DESC:
FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Ticagrelor in high yield and purity. The invention further relates to a process for purification of Ticagrelor.

BACKGROUND OF THE INVENTION
Ticagrelor is a cyclopentyltriazolopyrimidine and P2Y12 ADP receptor antagonist used for the prevention of stroke, heart attack and events with acute coronary syndrome.

It is chemically known as (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5¬-(propylthio)-3H-[1,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and is represented by Formula I. Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 µg/mL at room temperature.

Ticagrelor and related compounds are disclosed in International patent publication number WO 00/34283 and WO 99/05143.

US patent number 7,067,663 B2 discloses process for the preparation of ticagrelor as represented in Scheme-1 below:
Scheme-1:

US’663 further discloses crystallization of ticagrelor in ethyl acetate and isooctane or in isopropanol.

International patent publication number WO 01/92263 A1, WO 2010/030224 A1, WO2012/085665 A2, WO2012/138981 A2 and WO 2013/037942 A1 discloses various processes for preparing ticagrelor.

US patent number US 9,233,966 B2 discloses process for preparing ticagrelor as mentioned in the scheme 2 below:

Scheme 2:

IN 4252/DEL/2015, discloses process of deprotecting protected ticagrelor at a lower temperature of 0oC for 3h. It further discloses the purification of said ticagrelor in ethyl acetate. The above said process suffers from a serious drawback of maintaining a peculiar temperature of 0oC for hours which is a cumbersome task if required to be performed at large scale.

IN 729/CHE/2015, discloses process for preparation and purification of ticagrelor & it’s intermediate. It further discloses purification of Formula IV using mixture of ethyl acetate and cyclohexane.

The processes for the preparation of ticagrelor, described in the above mentioned prior art suffer from disadvantages as the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions that is to be carried under pressure and, longer reaction times, tedious work up procedures and/or multiple crystallizations or isolation steps.

Therefore, there remains a need to prepare ticagrelor and its intermediates with high purity and in high yields. Hence, the present invention is focussed towards the improved process for the preparation pure ticagrelor in high yields which are suitable for industrial use.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to develop improved process for the preparation of ticagrelor which are suitable for industrial use.

Another object of the present invention is to provide the process of the preparation of intermediates of ticagrelor wherein said intermediates are isolated with high purity.

Another object of the present invention is to develop a process for purification of ticagrelor wherein said ticagrelor is isolated with purity of 99% and above.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of ticagrelor wherein said process comprises the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of suitable base and suitable solvent to give 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 of Formula IV or salt thereof and wherein said compound of Formula IV or its salt is optionally purified using suitable solvent,
, and
b) converting the compound of Formula IV or its salt to ticagrelor.

In another aspect, the present invention provides a purification process of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent,
b) optionally heating the solution of step a) to suitable temperature; and
c) isolating the pure ticagrelor of Formula I.

In another aspect, the present invention provides a process for the purification of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) isolating solid mass;
c) adding ester solvent to the solid mass and heating at ambient temperature to reflux temperature of the ester solvent;
d) filtering hot followed by addition of hydrocarbon solvent;
e) stirring for 60-100min; and
f) isolating pure ticagrelor at 0-5oC.

In another aspect, the present invention provides a process for the purification of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) isolating solid mass;
c) adding ester solvent to the solid mass and optionally heating at suitable temperature;
d) optionally distilling the ester solvent of step c);
e) adding suitable hydrocarbon solvent to step c) or mixture of ester and hydrocarbon solvent to step d) to get precipitates; and
f) isolating pure ticagrelor.

In another aspect, the present invention provides a process for the purification of compound of Formula IV, comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent,
b) optionally heating the solution of step a); and
c) isolating to get pure compound of Formula IV.

In another aspect, the present invention provides a purification process of compound of Formula IV, wherein said process comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent ;
b) optionally distilling the solution of step a);
c) optionally adding suitable hydrocarbon solvent to step a) or b); and
d) isolating to get pure compound of Formula IV.

DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The term “pure” as used in the context of the present invention, means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, “pure” also means 99% of one enantiomer or diastereomer, as appropriate. “Substantially” pure means, the same as “pure except that the lower limit is about 98% pure or more.

All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures 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, a “room” or “ambient” temperature includes temperatures from about 15°C to about 35°C, from about 20° C to about 30°C, or about 25°C.

The term “suitable solvent” as used in the context of the present invention, is selected from polar or non-polar solvents selected from, but not limited to, the group comprising of alcohol such as, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neopentylalcohol, t-pentyl alcohol, t-amyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; dipolar aprotic solvents such as dimethylformamide and dimethyl sulfoxide, N-Methyl-2-pyrrolidone, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane,trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane,chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether,methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol,anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone (MIBK), methyl t-butyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane, iso-octane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; acetic acid; water; and mixtures thereof.

While the invention is susceptible to various modifications and forms, specific embodiment thereof, will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

In another embodiment, the present invention provides a process for the preparation of ticagrelor wherein said process comprises the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of suitable base and suitable solvent to give 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 of Formula IV or salt thereof and wherein said compound of Formula IV or its salt is optionally purified using suitable solvent,
, and
b) converting the compound of Formula IV or its salt to ticagrelor.

In another embodiment, the present invention provides an improved process for the preparation of ticagrelor, comprising the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H cyclopenta [d][1,3] dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of suitable base and suitable solvent to give 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 of Formula IV or salt thereof and wherein, said compound of Formula IV or its salt is optionally purified using suitable solvent,
,
b) cyclizing 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 of Formula IV or its salt in presence of diazotizing reagent to give 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 of Formula V or salt thereof, wherein said compound of Formula V or its salt is optionally not isolated;
;
c) condensing compound of Formula V or its salt with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 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 of Formula VII or its salt, wherein said compound of Formula VII or its salt is optionally not isolated;
; and
d) deprotecting compound of Formula VII or its salt in presence of suitable deprotecting agent and suitable solvent at a suitable temperature to give ticagrelor of Formula I;
.
In another embodiment, the diazotizing reagent used for preparing compound of Formula V is selected from the group comprising of sodium nitrite, potassium nitrite, lithium nitrite, butyl nitrite and isoamyl nitrite. The diazotization is performed in presence of suitable acid selected from acetic acid, propionic acid, hydrochloric acid, hydrobromide, pivalic acid and sulphuric acid.

In another embodiment, the deprotection of compound of Formula VII is performed at a temperature in the range from 0oC to room temperature, preferably, at 10-30oC, most preferably, at 10-20oC.

In another embodiment, the present invention provides a process of preparing ticagrelor wherein the intermediates are optionally isolated as salts which are selected from, but not limited to, hydrochloride salt, hydrobromide salt, hydrogen iodide, sulfate salt, nitrate salt, oxalate salt, fumarte salt, S-(+)mandelate salt, R-(-) mandelate salt, tartrate salt such as L-(+)tartrate salt, D-(-)tartrate salt, (-)-dibenzoyl-L-tartrate salt, (+)-dibenzoyl-D-tartrate salt, (-)-di-para-toluoyl-D-tartrate salt, (+)-di-para-toluoyl-D-tartrate salt, (1R)-(-)-10-camphorsulfonate salt, and (1S)-(+)-10-camphorsulfonate salt.

In another embodiment, the present invention provides a process for the preparation of ticagrelor, comprising the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol- 4-yl)oxy)ethan-1-ol tartrate salt of Formula III in presence of amine base and alcohol solvent to give 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 of Formula IV or salt thereof, and wherein said compound of Formula IV is purified in suitable hydrocarbon solvent,
; and
b) converting compound of Formula IV to ticagrelor.

In another embodiment, the present invention provides a purification process of compound of Formula IV, wherein said process comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent,
b) optionally heating the solution of step a); and
c) isolating to get pure compound of Formula IV.

