FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF TICAGRELOR"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivli (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for preparation of Ticagrelor, a compound of Formula (I).

Also, the present invention relates to a process for preparation of a crystalline form of Ticagrelor free base.
The process provides Ticagrelor in higher yield and purity compared to the previously known processes.
BACKGROUND OF THE INVENTION
Ticagrelor is an antagonist of the P2Yi2 receptor and is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor has been approved by FDA and is commercially available under the brand name BRILINTA®.
U.S. Pat. No. 6,525,060, hereinafter referred to as '060 patent, discloses a variety of triazole [4,5-d] pyrimidine derivatives such as Ticagrelor, processes for their preparation, pharmaceutical compositions comprising the derivatives and method of use thereof.
One of the key step in the synthesis of Ticagrelor is the condensation of pyrimidine moiety of Formula (X) with a substituted cyclopentanamine derivative of Formula (Y) to obtain a compound of Formula (Z). The process disclosed in the '060 patent is schematically represented in Scheme-1:


The '060 patent discloses the condensation of (X) and (Y) in presence of diisopropyl ethyl amine and tetrahydrofuran.
The '060 patent discloses a multi-step process and involves the use of toxic reagents like tribromomethane, triflic anhydride, methyl-2-(trifluoromethylsulfonyloxy)acetate; and the disadvantages of the process is that, introduction of the methoxycarbonyl methyl group is very difficult due to poor chemo selectivity, as the amino group also reacts with 2-(trifluoromethyl sulfonyloxy)acetate.
U.S. Pat. No. 7,067,663, hereinafter referred to as '663 patent, discloses a compound of Formula (A) and process for preparation of Ticagrelor by reacting compound of Formula (A) and L-tartaric acid salt of compound of Formula (B) in presence of an organic base (triethylamine) and an organic solvent (ethanol), to obtain final compound of Formula (C) and further process for conversion of obtained compound of Formula (C) into Ticagrelor. The process disclosed in the '663 patent is schematically represented in scheme-II:

The process disclosed in the '663 patent is very lengthy and time consuming, which is not industrially applicable as it requires 30 hours to complete the reaction.
International Publication No. WO/2017/072790, hereinafter referred to as '790 publication, discloses an improved process for preparation of ticagrelor, comprising reacting a compound of Formula (A) and compound of Formula (B) in water in presence of cesium carbonate as a base to obtain a compound of Formula (C), and finally converting the obtained compound of Formula (C) into Ticagrelor. The disadvantage of the process disclosed in the '790 publication is that it is very costly.
International Publication No. WO/2015/037016, hereinafter referred to as '016 publication, discloses an improved process for preparation of ticagrelor, comprising reacting a compound of Formula (A) with compound of Formula (B), in presence of base to obtain a compound of Formula (C), and finally converting the obtained compound of Formula (C) into Ticagrelor.

Further, the '016 publication discloses, amorphous form of Ticagrelor, crystalline form of Ticagrelor, crystalline ferulate salt of Ticagrelor and process for preparation thereof.
International Publication No. WO/2011/017108, hereinafter referred to as '108 publication, discloses a process for preparation of Ticagrelor, which involves preparation of compound of Formula (C) by reacting a compound of Formula (A) and a compound of Formula (B) 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 (C), and finally converting it into Ticagrelor. The process disclosed in the '108 publication is schematically represented in Scheme-Ill:

International Publication No. WO/2013/150495, discloses a process for preparation of Ticagrelor, by reacting a compound of Formula (A) and salt of compound of Formula (B) in presence of polar solvent selected from the group of alcohol, polar aprotic solvent, water or mixture 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 (C), and finally converting the obtained Formula (C) into Ticagrelor.
However, there is still a need for an efficient process for preparing Ticagrelor with higher yields and with higher purity of the final product, using mild solvents / reagents.
The process of the present invention has advantages of improved yield and increased productivity. The process is also industrially scalable and cost effective.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, Ticagrelor base of Formula (I) or its salt,


comprising the steps of:
(a) reacting 4,6-dichloro-2-propylthio-pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of an inorganic base and a suitable solvent to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta [d][l,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C);

