FORM 2
THE PATENT ACT 1970
(39 of 1 970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
"PROCESS FOR PREPARATION OF TICAGRELOR"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Gienmark House,
HDO- Corporate BIdg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to cyclopentane pyrimidine compounds, a process for their preparation and their use as intermediate compounds in the preparation of ticagrelor.
BACKGROUND OF THE INVENTION
Ticagrelor also known as [lS-[l[α],2[α]],3[ß](lS*,2R*),5[ß]]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropyIamino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, is represented by the structural formula

Ticagrelor is a P2Y12 platelet inhibitor, indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome. Ticagrelor is marketed under the tradename of Brilinta®.
United States Patent No.6,525,060 discloses ticagrelor and its salts. Various processes are disclosed for the preparation of ticagrelor and these processes proceed via coupling of a triazolo pyrimidine derivative with (lR-trans)-2-(3, 4-difluorophenyl) cyclopropanamine.
The objective of the present invention is to provide a novel method for the synthesis of ticagrelor which is more convenient and more efficient than currently available known methods.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing ticagrelor, compound of formula A, comprising:


a) reducing a compound of formula VII to obtain a compound of formula VIII,

wherein R is H or a suitable N-protecting group,
b) cyclizing compound of formula VIII to obtain a compound of formula IX; and

c) hydrolyzing the compound of formula IX to obtain Ticagrelor.
In one embodiment the present invention provides use of intermediate compounds VII or VIII in preparation of ticagrelor or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION
The first aspect of present invention relates to the process of preparing ticagrelor, compound of formula A, comprising:
a) reducing a compound of formula VII to obtain a compound of formula VIII,

wherein R is H or a suitable N-protecting group,
b) cyclizing compound of formula VIII to obtain a compound of formula IX; and

c) hydrolyzing the compound of formula IX to obtain Ticagrelor.
In step a) of the process directly described above, the reduction of the nitro group can be carried out by standard techniques, known in the art such as reduction using hydrogenation with a transition metal catalyst, Ni/Raney, tin metal, iron powder, Zn/NH4CI and SnCl2. Preferably the reduction is carried out by hydrogenation with palladium on charcoal.

In step b) of the above process, the cyclisation can be achieved by reacting the compound of formula VIII with a metal nitrite such as an alkali metal nitrite for example sodium nitrite in a suitable solvent or acid or with a C1-6 alkyl nitrite in an suitable solvent. The term alkyl refers to C1-6 alkyl which includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl.
The suitable solvents may be selected from but are not limited to the group consisting of ethers, chloro solvents, alcohols, esters, hydrocarbon, nitriles, amides, water and mixtures thereof. Preferably the solvent is acetonitrile.
In step c) of the above process, the hydrolysis is carried out using a mineral acid or an organic acid selected from but are not limited to hydrohalic acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid. Preferably the acid used is hydrochloric acid. The above process further includes splitting off when necessary the N-protecting groups in the compounds obtained.
In one embodiment, the present invention provides compound of formula VII and compound of formula VIII.

The second aspect of the present invention provides a process for the preparation of
compound of formula VII comprising:
a) coupling a compound of formula X with a compound of formula II,


to obtain a compound of formula XI; and
b) reacting compound of formula XI with an amine of formula V or its N-protected derivative or a salt thereof

to obtain a compound of formula VII,
wherein R is H or a suitable N-protecting group.
In step a) of the above process, the compound of formula X is coupled with compound of formula II to obtain a compound of formula XI in the presence of an organic or inorganic base in a suitable solvent. The reaction may also be carried out in the absence of base. The reaction may also be carried out in acidic condition such as using hydrochloric acid in isopropyl alcohol (IPA.HC1), ethanolic HC1. The suitable solvents may be selected from but are not limited to ethers, chloro solvents, alcohols, esters, hydrocarbon, nitriles, amides, sulfonamide, water and mixtures thereof. Preferably the solvent is dimethylformamide (DMF). The organic bases include triethylamine, N-methyl morpholine, N, N-diisopropylethyl amine, pyridine and dimethyl amino pyridine (DMAP); the inorganic bases include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisopropyl amide and n-butyl lithium.

