Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention generally relates to an improved process for the preparation of Ticagrelor and intermediates thereof.
• the present invention further relates to a process for preparation of Ticagrelor crystalline Form II.
• the present invention further relates to amorphous form of ticagrelor and its process for preparation thereof.
• the present invention further relates to crystalline ferulate salt of ticagrelor and its process for preparation thereof.
• Ticagrelor also known as (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane-l,2-diol, is represented by the following structure of Formula I:
• Ticagrelor is marketed by AstraZeneca in US under the trade name BRILINTA ® and in Europe under the trade name BRILIQUE ® is purportedly a reversibly binding oral P2Y12 ADP receptor antagonist and indicated for the use of platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome.
• the process disclosed in the '060 patent involves the condensation of Formula II and Formula Ilia in presence of diisopropyl ethyl amine in tetrahydrofuran.
• the synthetic process disclosed in the '060 patent is multi step process and involves use of toxic reagents like tribromomethane, triflic anhydride, methyl-2-(trifluoromethyl sulfonyloxy) acetate and the introduction of the methoxycarbonylmethyl group is very difficult due to poor chemo selectivity, as the amino group also react with 2-(trifluoromethyl sulfonyloxy)acetate.
• Patent publication No. WO2010/030224 (“the '224 publication”) disclosed an improved process for preparation of ticagrelor, which involves preparation of Formula IV by coupling of Formula ⁇ and oxalate salt of Formula III in presence of organic base like triethyl amine, organic solvent like ethylene glycol and specific reaction conditions like oxygen concentration below 2.0% by volume, finally converting the obtained intermediate of Formula IV in to ticagrelor yields less percentage of yield (79%).
• Patent publication No. WO 2011/017108 (“the ⁇ 08 publication”) disclosed a process for preparation of Ticagrelor, which involves preparation of Formula IV by coupling of dichloro nitro intermediate and amine intermediate in presence of organic solvent like tetrahydrofuran to obtain condensed monochloro nitro intermediate and followed by reducing the nitro group of obtained compound to yield compound of Formula IV, finally converting it into ticagrelor.
• the process disclosed in the ⁇ 08 publication is schematically represented as follows:
• Patent publication No. WO 2013/150495 (“the '495 publication”) disclosed a process for preparation of Ticagrelor, by coupling of Formula II and salt of Formula III in a polar solvent selected from alcohol, polar aprotic solvent, water or mixtures thereof and optionally in presence of additive such as potassium iodide, tetrabutyl ammonium iodide, tetrabutyl ammonium bromide, sodium iodide, lithium chloride and lithium iodide to obtain compound of Formula IV, finally converting the obtained Formula rv in to ticagrelor.
• a polar solvent selected from alcohol, polar aprotic solvent, water or mixtures thereof and optionally in presence of additive such as potassium iodide, tetrabutyl ammonium iodide, tetrabutyl ammonium bromide, sodium iodide, lithium chloride and lithium iodide
• ticagrelor salts such as hydrochloride, hydrobromide, succinate, fumarate, D- tartarate, L-tartarate, DPTTA, malonate, oxalate, maleate and citrate salts.
• Patent publication No. WO 2014/102830 (“the '830 publication”) disclosed a process for preparation of Ticagrelor, by coupling of Formula II and salt of Formula III in a solvent such as ethylene glycol and a base diisopropyl ethylamine in presence of catalyst selected from 1,8- Diazabicycloundec-7-ene (DBU), 1,5-Diazabicyclo (4.3.0) non-5-ene (DBN) to obtain compound of Formula rv, dimethylaminopyridine, alkali metal iodide selected from potassium iodide, Lithium iodide, sodium iodide, iodine; p-toluene sulfonic acid and tertiary alkyl ammonium halide, finally converting the obtained Formula rv in to ticagrelor.
• a solvent such as ethylene glycol and a base diisopropyl ethylamine
• catalyst selected from 1,8- Diazabi
• U.S. Patent No. 7,265,124 discloses four crystalline Forms of ticagrelor such as Form I, ⁇ , III, rv and Form a (substantially amorphous) processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (PXRD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
• PXRD powder X-ray diffraction
• DSC differential scanning calorimetry
• EP.Com Journal (2011), 11(7 A), 3 and (2011), 11(6B), 26 discloses new crystalline form and amorphous form of ticagrelor correspondingly. However, both the journal articles have not disclosed XRD data for the relevant forms.