(b) treating a dioxyl compound of Formula (C) obtained in step (a) above, with sodium nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a triazole compound of Formula (D);

reacting the triazole compound of Formula (D), in presence of ethyl acetate and triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[ 1,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain Ticagrelor base of Formula (I).
An object of the present invention is to provide a process for the preparation of a crystalline form of Ticagrelor base of Formula (I) or its salt.
Another object of the present invention is to provide a process for the preparation of Ticagrelor that has improved yield, increased productivity, industrial scalability and cost effectiveness.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention provides the polymorphic form of Ticagrelor base. Fig. 1 is a XRPD pattern of Ticagrelor base as obtained after example 4.

DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "inorganic base" refers to, but is not limited to, alkali metal carbonates selected from the group comprising of lithium carbonate, potassium carbonate, sodium carbonate and cesium carbonate; alkali metal bicarbonates selected from the group comprising of sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides selected from the group comprising of sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal hydrides selected from the group comprising . of lithium hydride, calcium hydride and aluminium hydride; metal alkoxides selected from the group comprising of sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal amides or liquor ammonia.
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to, alcohols such as methanol, ethanol, 2-methoxy ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol and the like; halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1-trichloroethane (methyl chloroform, chlorothene) and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert. butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-methyl-2-pyrrolidone; water or mixtures thereof.

comprising the steps of:
(a) reacting 4,6-dichloro-2-propylthiopyridimidine-5-amine, the compound of Formula (A);
The present invention provides an improved process for the preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, Ticagrelor base of Formula (I) or its salt,


with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, the compound of Formula (B),

in presence of an inorganic base and a suitable organic solvent to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta [d][l,3]dioxol-6-yloxy)ethanol, the dioxyl compound of Formula (C);

(b) treating the dioxyl compound of Formula (C) obtained in step (a) above, with sodium nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, the triazole compound of Formula (D);

reacting the triazole compound of Formula (D), in presence of ethyl acetate and triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, the protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain Ticagrelor base of Formula (I).
In one embodiment, the present invention provides a process for the preparation of Ticagrelor intermediate, a compound of Formula (C),

comprising, reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of inorganic base and suitable organic solvent.
In one embodiment, step (a) comprises reacting the compound of Formula (A) with the compound of Formula (B), in presence of inorganic base and suitable organic solvent at a temperature of about 100°C to 130°C, preferably at a temperature of about 115°C to 120°C, for about 10 to 30 hours, preferably at a temperature of about 15 to 20 hours.
After completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of the reaction in step (a), the reaction mixture may be cooled at a temperature of about 20°C to 40°C, preferably at a temperature of about 25°C to 35°C to obtain reaction mixture. The obtained reaction mixture may be diluted with suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvents used for dilution are water and toluene. In another embodiment, the reaction mixture may be further extracted with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used for extraction is toluene. The organic layer may be washed with water. The wet cake obtained may be treated under vacuum, to distill-off the toluene, at a temperature of about 40°C to 90°C, preferably at a temperature of about 50°C to 80°C, more preferably at a temperature of about 60°C to 70°C to obtain the reaction mixture. In another embodiment, a suitable solvent may be added to the obtained reaction mixture and heated to a temperature of about 40°C to 70°C, preferably at a temperature of about 45°C to 60°C, more preferably at a temperature of about 50°C to 55°C to obtain the compound of Formula (C). The suitable solvent used is as defined supra. Preferably, the solvent used for extraction is toluene. After completion of the reaction in step (a), the reaction mixture may be filtered and washed with suitable solvent. The suitable solvent used is n-heptane.
In one embodiment, step (a) comprises treating a compound of Formula (A) with a compound of Formula (B), in presence of lithium carbonate and 2-methoxy ethanol at a temperature of about 100°C to 130°C, preferably at a temperature of about 115°C to 120°C, for about 15 to 20 hours to obtain a compound of Formula (C).
In one embodiment, the present invention provides an improved process for the preparation of Ticagrelor base of Formula (I) or its salt,


comprising the steps of:
(a) reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of lithium carbonate and 2-methoxy ethanol to give,

2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta [d][l,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C).
Surprisingly, it has been found out by the inventors of the present invention that, treating a compound of Formula (A) with a compound of Formula (B), in presence of lithium carbonate as an inorganic base and 2-methoxy ethanol as solvent in step a), leads to increase in purity and yield as compared to the prior art processes.

