WO2014195861A2 - Préparation de ticagrélor - Google Patents

Préparation de ticagrélor Download PDF

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Publication number
WO2014195861A2
WO2014195861A2 PCT/IB2014/061912 IB2014061912W WO2014195861A2 WO 2014195861 A2 WO2014195861 A2 WO 2014195861A2 IB 2014061912 W IB2014061912 W IB 2014061912W WO 2014195861 A2 WO2014195861 A2 WO 2014195861A2
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Prior art keywords
formula
compound
ticagrelor
mixture
solvent
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PCT/IB2014/061912
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English (en)
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WO2014195861A3 (fr
Inventor
Raghupathi Reddy Anumula
Yakambram Bojja
Sreenivasulu Kurella
Veerender Murki
Ravi Ram Chandrasekhar Elati
Venkata Annapurna Sasikala Cheemalapati
Ugandar Reddy INUGALA
Thirupathi BALUGU
Subba Reddy Peddireddy
Kavitha Charagondla
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Dr. Reddy’S Laboratories Limited
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Priority to EP14807111.1A priority Critical patent/EP3004113A2/fr
Publication of WO2014195861A2 publication Critical patent/WO2014195861A2/fr
Publication of WO2014195861A3 publication Critical patent/WO2014195861A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms

Definitions

  • aspects of the present application relate to processes for preparing ticagrelor and its intermediates that are useful in the processes.
  • the drug compound having the adopted name "ticagrelor" has chemical names: [1 S-(1 ⁇ ,2 ⁇ ,3 ⁇ (1 S * ,2R * ),5p)]-3-[7-[2-(3,4-difluorophenyl-cyclopropyl]amino]- 5-(propylthio)-3H-1 ,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)- cyclopentane-1 ,2-diol; or (1 S,2S,3fl,5S)-3-[7- ⁇ [(1 fl,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino ⁇ -5-(propylthio)-3/--[1 ,2,3]-triazolo[4,5-c]pyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopen by Formula I.
  • Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active ⁇ 2 ⁇ (which is now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used, inter alia, as inhibitors of platelet activation, aggregation, or degranulation.
  • International Patent Application Publication Nos. WO 01/92263 and WO 2010/030224 A1 , WO2012085665 A2, WO2012138981 A2 and WO2013037942A1 disclose processes for preparing ticagrelor.
  • Ticagrelor is the active ingredient in the commercially available BRILINTA ® tablets for oral administration.
  • Ticagrelor and related compounds suffer from various disadvantages, since the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions under pressure and high temperature, longer reaction times, tedious work up procedures and multiple crystallizations or isolation steps, column chromatographic purifications and thus resulting in low overall yields of the product.
  • Ticagrelor obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Ticagrelor at various stages of the processes that are difficult to purify and thus get carried forward in the subsequent steps therefore affecting the purity of final compound.
  • the inventors of the present application have surprisingly found that when intermediates of Ticagrelor are isolated in the form of solid, purity of Ticagrelor got increased. For example, isolation of compound of Formula IV and/or compound of Formula VII in the form of solid avoided the carryover of related impurities to the further stages in the preparation of Ticagrelor and ultimately leads to the highly pure Ticagrelor .
  • An aspect of the present application provides process for preparing the compound of Formula I, embodiments comprising isolation of intermediate compounds of Formula IV and/or Formula VII in the solid form.
  • Formula IV Formula VII where R 2 and R 3 independently are hydroxy or protected hydroxy groups and HX is an acid moiety selected from organic or inorganic acid.
  • Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula IV, prepared according to Example 1 .
  • PXRD powder X-ray diffraction
  • Fig. 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula IV, prepared according to Example 2.
  • PXRD powder X-ray diffraction
  • Fig. 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula VII, prepared according to Example 6.
  • PXRD powder X-ray diffraction
  • Fig. 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula I, prepared according to Example 14.
  • PXRD powder X-ray diffraction
  • An aspect of the present application provides process for preparation of compound of Formula IV, embodiments comprising,
  • step a) providing a mixture of compound of Formula IV in a suitable solvent,
  • the mixture comprising compound of Formula IV in step a) may be a suspension or a solution.
  • the mixture of step a) may be obtained, for example, by providing an isolated compound of Formula IV in any form in a suitable solvent or alternatively said mixture may be obtained by a previous step of reaction between compound of Formula III or a salt thereof with compound of Formula I I or its salt. If it is intended to obtain a clear solution in step a), the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the compound of Formula IV is not compromised and a substantially clear solution is obtained.
  • the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent.