• Patent publication No. WO 2011/067571 discloses co-crystals of ticagrelor with a co-former molecule selected from glycolic acid, salicylic acid, decanoic acid, gentisic acid, glutaric acid, vanillic acid, succinic acid, malonic acid, or maltol.
• Patent publication No. WO 2012/0164286 discloses co-crystal of ticagrelor and co-former molecule where co-former molecule is acetyl salicylic acid.
• Patent publication No. WO 2014/083139 discloses amorphous form of ticagrelor and its process for preparation from alcohol solvent such as methanol.
• Patent publication No. IN 1498/MUM/2012 discloses four Forms of ticagrelor Form I, Form II, Form III, Form X and Form rv (amorphous Form) processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (PXRD).
• PXRD powder X-ray diffraction
• the present invention provides an improved process for the preparation of ticagrelor.
• the process according to the present invention provides ticagrelor in crystalline Form II with improved yield as compared to the prior-art processes as well as improved process efficiency and higher purity of the compound of Formula rv obtained without using any organic solvents and organic bases.
• the present invention further relates to an amorphous form of ticagrelor . and its process for preparation thereof.
• the present invention furthermore relates to crystalline ferulate salt of ticagrelor and its process for preparation thereof.
• the present invention encompasses an improved process for preparation of compound of Formula FV,
• the present invention provides an improved process for preparation of compound of Formula IV, comprising: reacting a compound of Formula II with a compound of Formula III or a salt thereof in water and potassium phosphate to obtain a compound of Formula TV.
• the present invention provides an improved process for preparation of ticagrelor of Fo
• the present invention provides an improved process preparation of ticagrelor of Formula I, comprising:
• the present invention provides a process for purification of ticagrelor of Formula I, comprising:
• the present invention provides a process for preparation of amorphous Form of ticagrelor, comprising:
• step c2) evaporating the step a2) or step b2) solution under vacuum to obtain a residue, d2) optionally adding suitable solvent to the step c2) residue, and
• the present invention provides a process for preparation of amorphous Form of ticagrelor, comprising:
• step b2) neutralizing the step a2) solution with a base
• step b2) evaporating the step b2) solution under vacuum to obtain a residue
• the present invention provides amorphous Form of ticagrelor characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 2.
• PXRD powder X-Ray diffraction
• the present invention provides crystalline ticagrelor ferulate salt.
• the present invention provides crystalline ticagrelor ferulate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3.
• PXRD powder X-Ray diffraction
• the present invention provides crystalline ticagrelor ferulate salt characterized by a differential scanning calorimetric (DSC) thermogram in accordance with Figure 4.
• DSC differential scanning calorimetric
• the present invention provides crystalline ticagrelor ferulate salt characterized by a thermo gravimetric analysis (TGA) thermogram substantially in accordance with Figure 5.
• TGA thermo gravimetric analysis
• the present invention provides a process for preparation of crystalline ferulate salt of ticagrelor, comprising:
• the present invention provides a pharmaceutical composition comprising ticagrelor prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
• Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of ticagrelor, prepared according to Example 5.
• Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous form of ticagrelor.
• Figure 3 is the characteristic powder X-ray diffraction (XRD) pattern of crystalline ticagrelor ferulate salt.
• Figure 4 is the characteristic differential scanning calorimetric (DSC) thermogram of crystalline ticagrelor ferulate salt.
• Figure 5 is the characteristic thermo gravimetric analysis (TGA) of crystalline ticagrelor ferulate salt.
• the present invention encompasses an improved process for preparation of ticagrelor and intermediates thereof.
• the present invention also relates to a process for preparation of ticagrelor in crystalline Form or amorphous form.
• the present invention further relates to ticagrelor ferulate salt, a process for its preparation and its use as intermediate in the preparation of tecagrelor.
• the present invention provides an improved process for preparation of compound of Formula rv,
• the present invention provides an improved process for preparation of ticagrelor of Formula I,
• the compound of Formula II can be prepared by using an adaptation of literature methods, such as described in US 7,067,663 and 7,799,914.
• a suitable salt of compound of Formula III employed in step a) is a salt of a mineral or organic acid, such as HC1, HBr, HI, H 0 3 , H 2 S0 4 , acetic acid, trifluoro acetic acid, formic acid, L- tartaric acid, oxalic acid; Preferably L-tartaric acid salt.
• the suitable inorganic base includes but are not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, potassium t-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, monopotassium phosphate, dipotassium phosphate, tripotassium phosphate and the like and mixtures thereof; preferably the base is tripotassium phosphate.
