Claims:1. An improved process for preparation of Ticagrelor in good yield and purity, which comprises the following steps;
i. Reacting 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) with tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) in presence of sodium bicarbonate, water and a phase transfer catalyst to obtain [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl] oxy]ethanol (III);

ii. Cyclizing compound (III) of step (i) with sodium nitrite and acid in water to obtain [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxole4-methanol (IV), extracting the product in solvent selected from ethyl acetate, methylene dichloride (MDC), toluene or chloroform or mixtures thereof for subsequent step;

iii. In-situ reacting 3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol -4-yl) oxy]ethanol (IV) of step (ii with mandelic acid salt of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (V) in presence of DIPEA and solvent to obtain compound 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 dimethyl-4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI), which is either isolated or extracted in solvent for subsequent step;

iv. Deprotecting 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) of step (iii), optionally in-situ, in presence of solvents selected from lower alcohols or 1:1 to 1:2 acid-water mixture to obtain ticagrelor;

and
v. isolating and purifying ticagrelor.

2. The improved process as claimed in claim 1, wherein the phase transfer catalyst in step (i) is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, methyl trioctyl ammonium chloride, Methyl- triethyl ammonium chloride, Tri-ethyl-benzyl-ammonium chloride, Tributyl methyl ammonium chloride, Tetrabutyl phosphonium chloride and the like.

3. The improved process as claimed in claim 1, wherein the acid for step (ii) is selected from acetic acid, c. HCl or H2SO4.

4. The improved process as claimed in claim 3, wherein the acid is acetic acid.

5. The improved process as claimed in claim 1, wherein the step of purification of ticagrelor comprises heating solution of ticagrelor dissolved in one or more solvents at a temperature in the range of 60-75oC to obtain clear solution, filtering and cooling the filtrate to obtain pure ticagrelor.

6. The improved process as claimed in any of the preceding claims, wherein the solvent is selected from polar or non-polar, protic or aprotic solvent such as lower alcohol, esters such as ethyl acetate, isopropyl acetate, aliphatic or aromatic hydrocarbons, ketones, nitriles, ethylacetoacetate, and the like either alone or combination thereof.

7. The improved process for preparation of Ticagrelor in good yield and purity, comprising;
i. Reacting 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) with tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) in presence of sodium bicarbonate, water and TBAB as phase transfer catalyst to obtain [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2dimethyl-3aH-cyclo penta-[a][1,3]dioxol-4-yl]oxy]ethanol (III);

ii. Cyclizing compound (III) of step (i ) with sodium nitrite and acetic acid in water to obtain [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol (IV) and extracting the product in solvent selected from ethyl acetate or methylene dichloride (MDC) for subsequent step;

iii. In-situ reacting 3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol -4-yl) oxy] ethanol (IV) of step (ii) with mandelic acid salt of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (V) in presence of DIPEA and solvent selected from toluene, DMSO or ethyl acetate to obtain compound 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI), which is either isolated or extracted in solvent such as ethyl acetate for subsequent step;

iv. Deprotecting 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) of step (iii), optionally in-situ, in solvents selected from lower alcohols such as methanol or in 1:1 to 1:2 acid–water mixture to obtain ticagrelor; and

v. isolating and purifying ticagrelor from the solvents selected from ethyl acetate, isopropyl acetate, methyl n-propyl ketone, ethylacetoacetate, toluene alone or mixture thereof.

8. Novel crystalline Ticagrelor polymorph characterized by an X-ray powder diffraction pattern having peaks at 5.15±0.2, 9.46±0.2, 13.73±0.2, 15.11±0.2, 19.98±0.2, 21.13±0.2, 22.31±0.2, 25.99±0.2 and 27.20 ± 0.2 degrees 2-theta.

9. The crystalline Ticagrelor polymorph as claimed in claim 5 characterized by DSC with melting range of 148-152°C.

10. The process for preparation of the crystalline polymorph of ticagrelor as claimed in claim 9 comprising dissolving crude Ticagrel in a mixture of methanol and water to obtain the said polymorph.

11. A pharmaceutical composition of ticagrelor prepared by the process as claimed in claim 1 along with pharmaceutically acceptable excipients.
, Description:Technical Field of the invention:
The present invention relates to an improved process for synthesis of Ticagrelor, its intermediates in good yield and purity. Further, the present invention relates to novel crystalline Ticagrelor polymorph as depicted in Fig 1.

Background and prior art:
Ticagrelor is a nucleoside analogue and is a platelet aggregation inhibitor used for the prevention of thrombotic events (for example stroke or heart attack) in people with acute coronary syndrome or myocardial infarction with ST elevation (source: Wikipedia).

Ticagrelor, the IUPAC name is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Di fluoro phenyl) cyclo propyl amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy ethoxy) cyclopentane-1,2-diol, with the structural formula;

It is marketed by Astra Zeneca under the trade name Brilinta in USA and Russia, Brilique and Possia in Europe.

Various processes for synthesis of ticagrelor are reported in WO00034283, WO01/92263 and WO10/030224 by AstraZeneca. The other Patent/Patent Applications which describe the synthesis of Ticagrelor or its related salts, enantiomers are described in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and European Patent Nos. EP0996621, EP1135391, EP2570405, EP2586773 and PCT published documents viz. WO2011017108, WO2012138981, WO2013150495 and WO2014102830.