In one embodiment, present invention provides a process for preparation of 2-
((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-
dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a compound of Formula (C),
comprising reacting a 4,6-dichloro-2-propylthio pyridimidine-5-amine, a compound of
Formula (A), with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-
cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, a compound of Formula (B), in presence of lithium carbonate and 2-methoxy ethanol.
In one embodiment, present invention provides a process for preparation of 2-
((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-
dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a compound of Formula (C),
comprising reacting a 4,6-dichloro-2-propylthio pyridimidine-5-amine, a compound of
Formula (A), with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-
cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, a compound of Formula (B), in presence of lithium carbonate and 2-methoxy ethanol, at a temperature of about 100°C to 130°C, preferably at a temperature of about 115°C to 120°C.
In one embodiment, step (b) comprises treating the compound of Formula (C) with sodium
nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-
6-yloxy)ethanol, a compound of Formula (D), then reacting compound of Formula (D), in
presence of triethylamine and ethyl acetate, with (1R, 2S)-2-(3,4-
difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H -[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a compound of Formula (E).
In one embodiment, step (b) comprises treating compound of Formula (C) with sodium nitrite and acetic acid in presence of water at a temperature of about 0°C to 10°C, preferably at a temperature of about 0°C to 5°C. to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a compound of Formula (D), then reacting compound of Formula (D), in presence of triethylamine and ethyl acetate, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, at a temperature of about 20°C to 40°C, preferably at a temperature of about 25°C to 30°C, to obtain 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H

-[l,2,3]triazole[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a compound of Formula (E).
After completion of the reaction in step (b), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (b), suitable solvent may be added to the reaction mixture. Preferably, the suitable solvent is water. After addition of the solvent, the reaction mixture may be stirred and layer may be separated. The organic layer may be washed with suitable acid solution. Preferably, the acidic solution is hydrochloric acid solution. The obtained mass may be again washed with sodium chloride solution. The wet cake obtained may be treated under vacuum, to distill-off the solvent. In another embodiment, a suitable solvent may be added to the obtained reaction mixture and may be heated to get clear solution. Preferably, the suitable solvent is methyl tert-butyl ether. In another embodiment, a suitable solvent may be added to the obtained reaction mixture at a temperature of about 40°C to 60°C, preferably at a temperature of about 50°C to 55°C. Preferably, the suitable solvent is n-heptane. In another embodiment, the obtained reaction mixture may be cooled at a temperature of about 20°C to 40°C, preferably at a temperature of about 25°C to 30°C, for about 3 to 4 hours. After completion of the reaction in step (b), the reaction mixture may be filtered and washed with a suitable solvent. The suitable solvent is n-heptane. In another embodiment, the obtained product may be dried at a temperature of about 30°C to 50°C, preferably at a temperature of about 40°C to 45°C, under vacuum.
In one embodiment, the present invention provides a process for preparation of Ticagrelor, a compound of Formula (I), wherein step (c) comprises deprotecting the compound of Formula (E) in presence of suitable solvent to obtain a compound of Formula (I).
In one embodiment, the present invention provides a process for preparation of Ticagrelor, a compound of Formula (I), wherein step (c) comprises deprotecting the compound of Formula (E) in presence of a suitable solvent. Preferably the suitable solvent is methanol. In another embodiment, the reaction mixture may be cooled at a temperature of about 10°C to 20°C, preferably, at a temperature of about 10°C to 15°C. In another embodiment, suitable acidic solution may be slowly added to the reaction mixture for about 1 to 1.5 hours. Preferably the suitable acidic solution is hydrochloric acid. In another embodiment, the obtained reaction mass may be stirred at temperature of about 20°C to 40°C, preferably at a temperature of about 25°C to 30°C, to obtain a compound of Formula (I).

