EP3004113A2 - Preparation of ticagrelor - Google Patents

Abstract

The present application relate to processes for preparing Ticagrelor and its intermediates.

Description

PREPARATION OF TICAGRELOR

INTRODUCTION

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 α,2α,3β(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.

Formula I

Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active Ρ₂τ (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.

The processes for the preparation of triazolo [4,5-d] pyrimidine derivatives preferably Ticagrelor and related compounds, described in the above mentioned prior art 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.

As a result in order to reduce the impurities it is necessary to carry out a number of purifications at final stage of Ticagrelor. Generally purification steps at the final stage of the compound leads to loss of material which increases the economics of production and thus is not recommended for commercial scale-up.

Therefore there remains a need to prepare Ticagrelor of high purity and in good yield where total synthesis time is short and while overcoming the drawbacks presented by the processes described in the art.

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 .

Formula IV Formula VII

SUMMARY

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 R₂ and R₃ independently are hydroxy or protected hydroxy groups and HX is an acid moiety selected from organic or inorganic acid.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula IV, prepared according to Example 1 .

Fig. 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula IV, prepared according to Example 2.

Fig. 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula VII, prepared according to Example 6.

Fig. 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of the compound of Formula I, prepared according to Example 14.

DETAILED DESCRIPTION

An aspect of the present application provides process for preparation of compound of Formula IV, embodiments comprising,

Formula IV

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. For example, 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 solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide or like; water; or any mixtures thereof. In a preferred embodiment, ethyl acetate is employed.

In compound of Formula IV, R₂ 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.

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. Preferably, 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.

Thus, within the acid addition salts of this invention 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.

c) isolating the compound of Formula IV from step b),

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.

Alternately, during crystallization by cooling, step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles.

d) optionally, drying the compound of Formula IV.

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.

Once obtained, 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.

In a further aspect, 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. In a preferred aspect, 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,

a) cyclizing a compound of Formula IV or its salt in the presence of sodium nitrite and suitable acid in a suitable solvent, to afford a compound of Formula V or its salts,

Formula IV Formula V where R₂ and R₃ independently are hydroxy or protected hydroxy groups.

Suitable solvents employed in step a) will generally be inert to the reaction conditions. In embodiments, reaction is carried out in water. In yet another embodiment, 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. Preferably, organic acid is employed and more preferably, acetic acid is used. In a preferred embodiment, on completion of reaction a suitable organic solvent preferably, aromatic hydrocarbon is added to the reaction mixture. In a more preferred embodiment, organic solution from step a) is used as such for subsequent step without distillation of organic solvent.

b) reacting a compound of Formula V with the compound of Formula VI or a salt thereof and isolating the compound of Formula VII as a solid,

Formula V Formula VI

Formula VI where R₂ and R₃ independently are hydroxy or protected hydroxy groups.

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. In a preferred embodiment, diisopropylethylamine is employed. Suitable solvents will generally be inert to the reaction conditions. In a preferred embodiment, toluene is employed.

In a preferred embodiment, on completion of reaction the solvent is removed from the mixture and compound of Formula VII is isolated as solid by conventional techniques mentioned above.

In yet another preferred embodiment, R₂ and R₃ are protected hydroxy groups.

c) deprotecting the compound of Formula VII under suitable conditions to afford Ticagrelor of Formula I.

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.

Suitable solvents in step c) will generally be inert to the reaction conditions. In a preferred embodiment, methanol is employed as a solvent.

In a further aspect, 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.

In yet another aspect, the present application provides an improved process for preparing ticagrelor, embodiments comprising,

a) reacting the compound of Formula III or a salt thereof with a compound of Formula II or a salt thereof, in the presence of a base in a suitable polar solvent selected from alcohols, polar aprotic solvents, water and mixtures thereof, optionally in the presence of an additive to form a compound of Formula IV,

Formula III Formula II Formula IV where R₂ and R₃ independently are hydroxy or protected hydroxy groups.

The step a) is carried out in the presence of a suitable base and suitable solvent.

Suitable bases that can be employed 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. In a preferred embodiment, 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, Ν,Ν-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, nitriles, such as acetonitrile and the like and any mixtures of two or more thereof. In a preferred embodiment, 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. Preferably, organic acid is employed and more preferably, L-tartaric acid is used.

In compounds of Formula II and IV, R₂ 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. 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.

b) reacting the compound of Formula IV with a suitable acid in a reaction inert solvent and isolating the compound of Formula IV in solid form.

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.

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.