Ticagrelor has six chiral centres which produces sixty four possible stereoisomers. The molecule further contains strained cyclopropane ring, the preparation of ticagrelor is therefore very challenging. Various methods of preparation of pure ticagrelor are disclosed in the art by modifying the reagents, reaction conditions, however, the processes are cumbersome, require high temperature, there is use of toxic solvents and excess work up procedures at each intermediate stages, require extensive purification and crystallization techniques such as using chromatographic techniques which increases the cost on industrial scale and are therefore not commercially viable. Ticagrelor obtained by the prior art processes does not have satisfactory overall yields.

It is therefore desired to provide an improved process for manufacture of ticagrelor by improving the reaction conditions in each process step such that it results in the formation of intermediate and the title compound in good yield and purity.

Summary of the invention:
Accordingly, the present invention provides an improved process for preparation of Ticagrelor in good yield and purity, which comprises the following steps;
i. Reacting 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) with tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) in presence of sodium bicarbonate, water and a phase transfer catalyst to obtain [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2 (propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-3aH-cyclopenta-[a] [1,3] dioxol-4-yl]oxy]ethanol (III);

ii. Cyclizing compound (III) of step (i ) with sodium nitrite and acid in water to obtain [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol (IV) and extracting the product in solvent selected from ethyl acetate, methylene dichloride (MDC), toluene or chloroform or mixtures thereof for subsequent step;

iii. In-situ reacting 3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol -4-yl) oxy] ethanol (IV) of step (ii) with mandelic acid salt of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (V) in presence of DIPEA and the solvent to obtain the compound 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI), which is either isolated or extracted in solvent for subsequent step;

iv. Deprotecting 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) of step (iii), optionally in –situ, in solvents selected from lower alcohols or and in 1:1 to 1:2 acid–water mixture to obtain ticagrelor; and

v. isolating and purifying ticagrelor.

In an aspect, the compound (VI) formed after the in-situ reaction is either isolated or is used as such in the subsequent step, Stage 4.
Accordingly, the step of deprotection of compound VI (step iv) is carried out in-situ in solvents selected from lower alcohols or and in 1:1 to 1:2 acid–water mixture to obtain ticagrelor.

In another aspect, the present invention provides a process for purification of crude ticagrelor which comprises;
1. providing a solution of ticagrelor in one or more solvents and heating at a temperature in the range of 60-75oC to obtain clear solution, optionally adding activated charcoal;
2. filtering and cooling the filtrate to obtain pure ticagrelor.
The solvents for purification are selected from polar or non-polar, protic or aprotic solvents such as lower alcohol, esters such as ethyl acetate, isopropyl acetate, aliphatic or aromatic hydrocarbons, ketones, nitriles, ethylacetoacetate and the like either alone or combination thereof.

In yet another aspect, the present invention provides novel crystalline polymorph of ticagrelor and to the process for preparation thereof.
Description of Figures:
Fig 1 depict powder X-ray diffraction (PXRD) pattern of Ticagrelor polymorph, prepared according to example 6.4
Fig 2 depict the DSC thermogram of Ticagrelor polymorph, prepared according to example 6.4

Detailed Description of the invention:
The embodiments of the present invention provides improved reaction conditions such as reduced time, selection of reagents and solvents such that it results in formation of intermediates and the title product of substantial good purity and yield. The process step does not use toxic solvents, harsh reaction conditions making it industrially and environmentally friendly.

The process steps of the present invention are detailed herein below:
Stage 1: The process step comprises preparation of [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III).

Accordingly, 4,6 –dichloro -2-(propylthio) pyrimidin-5-amine (I) is reacted with tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino –tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) in presence of suitable base, solvent and preferably in presence of phase transfer catalyst.

The process step of stage I is one of the key step in the preparation of ticagrelor and hence it is essential to have high conversion rate, increased rate of reaction, increased product specificity and is environmentally benign. To achieve this, the process step is preferably carried out in presence of phase transfer catalyst.

The phase transfer catalyst is selected from tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, methyl trioctylammonium chloride, Methyl-triethyl ammonium chloride, Tri-ethyl-benzyl-ammonium chloride, Tributyl methylammonium chloride, Tetrabutyl phosphonium chloride and the like; preferably the phase transfer catalyst used is tetrabutyl ammonium bromide (TBAB) and tetrabutyl ammonium chloride.

The use of phase transfer catalyst (PTC) reduces the reaction time and increases the yield and purity. The reaction takes place in about 12-16 hours at varying temperature ranging from 90oC-105oC.

The base is an inorganic base which includes but is not limited to alkali or alkaline earth metal hydroxides, carbonate or bicarbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or cesium carbonate and the like and mixtures thereof; preferably the base used is sodium bicarbonate.

The solvent system for the reaction includes polar protic solvent such as water or lower alcohols; preferably water.

After the reaction, [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) is isolated either from the biphasic system of water and solvent which may be further optionally washed with solvent. The solvent may be selected from polar or non-polar, protic or aprotic solvent such as water, lower alcohols, aliphatic or aromatic hydrocarbons, ethers, esters and such like or mixtures thereof.

Stage 2: The step comprises preparation of [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxole4-methanol (IV).
The compound (IV) is obtained by the process known in the art which includes cyclization of [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) with suitable nitrite in presence of acid.

The suitable nitrite for the reaction is selected from isoamyl nitrite, sodium nitrite and the like; preferably sodium nitrite.

The acid is selected from acetic acid, hydrochloric acid, sulphuric acid and the like; preferably the acid is acetic acid.

The solvent used in the process is generally inert to the reaction conditions and is preferably water.