In another embodiment, the present invention provides a purification process of compound of Formula IV, wherein said process comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent;
b) optionally distilling the solution of step a);
c) optionally adding suitable hydrocarbon solvent to step a) or b); and
d) isolating to get pure compound of Formula IV.

In another embodiment, the present invention provides a purification process of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent,
b) optionally heating the solution of step a);
c) optionally adding suitable solvent either to step a) or to step b); and
d) isolating the pure ticagrelor of Formula I.

In a preferred embodiment, the process of preparation of ticagrelor is performed in situ without isolation of intermediates.

In an optional embodiment, the present invention provides a process for the preparation of ticagrelor wherein the intermediates may be isolated after workup and/ or purified before proceeding to next step.

In another aspect, the present invention provides a process for the purification of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) isolating solid mass;
c) adding ester solvent to the solid mass and heating at ambient temperature to reflux temperature of the ester solvent;
d) filtering hot followed by addition of hydrocarbon solvent;
e) stirring for 60-100min; and
f) isolating pure ticagrelor at 0-15oC.

In another preferred embodiment, the present invention provides a process for the purification of ticagrelor of Formula I, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) heating the solution at a temperature of 40-80oC followed by cooling to 0-5oC and isolating solid;
d) adding ethyl acetate to the solid obtained in step b), followed by heating to 40 -80oC and filtering hot;
e) adding suitable hydrocarbon solvent followed by stirring for a period of 60 to 100 minutes; and
f) isolating the pure ticagrelor at 0-15oC.

In another preferred embodiment, the suitable hydrocarbon solvent used for purification of ticagrelor of formula I is selected from the group comprising of isooctane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene and mixture thereof.

In another embodiment, suitable heating temperature in synthesis and purification process of ticagrelor is about 20°C to about 120°C for duration of about 10 minutes to about 2 hours.

In another embodiment, the present invention provides pure compound of Formula IV characterized by purity of at least 99.0% and above, more preferably 99.5% and above, more preferably 99.9% and above as measured by HPLC, wherein said compound of Formula IV is used as intermediate for the preparation of ticagrelor.

In another embodiment, the present invention provides pure ticagrelor of Formula I characterized by purity of 99.5% and above, preferably 99.9% and above as measured by HPLC,

In another embodiment, the present invention provides crystalline Form II of Ticagrelor characterized by purity of 99% and above, preferably 99.5% and above as measured by HPLC.

In another embodiment crystalline form formed in the present invention, are pure and substantially not contaminated with any other crystal forms. In particular, crystalline Forms II prepared in the present invention is substantially not contaminated with any other crystal forms.

In other embodiment, the isolation of ticagrelor is performed by methods known in the art or any procedure disclosed in the present invention.

In further embodiment the present invention provides ticagrelor or a pharmaceutically acceptable salt thereof, characterized in that preferably at least 15% by volume, more preferably 20% by volume of the ticagrelor particles have a particle size in the range of below 1 µm. Preferably, the ticagrelor in a form such that at least 15-20 % of the ticagrelor particles have a particle size in the range of below 1µm. Further characterized by particle size distribution wherein D15 to D20 below 1µm.

Certain specific aspects and embodiments of the present application will be explained in details with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.

EXAMPLES
EXAMPLE 1: Preparation of 2-thio barbituric acid sodium salt
To a solution of dimethyl malonate, thiourea in methanol was added 30% sodium methoxide in methanol and heated the reaction mixture at 60-64oC for 2-4 hrs. After completion of reaction, reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with methanol and then dried.