  • Solvents employed for step a) include, but are not limited to: alcohols, such as, for example, methanol, ethanol, or 2-propanol; esters, such as, for example, ethyl acetate, isopropyl acetate, or t-butyl acetate; ketones such as acetone or methyl isobutyl ketone; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, THF, or methyl THF; halogenated hydrocarbons, such as, for example, dichloromethane, dichloroethane, chloroform, or the like; hydrocarbons, such as, for example, toluene, hexane, heptane, xylene, or cyclohexane; nitriles such as acetonitrile; dipolar aprotic solvent
  • R 2 and R3 independently are hydroxy or protected hydroxy groups.
  • Some suitable protecting groups are described by T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., 1 999, and other groups are described in the literature.
  • step b) reacting the mixture of step a) with a suitable acid
  • a suitable acid employed in step b) is mineral or organic acid.
  • Suitable mineral acids for salt formation include hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid.
  • Suitable organic acids include organic achiral acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids, and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p- toluoyl-L-tartaric acid, R-Mandelic acid and like.
  • organic acid is employed and more preferably, L-tartaric acid, R-mandelic acid are used.
  • the free acid can be directly added as solid/liquid or its mixture in a solvent can be employed. Suitable inert solvents can be selected from the list mentioned for step a). Non-dissolved particles from a mixture of step b) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.
  • the acids are employed in salt preparation-depending on whether a mono- or polybasic acid is concerned and depending on which salt is desired in an equimolar quantitative ratio or one differing therefrom.
  • the acid and the free compound may be substantially in 1 :1 stoichiometry or one differing therefrom, such as e.g. from about 1 :2 to about 2:1 stoichiometry.
  • Non-stoichiometric ratios may also be possible, such as e.g. 1 :1 .5 or 1 .5:1 .
  • the reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for a time from about 10 minutes to about 5 hours or longer.
  • Suitable temperatures for crystallization are from about 0°C to about 50°C, from about 10 to about 30°C, or any other suitable temperatures may be used.
  • Suitable times for crystallization will vary, and can be from about 10 minutes to about 10 hours, or longer.
  • the product so formed in step c) can be isolated by conventional methods including decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, or other techniques known in the art for the recovery of solids.
  • the isolation may be optionally carried out at atmospheric pressure or under a reduced pressure.
  • step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles.
  • the resulting solid of compound of Formula IV may optionally be further dried. Drying may be suitably carried out using equipment such as a tray dryer (VTD or ATD), vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
  • crystals of compound of Formula IV may be used as the nucleating agent or "seed" crystals for subsequent crystallizations of compound of Formula IV from solutions.
  • the present invention relates to compound of Formula IV (including their solvates and hydrates) in solid forms, including amorphous, semi- amorphous, semi-crystalline and crystalline forms, as well as mixtures thereof.
  • acid in compound of Formula IV of the present invention are L- tartaric acid, mandelic acid and like.
  • Another aspect of the present application further provides process for preparation of Ticagrelor, embodiments comprising,
  • Formula IV Formula V where R 2 and R 3 independently are hydroxy or protected hydroxy groups.
  • Suitable solvents employed in step a) will generally be inert to the reaction conditions.
  • reaction is carried out in water.
  • mixture of organic solvent such as ethyl acetate and water is employed.
  • Suitable acid in step a) can be inorganic or organic acid.
  • Inorganic acid selected includes but not limited to hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid.
  • Suitable organic acids include organic acids such as acetic, trifluoroacetic and like.
  • organic acid is employed and more preferably, acetic acid is used.
  • a suitable organic solvent preferably, aromatic hydrocarbon is added to the reaction mixture.
  • organic solution from step a) is used as such for subsequent step without distillation of organic solvent.
  • the compound of Formula VI can be prepared by using methods known in the art. If a salt of the compound of Formula VI is employed, then a free base may be generated in situ during the reaction.
  • the reaction is carried out in the presence of a suitable base, such as, but not limited to, organic bases like triethylamine, diisopropylethylamine, morpholine, DABCO (1 ,4-diazabicyclo [2.2.2]octane) and the like.
  • a suitable base such as, but not limited to, organic bases like triethylamine, diisopropylethylamine, morpholine, DABCO (1 ,4-diazabicyclo [2.2.2]octane) and the like.
  • diisopropylethylamine is employed.
  • Suitable solvents will generally be inert to the reaction conditions.
  • toluene is employed.
  • R 2 and R 3 are protected hydroxy groups.
  • Deprotection of a compound of Formula VII is carried out by using methods known in the art, such as by treatment with a suitable acid such as inorganic or organic acids like aqueous hydrochloric acid, aqueous sulfuric acid, oxalic acid, acetic acid and the like. Further, suitable resins can also be employed such as Dowex.