After the reaction, the compound (IV) is isolated from the biphasic system of water and organic solvent selected from polar protic or aprotic solvent or non-polar solvents selected from ethyl acetate, THF, methylene dichloride (MDC) and the like or mixtures thereof; preferably the solvent is ethyl acetate.

The intermediate compound (IV) being unstable in isolated form as such may degrade leading to formation of impurities which will lead to loss of yield and purity. Therefore, in the preferred embodiment, the impurity formation in stage 2 is reduced by dissolving the compound (IV) in the said solvent. The intermediate (IV) is highly soluble in said solvent and the solution of intermediate compound (IV), is stable, and is used as such in the subsequent step.

Stage 3: The process step comprises in-situ preparation of 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI).
Accordingly, to [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxole4-methanol (IV) in solvent of Stage 2 is charged (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate of formula (V), in presence of base and solvent to obtain 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI).

In an embodiment, the compound (VI) formed in the in-situ reaction is either isolated or is used as such in the subsequent step, Stage 4.

The isolation step comprises adding water to the product (VI) to obtain the biphasic system and separating the organic layer. The organic layer is further washed and the solvent layer is concentrated to afford compound (VI).

The use of the intermediate (IV) obtained in step (ii) without isolation for the reaction with mandelate salt of compound (V) also results in formation of intermediate compound (VI) in high yield and purity.

The base is selected from organic base such as triethylamine, diisopropylethylamine (DIPEA), ethylamine, pyridine and the like; preferably the base is diisopropylethylamine (DIPEA).

The solvent is selected from polar or non-polar, protic or aprotic, aliphatic or aromatic solvents such as Toluene, n-hexane, DMSO, ethyl acetate and the like alone or mixtures thereof.

The compound (V) or its salt may be prepared by the methods known in the art. The free base may be generated in situ during the reaction when the salt of compound (V) is used.
Stage 4: The process step comprises preparation of the title compound, ticagrelor.
Accordingly, the step includes deprotection of the dioxolo group of compound (VI), optionally in in-situ, in presence of lower alcohols such as methanol, isopropyl alcohol (IPA), n-propanol or n-buatnol in 1:1 or 1:2 acid- water mixture inert to the reaction conditions at a temperature in the range of 15-30oC.
The acid-water mixture is either 1:1 HCl –water solution or 1:2 H2SO4-water solutions.

After the reaction, the product is extracted in a solvent mixture and the pH of the organic layer is adjusted in the range of 7-8. The organic layer is further washed, dried, concentrated and filtered to obtain ticagrelor.

In a preferred embodiment, the present invention discloses an improved process for preparation of Ticagrelor in good yield and purity, comprising;
i. Reacting 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) with tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) in presence of sodium bicarbonate, water and TBAB as phase transfer catalyst to obtain [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III);

ii. Cyclizing compound (III) of step (i ) with sodium nitrite and acetic acid in water to obtain [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol (IV) and extracting the product in solvent selected from ethyl acetate or methylene dichloride (MDC) for subsequent step;

iii. In-situ reacting 3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol -4-yl) oxy] ethanol (IV) of step (ii) with mandelic acid salt of (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine (V) in presence of DIPEA and solvent selected from toluene, DMSO or ethyl acetate to obtain compound 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI), which is either isolated or extracted in solvent for subsequent step;

iv. Deprotecting 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl]amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) of step (iii), optionally in-situ, in solvents selected from lower alcohols in 1:1 to 1:2 acid–water mixture to obtain ticagrelor; and

v. isolating and purifying ticagrelor.
The compound (VI) formed after the in-situ reaction is either isolated or is used as such in the subsequent step iv.

Accordingly, the step of deprotection of compound VI (step iv) is carried out in-situ in solvent selected from lower alcohols or in 1:1 to 1:2 acid–water mixture to obtain ticagrelor.

Purification: The purification process comprises heating ticagrelor dissolved in solvent selected from polar or non-polar, protic or aprotic solvents such as lower alcohol, esters such as ethyl acetate, isopropyl acetate, aliphatic or aromatic hydrocarbons, ketones, nitriles, ethylacetoacetate and the like either alone or combination thereof to a temperature in the range of 60-70oC until clear solution. This is followed by addition of activated charcoal, filtering through hyflow bed, cooling to get crystalline ticagrelor of high purity and yield. Preferably the solvent for purification is selected from ethyl acetate, isopropyl acetate, methyl n-propyl ketone, ethylacetoacetate, toluene alone or mixture thereof.

In yet another embodiment, the present invention discloses novel crystalline polymorph of Ticagrelor characterized by means of Powder X-ray Diffraction Pattern (PXRD), Differential scanning calorimetry (DSC).

Accordingly, the present invention discloses crystalline polymorph of ticagrelor characterized by PXRD peaks at 5.159±0.2, 9.465±0.2, 13.73±0.2, 15.11±0.2, 19.98±0.2, 21.13±0.2, 22.31±0.2, 25.99±0.2 and 27.20 ± 0.2 degrees 2-theta (Fig 1) and has the melting range of 148-152°C as shown in the DSC endotherm in Fig 2 respectively.

In another embodiment, to obtain the crystalline ticagrelor polymorph the present inventors experimented using various solvents selected from polar or non-polar solvents; protic or aprotic solvents such as water, C1-C3 alcohols, ketones, nitriles, DMF, THF and the like or combination thereof as described in examples 6.1 to 6.5 below and observed that using methanol as solvent produced stable crystalline polymorph of ticagrelor as shown in Fig 1.