EXAMPLE 2: Preparation of 2-(propylsulfanyl)pyrimidine-4.6-diol
2-thio barbituric acid sodium salt / Sodium-2-thiobarbiturate was added to the mixture of water and methanol under stirring, followed by the addition of an n-propyl bromide at 25-30° C. The resulting mass was stirred for 15 minutes at 25-30° C., followed by the addition of an aqueous sodium hydroxide solution, while maintaining the temperature between 25-30° C. The resulting reaction mixture was stirred for 24 hours at 25-35°C. After completion of the reaction, water was added to the reaction mass, followed by pH adjustment to acidic pH by the addition of concentrated hydrochloric acid. The resulting slurry was stirred for 1 hour and the product was isolated by filtration and washed successively with water. The wet product was dried under reduced pressure at 50-55°C to produce 2-(propylsulfanyl) pyrimidine-4.6-diol.

EXAMPLE 3: Preparation of 5-nitro-2-propylthiopyrimidine-4,6-diol
To a clean and dry reaction assembly containing acetic acid was added fuming nitric acid at a temperature between 40-45° C. 2-Propylthio-pyrimidine-4,6-diol was added to the mixture at 40-45°C. The resulting mass was stirred for 2-4 hour at 40-45° C. After completion of the reaction, water was added to the mass for 20 minutes at 25-30°C. The resulting slurry was stirred for 1 hour at 25-30° C. The product was isolated by filtration and washed successively with water. The wet product was dried under reduced pressure at 50-55°C to produce the 5-nitro-2-propylthiopyrimidine-4,6-diol.

EXAMPLE 4: Preparation of 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine
To a solution of 5-Nitro-2-propylthiopyrimidine-4,6-diol in toluene was added phosphorus oxychloride followed by slow addition of N,N-diisopropyl ethylamine over a period of 20 to 30 minutes and maintaining the temperature at below 25° C. The resulting mixture was heated at 70-80°C for 2-4 hrs. After completion of the reaction, the reaction mass was slowly quenched into water while maintaining the temperature below 30° C, followed by stirring for 10 minutes. The reaction mass was extracted with dichloromethane, followed by washing the organic layer with saturated sodium bicarbonate, saturated sodium chloride solution, and water. The dichloromethane was evaporated at 50-55°C under reduced pressure to produce 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.

EXAMPLE 5: Preparation of 4,6-dichloro-2-propylthiopyrimidine-5-amine
Iron powder was added to a solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine in methanol and acetic acid at ambient temperature. The resulting reaction mixture was stirred for 2-5hrs at 40-50°C. The reaction mixture was then passed through a diatomaceous earth (Celite) pad or Silica gel. Water (400 mL) was added and the mixture was extracted with toluene. The combined organic layer was washed with sodium bicarbonate solution followed by brine solution. The toluene layer was concentrated to give crude compound which is further purified to give 4,6-dichloro-2-propylthiopyrimidine-5-amine.

EXAMPLE 6: Preparation of Methyl 2,3-O-isopropylidene-ß-D-ribofuranoside
A mixture of D-ribose and acetone was refluxed till completion of reaction. After completion of reaction, added aqueous sodium bicarbonate solution, and the acetone was distilled off under reduced pressure. The obtained reaction mass was treated with methanol in presence of HCl followed by sodium carbonate treatment to give title compound.

EXAMPLE 7: Preparation of methyl 2,3-Isopropylidene-5-p-toluene sulfonyl-D-ribofuranoside
To a solution of Methyl 2,3-O-isopropylidene-ß-D-ribofuranoside in dichloromethane was added p-toluene sulfonyl chloride followed by addition of pyridine. The solution was stirred at room temperature overnight. After completion of reaction, quenched the reaction with water and extracted the compound in dichloromethane. Concentrated the organic layer to get crude mass which is then purified using ethanol to get methyl 2,3-Isopropylidene-5-p-toluene sulfonyl-D-ribofuranoside.

EXAMPLE 8: Preparation of methyl 5-deoxy-5-iodo-2,3-O-(1-methylethylidene)-D-Ribofuranoside / Methyl 5-Deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside
To a solution of methyl 2,3-Isopropylidene-5-p-toluene sulfonyl-D-ribofuranoside in dimethyl formamide was added iodine at ambient temperature. Heated the reaction under stirring till competition of reaction. After completion of reaction separated, extracted with toluene/water. The combined extracts were dried over
Na2SO4, filtered and evaporated under reduced pressure to give title compound.