  • a suitable acid such as inorganic or organic acids like aqueous hydrochloric acid, aqueous sulfuric acid, oxalic acid, acetic acid and the like.
  • suitable resins can also be employed such as Dowex.
  • Suitable solvents in step c) will generally be inert to the reaction conditions.
  • methanol is employed as a solvent.
  • the present invention relates to compound of Formula VII (including their solvates and hydrates) in solid forms, including amorphous, semi- amorphous, semi-crystalline and crystalline forms, as well as mixtures thereof.
  • Yet another aspect of the present application provides use of compound of Formula VII in the form of solid for preparation of Ticagrelor.
  • the present application provides an improved process for preparing ticagrelor, embodiments comprising,
  • the step a) is carried out in the presence of a suitable base and suitable solvent.
  • Suitable bases include, but are not limited to: inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N- methyl Morpholine, DABCO (1 ,4-diazabicyclo[2.2.2]octane) and the like.
  • inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like
  • organic bases such as triethylamine, diisopropylethylamine, morpholine, N- methyl Morpholine, DABCO (1 ,4-diazabicyclo[2.2.2]octane) and the like.
  • sodium bicarbonate has been employed.
  • Suitable additives include but not limited to potassium iodide, tetrabutyl ammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), sodium iodide, lithium chloride, lithium iodide and like.
  • Suitable polar solvents that can be employed include, but are not limited to: polar protic solvents and polar aprotic solvents.
  • Polar protic solvents include but not limited to alcohols, such as methanol, 2-propanol, n-butanol, isoamylalcohol and water and any mixtures of two or more thereof.
  • Polar aprotic solvents include but not limited to N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, nitriles, such as acetonitrile and the like and any mixtures of two or more thereof.
  • water is employed as a polar protic solvent and dimethyl sulfoxide is employed as a polar aprotic solvent.
  • Mixtures of polar protic and polar aprotic solvent can also be employed.
  • a suitable salt of compound of Formula II employed in step a) is a salt of a mineral or organic acid.
  • Suitable mineral acids for salt formation include hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid.
  • Suitable organic acids include organic achiral acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids, and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid.
  • organic acid is employed and more preferably, L-tartaric acid is used.
  • R 2 and R 3 independently are hydroxy or protected hydroxy groups.
  • Some suitable protecting groups are described by T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, Inc., 1 999, and other groups are described in the literature.
  • the compounds of Formulas II I can be prepared by using an adaptation of literature methods, such as described in European Patent Application 508687 A1 , and U.S. Patent Nos. 7,067,663 and 7,799,914.
  • step b) The suitable acid employed in step b) can be selected from the list mentioned above in previous aspects of the invention.
  • Suitable solvent employed in step b) is inert to the reaction condition.
  • step b) The product so formed in step b) can be recovered by using conventional techniques known in the art and are explained in previous aspect of invention.
  • step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles.
  • crystalline forms may also be obtained by heating or melting a form obtained followed by gradual or fast cooling; in this manner one polymorph or one crystalline form may be converted to another.
  • the compound of Formula IV may be purified by using conventional crystallization techniques or by a basification-acidification process.
  • the suitable crystallization techniques include, but are not limited to precipitation or slurrying in a solvent, concentrating, cooling, stirring or shaking a solution containing the compound, combining a solution containing a compound with an anti-solvent, seeding and partial removal of the solvent or combinations thereof, evaporation, flash evaporation and the like.
  • An anti-solvents as used herein refers to a liquid in which a compound of Formula IV is poorly soluble.
  • Compound of Formula IV can be subjected to any of the purification techniques more than one time until the desired purity for a compound of Formula IV is attained.
  • the compound of Formula IV can also be purified by re-crystallization from an appropriate re-crystallization solvent or mixture of solvents by methods customary to one of skill in the art.
  • the compound of Formula IV can be converted to compound of Formula I by following the aforementioned aspect of the application. Yet another aspect of the present application provides use of compound of Formula IV for preparation of Ticagrelor.
  • Yet another aspect of the present application comprises a process for preparation of Ticagrelor wherein one or more intermediate compounds may not be isolated and used in organic solution itself for next step.
  • compound of Formula III or a salt thereof can be reacted with compound of Formula I I or a salt thereof to give compound of Formula IV which optionally without isolation is reacted with a suitable acid to afford compound of Formula IV in solid form.