Alternately, during crystallization by cooling, step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles.

Particularly, 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.

c) optionally, purifying the compound of Formula IV by suitable purification techniques.

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.

d) converting the compound of Formula IV to compound of Formula I or pharmaceutically acceptable salts thereof.

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. For example, 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.

Another aspect of the present application involves isolation of Ticagrelor in solid form by a process comprising,

a) deprotection of compound of Formula VI I in a suitable solvent to afford Ticagrelor of Formula I,

b) changing the solvent from the step a) with suitable solvent and inducing solid formation,

c) isolating compound of Formula I in solid form.

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 thereof. In a preferred embodiment, acetonitrile is employed. In yet another preferred embodiment, MIBK and cyclohexane are employed.

The solid formation in step b) is induced either by precipitation techniques known in the literature.

For example techniques employed in 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. Optionally, 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. For example, 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.

Another aspect of the present application involves process for preparation of Ticagrelor of high purity embodiments comprising:

a) deprotecting compound of Formula VII in a suitable solvent,

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.

b) washing the mixture of step a) with a suitable non-polar solvent, 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. In a preferred embodiment, toluene is employed.

c) 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. In a preferred embodiment, potassium bicarbonate is employed.

d) extracting Ticagrelor from step c) in a suitable water immiscible solvent comprising anti-oxidant,

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. In a preferred embodiment, 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.

e) isolating compound of Formula I.

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,

a) providing Ticagrelor in a suitable water immiscible solvent comprising antioxidant.

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. For example, the dissolution temperature may range from about 20oC to about reflux temperature of solvent.

b) adding suitable solvent to mixture of step a)

Suitable solvent in step b) is non-polar solvent. In a preferred embodiment, cyclohexane is employed.

c) isolating compound of Formula I.

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. Typically, the Ticagrelor is of high purity, such as at least about 99%, 99.5%, or 99.9%, by weight pure. Correspondingly, 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.

Yet another aspect of the present application involves process for preparation of amorphous form of Ticagrelor embodiments comprising:

a) providing a solution of Ticagrelor in a suitable solvent; and

b) isolating amorphous Ticagrelor.

In an aspect, the present application provides pharmaceutical formulation comprising an amorphous form of Ticagrelor, together with one or more pharmaceutically acceptable excipients. In embodiments of step a), 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

ii) dissolving Ticagrelor in a suitable solvent; or

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.

In embodiments of step a), any physical form of Ticagrelor or may be utilized for providing the solution of Ticagrelor. 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. Optionally, 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. Depending upon the concentration and temperature of the solution and the equipment used, the filtration apparatus may optionally be preheated to avoid premature crystallization.

In embodiments of step a), 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, 1 ,2- dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 -trichloroethane, 1 ,1 ,2- trichloroethane, chloroform, and carbon tetrachloride; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and Ν,Ν-dimethylacetamide; sulfoxides, such as dimethylsulfoxide; and any mixtures of two or more thereof. In a preferred embodiment, water immiscible solvent is employed, more preferably selected from ethyl acetate, isopropyl acetate and MEK.

Optionally, 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).

In embodiments of step b), 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 (lyophilization) 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.

In embodiments of step b), 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. Optionally, the combination with an anti-solvent may be carried out after concentrating the solution obtained in step a). Suitable anti-solvents that may be used include, but are not limited to: aliphatic or alicyclic hydrocarbon liquids; aromatic hydrocarbon liquids; ethers; and any mixtures thereof. In a preferred embodiment, 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.

In further aspect, 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.

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 Ν,Ν-dimethylformamide, N,N- dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.

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. 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. Optionally, 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 mixtures of two or more thereof.

The compounds at various stages of the process may be recovered using conventional techniques known in the art. For example, 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 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.

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. 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.

Generally, a diffraction angle (2Θ) 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°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7 ° to 8.1 °". Although 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. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by ± about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not). DEFIN ITIONS

The following definitions are used in connection with the present application, unless the context indicates otherwise.

All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and atmospheric pressure unless otherwise designated. All ranges recited herein include the endpoints, including those that recite a range "between" two values. As used herein, 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.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, or instrument error for a given technique used to measure a value.

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.

An "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, C₂-6 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 "ketone" is an organic liquid containing a carbonyl group -(C=0)- bonded to two other carbon atoms, including, but not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 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, cycloheptane, C₅-C₈ aliphatic hydrocarbons, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C₆-Cio aromatic hydrocarbons, and the like.

