DESC:FIELD OF THE INVENTION
The present application provides one-pot process for the preparation of a Ticagrelor with good yield and purity which is commercially viable, industrially advantageous, cost effective and eco-friendly.

BACKGROUND OF THE INVENTION
Ticagrelor is a platelet aggregation inhibitor which 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 and whose chemical structure is the following.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation.
Several processes have been discussed in the literature for the preparation of Ticagrelor and their pharmaceutically acceptable salts, which are disclosed in US6525060, US7067663, US7250419, W02000/034283, WO2008018823 and W02010030224.
The patent WO200192263 discloses a process for the preparation of Ticagrelor as mentioned below.

The patent W02010030224 discloses a process for the preparation of Ticagrelor as mentioned below.

The patent WO2013092900 discloses a process for the preparation of Ticagrelor as mentioned below.

The patent US7067663 discloses a process for the preparation of Ticagrelor as mentioned below.

All the above prior art methods for the preparation of compound of formula (I) have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates. Therefore, still there is need for the development of commercially viable, cost-effective and eco-friendly process for the preparation of substantially pure (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 of compound of formula (I).

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide one-pot process for the preparation of Ticagrelor (I) in high yields, purity and suitable for manufacturing in commercial scale.
Yet another object of the present invention is to provide a process for the preparation of Ticagrelore (I) which avoids isolation of intermediates formed during the synthesis.
Yet another object of the present invention is to provide a process for the preparation of Ticagrelor (I) which is simple, economical and suitable for industrial scale-up.

SUMMARY OF THE INVENTION
The present invention relates to a one pot synthesis of Ticagrelor with high yield and purity disclosed herein has the following advantages over the processes described in the prior art:
i) The prior art processes disclosed reaction conditions which are not cost effective, and moreover involves tedious workup and extractions, distillations, purifications and multiple isolations;
ii) The present invention provides one-pot process to reduce the number of the required reaction steps, which are industrially applicable and economically beneficial;
iii) using toluene solvent and one-pot synthesis shows significant improvement in yields and purity;
iv) better impurity profile and improved the yield, single maximum impurities are controlled at a level of not more than 0.10;
v) The present invention simplifies the reaction conditions and provides cost-effective process with minimum downstream activity;
vi) The present invention provides a significant amount of toluene recovery process when used in this toluene in situ process; solvent recovery is an eco-friendly, economical, and cost-effective method of reducing waste and an option to the greenness of industrial processes;
vii) The present in situ process avoids tedious distillations and filtration which will reduce the manufacturing tenure and energy;
viii) solvent recovery is a form of waste reduction eco-friendly and alternative to improving the greenness of industrial processes and which makes the process economic cost effective and environment friendly;
ix) the present invention provides not only eco-friendly commercial adoptable but also provides high yield with high pure compound;
x) using the inexpensive solvents and alkali hydroxide, alkaline metal alkoxy base characterized in that said bases reaction is cost effective;
xi) Toluene can be recovered with minimum operational loss and the recovered toluene can be reused without any further purification;
xii) The process avoids the use of expensive, non-recoverable materials;
xiii) the overall yield of the product is increased, and it is also substantially pure.
The present invention provides a one-pot process for the preparation of substantially pure (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 compound of formula (I).

Formula (I)
In one aspect of the present application provides a one-pot process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts amorphous and crystalline forms and hydrates and solvates thereof;

Formula (I)
which comprises:
a) reacting 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl) oxy)ethan-1-ol or salt of formula (II) with 4,6-dichloro-2-(propylthio)-5-pyrimidinamine of formula (III) or salt in suitable solvent and appropriate base and optionally in presence of a catalyst to obtain compound of formula (IV);

Formula (II) Formula (III) Formula (IV)
b) in-situ reacting compound of formula (IV) of step (a) with a diazotizing agent in presence of acid and suitable solvent gives compound of formula (V);

Formula (IV) Formula (V)

c)in-situ reacting compound of formula (V) with (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine or salt of formula (VI) in suitable solvent, appropriate base, and optionally in presence of a catalyst gives compound of formula (VII);

Formula (V) Formula (VII)
d) deprotecting compound of formula (VII) using aqueous acid in suitable solvent to obtain ticagrelor of formula (I);

Formula (VII) Formula (I)
e) optionally purifying the compound of formula (I) in a suitable solvent;

f) isolating ticagrelor by using ethylacetate and cyclohexane, isopropylacetate, toluene, acetone, acetonitrile, ethylacetoacetate or mixture thereof;

g) isolating pure crystalline Form II of ticagrelor from acetonitrile and toluene or mixture thereof; wherin single maximum impurities are controlled at a level of not more than 0.10; wherein crystallization can be initiated by seeding.

DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.”
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly indictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable.
The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it is individually recited herein.
All processes described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description that follows, and the embodiments described herein, is provided by way of illustration of an example, or examples, of embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
It should also be appreciated that the present invention can be implemented in numerous ways, including as a system, a method, or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention.
Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
The term, “halogen” as used herein refers to chlorine, fluorine, bromine or iodine.
In one embodiment of the present invention is to provides a one-pot process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts, amorphous and crystalline forms and hydrates and solvates thereof;

Formula (I)
which comprises:
a) reacting 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl) oxy)ethan-1-ol or salt of formula (II) with 4,6-dichloro-2-(propylthio)-5-pyrimidinamine of formula (III) or salt in suitable solvent and appropriate base and optionally in presence of a catalyst to obtain compound of formula (IV);

Formula (II) Formula (III) Formula (IV)
b) in-situ reacting compound of formula (IV) of step (a) with a diazotizing agent in presence of acid and suitable solvent gives compound of formula (V);

Formula (IV) Formula (V)

c)in-situ reacting compound of formula (V) with (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine or salt of formula (VI) in suitable solvent, appropriate base, and optionally in presence of a catalyst gives compound of formula (VII);

Formula (V) Formula (VII)
d) deprotecting compound of formula (VII) using aqueous acid in suitable solvent to obtain ticagrelor of formula (I);

Formula (VII) Formula (I)
e) optionally purifying the compound of formula (I) in a suitable solvent;

f) isolating ticagrelor by using ethylacetate and cyclohexane, isopropylacetate, toluene, acetone, acetonitrile, ethylacetoacetate or mixture thereof;

g) isolating pure crystalline Form II of ticagrelor from acetonitrile and toluene or mixture thereof; wherin single maximum impurities are controlled at a level of not more than 0.10; wherein crystallization can be initiated by seeding.

In one embodiment of the present invention provides,, wherein the steps (a) to (e) are carried out in one-pot; wherein compounds of formula IV, V, VII and formula I are formed in-situ, and isolated formula I in-situ; isolating pure crystalline Form II of ticagrelor from acetonitrile and toluene or mixture thereof; wherein crystallization can be initiated by seeding.

In one embodiment of the present invention, provides a one pot process for the preparation of Ticagrelor of formula (I), comprising the steps of; a) 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (III) is reacted with 2-(((3aR,4S,6R,6aS)-6- amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)ox)ethanol L-tartaric acid salt (II) in presence of sodium carbonate/water to obtain 2-(((3aR,4S,6R,6aS)-6-((5- amino-6-chloro-2-(propylthio) pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)ox) ethanol (IV). b) The compound of formula (IV) undergoes cyclisation in presence of NaNO2 to obtain 2- (((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][ 1,3]dioxo-4-yl)ox)ethan-1 -ol (V). c) The compound of formula (V) is reacted with (1R,2S)-2-(3,4-difluorophenyl) cyclopropane amine hydrochloride salt (VI) in presence of base / solvent to obtain 2-(((3aR,4S,6R,6aS)-6- (7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,2]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d] [1,3] dioxol -4-yl) ox) ethan-1 -ol (VII). d) The compound of formula (VII) is deprotected in presence of acid to obtain Ticagrelor compound of formula(I).
In an embodiment of the present invention provides, wherein the solvent is selected from ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dichloride, ethylene dichloride, dimethyl formamide, tetrahydrofuran, acetonitrile, toluene and xylene.
In an another embodiment of the present invention provides, wherein the base is selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, triethyl amine, diisopropyl ethyl amine, triisopropyl amine or mixture thereof.
In further embodiment of the present invention provide, wherein the acid is selected from, Trifluoro acetic acid, acetic acid, hydrochloric acid, methane sulphonic acid or mixtures thereof.
In another embodiment of the present invention provides a process for the preparation of 2- (((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)ox) ethanol (IV) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (III) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aHcyclopenta[d][1,3] dioxol-4-yl)ox)ethanol L-tartaric acid salt (II) in presence of sodium carbonate and sovent water.
In another aspect of the present invention provides an process for the preparation of 2- (((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)ox) ethanol (IV) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (III) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aHcyclopenta[d][1,3] dioxol-4-yl)ox)ethanol L-tartaric acid salt (II) in presence of sodium carbonate and solvent.
In another embodiment the present invention particularly describes one pot process for the preparation of substantially pure Ticagrelor compound of formula (I) is illustrated in the following synthetic scheme:

Scheme 1
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An antisolvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, xylene, chlorobenzene, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
The term "in-situ" typically means "in the reaction mixture" or "not in isolated form" or "existing as residue".
In another embodiment the below are the abbreviations are used in the specification;
HCl-Hydrochloric acid; NaOH- Sodium Hydroxide; MTBE- Methyl tert-butyl ether, TLC- Thin layer chromatography; TBAB- Tetrabutylammonium bromide, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography; DCM-Dichloromethane; MDC-Dichloromethane; Pd/C-Palladium Carbon; H2-Hydrogen gas; NH4Cl-Ammonium chloride; K2CO3- Potassium Carbonate; Na2CO3-Sodium Carbonate; NaHCO3- Sodium bicarbonate; NaH- Sodium hydride; MeOH- Methanol; BHT- butylated hydroxy toluene; Na2s2O4-Sodium hydrosulfite; Na2s2O3-Sodium thiosulfate; EtOAc-Ethyl acetate; CH3CN-Acetonitrile; NaNO2-Sodiumnitrite; g-grams; H2O-Water
The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.
EXAMPLES
Example-1: Synthesis of (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 (Ticagrelor) compound of formula-I
To a stirred solution of Formula- II (100 g) in 200 ml water charged 65 g of Formula-III and then added 87 g sodium carbonate at room temperature. Reaction mass temperature was raised to 95°C to 100°C. Reaction was monitored by TLC, after completion of starting material Formula-III cool the reaction mass to 65°C to 70°C and quench with 200 ml of water followed by the addition of 350ml toluene. Two layers were separated at 65°C to 70°C and compound was re extracted from aqueous layer with additional 100 ml toluene. Both organic layers were mixed and proceeded for further reaction without any further isolation. The above toluene layer was cooled to 10°C to 15°C charged 100 ml acetic acid and then slowly add a solution of 19g sodium nitrite solution in 50 ml of water and monitor the reaction by TLC. After completion of starting material the reaction mass pH was adjusted to 7.0 to 8.0 with diluted sodium carbonate solution. Raise the reaction mass temperature to 25°C to 30°C. Two layers were separated and compound was re extracted from aqueous layer with additional 50 ml of toluene. Both organic layers were mixed and proceeded for further reaction without any further isolation. The toluene layer was added to a suspension of Formula-VI in 370 ml of aqueous sodium carbonate (72 g) at 20°C to 25°C and starting material was monitored by TLC. After completion of starting material reaction mass was quenched with 350 ml of water at 20°C to 25°C. Organic layer was washed with diluted acetic acid (2 x 300 ml) twice and the organic layer proceeded further reaction without any further isolation. Cooled the organic layer to 0°C to 5°C slowly add a solution of aqueous 250 ml of Hydrochloric acid in 450 ml of methanol at 0°C to 5°C. Raise the reaction mass temperature to 13°C to 17°C and monitor the reaction by TLC. After completion of starting material top layer was separated and aqueous layer pH was adjusted to 7.0 to 8.0 with aqueous sodium carbonate solution. Product was extracted into 2 x 400 mL ethyl acetate and washed with brine solution. Final organic layer was treated with activated carbon and filtered over hy-flow bed. FML’s were distilled and charged 1300 ml of 10% acetonitrile in toluene solution, raise the reaction mass to 60°C to 70°C to get clear solution. Pass the hot solution through hy-flow bed and washed with 50ml of 10% acetonitrile in toluene solution. Maintain the reaction mass for 20 to 30 min. gradually cool the reaction mass to 0°C to 5°C and maintain for 1 to 2 hours and filter the solid and wash with a solution of toluene and acetonitrile, dried the material at 55°C to 60°C to get the 110 g of pure compound of formula-I (Ticagrelor). The above five stages were carried out in one-pot process.
Example-2(Stage-1): Synthesis of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol
To a stirred solution of Formula- II (100 g) in 200 ml water charged 65 g of Formula-III and then added 87g sodium carbonate at room temperature. Reaction mass temperature was raised to 95°C to 100°C. Reaction was monitored by TLC, after completion of Starting Material Formula-III cool the reaction mass to 65 to 70°C and quench with 200 ml of water followed by the addition of 350 ml toluene. Two layers were separated at 65°C to 70°C and compound was re extracted from aqueous layer with additional 100 ml toluene. Both organic layers were mixed and proceeded further (around 114g of formula- IV in 500 ml toluene ) reaction without any further isolation.
Example-2.1(Stage-2): Synthesis of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol
Formula-IV toluene layer (550 ml which contains 114g of formula- IV) which was cooled to 10°C to 15°C charged 100 ml acetic acid and then slowly add a solution of 19g sodium nitrite solution in 50 ml of water and monitor the reaction by TLC. After completion of starting material the reaction mass pH was adjusted to 7.0 to 8.0 with diluted sodium carbonate solution. Raise the reaction mass temperature to 25°C to 30°C. Two layers were separated and compound was re extracted from aqueous layer with additional 50 ml of toluene. Both organic layers were mixed and proceeded further (around 117g of formula-V in 600ml toluene) reaction without any further isolation.
Example-2.3(Stage-3): Synthesis of 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol
The toluene layer of Formula-V was added to a suspension of Formula-VI in 370ml of aqueous sodium carbonate (72 g) at 20°C to 25°C and completion of starting material was monitored by TLC. After completion of starting material reaction mass was quenched with 350 ml of water at 20 to 25°C. Organic layer was washed with diluted acetic acid (2 x 300 ml) twice and the organic layer proceeded further (around 153g of formula-V in 600 ml toluene) reaction without any further isolation.
Example-2.4(Stage-4):Synthesis of (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
Cooled the organic layer of formula-VII to 0°C to 5°C, slowly added a solution of aqueous 250 ml of Hydrochloricacid in 450 ml of methanol at 0°C to 5°C. Raise the reaction mass temperature to 13°C to 17°C and monitor the reaction by TLC. After completion of starting material top layer was separated and aqueous layer pH was adjusted, to 7.0 to 8.0 with aqueous sodium carbonate solution. Product was extracted into 2 x 400 mL ethyl acetate and washed with brine solution. Final organic layer was treated with activated carbon and filtered over hy-flow bed. FML’s were distilled and charged 1300 ml of 10% acetonitrile in toluene solution, raise the reaction mass to 60°C to 70°C to get clear solution. Pass the hot solution through hy-flow bed and washed with 50 ml of 10% acetonitrile in toluene solution. Maintain the reaction mass for 20 to 30 min. gradually cool the reaction mass to 0°C to 5°C and maintain for 1 to 2 hours and filter the solid and wash with a solution of toluene and acetonitrile, dry the material to get pure Formula- I (Ticagrelor).
,CLAIMS:1. A one-pot process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts, amorphous and crystalline forms and hydrates and solvates thereof;