  • the compound of Formula IV as such or optionally after neutralization is subjected to cyclization to afford compound of Formula V which optionally without isolation on subsequent reaction with compound of Formula VI or its salt results in compound of Formula VI I which optionally without isolation can further be converted to compound of Formula I.
  • Ticagrelor in solid form by a process comprising,
  • step a) Deprotection of a compound of Formula VII in step a) is carried out by using methods known in the art and as explained in aforementioned aspects of the present application.
  • Step b) involves change of solvent from step a) to a suitable solvent and inducing the solid formation.
  • the change of solvent in step b) can be materialized by conventional techniques known in the art such as by removal of solvent from step a) followed by addition of suitable solvent, by addition of suitable solvent which is miscible with the mixture of step a), by addition of suitable solvent which is non-miscible with mixture of step a) and like.
  • Suitable solvent can be selected from but not limited to alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; hydrocarbons such as heptane, cyclohexane, and the like, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile, and the like; water; and any mixtures of two or more
  • step b) The solid formation in step b) is induced either by precipitation techniques known in the literature.
  • step b) includes but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like.
  • An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble.
  • precipitation at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product.
  • the isolation of compound in step c) is done by conventional techniques known in the art.
  • useful techniques include, but are not limited to, decantation, filtration, concentrating, rotational drying, spray drying, thin-film drying, freeze-drying, and the like.
  • the isolation may be optionally carried out at atmospheric pressure or under a reduced pressure.
  • the solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
  • Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure.
  • Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
  • step a) Deprotection of a compound of Formula VII in step a) is carried out by using methods known in the art and as explained in aforementioned aspects of the present application.
  • Suitable non-polar solvent in step b) can be selected from but not limited to, hydrocarbons such as toluene, chlorobenzene, heptane, cyclohexane, and the like, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), methyl THF.
  • toluene is employed.
  • step b) adjusting the pH of aqueous layer from step b) to 7.5-9.5 using a suitable base
  • the pH of aqueous layer can be adjusted with a suitable base selected from but are not limited to inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, and the like.
  • a suitable base selected from but are not limited to inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium carbonate, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, and the like.
  • potassium bicarbonate is employed.
  • Suitable water immiscible solvent in step d) can be selected from but are not limited to esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; and any mixtures of two or more thereof.
  • esters such as ethyl acetate, isopropyl acetate, and t-butyl acetate
  • ketones such as acetone and methyl isobutyl ketone
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and the like
  • ethyl acetate is employed.
  • Anti-oxidant can be selected but are not limited to ascorbic acid, butylated hydroxytoluene, etc. In a preferred embodiment, BHT is employed.
  • Ticagrelor can be isolated by conventional methods provided in the application like by evaporation of solvent, by addition of suitable anti-solvent or by combination of both etc.
  • Another aspect of the present application involves process for purification of Ticagrelor, embodiments comprising,
  • Suitable water immiscible solvent and anti-oxidant can be selected from aforementioned aspect of application.
  • the mixture of step a) can be heated to dissolution temperature that can be any temperature as long as stability of the Ticagrelor is not compromised and s substantially clear solution is obtained.
  • the dissolution temperature may range from about 20oC to about reflux temperature of solvent.
  • step b) adding suitable solvent to mixture of step a)
  • Suitable solvent in step b) is non-polar solvent.
  • cyclohexane is employed.
  • Ticagrelor can be isolated by conventional methods provided in the application like by evaporation of solvent, by addition of suitable anti-solvent or by combination of both etc.
  • Ticagrelor obtained by above process is substantially free from impurities.
  • the Ticagrelor is of high purity, such as at least about 99%, 99.5%, or 99.9%, by weight pure.
  • the level of impurities may be less than about 1 %, 0.5%, or 0.1 %, by weight, as determined using high performance liquid chromatography (HPLC).
  • the present invention includes Ticagrelor of Formula I, substantially free from below impurities.
  • the presence of impurities in Ticagrelor may pose a problem for pharmaceutical product formulation, in that impurities often affect the safety and shelf life of a formulation.
  • the present invention provides a method for ameliorating the effect of an impurity present in formulations of Ticagrelor by reducing the amount of the impurities during synthesis.
  • the present application provides pharmaceutical formulation comprising an amorphous form of Ticagrelor, together with one or more pharmaceutically acceptable excipients.
  • providing a solution of Ticagrelor may include: i) direct use of a reaction mixture containing Ticagrelor that is obtained in the course of its synthesis and that comprises a suitable solvent, or by combining a suitable solvent with the reaction mixture; or
  • Ticagrelor iii) neutralizing salt of Ticagrelor using a suitable agent to afford free form of Ticagrelor in a suitable solvent.