A "nitrile" is an organic liquid containing a cyano -(C≡N) bonded to another carbon atom, including, but not limited to, acetonitrile, propionitrile, C₂-6 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 γ-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,

2- methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethylsulfolane,

3- sulfolene, and sulfolane.

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, ethanesulfonic, 2-hydroxyethanesulphonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulphonic, and camphorsulfonic acids), and amino acids (for example, ornithinic, glutamic, and aspartic acids).

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

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)

A flask is charged with 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 (1 g) and ethyl acetate (5 mL). The mixture is stirred for dissolution and then L-tartaric acid (0.39 g) is added followed by heating of the mixture at 50°C for clear solution. The mixture is further stirred for 60 minutes at room temperature followed by addition of n-hexane (25 mL) and stirring for solid separation. The solid is isolated by filtration and washed with n-hexane (5 mL) followed by drying of the solid under vacuum at below 50°C to afford the title compound in about 88% yield.

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)

A flask is charged with 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 (1 g) and ethyl acetate (5 mL). The mixture is stirred for dissolution and then R(-)-mandelic acid (0.4 g) was added and the mixture is further stirred for 60 minutes at room temperature. Then n-hexane (25 mL) is added to the mixture and it is stirred for solid separation. The solid is isolated by filtration and washed with n-hexane (5 mL) followed by drying of the solid under vacuum at below 50°C to afford the title compound in about 99% yield.

EXAMPLE 3: 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)

A flask is charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (10 g), 2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1 ,3]dioxol-4- yl)oxy)ethanol L-tartaric acid salt (17 g), water (30 mL) and sodium bicarbonate (21 .2 g). The mixture is heated to about 90-100°C and maintained at the same temperature for about 18-20 hours and completion of the reaction is monitored by TLC. After completion of reaction, mixture is cooled to about 80°C followed by addition of 2-butanol (20 mL) and water (120 mL). The mixture is further cooled to about 28°C and maintained for 4 hours. The solid obtained is isolated by filtration and washed with water (20 mL) and then subjected to drying under vacuum at 55°C for 8 hours to afford the title compound in about 88% yield having HPLC purity of about 98%.

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

(FORMULA V)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol- 4-yl)oxy)ethan-1 -ol L-tartaric acid salt (0.2 g), acetic acid (2 mL) and water (0.2 mL). The mixture is stirred and cooled to 0-5°C followed by slow addition of aqueous sodium nitrite solution (25 mg sodium nitrite in 0.2 mL water). The mixture is stirred at the same temperature for 1 hour at which point completion of the reaction is confirmed by TLC.

EXAMPLE 5: 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)

(1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (7.64 g), di-isopropyl ethylamine (14.56 mL) and ethyl acetate (10 mL) are charged in a flask. 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. The organic layer is washed with 2% aqueous hydrochloric acid solution (2x50 mL). The organic layer is subjected to complete distillation under vacuum at 55°C to afford the crude compound. Then cyclohexane (150 mL) is added to the crude compound and mixture is stirred at 30°C for overnight. The solid obtained is filtered and washed with cyclohexane (20 mL) followed by drying under vacuum at 55°C to afford the title compound in about 78% yield having HPLC purity of about 99%.

EXAMPLE 6: 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

(1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (7.6 g), di-isopropyl ethylamine (10.78 g) and toluene (10 mL) are charged in a flask. The mixture is stirred at 28°C for 10 minutes followed by addition of mixture 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 (10.94 g) in toluene (100 mL) over a period of 70 minutes. The mixture is stirred at 28°C for about 3.5 hours for completion of reaction as verified by TLC. After completion of reaction, water (50 mL) is charged to the mixture and layers are separated. The organic layer is sequentially washed with 2% aqueous hydrochloric acid solution (2x50 mL) and water (50 mL). The organic layer is then subjected to complete distillation under vacuum at 55°C to afford the crude compound. Then n-heptane (100 mL) is added to the crude compound and mixture is stirred at 26°C for overnight. The solid obtained is filtered and washed with n-heptane (1 0 mL) followed by drying under vacuum at 55°C to afford the title compound in about 89% yield having HPLC purity of about 98.6%.

EXAMPLE 7: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (10 g), methanol (80 mL) followed by slow addition of aqueous hydrochloric acid (cone. HCI 19 mL in 19 mL water) over a period of 15 minutes. The mixture is stirred for about 2 hours for completion of reaction as verified by TLC. After completion of reaction, the pH of the mixture is adjusted to 8.5-9.0 with 10% aqueous potassium carbonate solution (100 mL). Then water (100 mL) is added to the mixture and it is stirred for about 3 hours. The solid is isolated by filtration and washed with water (10 mL) followed by drying under vacuum at 55°C to afford the title compound in about 82% yield.