The compounds/intermediates obtained in the process steps of the present invention may be used for subsequent steps without purification or may be separated employing extracting the compound/intermediate or recrystallization technique at ambient temperature in good yield and purity. The suitable solvents for extraction of the compound/intermediates may be selected from polar or non-polar, protic or aprotic solvent such as water, lower alcohols, esters, ketones, nitriles, aliphatic or aromatic hydrocarbons and such like alone or combination thereof.

The present process employs simple procedure for isolation and purification of the intermediates as well as the final product which does not include costly procedures such as chromatography.

The temperature for the process of the present invention is maintained which is suitable for the process steps viz. Stage 1 to Stage 4 to carry out the reactions.

In an embodiment, the process encompasses the preparation of ticagrelor or its pharmaceutically acceptable salts, its tautomeric forms, stereoisomeric forms including enantiomers and to mixtures thereof including racemates.

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.

Example 1: (Stage I)- Preparation of [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a] [1,3] dioxol-4-yl]oxy]ethanol (III).
Ref Example:
To the RBF was charged sodium bicarbonate (53gm; 0.630moles) and water (75ml) at 25-30°C followed by slow addition of tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) (38.6gm; 0.105moles). Then, added 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) ( 25gm; 0.1049moles) I) at 25-30°C to the reaction mass. Heated the reaction mass to 95-100°C and maintained the reaction for 22-24 hrs at 95-100°C.Checked the TLC for the absence of compound (I). After completion of the reaction, cooled the reaction to 25-30°C and charged water(150ml),ethyl acetate(150ml). Separated the organic layer and extracted the aqueous layer using ethyl acetate (150 ml). The total organic layer was washed with water followed by washing with 10%NaCl solution. Concentrated the organic layer and to the mass was added n-hexane (200ml), filtered and dried to obtain the solid.
Yield: 75%; HPLC purity: 90.0%

Example 1.1
To the RBF was charged sodium bicarbonate (53gm; 0.630moles) and water (75ml) at 25-30°C followed by addition of tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) (38.6gm; 0.105moles). Then, added 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) (25gm; 0.1049moles) and TBAB(0.25gm) at 25-30°C to the reaction mass. Heated the reaction mass to 95-100°C. Maintained the reaction for 14-16hrs at 95-100°C. Checked the TLC for the absence of compound (I). After completion of the reaction, cooled the reaction to 25-30°C and charged water(150ml),ethyl acetate(150ml). Separated the organic layer and extracted aqueous layer using ethyl acetate (150 ml). The total organic layer was washed with water followed by washing with 10%NaCl solution. Concentrated the organic layer and to the mass was added n-hexane (200ml), filtered and dried to obtain the solid.
Yield: 90%; HPLC purity: 98.40%

Example 1.2
To the RBF was charged sodium bicarbonate (212gm; 2.52moles) and water (300ml) at 25-30°C followed by addition of tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) (154gm; 0.42moles). Then, added 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) (100gms; 0.42 moles) and TBAB(1 gm) at 25-30°C to the reaction mass. Heated the reaction mass to 95-105°C and maintained the reaction for 14-16 hrs at 95-100°C. Checked the TLC for the absence of compound (I). After completion of the reaction, cooled the reaction to 60-70°C and charged IPA(120ml),water (680ml). Stirred to get free solid and cooled to 25-30°C. Filtered the solid and washed with water.
Yield: 96%; HPLC purity: 99.50%

Example 1.3
To the RBF was charged sodium bicarbonate (212gm; 2.52moles) and water (300ml) at 25-30°C followed by addition of tartrate salt of [3aR-(3aa, 4a, 6a. 6aa) -6-amino–tetrahydro-2,2 dimethyl -4H-cyclopenta-1,3 dioxol-4-ol (II) (154gm; 0.42moles). Then, added 4,6–dichloro -2-(propylthio) pyrimidin-5-amine (I) (100gms; 0.42 moles) and TBAB(1 gm) at 25-30°C to the reaction mass. Heated the reaction mass to 100-105°C and maintained the reaction for 14-16 hrs at 95-100°C. Checked the TLC for the absence of compound (I). After completion of the reaction, cooled the reaction to 60-70°C and charged IPA(120ml), water(680ml). Stirred to get free solid and cooled to 25-30°C. Filtered the solid and washed with water followed by washing with cyclohexane.
Yield: 97%; HPLC purity: 99.60%

Example 2: Stage II: Preparation of [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxolo4-methanol (IV)
Ref Example: 2.0
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) of Stage 1(example 1.3) (74gm; 0.1766moles) and water (300ml) followed by slow addition of conc. HCl (150ml) at 25-30°C. Prepared the solution of NaNO2 (18.28gm; 0.2649moles) in water (90ml). Added the as prepared NaNO2 solution to the mixture at 25-30°C and maintained the reaction for 3-4 hrs at 25-30°C. Checked the TLC for the absence of compound (III). After completion of the reaction, cooled the reaction to 10-15°C and adjusted the pH to 7-8 using NaOH solution. Extracted the product (IV) with ethyl acetate and concentrated the organic mass to get the oil.
Oil weight: 51gm; HPLC purity : 62.54%

