DESC:FIELD OF THE INVENTION
The present invention relates to a process for the purification of ticagrelor. More specifically, the present invention relates to an efficient process for the purification of ticagrelor which substantially eliminates the potential impurities formed during the course of reaction.
BACKGROUND OF INVENTION
Ticagrelor is a cyclopentyltriazolopyrimidine derivative and a potent antagonist of the platelet P2Y12 receptor that prevents ADP-mediated P2Y12 dependent platelet activation and aggregation. It is chemically known as (1S,2S,3R,5S)-3-[7-{[(1R,2S)-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, whose chemical structure is depicted by formula I:

Formula I
Ticagrelor and its related compounds was first time described in the PCT publication WO 2000/034283. The process involves reaction of [3aR-(3aa,4a,6a,6aa)]-[[6-[7-amino-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol]oxy]acetic acid, methyl ester with isoamylnitrile and bromoform to replace 7-amino group with bromine, this bromo intermediate is coupled with (lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine in presence of diisopropylethylamine to afford [3aR-[3aa,4a,6a(lR*,2S*),6aa]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-yl]oxy]-acetic acid methyl ester. It is then reduced using diisobutylaluminium hydride (DIBAL-H) followed by deprotection of diol group in presence of aqueous trifluoroacetic acid leads to ticagrelor. Further, the product formed by this method requires purification by column chromatography in order to control unacceptable amounts of critical and potential impurities formed in reaction and thus it is difficult to provide International Conference on Harmonization (ICH) grade material, suitable for formulation and thus process is not feasible at industrial scale.
Another improved process for the preparation of ticagrelor is disclosed in PCT publication WO 2001/092263 which involves preparation of key intermediates and their use for the preparation of ticagrelor. The process involves conversion of [3aR-(3aa,4a,6a,6aa)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-l,3-dioxol-4-yl]oxy]-ethanol into an acid addition salt and then reacted with 4,6-dichloro-2-(propylsulfanyl)-5-pyrimidinamine to afford diamino compound which is then cyclized to triazole, coupled, with (lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine and finally treated with an acid to afford ticagrelor. However, the reaction conditions involved in this approach require high temperature and longer reaction time. Moreover, the product formed by this process requires column chromatographic purification to control critical impurities formed during the reaction, thus making the process incompatible for large scale productions.
US patent 9,056,838 unveils novel intermediates and processes for preparing ticagrelor. As per one of the processes exemplified, purification process of ticagrelor have been disclosed wherein crude ticagrelor is purified by crystallization either from a mixture of methyl tert-butyl ether (MTBE) and cyclohexane or MTBE alone to give the pure ticagrelor.
A Chinese patent publication CN105801583 divulges a method of purifying ticagrelor. The method comprises of dissolving crude ticagrelor in a first solvent by heating followed by hot filtration and adding a second solvent to the hot filtrate which is then cooled to get solid precipitates, filtered and dried to obtain pure ticagrelor, wherein the first solvent is dichloromethane, acetonitrile, acetone, methanol, ethanol, n-butanol or ethyl acetate; the second solvent is n-hexane, cyclohexane, pentane, isooctane or cyclopentane. However, the process involves use of large volumes of solvent (about 10 to 35 times), which is not economical, nor desirable, from an environmental perspective.
Another Chinese patent publication CN106866677 discloses a purification process of ticagrelor. In the process disclosed within the publication, firstly crude ticagrelor is mixed with ethyl acetate in a fixed ratio followed by stirring for 7 hours. After complete dissolution, the solution is cooled at a temperature -20 °C for 22 hours to precipitate ticagrelor crystals.
In one another Chinese patent publication CN109705123, a purification process of ticagrelor is divulged. The purification process includes following steps; adding crude ticagrelor in a single solvent followed by heating the mixture to 50-60° C for complete dissolution. Afterwards, a certain amount of activated carbon is added to the solution. followed by filtering the hot solution, cooling to a certain temperature for precipitation of solid ticagrelor.
A PCT publication WO2019/127294 also discloses a method for purifying ticagrelor, which comprises of dissolving crude ticagrelor in acetate solvent in the presence of an alkyl tertiary amine followed by adding isooctane as an antisolvent to crystallize the ticagrelor of desired purity.
In most of the above-mentioned prior arts, when repeated, the purity of ticagrelor obtained after purification is not up to the mark. This may be attributed due to the presence of impurities which originate mainly during the synthetic process from the raw materials, solvents, intermediate and by-products. The purity of an API depends on several factors such as starting material, reaction kinetics and the crystallization process. The presence of these impurities even in small amounts may affect the efficacy and safety of pharmaceutical products. Therefore, the identification, quantitation, qualification, and control of impurities are a critical part of the drug development process.
According to regulatory guidelines, a drug manufacturer must submit data demonstrating that the product intended for marketing complies with regulations with regard to the content of impurities. The content of an unidentified impurity cannot exceed 0.1% (1000 ppm) by weight, while the amount of a known impurity cannot exceed 0.15% (1500 ppm). The drug manufacturer usually submits analytical data to the regulatory authority demonstrating that the content of each impurity is in accordance with regulations. The regulatory authority checks the submitted data in order to ensure that the drug is having acceptable level of impurities and is suitable for marketing.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Nevertheless, besides the existing routes of purification of ticagrelor there is a continuing need in the art to optimize the purification condition of ticagrelor which will purge the impurities down to the desired level as per ICH guidelines.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient process for the purification of ticagrelor wherein known and unknown impurities are removed simultaneously.
Another object of the present invention is to provide a process for the purification of ticagrelor, wherein impurities level have been controlled as per ICH guidelines.
Yet one another object of the present invention is to provide a process for the purification of ticagrelor using mild reaction conditions.
SUMMARY OF INVENTION
Accordingly, the present invention provides an efficient process for the purification of ticagrelor wherein the content of an individual impurity is controlled in accordance with the ICH recommendations.
In an embodiment, the present invention provides an efficient process for the purification of ticagrelor of formula I,