  • the salt of Ticagrelor can be made either with suitable acids or suitable bases. Depending on nature of salt, suitable neutralizing agents are chosen by a skilled person.
  • the dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, or any other suitable temperatures, as long as a clear solution of Ticagrelor is obtained without affecting its quality.
  • the solution may optionally be treated with carbon, flux- calcined diatomaceous earth (Hyflow), or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities that are adsorbable on such material.
  • the solution obtained may be treated to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques, under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may optionally be preheated to avoid premature crystallization.
  • suitable solvents used for providing a solution of Ticagrelor include, but are not limited to water; alcohols, such as ethanol, 1 - propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, iso-butyl alcohol, t- butyl alcohol, and C1 -C6 alcohols; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopropylmethyl ether, dioxane, and dimethoxyethane; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate; halogenated hydrocarbons, such as dichloromethane
  • an anti-oxidant may be added to the mixture of step a) to alleviate formation of oxidative impurities.
  • Preferred anti-oxidant is butylated hydroxytoluene (BHT).
  • isolating an amorphous form of Ticagrelor may be effected by removing the solvent, or by a precipitation technique.
  • Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, thin film drying, freeze drying (lyophilization), and the like, or any other suitable techniques.
  • the solvent may be removed, optionally under reduced pressures, at temperatures less than about 100°C, less than about 75°C, less than about 60°C, less than about 50°C, or any other suitable temperatures.
  • Freeze drying may be carried out by freezing a solution of Ticagrelor at low temperatures and reducing the pressure as required to remove the solvent from the frozen solution of Ticagrelor. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of Ticagrelor, may range from about -80°C to about 0°C, or up to about 20°C. Temperatures that may be required to remove the solvent from the frozen solution may be less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
  • isolation may also include combining the solution of step a) with a suitable anti-solvent. Adding the solution obtained in step a) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a), to effect a precipitation are both within the scope of the present application.
  • the combination with an anti-solvent may be carried out after concentrating the solution obtained in step a).
  • Suitable anti-solvents include, but are not limited to: aliphatic or alicyclic hydrocarbon liquids; aromatic hydrocarbon liquids; ethers; and any mixtures thereof.
  • spray drying is employed for isolation of amorphous form of Ticagrelor.
  • the solid obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford an amorphous form of Ticagrelor.
  • Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
  • the drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 50°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 15 minutes to 24 hours, or longer.
  • the dried product may be optionally subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.
  • the amorphous Ticagrelor can be stored under nitrogen atmosphere and packed in a clear polyethylene bag and sealed. Then keeping the primary packing containing amorphous Ticagrelor under nitrogen atmosphere inside a black color polyethylene bag containing molecular sieves and sealing it, placing the above double polyethylene bag inside Metalized poly(ethylene terephthalate) [METPET] bag under nitrogen atmosphere along with molecular sieves and sealing it. Then placing the above bag inside triple laminated bag with molecular sieves and sealing it with vacuuming nitrogen flushing and sealing machine (VNS sealer) and finally placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container and storing in controlled environment chamber at about 25°C and/or 40°C.
  • VNS sealer vacuuming nitrogen flushing and sealing machine
  • the chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or any of their combinations.
  • Suitable solvents inert to the reaction conditions include but not limited to but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert- butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile; polar aprotic solvents, such as ⁇ , ⁇ -dimethylformamide, N,N-
  • the compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
  • a conventional method well known to those skilled in the art such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH.
  • Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques or by salt preparation and neutralization wherever feasible.
  • the suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like.
  • An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
  • Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity.
  • precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product.
  • Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any
  • the compounds at various stages of the process may be recovered using conventional techniques known in the art.
  • useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like.
  • the isolation may be optionally carried out at atmospheric pressure or under a reduced pressure.
  • the solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
  • Evaporation refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure.
  • Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
  • a recovered solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 1 00°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer. Any of the above-described compounds in racemic as well as optically active forms, and in all of their polymorphic forms, are included within the scope of this application.
  • the solid compounds of this application are best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art.
  • PXRD data reported herein was obtained using CuKa radiation, having the wavelength 1 .5418 A and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer.
  • Bruker AXS D8 Advance Powder X-ray Diffractometer For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:91 1 -929.
  • a diffraction angle (2 ⁇ ) in powder X-ray diffractometry may have an error in the range of ⁇ 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ⁇ 0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ⁇ 0.2°.
  • the phrase "having a diffraction peak at a diffraction angle (2 ⁇ ⁇ 0.2°) of 7.9°” means “having a diffraction peak at a diffraction angle (2 ⁇ ) of 7.7 ° to 8.1 °".