Example 2.1
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) of Stage 1 (example 1.3) (25gm; 0.059moles) and water (100ml) followed by slow addition of conc. HCl (50ml) at 25-30°C. Cooled the reaction to 5-10°C. Prepared the solution of NaNO2 (6.18gm; 0.089moles) in water (25ml). Added the as prepared NaNO2 solution at 5-10°C to the mixture and maintained the reaction for 1 hr at 5-10°C. Raised the temperature to 25-30°C and maintained for 2 hrs. Checked TLC for the absence of compound (III). After completion of the reaction was charged ethyl acetate and separated the organic layer. Washed the organic layer with 10% sodium bicarbonate solution. The organic layer was used as such for Stage III. HPLC purity: 82.5%

Example 2.2
To the RBF was charged 20% H2SO4 (40ml) and cooled to 0-5°C. Added [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) (10gm; 0.02387moles) of Stage-1 (example 1.3) lot wise. Added NaNO2 soln.(2.0gm in 7.0ml water). Maintained the reaction for 3-4 hrs at 5-10°C. Checked the TLC for absence of compound (III). After completion of the reaction the product was extracted with ethyl acetate. Washed the organic layer with 10%sodium bicarbonate solution and concentrated the organic mass.
Oil weight: 8gm; HPLC purity: 63.5%

Example 2.3
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) (20gm; 0.046moles) of Stage 1 (example 1.3) and acetic acid (100ml). Cooled the reaction mass to 15-20°C. Prepared the solution of NaNO2 (4.77gm; 0.070moles) and water(10ml). Added the as prepared NaNO2 solution at 20-25°C to the reaction mass and maintained the reaction for 0.5-1 hr at 25-30°C. Checked TLC for the absence of compound (III). After completion of the reaction, extracted the product with ethyl acetate and washed the organic layer with 10% sodium bicarbonate solution and concentrated the organic mass to obtain the oil.
Oil weight-23gm; HPLC purity: 75.25%

Example 2.4
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) (25gm; 0.059moles) of Stage 1 (example 1.3) and acetic acid(75ml). Cooled the reaction mass to 0-10°C. Prepared the solution of NaNO2 (4.5gm; 0.065moles) and water(15ml). Added the as prepared NaNO2 solution at 5-10°C to the reaction mixture and maintained the reaction for 1-2 hrs at 5-10°C. Checked the TLC for the absence of compound (III). After completion of the reaction, was charged water (125ml) and chloroform (125ml) to the reaction mass and stirred. Separated the organic layer and washed the organic layer with 20% sodium carbonate solution followed by washing with 10% NaCl solution. Distilled out the chloroform to obtain the oil.
Oil weight-28gm; HPLC purity: 78.2%

Example 2.5
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) (45gm; 0.1187moles) of Stage 1 (example 1.3), water(35ml) and acetic acid(135ml). Cooled the mixture to 5-10°C. Prepared the solution of NaNO2 (9.0gm; 0.1304moles) and water (40ml). Added the as prepared NaNO2 solution to the reaction mixture at 5-10°C and maintained the reaction for 1-2 hrs at 5-10°C. Checked TLC for the absence of compound (III). After completion of the reaction, was charged water (200ml) and ethyl acetate (250ml) to the mass and stirred. Separated the organic layer and washed the ethyl acetate layer with 20% sodium carbonate solution followed by washing with 10% NaCl solution. The organic layer was used as such for Stage III. HPLC purity: 93.4%

Example 2.6
To the RBF was charged [3aR-(3aa, 4a, 6a. 6aa) 2-[[-6-[[5-amino–6-chloro-2(propylthio )-4-pyrimidinyl]amino]tetrahydro-2,2 dimethyl-3aH-cyclopenta-[a][1,3]dioxol-4-yl]oxy]ethanol (III) (150gm; 0.3580moles) of Stage 1 (example 1.3), water(90ml) and acetic acid(450ml). Cooled the reaction mass to 5-10°C. Prepared the solution of NaNO2 (27.10gm; 0.0.3927moles) and water (90ml). Added the as prepared NaNO2 solution at 5-10°C to the reaction mass and maintained the reaction for 1-2 hrs at 5-10°C. Checked TLC for the absence of compound (III). Charged water (600ml) and MDC (600ml) to the reaction mass and stirred. Separated the organic layer. Washed the MDC layer with water followed by washing with 20% sodium carbonate solution and finally with 10% NaCl solution. The organic layer was used as such for Stage III. HPLC purity: 95.6%

Example 3: Stage III: Preparation of 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI)

Example 3.1
To the RBF was charged (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (7.6 gm; 0.02365moles) followed by addition of DIPEA (10.78gm) and Toluene (10ml) and the reaction mixture was stirred for 10-15 mins. Added [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclo penta-1,3-dioxol-4-methanol (IV) (10.94gm; 0.02659moles) of example 2.4 of Stage 2 in toluene (100ml) to the reaction mass slowly over a period of 1 hr. Maintained the reaction for 3-4 hrs at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction, charged water (50ml) to the mass and separated the organic layer. Washed the organic layer with 2% HCl solution and concentrated to obtain the oil.
Oil weight -5gm; HPLC purity: 75.2%

Example 3.2
To the RBF was charged (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (14.77 gm; 0.04597 moles) at 25-30°C followed by addition of DMSO (40ml) and DIPEA (26ml). The reaction mixture was stirred for 10-15 mins. Added [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol (IV) (20gm; 0.05130moles) of example 2.4 of stage 2 in DMSO (40ml) slowly over a period of 1 hr and maintained the reaction for 3-4 hrs at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction, quenched the reaction mass in precooled water (250ml). Charged ethyl acetate (200ml) and separated the organic layer. Washed the organic layer with water (200ml) followed by washing with 10%NaCl solution. Concentrated the organic layer followed by addition of acetonitrile (75ml) at 50-55°C. Stirred overnight and filtered the solid.
Solid weight-12gm; HPLC purity: 78.5%