EXAMPLE 9: Preparation of N-(((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methylene)-1-phenylmethanamine oxide
To a solution of Methyl 5-Deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside in methanol was added zinc powder and stirred the reaction under ambient temperature till complete conversion of methyl 2,3-Isopropylidene-5-iodo-D-ribofuranoside. To the above solution was added N-benzyl oxammonium hydrochloride followed by addition of sodium carbonate. Stirred the reaction till completion. After completion of reaction, quenched the reaction with water and extracted the compound in ethyl acetate or dichloromethane. Distilled the organic layer to get N-(((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methylene)-1-phenylmethanamine oxide.

EXAMPLE 10: Preparation of (3aS,4S,7R,7aS)-6-benzyl-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine
A mixture of N-(((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methylene)-1-phenylmethanamine oxide and toluene and IPA was stirred at reflux temperature for 5 hours. The solution was cooled, activated charcoal was added and the resulting mixture was stirred at 90 °C for 10 minutes. Charcoal was filtered off and the solvent was removed under reduced pressure to give (3aS,4S,7R,7aS)-6-benzyl-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3]dioxolo[4,5-d][1,2]oxazine (34.36 g, 98 %) as yellowish crystals.

EXAMPLE 11: Preparation of [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol
Added (3aS,4S,7R,7aS)-6-benzyl-2,2-dimethyltetrahydro-3aH-4,7-methano[1,3] dioxolo[4,5-d][1,2]oxazine in methanol followed by addition of Pd/C. Refluxed the solution for one hour in presence of hydrogen source (either H2, or ammonium formate). After completion of reaction, cooled the reaction mixture, filtered through celite and concentrated the methanol to get [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol.

EXAMPLE 12a: Preparation of [3aS-(3aa, 4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid phenylmethyl ester
Potassium carbonate (39.3 g) was added to a suspension of [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol in MIBK, followed by dropwise addition of benzyl chloroformate. The reaction mixture was stirred at room temperature for 2-4 hours before the organic phase was separated. The aqueous phase was extracted with MIBK. The combined organics were concentrated and isolated using hexane to give [3aS-(3aa, 4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid phenylmethyl ester.

EXAMPLE 12b: Preparation of tert-butyl [3aS-(3aa,4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamate
Titiled compound is prepared by a process disclosed in example 12a by replacing benzyl chloroformate with Di-tert-butyl dicarbonate and solvent used for reaction is MIBK+water.

EXAMPLE 13a: Preparation of [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid phenylmethyl ester
Potassium carbonate in DMF was added over 5 minutes to a solution of [3aS-(3aa, 4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid phenylmethyl ester in DMF. After 15 minutes, ethyl bromoacetate in DMF was added dropwise. The reaction mixture was stirred at 0° C. followed by stirring at room temperature. After completion of reaction quenched the reaction with ethyl acetate and concentrated the combined organic layer to give a solid. To the solid so obtained was added ethanol followed by slow addition of sodium borohydride. Stirred the reaction at room temperature till completion of reaction. After completion of reaction, quenched the reaction with water and extracted the compound in ethyl acetate. Concentrated the combined organic layer followed by purification in ethanol to get [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester.

EXAMPLE 13b: Preparation of tert-butyl [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamate
To a solution of tert-butyl[3aS-(3aa, 4a,6a,6aa)]-[tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamate in DMF was added ethyl bromoacetate and sodium hydride in DMF at -20 to -15°C. Stirred the reaction at -20 to -15°C for 4 hrs. After completion of reaction, quenched the reaction by water and extracted the compound by ethyl acetate. Combined the organic layer and concentrated to get oily mass. Added ethanol to the oily mass and added sodium borohydride in ethanol. Stirred the reaction at 50-60°C for 4 hrs. After completion of reaction, quenched the reaction with dilute hydrochloric acid and distilled the ethanol. Added water and extracted the compound in ethyl acetate. Combined the organic layer and concentrated to get oily mass of tert-butyl [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamate.