EXAMPLE 8: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (2 g) and methanol (10 mL). To the mixture, Dowex resin (2 g) is added and mixture is maintained for 24 hours for completion of reaction as verified by TLC. After completion of reaction, the mixture is filtered under vacuum and resin is washed with methanol (5 mL). To the filtrate, water (10 mL) and ethyl acetate (10 mL) are added and mixture is stirred. The organic layer is separated and aqueous layer is further extracted with ethyl acetate (10 mL). Then total organic layer is subjected to distillation under vacuum at 50°C to afford the title compound. EXAMPLE 9: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (5 g), methanol (25 mL). The mixture is cooled to about 10°C followed by addition of aqueous hydrochloric acid (10 mL cone. HCI + 10 mL water) over a period of 40 minutes. The mixture is stirred for 6 hours and completion of the reaction is monitored by TLC. After completion of reaction, toluene (25 mL) is charged to the mixture and after stirring the mixture layers are separated. The aqueous layer is washed with toluene (25 mL). Then pH of the aqueous layer is adjusted to 8.5 with 20% aqueous potassium carbonate solution (55 mL), subsequently water (20 mL) and ethyl acetate (25 mL) are charged. The mixture is stirred for 20 minutes and layers are separated. Then aqueous layer is extracted with ethyl acetate (25 mL). The organic layers are combined and subjected to complete distillation under vacuum at 35°C followed by addition of ethyl acetate (25 mL). The mixture is stirred for 20 minutes followed by addition of cyclohexane (75 mL) over a period of 30 minutes at 40°C. The mixture is further stirred for about 4 hours at room temperature. The solid obtained is isolated by filtration and washed with cyclohexane (10 mL), then subjected to drying under vacuum at 60°C for about 10 hours to afford the title compound in about 78% yield having 98.9% HPLC purity.

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

(FORMULA V)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol- 4-yl)oxy)ethan-1 -ol (5 g), acetic acid (26.5 mL) and water (5 mL). The mixture is stirred and cooled to 0-5°C followed by slow addition of aqueous sodium nitrite solution (0.86 g sodium nitrite in 5 mL water). The mixture is stirred at the same temperature for 1 .5 hours at which point completion of the reaction is confirmed by TLC. To the mixture, 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)

(1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (3.82 g), di-isopropyl ethylamine (6.25 mL) and toluene (5 mL) are charged in a flask. 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.

EXAMPLE 12: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (5 g), methanol (40 mL). To the mixture aqueous hydrochloric acid solution (9.25 mL cone. HCI + 9.25 mL water) is added over a period of 1 5 minutes. The mixture is stirred for about 1 .5 hours and completion of the reaction is monitored by TLC. After completion of reaction, sequentially water (50 mL) and 20% aqueous potassium carbonate solution (100 mL) are added. Then the mixture is extracted with ethyl acetate (2x25 mL). The organic layers are separated and subjected to complete distillation to afford the crude compound. The crude compound is dissolved in acetonitrile (25 mL) and the mixture is cooled to 0-5°C. The resultant mixture is maintained at the same temperature for about 3.5 hours. The solid obtained is filtered and washed with acetonitrile (10 mL). The solid is then subjected to drying under vacuum at about 50°C for about 5 hours to afford the title compound in 78% yield having about 99.4% HPLC purity.

EXAMPLE 13: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (10 g), methanol (50 mL). 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. After completion of reaction, toluene (20 mL) and 20% aqueous potassium carbonate solution (120 mL) to adjust the pH about 9-10 are added to the mixture. Then, methyl iso-butyl ketone (50 mL) is added and layers are separated. The aqueous layer is extracted with methyl isobutyl ketone (10 mL). Total organic layers are combined and washed with 20% aqueous sodium chloride (2x50 mL). The organic layer is separated and subjected to distillation under vacuum at 60°C. To the crude obtained, MIBK (30 mL) is added and mixture is stirred at room temperature followed by addition of cyclohexane (150 mL) under stirring. The mixture is stirred for about 2 hours and solid obtained is isolated by filtration and washed with cyclohexane (10 mL). The solid is subjected to drying under vacuum at 55°C to afford title compound in about 86% yield having HPLC purity of 98.7%.

