FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
1. TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF TICAGRELOR"
2. APPLICANT(S)
(a) NAME: ZCL CHEMICALS LIMITED
(b) NATIONALITY: INDIA
(c) ADDRESS: 215 ATRIUM, C WING, 8TH FLOOR, 819-821,
ANDHERI-KURLA ROAD, CHAKALA, ANDHERI (E), MUMBAI 400 093, MAHARASHTRA, INDIA.
COMPLETE
3. The following specification particularly describes the invention and the manner in which it is to be
performed.

TITLE: AN IMPROVED PROCESS FOR THE PREPARATION OF
TICAGRELOR
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Ticagrelor. More particularly, the present invention relates to the improved process parameters such as reaction conditions, solvents, temperatures etc to prepare Ticagrelor-the process which is industrially advantageous and economically significant,
BACKGROUND OF THE INVENTION
Ticagrelor, also known as (1S,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, is represented by the following structure:

Ticagrelor is marketed by AstraZeneca in U.S.A under the trade name BRILINTA® and in Europe under the trade name BRILIQUE® which is a reversibly binding oral P2Y12 At)P receptor antagonist and indicated for the use of platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome.

There exist many prior art methods in the Literature disclosing the preparation of Ticagrelor.
United states patent No. 6,525,060 discloses a process for the preparation of Ticagrelor. The process disclosed in the '060 patent is a multi-step process and involves use of toxic reagents like tribromomethane, triflic anhydride, methyl-2-(trifluoromethyl sulfonyloxy) acetate. Further, in the '060 disclosed process the introduction of the methoxycarbonyl methyl group is very difficult due to poor chemoselectivity, as the amino group also react with 2-(trifluoromethyl sulfonyloxy)acetate.
U.S. Patent No.7,067,663 discloses a process for preparation of Ticagrelor by coupling compound of formula I and L-tartaric acid salt of Formula II in presence of ethanol and Triethylamine base and subsequently converting the obtained Formula III in to Ticagrelor.

The condensation reaction of Formula-I with Formula-II has been the key step in the preparation of Ticagrelor and many prior art documents disclose the improvements revolving around this key step.
The PCT application WO2010/030224 discloses an improved process for preparation of Ticagrelor by the coupling reaction of formula I with oxalate salt of Formula II in

presence of organic base like triethyl amine and ethylene glycol solvent. The obtained compound of formula III was subsequently converted to Ticagrelor.
Another PCX application WO 2013150495 discloses a process for preparation of Ticagrelor by coupling of Formula I and salt of Formula II in a polar solvent selected from alcohol, water or mixtures thereof and optionally in presence of additive such as potassium iodide, tetrabutyl ammonium iodide, tetrabutyl ammonium bromide, sodium iodide, lithium chloride and lithium iodide to obtain compound of Formula III and subsequently converting the obtained Formula III in to Ticagrelor.
PCT application WO 2014/102830 discloses a process for preparation of Ticagrelor, by coupling of Formula I and salt of Formula II in ethylene glycol solvent and diisopropyl ethylamine base in presence of catalyst selected from 1,8-Diazabicycloundec-7-ene (DBU), 1,5-Diazabicyclo (4.3.0) non-5-ene (DBN), dimethylaminopyridine, potassium iodide, Lithium iodide, sodium iodide, iodine; p-toluene sulfonic acid and tertiary alkyl ammonium halide. The compound of formula III obtained is converted in to Ticagrelor in further stages.
All the prior arts discussed above suffer from many disadvantages like tedious and cumbersome work up procedures, high temperature conditions, longer reaction times, multiple crystallizations or isolation steps, use of excess reagents and solvents and column chromatographic purification etc. which affect the overall yield as well as the quality of the final product.
Thus there is a need for improved process for the preparation of Ticagrelor of high purity and yield which overcomes the drawbacks of prior publications. The present inventors have found an efficient process for the preparation of Ticagrelor which offers advantage over the prior processes in terms of diastereoselectivity, enantio-

selectivity, high yield, purity, less effluents and simple scalable procedure suitable for large scale production.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to a process for the preparation of Ticagrelor comprising:
a) reacting compound of formula I with a compound of formula II or a salt thereof in
presence of a base and an organic solvent to obtain a compound of formula III;

b) reacting compound of formula III with acetic acid and a metal nitrite in presence
of an organic solvent to obtain compound of formula IV;

c) reacting compound of formula IV with trans-(1R,2S)-2-(3,4-difluorophenyl)-
cyclopropylamine or its salt to obtain compound of formula VI; and