Formula I
which comprises:
i. providing a solution of ticagrelor in a mixture of organic solvents,
ii. adding an antisolvent to the solution of step (i) to precipitate a solid,
iii. isolating the pure ticagrelor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous process for the preparation of ticagrelor wherein the use of specific solvent antisolvent system leads to pure ticagrelor thereby minimizing the possibilities of impurities formation.
As used herein, the term “pure” represents a compound having purity greater than 98.5% w/w by HPLC, preferably greater than 99.0% w/w by HPLC, more preferably greater than 99.5% w/w by HPLC and any individual impurity [known] present in an amount less than 0.15% w/w by HPLC, any unknown impurity present in an amount of less than 0.10% w/w by HPLC and total impurities present in an amount less than 0.50% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature 25?± 5?.
Impurities in ticagrelor are undesirable and may be harmful to a patient being treated with a dosage form of the API in which a sufficient level of impurities are present. Furthermore, the undesired impurities reduce efficacy of API and pharmaceutical composition too.
Another object of the present invention is to provide a process for the purification of ticagrelor that overcome the limitations of the prior methods i.e., multiple crystallizations or isolation steps, column chromatographic purifications.
The ICH Q7A guidance for drug manufacturers requires that process wherein impurities to be maintained as per ICH limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
In one aspect the present invention provides a process for the purification of ticagrelor. The process comprises dissolving ticagrelor in a mixture of organic solvents, adding an antisolvent to the solution to precipitate a solid, and isolating the pure ticagrelor.
The ticagrelor used for the purification can be prepared by the methods reported in literature. Any form of ticagrelor is acceptable for use as a starting material in the process of purification. This includes, without limitation, any amorphous or crystalline forms, or any solvates, hydrates, or anhydrous forms or mixture thereof. Ticagrelor can be dissolved in a mixture of organic solvents at ambient temperature till complete dissolution.
Generally, the organic solvents used herein may include solvents in which ticagrelor is soluble. Examples of such solvents are, but not limited to: alcoholic solvents such as methanol, ethanol, propanol, butanol, and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, and the like; aliphatic solvents such as n-butane, n-pentane, n-hexane, n-heptane and the like; ketonic solvents such as acetone, ethyl methyl ketone, and the like; esters such as ethyl acetate, n-butyl acetate, t-butyl acetate, and the like; ether solvents such as diethyl ether, di-isopropyl ether, and methyl tert-butyl ether; tetrahydrofuran; and hydrocarbon solvents such as toluene, xylene, and the like. Mixtures of any two or more solvents from a chemical class, as well as mixtures of solvents from different chemical classes, can be used for the dissolution of ticagrelor. Preferably, solvents that can be used as a mixture are alcoholic solvents such as methanol, ethanol, propanol, butanol, and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, and the like. More preferably, the solvent can be a mixture of methanol and dichloromethane.
The solution of ticagrelor can be obtained by dissolving the ticagrelor in the mixture of solvents at ambient temperature and resulting reaction mass can be heated at temperature ranging from about 30-45°C, preferably at 35-40 °C.
Thereafter, an antisolvent can be added to the solution of ticagrelor at same temperature or at ambient temperature for the precipitation of solid.
The antisolvent used herein may include but not limited to: alcoholic solvents such as methanol, ethanol, propanol, butanol, and the like; halogenated solvents such as dichloromethane, chloroform, ethylene dichloride, and the like; aliphatic solvents such as n-butane, n-pentane, n-hexane, n-heptane and the like; ketonic solvents such as acetone, ethyl methyl ketone, and the like; esters such as ethyl acetate, n-butyl acetate, t-butyl acetate, and the like; ether solvents such as diethyl ether, di-isopropyl ether, and methyl tert-butyl ether; tetrahydrofuran; and hydrocarbon solvents such as toluene, xylene, and the like. Preferably the solvent is chosen from ether, more preferably the ether is methyl tert-butyl ether.
Afterwards, the reaction mass can be cooled to a temperature of about 0-20°C, preferably at 5-15°C and stirred for 4-10 hours for isolation of solid from the precipitate. Preferably, the reaction mass can be stirred over a period of about 5-8 hours, more preferably, about 6-8 hours.
The resulting reaction mass can be filtered to remove any undissolved particles, using various filtration techniques such as pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art. The reaction mass containing the ticagrelor obtained in above step may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, evaporation, a layer separation, decolourization, a carbon treatment, or a combination thereof.
Thereafter, the resulting solid can be dried at 50-80? for about 5-25 hours to obtain pure ticagrelor substantially free from impurities as per ICH guidelines. The preferable drying temperature can be 55-60°C and preferably, the solid can be dried for 7-23 hours and more preferably for 10-20 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.
The resulting pure ticagrelor of present invention have purity of greater than 99.0%, preferably 99.50% and more preferably 99.60% and all impurities have been reduced to less than 0.50% w/w by HPLC, specifically, level of impurity A reduced less than 0.15% from 0.42% and an unknown impurity (at RRT 0.22 ~0.23) to less than 0.06% from 0.10%.
It has been observed by the inventors of present invention that purification of ticagrelor through prior art processes leads to provide a poor quality of the product wherein it is very difficult to remove impurities at final stage or in case it may be removed, the process involves use of tedious and cumbersome procedures like low temperatures, multiple process steps, column chromatographic purifications, multiple isolations / re-crystallizations. Even though the final stage purification to reduce the level of impurities usually causes yield loss of the final product, thereby making the process commercially unfeasible. Therefore, it becomes more challenging to remove impurities in order to obtain pure ticagrelor of desired quality. The comparative example of the present invention clearly indicates that presence of high level of impurities even after purification which makes product unacceptable as per regulatory requirements for drug formulation.
After extensive experimentation, the process of present invention has been developed to remove known or unknown impurities to get the desired quality of ticagrelor.
According to an embodiment of the present invention it was also unexpectedly found that a good reliableness of the pure ticagrelor can be obtained by using solvent antisolvent system in a specific ratio. The ratio of solvent antisolvent may vary from 1 to 3: 4 to 9, preferably 2 to 3:6 to 9. In specific ratio, solvent may be the mixture of two or more organic solvents.
The present invention provides a process to reduce the level of impurity A, namely, (1S,2S,3R,5S)-3-[7-amino-5-(propylsulfanyl)-3H-U,2,3)triazolol4,5-dlpyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol of Formula II,