EXAMPLE 14a: Preparation of 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid
A slurry of 5% palladium on charcoal in ethanol was added to a solution of [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid phenylmethyl ester in ethanol and the mixture was hydrogenated at 1.2 bar for 20 hours. The catalyst was filtered off and the filtrate was concentrated to give a solid mass. A stirred solution of the product so obtained in ethanol/isoproanol was heated to 35° C. L-tartaric acid was added (temperature rise to 45° C.) and the mixture was stirred at 40-45° C. for 1 h. The mixture was cooled to 20° C. and the resulting thick slurry stirred for 16 h then filtered. The collected solid was washed with two portions of isopropanol and dried in vacuum at 40°C to give 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid as white crystals.

EXAMPLE 14b: Preparation of 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid
tert-butyl [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamate was added to ethylene glycol, stir at 100-120°C for 4-8 hours followed by extraction using water / dichloromethane. The combined organic layer is dried and concentrated to give a solid mass. A stirred solution of the product so obtained in isoproanol was heated to 35° C. L-tartaric acid was added (temperature rise to 45° C.) and the mixture was stirred at 40-45° C. for 1 h. The mixture was cooled to 20° C. and the resulting thick slurry stirred for 16 h then filtered. The collected solid was washed with two portions of isopropanol and dried in vacuum at 40°C to give 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid as white crystals.

EXAMPLE 15: 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 of Formula IV
To a solution of 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid in ethanol (500ml) was added 4,6-dichloro-2-propylthiopyrimidine-5-amine and triethylamine in a autoclave at 20-35ºC. Closed the autoclave and filled 2-6 Kg/cm2 nitrogen pressure and heated at 90-120ºC. Stirred the reaction mixture at 90-120ºC for 18-24 hours. After completion of reaction, cooled the reaction mixture to room temperature followed by treating with charcoal. Distilled the solvents under vacuum. Extracted with ethyl acetate and washed with brine solution. Separated the layers and treated the organic layer with charcoal. Filtered and distilled under reduced pressure. Obtained material was crystallized with n-heptane followed by toluene to give desired compound.

EXAMPLE 16: 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 of Formula IV
To a solution of 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol L-tartaric acid in ethanol (500ml) was added 4,6-dichloro-2-propylthiopyrimidine-5-amine and triethylamine in a autoclave at 20-35ºC. Closed the autoclave and filled 2-6 Kg/cm2 nitrogen pressure and heated at 90-120ºC. Stirred the reaction mixture at 90-120ºC for 18-24 hours. After completion of reaction, cooled the reaction mixture to room temperature and distilled the solvents under vacuum. Extracted with ethyl acetate and washed with brine solution. Separated the layers and distilled under reduced pressure. Cyclohexane was charged to obtained reaction mass, heated to 35-60?, cooled to 15-20? and filtered. Toluene was added to obtained reaction mixture, heated to 40-80?, cooled to 0-5?, filtered, washed with n-heptane and dried under vacuum at 40-60?.