d) deprotecting the compound of formula VI with an acid to obtain Ticagrelor.
Another aspect of the present invention relates to a process for the preparation of Ticagrelor comprising:
a) reacting compound of formula I with a compound of formula II or a salt thereof in
presence of a base and a non-polar organic solvent to obtain a compound of
formula III;

and
b) converting the compound of Formula III into Ticagrelor.
Another aspect of the present invention provides a process for the preparation of Ticagrelor wherein the intermediate compounds formed during the process do not

require a further purification unlike the prior art processes. In one aspect, the intermediate compounds formed during the process were not isolated and proceeded to the next stage as such.
DEFINITIONS
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25° C and normal pressure unless otherwise designated.
All temperatures used herein are in degrees Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
DETAILED DESCRIPTION
While the following specification concludes with claims particularly pointing out and distinctly claiming the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and also by studying the included examples.
The best methods and materials of performing the present invention are described here.

In an attempt to develop an improved process for the preparation of Ticagrelor and to overcome the disadvantages of prior art, the present inventors have developed a process which results in high purity and good yield of Ticagrelor.
The process of preparation of Ticagrelor as per the present invention can be summarized in the following schematic representation:

An embodiment (embodiment-1) of the present invention encompasses a process to prepare Ticagrelor comprising:
a) reacting compound of formula I with compound of formula II or a salt thereof in presence of a base and an organic solvent to obtain a compound of formula III;


b) reacting compound of formula III with acetic acid and a metal nitrite in presence
of an organic solvent to obtain compound of formula IV;

c) reacting compound of formula IV with trans-(1R,2S)-2-(3,4-difluorophenyl)-
cyclo propylamine or its salt to obtain compound of formula VI; and

d) deprotecting the compound of formula VI with an acid to obtain Ticagrelor.
Another embodiment (embodiment-2) of the present invention provides a process to prepare compound of formula III comprising: reacting compound of formula I with a compound of formula II or a salt thereof in presence of a base and a non-polar organic solvent to obtain the compound of formula III.


One more embodiment (embodiment-3) of the present invention provides a process to prepare Ticagrelor comprising: a) reacting compound of formula I with a compound of formula II or a salt thereof in
presence of a base and a non-polar organic solvent to obtain a compound of
formula III;

In the process of step-a) of embodiments 1 or 2 or 3, the compound of formula II used is either in its free base form or any of its salt form. The salt form may be selected from HC1, HBr, HI, HNO3, H2SO4, acetic acid, oxalic acid, mandelic acid, succinic acid, trifluoro acetic acid, p-toluenesulphonic acid, dibenzoyl-L-tartaric acid, di-ptoluoyl-L-tartaric acid, formic acid, L-tartaric acid; preferably the L-tartaric acid salt.

In the same embodiments of step-a, the organic solvent used may be non-polar organic solvent selected from aromatic hydrocarbons such as toluene and xylene, alkanes and cycloalkanes such as hexane, heptane and cyclohexane; polyhalogenated hydrocarbons such as chloroform and carbon tetrachloride. Mixtures of these non-polar solvents can also be used. In a preferred embodiment, Toluene is used as reaction solvent of step-a.
The present inventors have observed that by carrying out the reaction of step-a in a non-polar organic solvent leads to a simpler process steps suitable for large scale production, less waste, easy recovery and recycling of solvents compared to prior art methods where solvents such as monoehtylene glycol were used.
In the same embodiments of step-a, the base used is selected from, but is not limited to, inorganic bases such as potassium bicarbonate, potassium carbonate, potassium hydroxide, sodium carbonate, cesium carbonate, sodium bicarbonate and sodium hydroxide and the like; or organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl morpholine, DABCO and the like. In a preferred embodiment, sodium bicarbonate is employed as base in the reaction of step-a.
In the embodiments of step-b, the cyclization or diazotization reaction can be carried out in. the presence of a metal nitrite and a suitable acid. The metal nitrite used is selected from sodium nitrite, potassium nitrite, lithium nitrite and the like preferably sodium nitrite.

