (b) can also be alternatively performed by:
  • step (i) drying the compound of formula (XXI) obtained from step (i); and iii. crystallizing the said dried compound of formula (XXI) using solvent to obtain purified compound of formula (XXI) as solid.
  • the solvent used for purification of compound of the formula (XXI) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate and the like; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, pentane and the like; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride and the like; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; cyclic solvent selected from the group consist
  • the catalyst used in step (c) for preparation of compound of formula (I) is selected from organic, inorganic catalyst or phase transfer catalyst.
  • the organic catalyst is selected from 1 ,8-Diazabicycloundec-7-ene (DBU) or 1 ,5-Diazabicyclo(4.3.0)non-5-ene (DBN) or dimethylaminopyridine and like.
  • the inorganic catalyst is selected from groups comprising alkali metal iodide, iodine, potassium iodide, p-toluene sulfonic acid, tertiary alkyl ammonium halide, sodium iodide, lithium iodide and the like.
  • ticagrelor compound of formula (I) may be isolated as a crystalline solid.
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (c) comprises the steps of:
  • step (iv) optionally, purifying the ticagrelor compound of formula (I) obtained in step (iv) by
  • the solvent used for extraction of ticagrelor compound of formula (I) comprises of esters such as but not limited to ethyl acetate, isopropyl acetate, methyl acetate and the like, aliphatic hydrocarbons such as but not limited to n- heptane, iso-octane * , n-hexane, cyclohexane and the like, aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene and the like, ethers such as but not limited to diisopropyl ether, diethyl ether and the like, cyclic ethers such as but not limited to tetrahydrofuran, 2-methyl tetrahydrofuran, and the like, alcohol such as but not limited to methanol, ethanol, Isopropanol, iso-butanol and the like, ketone such as but not limited to esters such as but not limited to ethy
  • isolation of ticagrelor compound of formula (I) from reaction mass of step (c) can also be alternatively performed by:
  • the solvent used for purification of ticagrelor compound of formula (I) includes, but does not limit to nitriles, ketones, alkylacetates, dimethyfomamide, dimethylsulfoxide, ethers, esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons, halogenated aliphatic hydrocarbons, cyclic ethers, substituted cyclic ethers, dialkylacetamides, ionic liquids, and water or mixtures thereof
  • ticagrelor of formula (I) obtained is subjected for reduction in particle size by any of the processes known in the art such as milling, micronizination and the like to obtain stable microcrystalline of ticagrelor with d(90) less than about 40 ⁇ , preferably less than 20 ⁇ and more preferably less than 10 ⁇ .
  • Figure 1 illustrates X-ray powder diffraction (XRD) pattern of compound of formula (XVI), prepared according to example 1. It demonstrates the crystalline nature of compound of formula (XVI).
  • the X-ray diffractogram was measured on Brul er Axe, DS advance Powe r X-ray Diffracto meter with Cu K alpha-1 Radiation source having the wavelength 1 .541A".
  • Figure 3 illustrates X-ray powder diffraction (XRD) pattern of ticagrelor compound of formula (I), prepared according to example 4. It demonstrates the crystalline nature of compound of formula (I).
  • the X-ray diffractogram was measured on Brul er Axe, DS advance Power X-ray Diffracto meter with Cu K alpha-1 Radiation source having the wavelength 1 .541A°.
  • Figure 4 illustrates Infrared spectrum (IR) of compound of formula (I), prepared according to example 4.