Formula II
from 0.42% to less than 0.15% and an unknown impurity (at RRT 0.23) from 0.10% to less than 0.06%.
Nonetheless by the use of these particular purification process as set out in present invention, ticagrelor may be conveniently obtained in high purity having acceptable limits of impurities that is suitable for use in medicament.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Purification of ticagrelor
Ticagrelor (25 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.22] was dissolved in a mixture of methanol (12.5 ml) and methylene dichloride (50ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (125 ml) was added to the reaction mass at the same temperature. Further, the reaction mass was stirred at the same temperature for 3 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 8 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (12.5 ml). Finally, the filtered material was dried at 60-70°C for 20 hours to obtain pure ticagrelor (22.5 g) having HPLC purity [w/w] = 99.61%; impurity A = 0.11%; other impurity = 0.06% at RRT 0.22.
Example 2: Purification of ticagrelor
Ticagrelor (25 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.23] was dissolved in a mixture of methanol (6.3 ml) and methylene dichloride (50ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (125 ml) was added to the reaction mass at the same temperature. Further, the reaction mass was stirred at the same temperature for 2 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 7 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (12.5 ml). Finally, the filtered material was dried at 60-70°C for 15 hours to obtain pure ticagrelor (22.5 g) having HPLC purity [w/w] = 99.53%; impurity A = 0.15%; other impurity = 0.05% at RRT 0.22.
Example 3: Purification of ticagrelor
Ticagrelor (25 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.23] was dissolved in a mixture of acetone (12.5 ml) and methylene dichloride (50ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (125 ml) was added to the reaction mass at the same temperature. Further, the reaction mass was stirred at the same temperature for 3 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 6 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (12.5 ml). Finally, the filtered material was dried at 60-70°C for 10 hours to obtain pure ticagrelor (22.5 g) having HPLC purity [w/w] = 99.51%; impurity A = 0.15%; other impurity = 0.05% at RRT 0.22.
Example 4: Purification of ticagrelor
Ticagrelor (25 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.23] was dissolved in a mixture of methanol (25 ml) and methylene dichloride (50ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (200 ml) was added to the reaction mass at same temperature. Further, the reaction mass was stirred at the same temperature for 2-3 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 6 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (12.5 ml). Finally, the filtered material was dried at 60-70°C for 10 hours to obtain pure ticagrelor (20 g) having HPLC purity [w/w] = 99.68%; impurity A = 0.09%; other impurity = 0.03% at RRT 0.22.
Comparative example 1: Purification of ticagrelor
Ticagrelor (25 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.23] was dissolved in methylene dichloride (30ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (75 ml) was added to the reaction mass at same temperature. Further, the reaction mass was stirred at the same temperature for 3 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 8 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (4.5 ml). Finally, the filtered material was dried at 60-70°C for 20 hours to obtain pure ticagrelor (13.5 g) having HPLC purity [w/w] = 99.68%; impurity A = 0.19%; other impurity = 0.09% at RRT 0.22.
Comparative example 2: Purification of ticagrelor
Ticagrelor (15 g) having [HPLC purity [w/w] = 99.6 % containing impurity A = 0.21%; other impurity = 0.10% at RRT 0.22] was dissolved in methylene dichloride (30ml). Thereafter, the mixture was stirred at ambient temperature till complete dissolution. The reaction mass thus obtained was heated at 35-40°C followed by continuous stirring. Afterwards, methyl tert-butyl ether (75 ml) was added to the reaction mass at the same temperature. Further, the reaction mass was stirred at the same temperature for 2 hours. The resulting reaction mass was cooled at 5-15°C followed by stirring for another 6 hours. Thereafter, the resulting residue was filtered, washed with methyl tert-butyl ether dried (4.5 ml). Finally, the filtered material was dried at 60-70°C for 10 hours to obtain pure ticagrelor (13.2 g) having HPLC purity [w/w] = 99.45%; impurity A = 0.20%; other impurity = 0.08% at RRT 0.22.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the purification of ticagrelor of formula I,