• the source of base can be added either as solution in water or it may be added as solid to the solution of reaction mixture.
• the step a) reaction is carried out at a temperature of about 60°C to reflux for a period of about 4 hours to about 20 hours; preferably at about 90°C to about 95°C for a period of about 8 hours.
• additional water may be added to the reaction mass for further dilution and extract the product with water immiscible organic solvent.
• the product containing water immiscible organic solvent may be evaporated under vaccum and then crystallization using one or more organic solvents to obtain the compound of Formula IV.
• the water immiscible organic solvent include, but are not limited to esters such as ethyl acetate, isopropyl acetate and the like; ethers such as methyl tertiary butyl ether, diethyl ether and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated solvents such as methylene chloride, chloroform and the like and mixtures thereof; preferably the water immiscible organic solvent is toluene, ethyl acetate or mixtures thereof.
• the one or more organic solvents include, but are not limited to alcohols, esters, ethers, nitriles, halogenated solvents, aromatic hydrocarbons, cyclic hydrocarbons and the like and mixtures thereof.
• alcohols such as methanol, ethanol, isopropanol and the like
• esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like
• ethers such as tetrahydrofuran, methyl tertiary butyl ether, diethyl ether and the like
• nitriles such as acetonitrile, propionitrile and the like
• halogenated solvents such as methylene chloride, chloroform and the like
• aromatic hydrocarbons such as toluene, xylene and the like
• cyclic hydrocarbons such as hexane, cyclohexane, heptanes and the like; and mixtures thereof; preferably
• the present invention provides an improved process for the preparation of ticagrelor, comprising providing a compound of Formula IV as obtained by the process described above, as a starting material or as an intermediate, where the yield and the purity of the ticagrlor may have a purity equal to or greater than about 99.5% as determined by HPLC.
• the present invention provides an improved process for preparation of ticagrelor of Formula I, comprising:
• the entire process is carried without isolating any intermediates in steps ii), iii) and iv).
• the cyclization of the compound of Formula rV is carried out in presence of sodium nitrite and acetic acid in water at a temperature of about 30°C to 70°C to obtain a compound of Formula V.
• the reaction mass may be basified with a suitable aqueous base such as sodium carbonate, potassium carbonate and the like and then separating the organic layer and proceed for further stage.
• the step iii) of the aforementioned process involves condensation of the compound of Formula V with a compound of Formula Va in presence of a suitable solvent and suitable base to obtain a compound of Formula VI.
• the suitable solvent of step iii) includes, but is not limited to halogenated hydrocarbons, aromatic hydrocarbons, ethers, amides, nitriles and the like and mixtures thereof.
• halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tertrachloride and the like and mixtures thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene, chlorobenzene and the like and mixtures thereof; ethers include, but are not limited to dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and the like and mixtures thereof; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like and mixtures thereof; nitriles include, but are not limited to acetonitrile, propionitrile and the like; water and mixtures thereof; preferably toluene.
• the suitable base for condensation of compound of Formula V and compound of Formula Va is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, triethylamine ⁇ , ⁇ -diisopropyl ethyl amine and the like and mixtures thereof; preferably potassium carbonate.
• the condensation of the compound of Formula V and compound of Formula Va is carried out at a temperature of about 30°C to 60°C. After completion of the reaction, the reaction mass may be washed with aqueous acetic acid and then separating the organic layer and proceed for further stage.
• the step iv) of deprotecting the compound of Formula VI is carried out with an acid source to obtain ticagrelor.
• the suitable acid for deprotection of compound of Formula VI is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the like and mixtures thereof; preferably hydrochloric acid.
• the acid source may be in the form of an aqueous, anhydrous or gas form, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas, preferably a solvent containing hydrochloric acid can be used.
• the solvent may be used for dissolving acid source is selected from the group consisting of methanol, ethanol, isopropanol and the like and mixtures thereof.
• the reaction mass may be separated off and the obtained product containing aqueous layer may be basified with a suitable aqueous base such as sodium carbonate, potassium carbonate and the like and then extracting the product with an water immiscible organic solvent such as ethyl acetate, methylene chloride and the like.
• the ticagrelor product can be isolated from the resultant water immiscible organic solvent by adding another solvent such as cyclohexane, hexane, heptane and the like.
• the present invention provides a process for purification of ticagrelor of Formula I, comprising: al) providing a solution of ticagrelor in one or more organic solvents,
• the starting ticagrelor can be prepared by any known methods or can be prepared as per procedure described just as above.