EXAMPLE 17: Preparation of Ticagrelor
Charged acetic acid, DM water and compound of Formula IV in the round bottom flask at 20-25º. Cooled the reaction mixture at 0-5ºC. Charged sodium nitrite and DM water and stirred for 1 hour. After completion of reaction, quenched the reaction mass in dichloromethane and 30% potassium carbonate solution in water. Stirred and separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V in organic layer. Proceeded the organic layer i.e. dichloromethane layer as such in next step. Added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI hydrochloride salt to dichloromethane layer followed by slow addition of diisopropyl ethylamine. Stirred at 3-5 hours and added water to the reaction mixture so obtained. Separated the layers to get 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 in the organic layer. Partially distilled the organic layer and added methanol to the organic layer and stir it for 12-18 hours at 12-18oC. Adjusted the pH to 5-9 with the help of NaOH solution. Distilled out the methanol completely. Charged Ethyl acetate and 10% sodium chloride solution followed by stirring and separating the layers. Distilled out the organic layer completely to get crude ticagrelor. Added acetonitrile and Isopropyl ether. Heated the reaction mass at 55-60ºC and cooled to 0-5ºC and filtered. Solid so obtained was dissolved in ethyl acetate by heating at 50-65ºC followed by addition of isooctane to the solution. Stirred and filtered the solid at 0 to 5oC. Obtained solid was dried at 45-55ºC.

EXAMPLE 18: Preparation of Ticagrelor
Charged acetic acid, DM water and compound of Formula IV, in the round bottom flask at 20-25º. Cooled the reaction mixture at 0-5ºC. Charged sodium nitrite and DM water and stirred for 1 hour. After completion of reaction, quenched the reaction mass in dichloromethane and 30% potassium carbonate solution in water. Stirred and separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V in organic layer. Proceeded the organic layer i.e. dichloromethane layer as such in next step. Added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI hydrochloride salt to dichloromethane layer followed by slow addition of diisopropyl ethylamine. Stirred at 3-5 hours and added water to the reaction mixture so obtained. Separated the layers to get 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 in the organic layer. Distilled the organic layer and added methanol to the crude solid so obtained. Cooled the reaction mixture to 12-18oC and added conc. HCl diluted with methanol to the reaction mixture. Stirred for 12-18hours at 12-18oC. Adjusted the pH to 5-12 with the help of NaOH solution. Distilled out the methanol completely. Charged Ethyl acetate and 10% sodium chloride solution followed by stirring and separating the layers. Distilled out the organic layer completely under vacuum to get crude ticagrelor. Added acetonitrile and Isopropyl ether and heated the reaction mass at 55-60ºC followed by cooling to 0-5ºC and filtered. Solid so obtained was dissolved in ethyl acetate by heating at 50-65oC. Distilled out the ethyl acetate completely. Added mixture of Ethyl acetate and Isooctane. Heated the slurry mass so obtained at 50-65ºC followed by cooling to obtain the product.

EXAMPLE 19: Preparation of Ticagrelor
Charged compound of Formula IV, acetic acid and DM water into a round bottom flask at 25-35°C. Added aqueous sodium nitrite solution to the above solution. Stirred the solution at 25-35oC till completion of reaction. After completion of reaction, added dichloromethane and DM water to the reaction mass at 5-30ºC. Separated the organic layer and washed with 30% potassium carbonate solution at 40-60?. Stirred and separated the layers to get 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 of Formula V in organic layer. To the obtained organic layer, was added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine hydrochloride at 20-25ºC, followed by slowly addition of diisopropyl ethyl amine at 15-35ºC. Stirred the reaction mass at 20-30ºC. After completion of reaction, added water to the reaction mass. Separated the layers and washed the organic layer with dilute HCl solution followed by water washing. Distilled out the organic layer under vacuum and stripped it out with methanol. Added methanol to the crude compound so obtained. Cooled the crude mass in methanol at 12-18ºC and added conc. HCl (diluted with methanol) to the above reaction mass. Stirred for 15-24 hours at 12-18ºC. Distilled acetone and adjusted the pH of reaction mass to 5-12 by using sodium hydroxide solution. Distilled out the methanol completely under vacuum. Extracted with ethyl acetate and washed it with sodium chloride solution. Distilled the organic layer and added acetonitrile and isopropyl ether to the solid mass so obtained. Stirred under heating at 55-70ºC. Cooled the solution to 0-5ºC and filtered. Dried it under vacuum at 45- 55ºC. Added ethyl acetate to the solid so obtained and heated at 55-70ºC followed by addition of isooctane. Cooled the suspension, filtered and dried to get Ticagrelor.