Example 3.3
To the RBF was charged (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (34.5gm; 0.08714moles) at 25-30°C. This was followed by addition of ethyl acetate (80ml) and DIPEA (48ml) and stirred the reaction mass for 25-30 mins. Added [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol (IV) (38gm; 0.09747moles) of example 2.5 of stage 2 in ethyl acetate (80ml) slowly over a period of 1 hr and maintained the reaction for 1-2hrs at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction was charged water (200ml) to the reaction mass and separated the organic layer. Washed the organic layer with water (200ml) followed by washing with 10%NaCl solution. The organic layer was concentrated and to the concentrated mass was added ethyl acetate (38ml) and cyclohexane (228ml) at 50-55°C. Stirred the mixture overnight and filtered the solid.
Solid weight- 46.0gm; HPLC purity: 98.67%

Example 3.4
To the RBF was charged (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (37gm; 0.1139moles) and ethyl acetate (100ml) at 25-30°C followed by addition of DIPEA (70ml) .Stirred the reaction mass for 25-30 mins. Added [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclo penta-1,3-dioxol-4-methanol (IV) in ethyl acetate (350ml) of example 2.5 of stage 2 slowly over a period of 1 hr and maintained the reaction for 1-2hrs at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction was added water (250ml) to the mass and separated the organic layer. The organic layer was washed with water (200ml) followed by washing with 2%HCl solution, then 10% NaCl. The organic layer was concentrated to obtain the oil.
Oil weight-70gm; HPLC purity: 95.0%

Example 3.5
To the RBF was charged [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclo penta-1,3-dioxol-4-methanol (IV) (51.31gm; 0.1193moles) in ethyl acetate (300ml) of example 2.6 of stage 2 and DIPEA (55gm; 0.4263moles) at 25-30°C. Added (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (40gm; 0.1244moles) slowly lot wise. Maintained the reaction mass for 1-2 hr at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction was added water (250ml) to the reaction mass and separated the organic layer. Washed the organic layer with water (200ml) followed by washing with 2%HCl solution and 10% NaCl. The organic layer was concentrated to obtain the oil.
Oil weight-78gm; HPLC purity: 94.0%

Example 3.6
To the RBF was charged [3aR-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetrahydro-2,2dimethyl-4H-cyclo penta-1,3-dioxol-4-methanol (IV) (20gm; 0.046moles) in MDC layer (100ml) of example 2.6 and DIPEA (22gm; 0.17moles) at 25-30°C. Added (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine mandelate (V) (16gm; 0.049moles) slowly lot wise. Maintained the reaction mass for 1-2hrs at 25-30°C. Checked the TLC for absence of compound (IV). After completion of reaction was added water (250ml) to the reaction mass and separated the organic layer. Washed the organic layer with water (200ml) followed by washing with 2%HCl solution and 10% NaCl. The organic layer is taken in the next step. HPLC purity: 98.5%
Example 4: Stage IV: Preparation of Ticagrelor

Example 4.1
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (25 gm) ) of example 3.3of Stage 3 and methanol (75ml) at 25-35°C. Cooled the reaction mass to 5-10°C. Prepared 1:1 HCl solution (100ml) and added the HCl solution slowly over a period of 3-4 hrs to the reaction mass in RBF. Maintained the reaction for 1-2 hrs at 5-10°C. Checked TLC for absence of compound (VI). After completion of reaction was charged water (100ml) and ethyl acetate (125ml) to the reaction mass and stirred for 10-15mins. Separated the organic layer and adjusted the pH of the aqueous layer to 8-9 with 25%NaOH solution. Extracted the product twice with ethyl acetate (125ml). Washed the total organic layer with 10%Na2CO3 solution followed by washing with 10% NaCl solution and concentrated the organic layer. To the concentrated organic layer was added toluene (100ml) and stirred the mixture for 4-5 hrs. Filtered the solid and washed the solid with toluene (25ml) and dried to afford the title product.
Yield-16.29gm; HPLC purity: 95.6%

Example 4.2
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (25gm) of example 3.3 of Stage 3 and methanol (75ml) at 25-35°C. Prepared 1:1 HCl solution (100ml) and added the HCl solution slowly to the reaction mass in RBF over a period of 1 hr. Maintained the reaction for 2-3 hrs at 25-30°C. Checked TLC for absence of compound (VI). After completion of reaction, distilled out methanol at 35-40°C. Charged water (50ml) to the reaction mass and adjusted the pH to 7-8 with 25%NaOH solution. Extracted the product twice with ethyl acetate (125ml).Washed the total organic layer with 10% NaCl solution. Concentrated the organic layer and to the concentrate was added toluene (100ml). Stirred the mixture for 1-2 hr. Filtered the solid and washed the solid with toluene (25ml) and dried to afford the title product.
Yield-16.25gm; HPLC purity: 94.0%