  • the process of the present invention has less than about 0.20% (1S,2S,3R,5S)-3-[7- ⁇ [(1 R, 2S)-2-(3,4- diflurophenyl)-cyclopropyl] amino ⁇ -5- (propylthio)-3H-[1 ,2,3]triazolo[4,5-d] pyrimidin-3-yl]- 5-(oxyethylacetate)-1 ,2- cyclopentanediol compound of formula (IMP- ),
  • Reaction mixture was heated at 120-125°C stirred and maintained at same temperature for 2-3 hours, until completion of reaction (monitored by TLC). After completion of reaction, resulting mass was cooled to 20-30 °C, diluted with water (1000 ml) and pH of solution was adjusted to 4.5 using concentrated hydrochloric acid.
  • Ethyl acetate was evaporated at 50-55°C under reduced pressure to produce 80.0 gm of 2- [((3a 4S,6f?,6aS)-6- ⁇ [5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino ⁇ - 2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1 ,3] dioxol-4-yl)oxy]-1 -ethanol as oil. Obtained oil was dissolved in ethyl acetate (120.0 ml), stirred and the solution was heated at 50°C, followed by addition of n-heptane (600 ml) at 50°C and maintained for 30 min.
  • reaction mass was stirred for 60-90 min at room temperature. The progress of reaction was monitored by HPLC. After completion of reaction, resin was filtered and washed with acetonitrile (10 ml). The mother liquor was combined, followed by addition of purified water (100.0 ml) and ethyl acetate (100.0 ml), stirred followed by separation of aqueous and ethyl acetate layer. Ethyl acetate layer was washed with purified water ( 00 ml), then 15 % W/V sodium chloride solution.
  • reaction mass was stirred for 20-30 min at room temperature. The progress of reaction was monitored by TLC. After completion of reaction, resin was filtered and washed with MDC (100 ml). The mother liquor was combined, followed by addition of purified water (100.0 ml), stirred followed by separation of aqueous and MDC layer. MDC layer was washed with 5% sodium bicarbonate solution (100 ml), and then wash using purified water (100 ml).
  • the MDG was evaporated at 35-40X under reduced pressure to produce 13.0 gm of 2- ( ⁇ (3a ,4S,6 6aS)-6-[7- ⁇ [(1 2S)-2-(3,4-diflurophenyl)-cyclopropyl]amino ⁇ -5- (propylthio)-3H-[1 ,2,3]triazolo[4,5-Gf]pyrimidin-3-yl]-2,2-dimethyltetrahydro- 3aH-cyclopenta [cfl[1 ,3]dioxal-4-yl ⁇ oxy)-1 -ethanol as an oil.
  • reaction mass was washed with water (100 ml) and product was extracted twice with ethyl acetate (100 ml + 50 ml), followed by washing ethyl acetate layer with water (100 ml) and 15% W/V sodium chloride solution (100 ml).
  • reaction mass was heated and maintained at 50-55 °C for 3-4 hrs. The progress of reaction was monitored by TLC. After completion of reaction, resulting mass was filtered and mother liquor was distilled under reduced pressure. The obtained residue was diluted with water (100 ml) and (1R,2R,3S,5R)-3- ⁇ [5-amino-6-chloro-2-(propylthio) pyrimidin-4-yl]amino ⁇ -5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol was extracted twice with methylene dichloride (100 ml + 50 ml), followed by washing methylene dichloride layer with water (100 ml).
  • reaction mass was diluted with purified water , basified using liquor ammonia and (1 R,2R,3S,5R)-3-[7-chloro-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol compound was extracted in ethyl acetate (100.0 ml). Ethyl acetate layer was washed with purified water (100 ml) then 15 % WW sodium chloride solution.
  • reaction mass was stirred for 90-120 min at room temperature. The progress of reaction was monitored by TLC. After completion of reaction, resin was filtered and washed with Ethyl acetate (500.0 ml). The mother liquor was combined, followed by addition of purified water (500.0 ml), stirred followed by separation of aqueous and Ethyl acetate layer. Ethyl acetate layer was washed with purified water (500.0 ml), and 5%sodium bicarbonate solution then 15 % W/V sodium chloride solution (500.0 ml).