  • the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term “about” means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art.
  • the relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed.
  • a "room” or “ambient” temperature includes temperatures from about 1 5°C to about 35°C, from about 20°C to about 30°C, or about 25°C.
  • an "alcohol” is an organic liquid containing a carbon bound to a hydroxyl group, including, but not limited to, methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 - propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, i- butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Ci- 6 alcohols, and the like.
  • ether is an organic liquid containing an oxygen atom -O- bonded to two carbon atoms, including, but not limited to, diethyl ether, diisopropyl ether, methyl t- butyl ether, glyme, diglyme, tetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C 2 -6 ethers, and the like.
  • a "halogenated hydrocarbon” is an organic liquid containing a carbon bound to a halogen, including, but not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 -trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like.
  • a “hydrocarbon” is a liquid compound formed from carbon and hydrogen atoms, and may be linear, branched, cyclic, saturated, unsaturated, non-aromatic, or aromatic. Examples include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane,
  • a “nitrile” is an organic liquid containing a cyano -(C ⁇ N) bonded to another carbon atom, including, but not limited to, acetonitrile, propionitrile, C 2 -6 nitriles, and the like.
  • a "polar aprotic solvent” has a dielectric constant greater than 15 and includes: amide-based organic solvents, such as hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT), and N-methylpyrrolidone, nitro- based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; ester-based organic solvents, such as ⁇ -butyrolactone, ethylene carbonate, propylene carbonate, butylene carbonate, dimethyl carbonate, and propiolactone; pyridine-based organic solvents, such as pyridine and picoline; and sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone,
  • amide-based organic solvents such as hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT), and N-methylpyrrol
  • Any organic solvents may be used alone, or any two or more may be used in combination, or one or more may be used in combination with water in desired ratios.
  • Acid addition salts are typically pharmaceutically acceptable, non-toxic addition salts with "suitable acids,” including, but not limited to: inorganic acids such as hydrohalic acids (for example, hydrofluoric, hydrochloric, hydrobromic, and hydroiodic acids) or other inorganic acids (for example, nitric, perchloric, sulfuric, and phosphoric acids); organic acids, such as organic carboxylic acids (for example, xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, and glutaric acids), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic,
  • EXAMPLE 1 PREPRATION OF L(+)-TARTRATE SALT OF 2-(((3aR,4S,6R,6aS)-6- ((5-AMINO-6-CHLORO-2-(PROPYLTHIO)PYRIMIDIN-4-YL)AMINO)-2,2- DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 ,3] DIOXOL -4- YI)OXY)ETHANOL (FORMULA IV)
  • EXAMPLE 2 PREPRATION OF R(-)-MANDELATE SALT OF 2-(((3aR,4S,6R,6aS)- 6-((5-AMINO-6-CHLORO-2-(PROPYLTHIO)PYRIMIDIN-4-YL)AMINO)-2,2- DIMETHYLTETRAHYDRO-3aH-CYCLOPENTA[d][1 ,3] DIOXOL -4- YI)OXY)ETHANOL (FORMULA IV)
  • EXAMPLE 4 PREPARATION OF 2-((3aR,4S,6R,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]DIOXOL-4-YLOXY)ETHANOL
  • the mixture is stirred at 28°C for 30 minutes followed by addition of organic layer containing 10g equivalent of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5- d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)ethan- 1 -ol (10 mL) over a period of 50 minutes.
  • the mixture is stirred at 28°C for about 4 hours for completion of reaction as verified by TLC. After completion of reaction, water (100 mL) is charged to the mixture and layers are separated.
  • EXAMPLE 10 PREPARATION OF 2-((3aR,4S,6R,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]DIOXOL-4-YLOXY)ETHANOL
  • the mixture is stirred at the same temperature for 1 .5 hours at which point completion of the reaction is confirmed by TLC.
  • toluene (25 mL) and water (50 mL) are charged and then layers are separated.
  • the aqueous layer is further extracted with toluene (25 mL), the total organic layers are combined and washed with 20% aqueous potassium carbonate solution (25 mL).
  • the separated organic layer is used as such for next step.
  • EXAMPLE 1 1 PREPARATION OF 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4- DIFLUOROPHENYL)CYCLOPROPYL)AMINO)-5-(PROPYLTHIO)-3H- [1 ,2,3]TRIAZOLO[4,5-d]PYRIMIDIN-3-YL)-2,2-DIMETHYLTETRAHYDRO-4H- CYCLOPENTA[d][1 ,3]DIOXOL-4-YL)OXY)ETHAN-1 -OL (FORMULA VII)
  • the mixture is stirred at room temperature for 15 minutes followed by addition of organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5- d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3] dioxol-4-yl)oxy)ethan- 1 -ol as obtained from previous example 10.