After completion of the reaction in step (c), suitable work up may be performed, as known to a skilled artisan. In one embodiment, the pH of the reaction mixture may be adjusted to about 7 to 7.5. In another embodiment, the suitable solvent may be added slowly to the obtained reaction mixture for about 0.5 to 1 hour to precipitate out the solid. Preferably the suitable solvent is water. In another embodiment, the reaction mixture may be stirred for about 2 to 3 hours. After completion of the reaction in step (C), the reaction mixture may be filtered and washed with suitable solvent. Preferably the suitable solvent is water. In another embodiment, the obtained wet cake may be dried at a temperature of about 40°C to about 65°C, preferably at a temperature of about 50°C to 55°C.
In one embodiment, the obtained product from step (c), is optionally purified in presence of organic solvent, preferably ethyl acetate, n-heptane and optionally mixture thereof.
In one embodiment, the present invention provides a process for preparation of Ticagrelor, a compound of Formula (I), wherein step (c) comprises deprotecting the compound of Formula (E) in presence of methanol, where, the reaction mixture is cooled at a temperature of about 10°C to 15°C, and aqueous hydrochloric acid is added slowly to the reaction mixture at a temperature of about 10°C to 15°C, to obtain Ticagrelor, a compound of Formula (I).
In one embodiment, the present invention provides a process for preparation of Ticagrelor, a compound of Formula (I), comprising:
a) a process for preparation of 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a compound of Formula (C), comprising, reacting a 4,6-dichloro-2-propylthio pyridimidine-5-amine, a compound of Formula (A), with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, a compound of Formula (B), in presence of lithium carbonate and 2-methoxy ethanol, at a temperature of about 115°C to 120°C;
b) treating compound of Formula (C) with acetic acid and sodium nitrite in presence of water at a temperature of about 0°C to 5°C to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a compound of Formula (D), then reacting compound of Formula (D), in presence of triethylamine and ethyl acetate as solvent, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, at a temperature of about 25°C to 30°C to obtain 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d] pyrimidin-3-yl)-

tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a compound of Formula (E);
c) deprotecting the compound of Formula (E) in presence of methanol, where, the reaction mixture may be cooled at a temperature of about 10°C to 15°C and aqueous hydrochloric acid is added slowly to the reaction mixture at a temperature of about 25°C to 30°C to obtain Ticagrelor, a compound of Formula (I).
In one embodiment, the present invention provides a process for preparation of crystalline
form of Ticagrelor a compound of Formula (I), comprising:
(a) reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of inorganic base and suitable organic solvent to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta [d][l,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C);

reacting a triazole compound of Formula (D), in presence of ethyl acetate and triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain
Ticagrelor base of Formula (I).
In one embodiment, the present invention provides a process for preparation of crystalline
form of Ticagrelor, a compound of Formula (I), comprising:
(a) reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of lithium carbonate and 2-methoxy ethanol to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta [d][l,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C);

(b) treating a dioxyl compound of Formula (C) obtained in step (a) above, with sodium nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a triazole compound of Formula (D);