Formula I
which comprises:
i. providing a solution of ticagrelor in a mixture of organic solvents,
ii. adding an antisolvent to the solution of step (i) to precipitate a solid,
iii. isolating the pure ticagrelor.

2. The process as claimed in claim 1, wherein organic solvent in step (i) is selected from alcoholic solvent, halogenated solvent, ketonic solvent, ester solvent or mixture thereof.

3. The process as claimed in claim 2, wherein alcoholic solvent is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; halogenated solvent is selected from dichloromethane, chloroform, ethylene dichloride, and the like; ketonic solvent is selected from acetone, ethyl methyl ketone, and the like; ester is selected from ethyl acetate, n-butyl acetate, t-butyl acetate, and the like; or mixture thereof.

4. The process as claimed in claim 1, wherein reaction mass in step (i) is heated at temperature ranging from about 30-45°C.

5. The process as claimed in claim 1, wherein antisolvent in step (ii) is selected from aliphatic solvent, ether solvent and hydrocarbon solvent.

6. The process as claimed in claim 5, wherein aliphatic solvent is selected from n-butane, n-pentane, n-hexane, n-heptane and the like; ether solvent is selected from diethyl ether, di-isopropyl ether, and methyl tert-butyl ether, tetrahydrofuran; and hydrocarbon solvent is selected from toluene, xylene, and the like.

7. The process as claimed in claim 1, wherein isolation in step (iii) is carried out by cooling of reaction mass at temperature of about 0-20°C.