In the embodiments of step-b, the suitable acid used may be selected from inorganic or organic acids. Inorganic acids include, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, sulphamic acid, and phosphoric acid. Examples of suitable organic acids include acetic acid, trifluoroacetic acid, p-toulene sulfonic acid, methane sulfonic acid and the like. In a preferred embodiment, an organic acid and more preferably, acetic acid is used in the reaction of step-b.
The suitable temperature for carrying out a diazotization reaction is well established in the art and accordingly the process of step-b is preferably carried at a temperature range of 0° to 35° C.
After the reaction completion, the product of step-b can be isolated from the reaction mixture or the organic layer containing product is taken to the next stage as such without isolating the product.
In the embodiments of step-c, compound of formula IV is reacted with trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine in presence of a suitable base and a suitable organic solvent. The trans-(lR,2S)-2-(3,4-difluorophenyl)-cyclopropylamine used is preferably in the form of its acid addition salt selected from, but not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, trifluoroacetic acid, acetic acid and the like, more preferable the hydrochloric acid salt.
In the embodiments of step-c; the suitable base used for condensation of compound of Formula IV and trans-(lR,2S)-2-(3,4-difluorophenyl)-cyclopro

pylamine is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, cesium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia, triethylamine N,N-diisopropyl ethyl amine and the like and mixtures thereof; preferably potassium carbonate.
After the reaction completion, the product of step-c can be isolated from the reaction mixture or the organic layer containing product is taken to the next stage as such without isolating the product.
In the embodiments of step-d, the deprotection of compound of Formula VI is carried out with an acid source to obtain Ticagrelor.
The suitable acid for deprotection of compound of Formula VI is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid and the. like and mixtures thereof; preferably hydrochloric acid.
The suitable solvent of step-d is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like; ethers such as tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran and the like; chlorinated solvents such as dichloromethane and the like; amides such as dimethylformamide and the like; aromatic hydrocarbons such as toluene, xylene and the like; water and

any mixtures thereof. In a preferred embodiment the deprotection is carried in presence of mixture of Dichloromethane and methanol solvents.
In the embodiments of step-d, after the completion of reaction, the product Ticagrelor can be isolated from reaction mixture using common techniques known in the art.
In one preferred embodiment, the product is isolated by separating the aqueous layer containing product from the reaction mixture followed by neutralizing the aqueous layer using either base or an acid and extracting the product using an organic solvent. The product can be isolated from the organic layer by solvent-anti solvent addition method or isolating the product by adding a solvent to the residue obtained after distillation of organic layer.
In any of the embodiments of steps a, b, c & d, the intermediate compounds obtained during the process can be isolated or can be taken as such to proceeded to further stages without involving any further purification (in-situ). In a preferred embodiment, the intermediate compounds of formula III, IV & VI were not isolated and taken to next stage.
The Ticagrelor obtained using above process can optionally be purified.

The starting materials of formulae I & II of the present invention are commercially available or can be prepared by any of the prior art processes such as the processes as described in, but not limited to, US 7,067,663 and 7,799,914.
EXAMPLES
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 1:
Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)
pyrimidin-4-yI)amino)-2,2-dimethyItetrahydro-3aH-cycIopenta[d][l,3]dioxoI-4-
yl)oxy)ethanol.
A round bottom 4-necked reaction flask was charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4- yl)oxy)ethanol L-tartaric acid salt (300 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (175 g), Toluene (1500 mL) and sodium bicarbonate (548 g). The reaction mixture was heated to 90-105° C and maintained at the same temperature. After completion of reaction, the reaction mixture was cooled to 40-50° C followed by addition of water. The reaction mixture was stirred for 30 minutes and layers were separated. The aqueous layer was extracted with Toluene at 40-50° C. The combined organic layer was washed with water at 20-30° C. The organic layer was separated and subjected to partial distillation under vacuum at 55-60° C followed by addition of n-heptane. The mixture was stirred for 3 hours followed by isolation of solid by filtration and washing with n-hexane. The solid isolated was subjected to drying under vacuum at 55- 60° C for 480 minutes to afford the title compound. Yield: 81% HPLC purity: 99%.

Example 2:
Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)
pyrimidin-4-yl)amino)-2,2-dimethyItetrahydro-3aH-cyclopenta[d][1,3]dioxoI-4-
yl)oxy)ethanoL
A reaction flask was charged with (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4- yl)oxy)ethanol L-tartaric acid salt (10 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (5.9 g), Xylene (50 mL) and sodium bicarbonate (13.7 g). The mixture was heated to 95-110°C and maintained at the same temperature for 33 hours. After completion of the reaction the product was isolated in a way similar to the work up procedure as explained in example 1 to obtain the title compound.
Example 3:
Preparation of 2-[[(3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo
[4,5-d]pyrimidin-3-yl)-2,2-dimethyItetrahydro-3aH-cycIopenta[d][l,3]dioxoI-4-
yl]oxy]ethanol.
In a round bottom reaction flask, added Dichloromethane (800 ml) to 80 gms of the compound of example 1 followed by addition of acetic acid (34.5 gm) at room temperature. Slowly added a solution of sodium nitrite (14.5 gm) in water (160 ml) at room temperature. The reaction mixture was stirred and the progress of reaction was monitored by HPLC. After completion of reaction, the layers were separated. The aqueous layer was extracted with Dichloromethane at room temperature. The combined organic layers were washed with water. The compound 2-[[(3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl]oxy]ethanol in organic layer was taken as such for next step.