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Abstract

L'invention concerne un procédé amélioré pour la préparation de ticagrelor et de ses intermédiaires, ledit procédé permettant d'éliminer sensiblement les impuretés éventuellement présentes.
PCT/IN2013/000812 2012-12-31 2013-12-30 Procédé de préparation de ticagrelor et de ses intermédiaires WO2014102830A1 (fr)

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WO2015067230A1 (fr) * 2013-11-08 2015-05-14 Zentiva, K.S. Procédé de production et nouvelle forme cristalline d'un intermédiaire pour la synthèse du ticagrelor
CN105153167A (zh) * 2015-09-06 2015-12-16 惠州信立泰药业有限公司 一种替格瑞洛结晶及含有该结晶的药物组合物
WO2016030704A1 (fr) * 2014-08-30 2016-03-03 Cipla Limited Forme solide d'intermédiaire de ticagrelor
CN105481861A (zh) * 2014-09-19 2016-04-13 北京普禄德医药科技有限公司 一种血小板聚集抑制剂及其制备方法和用途
CN105503876A (zh) * 2014-09-24 2016-04-20 海门慧聚药业有限公司 替卡格雷的制备新工艺
CN105669681A (zh) * 2016-04-11 2016-06-15 成都华宇制药有限公司 一种替格瑞洛的合成方法
CN105859720A (zh) * 2015-01-20 2016-08-17 上海方楠生物科技有限公司 一种替格瑞洛溶液的制备方法
WO2016128996A3 (fr) * 2015-02-14 2016-10-27 Strides Shasun Limited Procédé amélioré de préparation du ticagrelor et intermédiaires correspondants
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
CN106543191A (zh) * 2016-10-28 2017-03-29 天津红日药业股份有限公司 一种替格瑞洛制备工艺
CN108892670A (zh) * 2018-07-12 2018-11-27 江西国药有限责任公司 一种高纯度替格瑞洛的制备方法
CN110437237A (zh) * 2019-09-06 2019-11-12 上海汇伦生命科技有限公司 一种1,2-二醇化合物单一结晶的制备方法
CN110684019A (zh) * 2019-10-29 2020-01-14 株洲千金药业股份有限公司 一种替格瑞洛中间体氧化物杂质的制备方法

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
CN105940003A (zh) * 2013-11-08 2016-09-14 赞蒂瓦有限合伙公司 替格瑞洛合成中间物的制备方法和新颖结晶形式
WO2015067230A1 (fr) * 2013-11-08 2015-05-14 Zentiva, K.S. Procédé de production et nouvelle forme cristalline d'un intermédiaire pour la synthèse du ticagrelor
WO2016030704A1 (fr) * 2014-08-30 2016-03-03 Cipla Limited Forme solide d'intermédiaire de ticagrelor
CN105481861A (zh) * 2014-09-19 2016-04-13 北京普禄德医药科技有限公司 一种血小板聚集抑制剂及其制备方法和用途
CN105503876A (zh) * 2014-09-24 2016-04-20 海门慧聚药业有限公司 替卡格雷的制备新工艺
CN105859720A (zh) * 2015-01-20 2016-08-17 上海方楠生物科技有限公司 一种替格瑞洛溶液的制备方法
WO2016128996A3 (fr) * 2015-02-14 2016-10-27 Strides Shasun Limited Procédé amélioré de préparation du ticagrelor et intermédiaires correspondants
CN105153167A (zh) * 2015-09-06 2015-12-16 惠州信立泰药业有限公司 一种替格瑞洛结晶及含有该结晶的药物组合物
CN105669681A (zh) * 2016-04-11 2016-06-15 成都华宇制药有限公司 一种替格瑞洛的合成方法
CN106543191A (zh) * 2016-10-28 2017-03-29 天津红日药业股份有限公司 一种替格瑞洛制备工艺
CN106543191B (zh) * 2016-10-28 2019-03-01 天津红日药业股份有限公司 一种替格瑞洛制备工艺
CN108892670A (zh) * 2018-07-12 2018-11-27 江西国药有限责任公司 一种高纯度替格瑞洛的制备方法
CN110437237A (zh) * 2019-09-06 2019-11-12 上海汇伦生命科技有限公司 一种1,2-二醇化合物单一结晶的制备方法
CN110684019A (zh) * 2019-10-29 2020-01-14 株洲千金药业股份有限公司 一种替格瑞洛中间体氧化物杂质的制备方法
CN110684019B (zh) * 2019-10-29 2020-08-18 株洲千金药业股份有限公司 一种替格瑞洛中间体氧化物杂质的制备方法

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