Formula (I)
which comprises:
a) reacting 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl) oxy)ethan-1-ol or salt of formula (II) with 4,6-dichloro-2-(propylthio)-5-pyrimidinamine of formula (III) or salt in suitable solvent and appropriate base and optionally in presence of a catalyst to obtain compound of formula (IV);

Formula (II) Formula (III) Formula (IV)
b) in-situ reacting compound of formula (IV) of step (a) with a diazotizing agent in presence of acid and suitable solvent gives compound of formula (V);

Formula (IV) Formula (V)

c)in-situ reacting compound of formula (V) with (1R,2S)-2-(3,4-difluorophenyl)cyclopropan-1-amine or salt of formula (VI) in suitable solvent, appropriate base, and optionally in presence of a catalyst gives compound of formula (VII);

Formula (V) Formula (VII)
d) deprotecting compound of formula (VII) using aqueous acid in suitable solvent to obtain ticagrelor of formula (I);

Formula (VII) Formula (I)

e) optionally purifying the compound of formula (I) in a suitable solvent;

f) isolating ticagrelor by using ethylacetate and cyclohexane, isopropylacetate, toluene, acetone, acetonitrile, ethylacetoacetate or mixture thereof;

g) isolating pure crystalline Form II of ticagrelor from acetonitrile and toluene or mixture thereof; wherin single maximum impurities are controlled at a level of not more than 0.10; wherein crystallization can be initiated by seeding.

2. The process as claimed in claim 1, wherein the steps (a) to (e) are carried out in one-pot; wherein compounds of formula IV, V, VII and formula I are formed in-situ, and isolated formula I in-situ; isolating pure crystalline Form II of ticagrelor from acetonitrile and toluene or mixture thereof; wherein crystallization can be initiated by seeding.

3. The process as claimed in claim 1, wherein single maximum impurities are controlled at a level of not more than 0.10.

4. A process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol (IV); which comprises, 4,6-dichloro-2- (propylthio) pyrimidin-5-amine (III) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino- 2,2-dimethyltetrahydro-3aH-cyclopenta[d] [1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (II) in presence of appropriate base and solvent and extracted into suitable solvent;

Formula-II Formula-III Formula-IV

5. The process as claimed in claim 1 to 4, wherein the base is selected form sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, triethyl amine, diisopropyl ethyl amine, triisopropyl amine or mixture thereof.

6. The process as claimed in claim 1 to 4, wherein the solvent is selected from ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dic hloride, ethylene dichloride, dimethyl formamide, tetrahydrofuran, acetonitrile, toluene and xylene.

7. The process as claimed in claim 4, the solvent used for isolation is acetonitrile and toluene or mixture thereof.

8. The process as claimed in claim 1, wherein the diazotizing agent is selected from the group consisting of NaNO2.

9. The process as claimed in claim 1, wherein the acid is selected from, Trifluoro acetic acid, acetic acid, hydrochloric acid, methane sulphonic acid , sulphuric acid or mixture thereof.

10. A one-pot synthesis process of Ticagrelor of formula (I) as claimed in claim 1, wherein the reaction temperature is from 0°C to 100°C.