Example 4:
Preparation 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-y1)-2,2-
dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4yl]oxy]ethnol.
In a round bottom flask, to the organic layer of above example 3, added (1R, 2S)-2-(3,4-difluorophenyl) cyclopropanamine hydrochloride (40.1 gm) and potassium carbonate (79.2) at room temperature. The reaction mixture was stirred for 10 hrs and the progress of reaction was monitored by HPLC. On completion of reaction, slowly added water into the reaction mixture at room temperature. The mixture was stirred for 30 minutes and layers were separated. The organic layer was washed with water and then with 10 % brine solution at room temperature. The title product containing organic layer compound 2-[[(3aR,4S,6R,6aS)-6-(7-(((lR,2S)-2-(3,4-difluorophenyl)Cyclopropyl)amino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4yl]oxy]ethnol in organic layer was taken as such for next step.
Example 5:
Preparation of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)Cyclopropyl]
amino}-5-(ropylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy
ethoxy) cyclopentane-1,2-diol (Ticagrelor).
To the organic layer obtained from example 4, in a reaction flask, added methanol (240 ml) at room temperature and cooled the reaction mixture to 10-15° C. Slowly added concentrated Hydrochloric acid (240 ml) at the same temperature. The reaction mixture was then stirred for about 10 hrs at 10-15° C. The progress of reaction was monitored by HPLC. After completion of reaction, the reaction mixture was cooled to 5-15° C. The layers were separated and the aqueous layer was washed with methylene dichloride. Charged methylene dichloride to the aqueous layer and adjusted pH to 6.0

- 7.5 by using aqueous sodium carbonate solution in water at 5-15° C. Raised the temperature to 15-25° C and separated layers. Aqueous layer was extracted with methylene dichloride at room temperature. The combined organic layers were completely distilled out followed by stripping out the solvent with Acetonitrile. Charged acetonitrile to the residue and reaction mixture was heated to 60-70° C. Cooled the reaction mixture, stirred for 2 hrs and filtered the solid to obtain Ticagrelor. The obtained product was dried. Purity: 99.85% Yield: 68 gms

"AN IMPROVED PROCESS FOR THE PREPARATION OF TICAGRELOR"
WE CLAIM:
1. A process for the preparation of Ticagrelor comprising:
a) reacting compound of formula I with compound of formula II or a salt thereof
in presence of a base and an organic solvent to obtain a compound of formula

b) reacting compound of formula III with acetic acid and a metal nitrite in
presence of an organic solvent to obtain compound of formula IV;

c) reacting compound of formula IV with trans-(lR,2S)-2-(3,4-difluorophenyl)-
cyclopropylamine or its salt to obtain compound of formula VI; and

d) deprotecting the compound of formula VI with an acid to obtain Ticagrelor.

"AN IMPROVED PROCESS FOR THE PREPARATION OF TICAGRELOR"
2. The process according to claim 1, wherein the compound of formula II is used in its salt form.
3. The process according to claim 2, wherein the compound of formula II is L-Tartarate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-
cyclopenta[d][l ,3]dioxol-4- yl)oxy)ethanol.
4. The process according to claim 1, wherein the organic solvent of step-a) is a non-polar organic solvent selected from toluene, xylene, hexane, heptane and cyclohexane.
5. The process according to claim 4, wherein the non-polar organic solvent is Toluene.
6. The process according to claim 1, wherein the salt of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine is Hydrochloric acid salt.
7. The process according to claim 1, wherein in step-d), Ticagrelor is isolated from Acetonitrile.
8. The process according to claim 1 wherein steps b, c and d are performed in-situ.

"AN IMPROVED PROCESS FOR THE PREPARATION OF TICAGRELOR"
9. A process for the preparation of Ticagrelor comprising:
a) reacting compound of formula I with compound of formula II or a salt thereof in presence of a base and a non-polar organic solvent to obtain a compound of formula III;

and
b) converting the compound of Formula III into Ticagrelor.