In step b) of the process above, the compound of formula XI is reacted with a compound of formula V or its N-protected derivative or a salt thereof. The reaction may be carried out optionally in the presence of an inorganic or organic base. The organic base may be selected from triethylamine, N-methylmorpholine, N, N- diisopropylethyl amine, pyridine and dimethyl amino pyridine (DMAP); the inorganic base may be selected from carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisoptvpyl amide and n-butyl lithium. Preferably the base used is N, N-diisopropylethylamine. The reaction may be carried out in the presence of a suitable solvent. The suitable solvents include but are not limited to ethers, chloro solvents, alcohols, nitriles, water and mixtures thereof. The reaction may be carried out at lower, ambient or elevated temperatures. The product thus obtained is optionally protected with a suitable N-protecting group known in the art, by standard techniques. The N-protecting groups may be selected from but are not limited to carbobenzyloxy chloride (CBZ-C1, benzyl chloroformate), tert-butyl carbonate (BOC), benzyl bromide, p-nitro benzyl bromide.
The above process further includes splitting off when necessary the N-protecting groups in the compounds obtained.
In an embodiment the compound of formula VII thus obtained can be converted to ticagrelor by the process disclosed herein above.
In one embodiment the present invention provides a process for the preparation of ticagrelor represented schematically in scheme 1


In a third aspect, the present invention relates to a process for preparing a compound of formula VII comprising:
a) coupling a compound of formula I or a salt thereof with a compound of formula II to obtain a compound of formula III,

b) optionally protecting the amino group and reacting the compound of formula III or the N-protected derivative with an alkyl halo ester to obtain a compound of formula IV,


wherein X is a leaving group such as halogen, mesylate or tosylate and R is H or a suitable N- protecting group and Ak refers to alkyl group.
c) reacting compound of formula IV with an amine of formula V or its N-protected derivative or a salt thereof to obtain a compound of formula VI; and

d) reduction of compound of formula VI and optionally protecting the compound of formula VI with a suitable N-protecting group to obtain a compound of formula VII.

wherein R is H or a suitable N protecting group

In step a) of the process above, the compound of formula I is coupled with the compound of formula II in the presence of an organic or inorganic base in a suitable solvent to obtain a compound of formula III. The reaction can also be carried out in the absence of base. The reaction may also be carried out under acidic conditions such as using hydrochloric acid in isopropyl alcohol (IPA.HCI), ethanolic HC1. The suitable solvents include but are not limited to ethers, chloro solvents, alcohols, esters, hydrocarbon, nitriles, amides, sulfonamides; water or mixtures thereof. The reaction may be carried out optionally in the presence of inorganic or organic base. The organic base include triethylamine, pyridine, dimethyl amino pyridine (DMAP), N-methyl morpholine, N, N-diisopropylethyl amine; the inorganic base include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisopropyl amide and n-butyl lithium,
In step b) of the process above, the compound of formula III is optionally protected with a suitable N-protecting group known in the art, by standard techniques. The N-protecteing group may be selected from but are not limited to carbobenzyloxy chloride (CBZ-C1, benzyl chloroformate), tert-butyl carbonate, benzyl bromide or p-nitrobenzyl bromide. The compound of formula III or the N-protected compound of formula III is reacted with an alkyl halo ester selected from the group consisting of ethyl chloro acetate or ethyl bromo acetate. The term "alkyl" refers to C1-6 alkyl which includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl. The term halo refers to chlorine, bromine or iodine. Preferably compound of formula III is reacted with ethyl bromo acetate to obtain compound of formula IV.
In step c) of the process above, the compound of formula IV is reacted with a compound of formula V or its N-protected derivative or a salt thereof to obtain a compound of formula VI. The reaction may be carried out optionally in the presence of an inorganic or organic base. Organic base include such as triethylamine, pyridine, dimethylamino pyridine (DMAP), N-methylmorpholine, N, N-diisopropylethyl amine; inorganic base include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisopropyl amide and n-butyl lithium. Preferably the base used is N, N-diisopropylethyl amine. The reaction may also be carried out in the absence of a base. The reaction may be carried out in presence of a suitable solvent. The suitable solvents include but are not limited to ethers, chloro solvents, alcohols, sulfonamide; water or mixtures thereof. The reaction may also be carried out in acidic condition

such as using hydrochloric acid in isopropyl alcohol (IPA.HC.I), ethanolic HC1. The reaction may be carried out at lower, ambient or elevated temperatures.
In step d) of the process above, the ester groups may be reduced by hydride reagents like Diisobutylaluminium hydride (DEAL), isobutyl aluminium hydride (i-Bu2AlH), lithium aluminium hydride( LiAIH4), lithium borohydride (LiBH4). The product thus obtained is optionally protected with a suitable N-protecting group known in the art, by standard techniques. The N-protecting groups may be selected from but are not limited to carbobenzyloxy chloride (CBZ-CI, benzyl chloroformate), tert-butyl carbonate (BOC), benzylbromide or p-nitrobenzylbromide to obtain compound of formula VII.
The above process further includes splitting off when necessary the N-protecting groups in the compounds obtained.
in an embodiment the compound of formula VII thus obtained cao be converted to ticagrelor by the process disclosed herein above.
In one embodiment the present invention provides compound of formula IV and VI.