EXAMPLE 20: Purification of Ticagrelor
Charged acetonitrile and Isopropyl ether to crude ticagrelor and heated at 55-60ºC and then cooled to 0-5ºC to obtain the solid. Dried the obtained solid under vacuum at 45- 55ºC to get pure ticagrelor with purity 99.9% by HPLC.

EXAMPLE 21: Purification of Ticagrelor
Charged acetonitrile and Isopropyl ether to crude ticagrelor. Heated at 55-60ºC and then cooled to 0-5ºC. Filtered the solid so obtained and dissolved said solid mass in ethyl acetate at 50-65oC. Filtered hot and added isooctane to the mother liquor to initiate precipitation followed by stirring for 90-100 minutes. Filtered the precipitates at 0 to 5oC and dried to get pure ticagrelor.

CLAIMS:WE CLAIM
1. A process for the preparation of ticagrelor wherein said process comprises the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of suitable base and suitable solvent to give 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 of Formula IV or salt thereof and wherein said compound of Formula IV or its salt is optionally purified using suitable solvent,
, and
b) converting the compound of Formula IV or its salt to ticagrelor.

2. A process of purification of compound of Formula IV, wherein said process comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent,
b) optionally heating the solution of step a); and
c) isolating to get pure compound of Formula IV.

3. The process as claimed in claim 2, wherein said process further comprising the steps of:
a) providing a solution of compound of Formula IV in suitable solvent;
b) optionally distilling the solution of step a);
c) optionally adding suitable hydrocarbon solvent to step a) or b); and
d) isolating to get pure compound of Formula IV.

4. The process as claimed in claim 2, wherein the obtained compound of formula IV has a purity of at least about 99.0% as measured by area HPLC.

5. A process for the preparation of ticagrelor, comprising the steps of:
a) reacting 4,6-dichloro-2-(propylthio) pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H cyclopenta [d][1,3] dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of amine base and alcohol solvent to give 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 of Formula IV or salt thereof, and wherein said compound of Formula IV is purified in suitable hydrocarbon solvent,
; and
b) converting compound of Formula IV to ticagrelor.

6. A process as claimed in claim 5, wherein said process comprising the steps of:
a) reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H cyclopenta [d][1,3] dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of suitable base and suitable solvent to give 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 of Formula IV or salt thereof and wherein, said compound of Formula IV or its salt is optionally purified using suitable solvent,
,
b) cyclizing 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 of Formula IV or its salt in presence of diazotizing reagent to give 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 of Formula V or salt thereof, wherein said compound of Formula V or its salt is optionally not isolated;
;
c) condensing compound of Formula V or its salt with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 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 of Formula VII or its salt, wherein said compound of Formula VII or its salt is optionally not isolated;
; and
d) deprotecting compound of Formula VII or its salt in presence of suitable deprotecting agent and suitable solvent at a suitable temperature to give ticagrelor of Formula I;
.

7. A process for the purification of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent,
b) optionally heating the solution of step a);
c) optionally adding suitable solvent either to step a) or to step b); and
d) isolating the pure ticagrelor.

8. A process for the purification of ticagrelor, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) isolating solid mass;
c) adding ester solvent to the solid mass and optionally heating at suitable temperature;
d) optionally distilling the ester solvent of step c);
e) adding suitable hydrocarbon solvent to step c) or mixture of ester and hydrocarbon solvent to step d) to get precipitates; and
f) isolating pure ticagrelor.

9. The process as claimed in claim 8, wherein said process comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) isolating solid mass;
c) adding ester solvent to the solid mass and heating at ambient temperature to reflux temperature of the ester solvent;
d) filtering hot followed by addition of hydrocarbon solvent;
e) stirring for 60-100min; and
f) isolating pure ticagrelor at 0-15oC.

10. The process as claimed in claims 7 to 9, wherein said ticagrelor has a purity of at least 99.0%.