Example 4.3
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (25gm) of example 3.3 of Stage 3 and (175ml) MDC at 25-35°C. This was followed by addition of conc. HCl (75ml) at 25-30°C slowly over a period of 1 hr. Maintained the reaction for 2-3 hrs at 25-30°C. Checked the TLC for absence of compound (VI). After completion of reaction, cooled the reaction mass to 0-5°C and adjusted the pH to 9-11 with 25%NaOH solution. Distilled out MDC under vacuum at 30-40°C. Extracted the product with ethyl acetate (250ml). Washed the total organic layer with 2%HCl solution and then by 10% NaHCO3 solution. Concentrated the organic layer and added acetonitrile (100ml). Stirred the mixture for 1-2 hrs. Filtered the solid and washed the solid with acetonitrile (25ml) and dried to afford the title product.
Yield-10gm; HPLC purity: 98.0%

Example 4.4
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (20gm) of ) of example 3.4 of Stage 3 and methanol (100ml) at 25-35°C. Cooled the reaction mass to 10-15°C. Prepared 1:1 HCl solution (80ml) and added the HCl solution slowly over a period of 1 hr. Maintained the reaction for 2-3 hrs at 15-20°C. Checked the TLC for absence of compound (VI). Cooled to 0-5°C and adjusted the pH to 7-8 with 50%NaOH solution. Extracted the product twice with chloroform (100ml). Washed the total organic layer with 5% HCl solution, 10% NaHCO3 solution and finally with water (100 ml). This was followed by addition of methanol (20ml) to break the emulsion. Dried over sodium sulphate and to the dried mass was added toluene (100ml) at 70-75°C,stirred for 1-2 hrs at 25-30°C. Filtered the solid, washed with toluene (20ml) and dried to obtain the title compound.
Yield-16.55gm; HPLC purity: 98.5%

Example 4.5
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (90gm) of example 3.4 of Stage 3 and methanol (270ml) at 25-35°C. Cooled the reaction mass to 15-10°C. Prepared 1:1 HCl solution( 360ml) and added the HCl solution slowly over a period of 2 hrs. Maintained the reaction for 2-3 hrs at 15-20°C. Checked TLC for absence of compound (VI). Adjusted the pH to 9-10 with 50%NaOH solution. Extracted the product with MDC (900ml) and washed the aqueous layer with MDC (180ml). Dried over sodium sulphate and to the dried mass was added toluene (360ml) at 70-75°C, stirred for 1-2 hrs at 25-30°C. Filtered the solid, washed with toluene (90ml) and dried to obtain the title compound.
Yield-70gm; HPLC purity: 97.5%

Example 4.6
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3,4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) in MDC(26.0gm) (100ml) of example 3.6 of Stage-3 and methanol (50ml) at 25-35°C. Added conc HCl (40ml) slowly over a period of 2 hrs. Maintained the reaction for 2-3 hrs at 25-30°C. Checked the TLC for absence of Stage-III. Adjusted the pH to 7-8 with 50%NaOH solution. Separated the MDC layer and washed the aqueous layer with MDC (100ml). Dried the mass over sodium sulphate and to the dry mass was added (360ml) toluene at 70-75°C,stirred for 1-2 hrs at 25-30°C. Filtered the solid and washed the solid with toluene (20ml) to afford the product.
Yield- 20gm; HPLC purity: 98.67%
Example 4.7
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (35gm) MDC layer 175ml of example 3.6 of Stage 3 and isopropyl alcohol (105ml) at 25-35°C. Cooled the reaction mass to 20-25°C. Prepared 1:1 HCl solution (140ml) and added the HCl solution slowly over a period of 1 hr. Maintained the reaction for 2-3 hrs at 20-25°C. Checked TLC for absence of compound (VI). After completion of the reaction was added water (175ml) and MDC (175ml). Separated the organic (MDC) layer and adjusted the pH of the aqueous layer to 9-10 with 50%NaOH solution. Extracted the product in MDC ( 70ml). Washed the total organic layer with water (175ml) followed by washing with 5%HCl, and then with 10% NaHCO3 solution. Dried the mass over sodium sulphate and to the dry mass was added toluene (175ml) at 70-75°C,stirred for 1-2 hrs at 25-30°C. Filtered the solid, washed with toluene (35ml) and dried to obtain the product.
Yield-26gm; HPLC purity: 97.8%

Example 4.8
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (35gm) of example 3.4.of Stage 3 and isopropyl alcohol (105ml) at 25-35°C and cooled the reaction mass to 20-25°C. Prepared 1:2 H2SO4:water solution (105ml) and added the solution slowly over a period of 1 hr. Maintained the reaction for 2-3 hrs at 20-25°C. Checked TLC for absence of compound (VI). After completion of the reaction was added water (175ml) and MDC (175ml). Separated the organic layer and adjusted the pH of the aqueous layer to 9-10 with 50%NaOH solution. Extracted the product with ( 70ml) MDC. Washed the total organic layer with water (175ml) followed by washing with 5%HCl and then with 10%NaHCO3 solution. Dried the mass over sodium sulphate and to the dry mass was added (175ml) toluene at 70-75°C, stirred for 1-2 hrs at 25-30°C. Filtered the solid, washed the solid with toluene and dried to obtain the title compound.
Yield-24gm; HPLC purity: 92.34%