• the one or more organic solvents of step al) include, but are not limited to alcohols, esters, ethers, nitriles, halogenated solvents, aromatic hydrocarbons and mixtures thereof.
• alcohols such as methanol, ethanol, isopropanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran, methyl tertiary butyl ether and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated solvents such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like and mixtures thereof; more preferably methanol, isopropanol, ethyl acetate, methylene chloride and the like and mixtures thereof.
• the solution may be heated to dissolve the ticagrelor.
• the temperature suitable for dissolving ticagrelor depends on the amount of solvent used and the amount of ticagrelor in the solution.
• the solution is heated at a temperature of at about 25°C to about reflux temperature.
• the solution is heated at about 50°C to about 65°C.
• the pure ticagrelor can be isolated by adding another solvent such as cyclohexane, hexane, heptane and the like and mixtures thereof to precipitation. Then the ticagrelor can be recovered by any conventional techniques known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about 10°C, preferably at about -5°C to about +5°C.
• the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 40°C. The drying can be carried out for any desired time until the required product purity is achieved, e.g., a time period ranging from about 1 hour to about 10 hours. Ticagrelor recovered using the purification process of the present invention is crystalline form, , particularly crystalline Form II.
• the present invention provides ticagrelor as obtained by the process described above having purity of at least about 98%, as measured by HPLC; preferably at least about 99%, as measured by HPLC; and more preferably at least about 99.5%, as measured by HPLC.
• the present invention provides a process for preparation of amorphous Form of ticagrelor, comprising:
• step b2) optionally neutralizing the step a2) solution with a base
• step c2) evaporating the step a2) or step b2) solution under vacuum to obtain a residue, d2) optionally adding suitable solvent to the step c2) residue, and
• Any form of ticagrelor or its salt can be used as starting material in the process of making the amorphous ticagrelor of the present invention.
• the ticagrelor salt used to prepare ticagrelor amorphous form is any salt of ticagrelor; preferably ferulate salt of ticagrelor.
• the step a2) process involves providing a solution of ferulate salt of ticagrelor in one or more organic solvents at a temperature of about 25°C to about 35°C.
• the one or more organic solvents of step a2) include, but are not limited to esters, ethers, nitriles, halogenated solvents, aromatic hydrocarbons and mixtures thereof.
• esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran, methyl tertiary butyl ether, diethyl ether and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated solvents such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like and mixtures thereof; preferably ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile, methylene chloride, toluene and mixtures thereof.
• the step b2) process involves neutralizing the step a2) solution with a base, where in the base includes but are not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, triethylamine and mixtures thereof; preferably sodium bicarbonate.
• step c2) of the aforementioned process advantageously carried out evaporating the step b2) product containing organic layer under vacuum at a temperature of about 25°C to about 65°; preferably at about 45°C to about 55°C.
• the residue may be slurrying with a suitable solvent, wherein the suitable solvent includes, but are not limited to cyclohexane, hexane, heptanes, methyl cyclohexane and the like and mixtures thereof; preferably cyclohexane.
• the ticagrelor amorphous Form can be recovered by any conventional techniques known in the art, for example filtration.
• the temperature during stirring can range from about -10°C to about 30°C, preferably at about 20°C to about 30°C and the resultant product may optionally be further dried.
• the present invention provides amorphous Form of ticagrelor characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 2. .
• the present invention provides crystalline ticagrelor ferulate salt characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 3.
• the present invention provides crystalline ticagrelor ferulate salt characterized by a differential scanning calorimetric (DSC) thermogram in accordance with Figure 4.
• DSC differential scanning calorimetric
• the present invention provides crystalline ticagrelor ferulate salt characterized by a thermo gravimetric analysis (TGA) thermogram substantially in accordance with Figure 5.
• TGA thermo gravimetric analysis
• the present invention provides a process for preparation of ferulate salt of ticagrelor, comprising the steps of:
• Any form of ticagrelor or a solution of ticagrelor obtained from previous processing steps can be used as starting material in the process of making the crystalline ferulate slat of ticagrelor of the present invention.
• the organic solvents of step a3) include, but are not limited to alcohols, esters, ethers, nitriles, halogenated solvents, aromatic hydrocarbons and mixtures thereof.