EXAMPLE 14: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (5 g), methanol (25 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. After completion of reaction, mixture is washed with toluene (2x20 mL) at 10-15°C. Then 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). The total organic layers are combined and washed with 20% aqueous sodium chloride solution (2x25 mL). The organic layer is separated and subjected to distillation under vacuum at 60°C to afford the crude compound. To the crude, MIBK (10 mL) is added and mixture is stirred for 15 minutes at 60°C followed by cooling to room temperature and subsequent addition of cyclohexane (80 mL) over a period of 20 minutes. The mixture is stirred and solid obtained is isolated by filtration and washed with cyclohexane (10 mL). The solid is dried under vacuum at 60-65°C for 6-7 hours to afford the title compound in 75% yield having HPLC purity of about 99.58%.

EXAMPLE 15: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with crude Ticagrelor (2 g) and MIBK (10 mL). The mixture is stirred at reflux for 1 hour to obtain clear solution. The mixture is subsequently cooled to room temperature and maintained for 10-12 hours at same temperature. The solid obtained is isolated by filtration and washed with MIBK (5 mL). The solid is subjected to drying under vacuum at 60-65°C to afford Ticagrelor in 80% yield having HPLC purity of about 99.30%.

EXAMPLE 16: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (5 g) and ethylene glycol (25 mL), then mixture is cooled to 10-15°C. To the mixture aqueous hydrochloric acid solution (14 mL cone. HCI + 14 mL water) is added and mixture is stirred for about 6 hours at the same temperature and completion of the reaction is monitored by TLC. After completion of reaction, sequentially water (100 mL) and 20% aqueous potassium carbonate solution (100 mL) are added and mixture is kept for stirring for overnight. The solid obtained is isolated by filtration and washed with water (25 mL) and kept for drying at 52°C for about 7 hours to afford the title compound in about 87% yield having about 98% HPLC purity.

EXAMPLE 17: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (5 g) and methanol (25 ml_), then mixture is cooled to 10-15°C. To the mixture aqueous phosphoric acid solution (14.8 mL 88% H₃P0₄ + 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. After completion of reaction, sequentially 20% aqueous potassium carbonate solution (100 mL) and water (100 mL) are added and mixture is kept for stirring for about 7 hours. 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/cm² 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. The above is kept in 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.

S. No. Parameter Conditions 1 Inlet Temperature 73°C

2 Outlet Temperature 37°C

3 Aspirator 32%

4 Vacuum 70 mm of Hg

5 Air Pressure 3.6 psi

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

(FORMULA V)

A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol- 4-yl)oxy)ethan-1 -ol (100 g), acetic acid (530 mL) and water (100 mL). The mixture is stirred and cooled to -5 to 0°C followed by slow addition of aqueous sodium nitrite solution (17.1 g sodium nitrite in 100 mL water) at -5 to 0°C. The mixture is stirred at the same temperature for about 2 hours at which point completion of the reaction is confirmed by TLC. To the mixture, 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. EXAMPLE 31 : 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)

(1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine mandelate (76.7 g), di-isopropyl ethylamine (107.85 g) and toluene (100 mL) are charged in a flask. The mixture is stirred at room temperature for about 25 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 (about 100 g, 1240 mL). The mixture is stirred at about 30°C for about 4 hours for completion of reaction as verified by TLC. After completion of reaction, water (1000 mL) is charged to the mixture and layers are separated. The organic layer is sequentially washed with aqueous hydrochloric acid solution (40 mL cone. HCI in 960 mL of water) followed by water (2x500 mL). Then the organic layer is subjected to complete distillation under vacuum at 55°C to afford the crude compound followed by addition of methanol (500 mL) and subsequent complete distillation to afford the title compound.

EXAMPLE 32: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with 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 (135.4 g), methanol (672 mL). The mixture is heated to 50-55°C for about 20 minutes followed by cooling to 7±3°C. To the mixture 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). To this mixture, a solution of BHT in ethyl acetate (10.8 g in 1080 mL) is added and mixture is stirred at room temperature for about 20 minutes. Then layers are separated and aqueous layer is extracted with ethyl acetate containing BHT i.e. butylated hydroxytoluene (5.2 g in 520 mL). The organic layer is washed with aqueous methanol (68 mL methanol in 604 mL water). The layers are separated and organic layer is subjected to complete distillation under vacuum at 50-55°C. To the crude obtained ethyl acetate is added (672 mL) and solvent is distilled off completely under vacuum. Again ethyl acetate (675 mL) is charged to the crude compound and mixture is heated to 50-55°C to get clear solution followed by cooling to 40-45°C. Then cyclohexane (1620 mL) is added at the same temperature and mixture is cooled to room temperature. The mixture is maintained at room temperature for 3-4 hours. The solid obtained is isolated by filtration and washed with cyclohexane (270 mL). The solid is then subjected to drying under vacuum at about 60°C for about 2 hours to afford the title compound in 85% yield having about 99.5% HPLC purity, Sulfoxide impurity: 0.084%.