reacting a triazole compound of Formula (D), in presence of ethyl acetate and triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain
Ticagrelor base of Formula (I);
(d) treating the obtained compound of Formula (I) with n-heptane to get crystalline
Ticagrelor base of Formula (I).
In one embodiment, the crystalline form of compound of Formula (I) is characterized by an x-ray powder diffraction pattern comprising peaks at about 5.37, 6.67, 13.37, 18.19 and 24.15 ± 0.2 degree 29.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example-1: Preparation of 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio) pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cycIopenta[d][l,3]dioxol-6-yloxy) ethanol (Compound C)
4,6-dichloro-2-propylthio pyridimidine-5-amine, a compound of Formula (A) (20 g, 1 eq.), 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy) ethanol L-tartrate acid, a compound of Formula (B) (33.94g, 1.1 eq.), lithium carbonate (18.61g, 3.0 eq.) and 2-methoxy ethanol (100 mL) was added to the round bottom flask, then the reaction was heated at a temperature from about 115°C to 120°C. The reaction was maintained at a temperature from about 115°C to 120°C for about 15 hours to 20 hours. The reaction mass was cooled to about 25°C to 30°C. The reaction mass was then diluted with water (200 mL) and toluene (200 mL). Stirred the reaction mass and layer was separated. The product was extracted in 40 mL toluene. The organic layer was washed with water and toluene was distilled out under vacuum at a temperature of about 60°C to 70°C. n-Heptane was slowly added to the reaction mixture and temperature was raised to about 50°C to 55°C. The product was filtered and washed with n-Heptane, to obtain compound of Formula (C). Yield obtained was 28 g to 30 g (82.5%).
Example-2: Preparation of 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl) cycIopropylamino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol (Compound E)

2-((3aS, 4R, 6S, 6aR)-4-(5-amino-6-chloro-2-(propylthio) pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l ,3]dioxol-6-yloxy)ethanol, a compound of Formula (C) (25 g, 1 eq.) was taken in a round bottom flask and acetic acid (100 mL) was added and stirred the reaction mixture. The reaction mass was cooled to about 0°C to 5°C and the water was added (25 mL). Sodium nitrite solution (4.32 g, 1.05 eq.) dissolved in 25 mL water was slowly added to the reaction mixture. After completion of the reaction, the temperature was raised to about 25°C to 30°C. Water (190 mL) and ethyl acetate (150 mL) was added to reaction mass. Stirred the reaction mixture and layer was separated. Ethyl acetate layer was washed with 20% potassium carbonate solution (125 mL twice) and dried over sodium sulphate.
In another RBF, (lR,2S)-2-(3,4-difluorophenyl)cyclopropanaminium(R)-2-hydroxy-2-phenylacetate (18.3 g, 0.95 eq.), ethyl acetate (25 mL) and triethyl amine (15 g) was taken. The above reaction mass was added slowly in about 1 hour to 1.5 hours at a temperature of about 25°C to 30°C. The reaction was maintained for about 1 hour to 2 hours. Water (125 mL) was added, stirred and separated the layer. Organic layer washed with 2% hydrochloric acid solution (125 mL twice) and then with 20% sodium chloride solution (125 mL). Distilled out solvent under vacuum. Yield (crude product) obtained was 30 g to 35 g (100%). The obtained crude product (30 g) and methyl tert-butyl ether (75 mL) was taken in RBF. Reaction mass was heated to get clear solution and n-Heptane (150 mL) was added to the reaction mass at about 50°C to 55°C. Reaction mass was cooled to about 25°C to 30°C and maintained it for about 3 hours to 4 hours. The obtained product was filtered and washed with i n-Heptane. The product was dried at about 40°C to 45°C under vacuum. Yield obtained was 22 g to 25 g (83%).
Example-3: Preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl) cycIopropylamino)-5-(propylthio)-3H-[l,2,3]triazoIo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxy ethoxy)cyclopentane-l,2-diol (Compound I)
Methanol (280 mL), 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-
difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol was taken in RBF, cooled the reaction to about 10°C to 15°C. Hydrochloric acid solution (24.86 mL cone. HC1 in 99 mL water) was added slowly in about 1 hour to 1.5 hour and stirred the reaction mass for 10 hours at about 25°C to 30°C. Adjust the pH of the reaction mass 7 to 7.5. Slowly added water (400 mL) in about 0.5 hour to 1 hour to get solid precipitate out. Stirred the

reaction mass for about 2 hours to 3 hours. Filtered the product and washed it with water. Dried the product in tray dryer at about 50°C to 55°C. Yield obtained was 32 g to 34 g (88%).
Example-4: Purification and crystallization of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H- [1,2,3] triazolo [4,5-d] py rimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Compound I)
Ticagrelor (30 g), ethyl acetate (150 mL) was taken in RBF and heated to about 55°C to 60°C. n-Heptane (150 mL) was added slowly, in about 0.5 hour after clear solution was formed. Maintained the reaction for about 0.5 hour and cooled to about 25°C to 30°C. Stirred the reaction mass for 1 hour and washed the obtained product with n-Heptane (150 mL), dried the product under vacuum at about 50°C to 55°C. Yield obtained was 24 g to 26 g (83%) [Purity: 99.8%].