• alcohols such as methanol, ethanol, isopropanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran, methyl tertiary butyl ether, diethyl ether and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated solvents such as methylene chloride, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like and mixtures thereof; more preferably methanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile
• the solution may be heated to dissolve the ticagrelor.
• the solution is heated at a temperature of at about 25°C to about reflux temperature.
• the solution is heated at about 40°C to about 65°C.
• the crystalline ticagrelor ferulate salt can be isolated by cooling the reaction mass temperature to about 0°C to about 35°C.
• the solution is cooled to about 20°C to about 30°C to precipitation.
• the crystalline ticagrelor ferulate salt can be recovered by any conventional techniques known in the art, for example filtration.
• the temperature during stirring can range from about -10°C to about 30°C, preferably at about 20°C to about 30°C and the resultant product may optionally be further dried.
• the recovered ticagrelor ferulate can be used as intermediate in the process of preparing pure ticagrelor.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising ticagrelor prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
• Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, injectable solution, etc.
• reaction mixture temperature was allowed to cool 75°C and charged ethyl acetate (600 ml) further allowed reaction mixture temperature to 35°C, separated the aqueous and organic layers, aqueous layer was extracted with ethylacetate (200 ml). Washed the combined organic layer with DM water (2x400 ml) and the solvent was distilled by down-ward distillation at 40°C.
• cyclohexane (600 ml) and methylene chloride (50 ml) at 35°C and stirred for 1 hr, cooled the reaction mass temperature to 5°C and stirred for 1 hr. Precipitated solid was filtered and washed with cyclohexane (2x100 ml). The wet product was dryed at about 50°C to about 55°C under reduced pressure to provide the title compound as off white solid.
• aqueous layer was again washed with ethylacetate (2x100 ml).
• aqueous sodium chloride solution 50 gms in 150 ml DM water.
• ethyl acetate 540 ml
• charcoal 10 gms
• the water content in the ethylacetate solution was decreased to ⁇ 0.4% by vacuum distillation at 50°C.
• the reaction mass temperature was raised to about 55°C to ,60°C and fallowed by cooled to about 45°C to 55°C.
• reaction mass temperature allowed to cool to about 25°C to 30°C and stirred for 60-75 min. Further cooled to about 0°C to 5°C and stirred for 60-75 min. Precipitated solid was filtered and washed with 1 :1 mixture of ethyl acetate and cyclohexane (2x300 ml). The wet product was dryed at about 35°C to about 45°C under reduced pressure to provide the title compound.
• Ticagrelor ferulate 50g was dissolved in ethyl acetate (500 mL) and washed, sequentially, with saturated sodium bicarbonate (125 mL x 2), water (125 mL) and brine (125 mL). The separated organic layer concentrated under reduced pressure. The residue obtained was co- evaporated, sequentially, with dichloromethane (125 mL x 2) and cyclohexane (125 mL). To the residue was charged cyclohexane (500 mL) and the reaction mass slurred for another 30 min, at 30 ⁇ 5°C. The precipitated material was filtered, under suction and the wet material (36 gm) was dried at ambient temperature for 6h, to afford amorphous ticagrelor as off-white colored solid material.
• the combined organic layer was washed with sodium chloride solution (50 gms in 150 ml DM water) and concentrated under reduced pressure. The residue was co-evaporated with ethyl acetate (100 mL x 2) and dissolved in ethyl acetate (600 mL). Ferulic acid (37.2g) was added and the temperature of the reaction mixture was raised to 45 ⁇ 5°C. The homogeneous solution was maintained for 30 min at 45 ⁇ 5°C and gradually cooled to 25 ⁇ 3°C, when white colored solid material precipitated out. The reaction mixture was further slurred for 2h, at 25 ⁇ 3°C. The precipitated solid was filtered, under suction and the wet material (166gm) was dried at 25 ⁇ 3°C for 6h, to afford ticagrelor ferulate as off-white colored solid material.
• the DSC is set forth in Figure-4
• the TGA is set forth in Figure-5
• cyclopenta[d][l,3]dioxol-4-yl ⁇ oxy)ethanol of Formula-VI solution from the above example-3 was cooled to 15°C, a solution of concentrated aqueous hydrochloric acid (260 gms) in methanol was charged at below 15°C. Reaction mixture was stirred to complete reaction. After completion of the reaction the aqueous layer, containing the product, was separated and added to a slurry of sodium bicarbonate (235 gms) in water (320 ml), keeping the temperature below 20 to 25°C. The aqueous layer was extracted with ethyl acetate (340 + 100 + 100 mL).

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