  • the mixture is stirred at 28°C for about 4 hours for completion of reaction as verified by TLC. After completion of reaction, water (25 mL) is charged to the mixture and layers are separated.
  • the organic layer is sequentially washed with water (25 mL), 2% aqueous hydrochloric acid solution (25 mL) and again water (25 mL). Then the organic layer is subjected to complete distillation under vacuum at 55°C to afford the crude compound in about 97% yield.
  • the mixture is cooled to 10-15°C followed by addition of precooled solution of aqueous hydrochloric acid solution (28 mL cone. HCI + 28 mL water) over a period of 25 minutes.
  • the mixture is stirred for about 9 hours at the same temperature and completion of the reaction is monitored by TLC.
  • toluene (20 mL) and 20% aqueous potassium carbonate solution (120 mL) to adjust the pH about 9-10 are added to the mixture.
  • methyl iso-butyl ketone 50 mL is added and layers are separated. The aqueous layer is extracted with methyl isobutyl ketone (10 mL).
  • the mixture is cooled to 10-15°C followed by addition of precooled solution of aqueous hydrochloric acid solution (14 mL cone. HCI + 14 mL water) over a period of 25 minutes.
  • the mixture is stirred for about 8 hours at the same temperature and completion of the reaction is monitored by TLC.
  • mixture is washed with toluene (2x20 mL) at 10-15°C.
  • pH of the mixture is adjusted to about 9-10 by addition of 20% aqueous potassium carbonate solution (60 mL) followed by addition of MIBK (20 mL) at 10-15°C.
  • the mixture is stirred and aqueous layer is extracted with MIBK (10 mL).
  • aqueous phosphoric acid solution (14.8 mL 88% H 3 P0 4 + 14.8 mL water) is added over a period of 20 minutes and the mixture is stirred overnight at the same temperature for completion of the reaction as monitored by TLC, while monitoring the reaction excess of phosphoric acid is also added.
  • aqueous potassium carbonate solution 100 mL
  • water 100 mL
  • the solid obtained is isolated by filtration and washed with water (25 mL) and kept for drying at 50°C for about 2 hours to afford the title compound in about 87% yield having about 97.7% HPLC purity.
  • EXAMPLE 18 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (10 g) and methanol (100 mL) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution. The solution was subjected to spray drying at an inlet temperature of 65°C under a nitrogen pressure of 5 kg/cm 2 at a feed rate of 20%, to afford the title compound. The obtained amorphous Ticagrelor (0.7 g) is packed in polyethylene bag filled with nitrogen and sealed followed by placing it along with 1 g of molecular sieves pouch in black polyethylene bag filled with nitrogen and sealed.
  • METPET Metalized poly(ethylene terephthalate) bag filled with nitrogen along with 1 g molecular sieves pouch and sealed. Further, this is kept in triple laminated bag along with 1 g molecular sieves pouch and sealed with a VNS sealer (Vacuuming nitrogen flushing and sealing machine). Finally the instant pack is kept in HDPE container and stored under controlled environment.
  • EXAMPLE 19 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (10 g) and ethyl acetate (200 mL) and mixture is stirred at 30-35°C for clear solution and filtered to get a particle free solution. The solution was subjected to spray drying under below conditions to afford amorphous Ticagrelor.
  • EXAMPLE 20 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (10 g) and isopropyl acetate (300 mL) and mixture is stirred at 60-65°C for clear solution and filtered to get a particle free solution. The filtrate is cooled to room temperature and was subjected to spray drying under below conditions to afford amorphous Ticagrelor.
  • EXAMPLE 21 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (1 0 g) and methyl ethyl ketone (100 mL) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution. The filtrate was subjected to spray drying under below conditions to afford amorphous Ticagrelor.