We claim:
1. A process for the preparation of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H41,23]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, Ticagrelor base of Formula (I) or its salt,

comprising the steps of:
(a) reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);
with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of inorganic base and suitable organic solvent to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d] [1,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C);

(b) treating a dioxyl compound of Formula (C) obtained in step (a) above, with sodium nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a triazole compound of Formula (D);

reacting a triazole compound of Formula (D), in presence of ethyl acetate and
triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-
hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain Ticagrelor base of Formula (I).
2. The process as claimed in claim 1, wherein the inorganic base used in step (a) is alkali metal bicarbonates is selected from the group consisting of lithium carbonate, potassium carbonate, sodium carbonate and caesium carbonate.
3. The process as claimed in claim 1, wherein the organic solvent as used in step (a) is an alcoholic solvent selected from the group consisting of methanol, ethanol, 2-methoxy ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol or mixture thereof.
4. A process for the preparation of Ticagrelor intermediate, a compound of Formula (C),


comprising, reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo 4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of inorganic base and suitable organic solvent.
5. The process as claimed in claim 4, wherein the inorganic base used in step (a) is alkali metal bicarbonates is selected from the group consisting of lithium carbonate, potassium carbonate, sodium carbonate and caesium carbonate.
6. The process as claimed in claim 4, wherein the organic solvent as used in step (a) is an alcoholic solvent selected from the group consisting of methanol, ethanol, 2-methoxy ethanol, isopropyl alcohol, n-propyl alcohol, n-butanol, isobutanol or mixture thereof.
7. A process for the preparation of a crystalline form of (lS,2S,3R,5S)-3-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d] pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol, Formula (I) or its salt,


comprising the steps of:
(a) reacting 4,6-dichloro-2-propylthio pyridimidine-5-amine, compound of Formula (A);

with 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxo-4-yloxy)ethanol L-tartrate acid, compound of Formula (B),

in presence of lithium carbonate and 2-methoxy ethanol to give 2-((3aS,4R,6S,6aR)-4-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy)ethanol, a dioxyl compound of Formula (C);

(b) treating a dioxyl compound of Formula (C) obtained in step (a) above, with sodium nitrite and acetic acid to obtain 2-((3aS,4R,6S,6aR)-4-(7-chloro-5-(propylthio)-3H-
[l,23]triazolo[4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3] dioxol-6-yloxy)ethanol, a triazole compound of Formula (D);


reacting a triazole compound of Formula (D), in presence of ethyl acetate and
triethylamine, with (1R, 2S)-2-(3,4-difluorophenyl)cyclopropanaminium-(R)-2-
hydroxy-2-phenylacetate, a difluoro compound, to obtain a 2-((3aS,4R,6S,6aR)-4-(7-((lR,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[l,2,3]triazole [4,5-d]pyrimidin-3-yl)-tetrahydro-2,2-dimethyl-3aH-cyclopenta[d][l,3]dioxol-6-yloxy) ethanol, a protected Ticagrelor of Formula (E);

(c) deprotecting the protected Ticagrelor of Formula (E) in presence of methanol to obtain Ticagrelor base of Formula (I);
(d) treating the obtained Formula (I) with n-heptane to obtain crystalline Ticagrelor base of Formula (I).
8. The process as claimed in claim 8, wherein the crystalline form of compound of Formula (I) is characterized by an x-ray powder diffraction pattern comprising peaks at about 5.37, 6.67, 13.37,18.19 and 24.15 ± 0.2 degree 2θ.