EXAMPLE 33: PREPARATION OF TICAGRELOR (FORMULA I)

A flask is charged with Ticagrelor (10 g), ethyl acetate (80 mL) and butylated hydroxytoluene (BHT) (0.5 g). The mixture is heated to about 50°C and maintained for about 30 minutes followed by addition of carbon (0.5 g). The mixture is again stirred for about 15 minutes and filtered through Hy-flow at 50-55°C. The bed is washed with ethyl acetate (20 mL), followed by addition of cyclohexane (140 mL) to the filtrate at about 50°C over a period of 40 minutes. The mixture is stirred at room temperature for about 2.5 hours and solid obtained is isolated by filtration. The solid is washed with cyclohexane (20 mL) and is subjected to drying under vacuum at about 65°C to afford the title compound in 86% yield having HPLC purity of 99.55%, Sulfoxide impurity: 0.078%.

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)

A flask is charged with 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 (25 g), toluene (125 mL) and heated to about 60°C. The mixture is maintained at the same temperature for 20-30 minutes. The reaction mixture is cooled to 25-30°C followed by slow addition of cyclohexane (375 mL) over a period of 20 minutes. The mixture is maintained at the same temperature for 4 hours. 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)

A flask is charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (100 g), 2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1 ,3]dioxol-4- yl)oxy)ethanol L-tartaric acid salt (1 69.7 g), water (300 mL) and sodium bicarbonate (21 1 .6 g). The mixture is heated to about 96°C and maintained at the same temperature for about 18-20 hours and completion of the reaction is monitored by TLC. After completion of reaction, mixture is cooled to about 75°C followed by addition of 2-butanol (200 mL) and water (1700 mL), stirred for about 45 minutes. The mixture is cooled to about 30°C and stirring for about 3 hours. The solid obtained is filtered and wet cake is washed with water (200 mL). The wet compound is taken in water (1 200 mL) and stirred for about 30 minutes. Finally the compound is filtered and washed with water (500 mL) and then subjected to drying under vacuum at 55°C for about 3 hours to afford the title compound in about 90% yield having HPLC purity of about 98.8%.

Claims

Claims:

1 . A process for preparation of amorphous form of Ticagrelor comprising:

a) providing a solution of Ticagrelor in a suitable solvent; and

b) isolating amorphous Ticagrelor.

2. The process of claim 1 wherein suitable solvent in step a) is selected from alcohols, esters, ketones, hydrocarbons, ethers, nitriles, amides, water or mixtures thereof.

3. The process of claim 2 wherein suitable solvent in step a) is selected from esters, and ketones.

4. The process of claim 2 wherein in step b) the isolation is affected by evaporation, freeze drying, spray drying, lyophilization, by addition of suitable anti-solvent or any combination thereof.

5. The process of claim 4 wherein spray drying is employed in step b).

6. A process for preparation of compound of Formula IV, embodiments comprising,

Formula IV

a) providing a mixture of compound of Formula IV in a suitable solvent, b) reacting the mixture of step a) with a suitable acid,

c) isolating the compound of Formula IV from step b),

d) optionally, drying the compound of Formula IV.

7. The process of claim 6 wherein suitable solvent in step a) comprises of esters, ketones, hydrocarbons, alcohols and mixtures thereof.

8. The process of claim 6, wherein suitable acid in step b) is organic acid.

9. A process for preparation of Ticagrelor comprising preparation of compound of Formula IV,

Formula IV

10. The process of claim 9 further comprising,

a) cyclizing a compound of Formula IV in the presence of sodium nitrite and suitable acid in a suitable solvent, to afford a compound of Formula V or its salt

Formula IV Formula V where R₂ and R₃ independently are hydroxy or protected hydroxy groups, b) reacting a compound of Formula V with the compound of Formula VI or a salt thereof,

Formula V Formula VI

Formula VII where R₂ and R₃ independently are hydroxy or protected hydroxy groups. c) deprotecting the compound of Formula VII under suitable conditions to afford Ticagrelor of Formula I.