Example 4.9
To the RBF was charged 3aR-(3aa,4a,6a,6aa)]-2-[6-({7-[2(3, 4 difluorophenyl) cyclo propyl] amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-tetra hydro-2,2 di methyl -4H-cyclopenta-1,3-dioxol-4-yl) oxy]ethanol (VI) (123gm) of example 3.3 of Stage-3 and methanol (360ml) at 25-35°C and cooled the reaction mass to 10-15°C. Prepared 1:1 HCl solution (492ml) and added the HCl solution slowly over a period of 1 hr. Maintained the reaction for 2-3 hrs at 15-20°C.Checked the TLC for absence of compound (VI). After completion of the reaction was added chloroform (500ml) and adjusted the pH of the aqueous layer to 7-8 with 50%NaOH. Extracted the product with chloroform (200ml).Washed the total organic layer with water (300ml) followed by washing with 5%HCl and then with 10%NaHCO3 solution. Dried the mass over sodium sulphate and to the dry mass was added toluene (615ml) at 70-75°C, stirred for 1-2 hrs at 25-30°C. Filtered the solid, washed the solid with toluene (123ml) and dried to obtain the title compound.
Yield-103gm; HPLC purity: 96.7%
Example 5: Purification of Ticagrelor

Example 5.1
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and ethyl acetate (125ml) at 25-30°C. Heated the mixture to 60-65°C and maintained the temperature until clear solution was obtained. Activated carbon (1.25gm) was added to the clear solution and stirred for 10-15 mins. Filtered the solution through hyflow bed and cooled the filtrate to 25-30°C gradually to obtain pure Ticagrelor.
Purity-99.6%

Example 5.2
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and isopropyl acetate (125ml) at 25-30°C. Heated the mixture to 60-65°C and maintained the temperature until clear solution was obtained. Added activated carbon (1.25gm) was added to the clear solution and stirred for 10-15 mins. Filtered through hyflow bed and cooled the filtrate to 25-30°C gradually to obtain pure Ticagrelor.
Purity- 99.5%

Example 5.3
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and ethyl acetoacetate (100ml) at 25-30°C. Heated the mixture to 60-65°C and maintained the temperature until clear solution was obtained. Filtered the solution through hyflow bed and cooled the filtrate to 25-30°C gradually to obtain pure Ticagrelor.
Yield-19gm; Purity- 99.5%

Example 5.4
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and methyl n-propyl ketone (100ml) at 25-30°C. Heated the mixture to 60-65°C and maintained the temperature until clear solution was obtained. Filtered the solution through hyflow bed and cooled the filtrate to 25-30°C gradually to obtain pure Ticagrelor.
Yield-16gm; Purity- 99.5%

Example 5.5
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and ethyl acetate (125ml) to RBF at 25-30°C. Heated the reaction mixture to 60-65°C and maintained the temperature until clear solution was obtained. Added cyclohexane (125ml) to the solution slowly and stirred for 10-15 mins. Filtered the solution through hyflow bed and cooled the filtrate to 25-30°C gradually. The filtered solid was washed with cyclohexane and dried to obtain pure Ticagrelor.
Yield- 21.5gm; Purity-99.6%

Example 5.6
To the RBF flask was charged ticagrelor (25gm) of Stage 4 and ethyl acetate (125 ml), toluene (125ml) at 25-30°C. Heated the mixture to 70-75°C and maintained the temperature until clear solution was obtained. Added activated carbon (1.25gm) to the clear solution and stirred for 10-15 mins. Filtered the mass through hyflow bed and cooled the filtrate to 25-30°C gradually to get pure Ticagrelor.
Yield-20gm; Purity- 99.7%

Example 6: Preparation of Ticagrelor polymorph
Example 6.1
To the RBF was charged ticagrelor crude (20 gm) of example 4.6 and methanol (100 ml). Distilled out methanol completely and added cyclohexane (100ml). Cooled to RT and stirred to get free solid. Filtered the solid and washed with cyclohexane (20 ml) to obtain Ticagrelor polymorph.
Dry wt- 19 gm.

Example 6.2
To the RBF flask was charged ticagrelor crude (20 gm) of example 4 and DMF (24 ml). Heated the reaction mass to 50-55°C. Cooled to 0-5°C. Added Di-isopropyl ether (450 ml) slowly. Then added ethyl acetate (40 ml). Stirred the reaction mixture for 1-2 hrs. Filtered the solid and washed with diisopropyl ether (DIPE; 20 ml) to obtain Ticagrelor polymorph..
Dry wt-18 gm

Example 6.3
To the RBF flask was charged ticagrelor crude (10 gm) of example 4 and acetonitrile (20 ml). Heated the mixture to 55-60°C to get clear solution. Then cooled the reaction to room temperature gradually and stirred for 1-2 hrs. Filtered the solid and washed using chilled acetonitrile (20 ml) to obtain Ticagrelor polymorph.
Dry wt-6.3 gm

Example 6.4
To the RBF flask was charged ticagrelor crude (10 gm) of example 4 and methanol (50 ml) at RT. Added water (75ml) slowly. Stirred the reaction mass for 1-2 hrs to get free solid. Filtered the solid and washed with water (20 ml) to obtain Ticagrelor polymorph characterized by an X-ray powder diffraction pattern having peaks at 5.15±0.2, 9.46±0.2, 13.73±0.2, 15.11±0.2, 19.98±0.2, 21.13±0.2, 22.31±0.2, 25.99±0.2 and 27.20 ± 0.2theta degrees 2-theta.
Dry wt-9 gm

Example 6.5
To the RBF flask was charged ticagrelor crude (50 gm) of example 4 and isopropyl alcohol (250 ml). Heated to 55-60°C to get clear solution. Added Eno carbon (2.5 gm) and stirred for 15-20 mins. Filtered the reaction mixture through hyflow bed. Cooled the filtrate to RT gradually and then to 0-5°C. Filtered the solid and washed with chilled IPA (50ml) to obtain Ticagrelor polymorph.
Dry wt-38gm