  • EXAMPLE 22 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (2 g) and dichloromethane:methanol (10 mL, 9:1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with dichloromethane:methanol (4 mL, 9:1 ). The filtrate was subjected to vacuum distillation at 45°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 23 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (5 g) and methanol :water (30 mL, 9:1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with methanol :water (10 mL, 9:1 ). The filtrate was subjected to vacuum distillation at 50°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 24 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (5 g) and dichloromethane (50 mL) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution. The filtrate was subjected to vacuum distillation at 45°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 25 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (5 g) and acetone:methanol (25 mL, 1 :1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with acetone:methanol (10 mL, 1 :1 ). The filtrate was subjected to vacuum distillation at 50°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 26 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (5 g) and pentane:methanol (70 mL, 1 :1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with pentane:methanol (5 mL, 1 :1 ) . The filtrate was subjected to vacuum distillation at 45°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 27 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (2 g) and ethyl acetate:methanol (20 mL, 1 :1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution. The filtrate was subjected to vacuum distillation at 50°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 28 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (2 g) and MTBE:methanol (14 mL, 1 :1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with MTBE:methanol (2 mL, 1 :1 ). The filtrate was subjected to vacuum distillation at 50°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 29 PREPARATION OF AMORPHOUS TICAGRELOR (FORMULA I) A flask is charged with Ticagrelor (2 g) and n-propyl acetate:methanol (10 mL, 1 :1 ) and mixture is stirred at room temperature for clear solution and filtered to get a particle free solution, bed was washed with n-propyl acetate:methanol (2 mL, 1 :1 ). The filtrate was subjected to vacuum distillation at 50°C followed by drying to afford amorphous Ticagrelor.
  • EXAMPLE 30 PREPARATION OF 2-((3aR,4S,6R,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]DIOXOL-4-YLOXY)ETHANOL
  • the mixture is stirred at the same temperature for about 2 hours at which point completion of the reaction is confirmed by TLC.
  • toluene (500 mL) and water (1000 mL) are charged and then layers are separated.
  • the aqueous layer is further extracted with two lots of toluene (500mL, 200 mL), the total organic layers are combined and washed with 20% aqueous potassium carbonate solution (500 mL).
  • the separated organic layer is used as such for next step.
  • aqueous hydrochloric acid solution (374 mL cone. HCI + 374 mL water) is added over a period of 2 hours. The mixture is stirred for about 3-4 hours at the same temperature and completion of the reaction is monitored by TLC. After completion of reaction, toluene (670 mL) is charged to the mixture at 7 ⁇ 3°C and stirred for 20-30 minutes. The layers are separated and aqueous layer is washed with toluene (670 mL). The aqueous layer is separated and cooled to 5°C, then pH is adjusted to about 7.5-9.5 with aqueous potassium carbonate solution (324 g in 1620 mL water).
  • EXAMPLE 34 PREPARATION OF 2-(((3aR,4S,6R,6aS)-6-((5-AMINO-6-CHLORO- 2-(PROPYLTHIO)PYRIMIDIN-4-YL)AMINO)-2,2-DIMETHYLTETRAHYDRO-3aH- CYCLOPENTA[d][1 ,3] DIOXOL -4-YL)OXY) ETH ANOL (FORMULA IV)
  • the solid obtained is filtered and washed with cyclohexane (50 mL).
  • the solid obtained is dried under vacuum at 60°C for about 8 hours, then water is added and mixture is stirred for about 4 hours at room temperature.
  • the solid is filtered under vacuum and washed with water (50 mL) followed by drying under vacuum at about 65°C to afford the title compound having 99.65% of HPLC purity.
  • EXAMPLE 35 PREPARATION OF 2-(((3aR,4S,6R,6aS)-6-((5-AMINO-6-CHLORO- 2-(PROPYLTHIO)PYRIMIDIN-4-YL)AMINO)-2,2-DIMETHYLTETRAHYDRO-3aH- CYCLOPENTA[d][1 ,3] DIOXOL-4-YL)OXY)ETHANOL (FORMULA IV)

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Abstract

La présente invention concerne des procédés de préparation de ticagrelor et de ses intermédiaires.
PCT/IB2014/061912 2013-06-04 2014-06-03 Préparation de ticagrélor WO2014195861A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016030704A1 (fr) * 2014-08-30 2016-03-03 Cipla Limited Forme solide d'intermédiaire de ticagrelor
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
US10017515B2 (en) * 2014-08-11 2018-07-10 Sun Pharmaceutical Industries Limited Stable amorphous ticagrelor and a process for its preparation
CN110183436A (zh) * 2019-06-21 2019-08-30 南通常佑药业科技有限公司 一种非晶型替卡格雷的制备方法
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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013407D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound

Cited By (6)

* 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
US10017515B2 (en) * 2014-08-11 2018-07-10 Sun Pharmaceutical Industries Limited Stable amorphous ticagrelor and a process for its preparation
WO2016030704A1 (fr) * 2014-08-30 2016-03-03 Cipla Limited Forme solide d'intermédiaire de ticagrelor
CN110183436A (zh) * 2019-06-21 2019-08-30 南通常佑药业科技有限公司 一种非晶型替卡格雷的制备方法
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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EP3004113A2 (fr) 2016-04-13

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