In one embodiment, the present invention provides a process for preparing ticagrelor represented schematically in scheme 2


In a fourth aspect, present invention provides process for preparing compound of formula XI comprising:
a) converting compound of formula in or the N-protected compound of formula III to a compound of formula XI,


In step a) of the process above, the compound of formula III is optionally protected with a suitable N-protecting group and reacted with an oxirane ring or a halo ethanol or monotosylated & mesylated ethyleneglycol. The halogen may be selected from chlorine, bromine or iodine. Preferably the compound of formula III or its N-protected derivative is reacted with bromoethanol. The reaction is carried out in a suitable solvent selected from chloro solvents alcohols solvents, hydrocarbons, esters, amides, nitrile, sulfoxide; water or mixtures thereof. Preferably the reaction is carried out in dimethyl formamide (DMF). The reaction is carried out in the presence of an organic or inorganic base. The organic base include triethylamine, N-methylmorpholine, N, N-diisopropylethyl amine pyridine, dimethyl amino pyridine (DMAP).; the inorganic base include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, n-butyl lithium, lithium diisopropyl amide (LDA).
The process further includes splitting off when necessary the N-protecting group in the compounds obtained.
In an embodiment the compound of formula XI thus obtained can be converted to ticagrelor by the process disclosed herein above.
In one embodiment, the present invention provides a process for preparing ticagrelor as schematically shown in scheme 3


In a fifth aspect, the present invention provides a process for the preparation of compound of formula VI comprising:
a) coupling compound of formula V or its N-protected derivative or a salt thereof with compound of formula II to obtain a compound of formula XII,

b) optionally protecting the compound of formula XII with a suitable N-protecting group known in the art, by standard techniques and coupling compound of formula XII or the N-protected

derivative with compound of formula I or its salt thereof to obtain compound of formula XIII, wherein R = H or a suitable N-protecting group; and

c) reacting compound of formula XIII with an alkyl halo ester to obtain a compound of formula VI.

In step a) of the process above, the compound of formula V or its N-protected derivative or a salt thereof is reacted with a compound of formula II to obtain a compound of formula XII. The reaction may be carried out optionally in the presence of an inorganic or organic base. The organic base include triethyiamine, pyridine, dimethyl amino pyridine (DMAP), N-methylmorpholine, N, N-dnsopropylethyl amine ; the inorganic base include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisopropyl amide, n-butyl lithium. Preferably the base used is N, N-diisopropylethyl amine. The reaction may also be carried out in acidic condition such as using hydrochloric acid in isopropyl alcohol (IPA.HC1), ethanolic HC1.

The reaction may be carried out in presence of a suitable solvent. The suitable solvents include but are not limited to ethers, chloro solvents, alcohols, amides, nitriles sulfoxides; water or mixtures of thereof. Preferably the solvent is dimethyl formamide (DMF). The reaction may be carried out at lower, ambient or elevated temperatures.
In step b) of the process above the compound of formula XII may be optionally treated with a suitable N-protecting group known in the art, by standard techniques. The N-protecting groups may be selected from but are not limited to carbobenzyloxy chloride (CBZ-CL, benzyl chloroformate), di-tert-butyl caronate (BOC), benzyl bromide, p-nitrobenzylbromide. The reaction may be carried out in a suitable solvent selected from but not limited to ethers, chloro solvents, alcohols, esters, hydrocarbon, nitriles, amides sulfoxide; water or mixtures thereof. Preferably the solvent is dichloromethane.
The compound of formula XII or the N-protected compound of formula XII is reacted with a compound of formula I or its salt thereof to obtain compound of formula XIII. The reaction may be carried out in the presence of a suitable organic or inorganic base in a suitable solvent. The organic base include triethylamine, pyridine, dimethyl amino pyridine (DMAP), N-methylmorpholine, N, N-diisopropylethyl amine; the inorganic base include carbonates, bicarbonates, hydroxides, hydrides, such as sodium hydroxide, sodium carbonate, potassium bicarbonate, lithium diisoproyl amide, n-butyl lithium. The reaction can also be carried out in the absence of base. The suitable solvents may be selected from but not limited to ethers, chloro solvents, alcohols, esters, hydrocarbon, nitriles, amides, sulfoxides, water or mixtures thereof. Preferably the solvent is dichloromethane (DCM).The reaction may also be carried out in acidic condition such as using hydrochloric acid in isopropyl alcohol (IPA.HC1), ethanolic HC1.
In step c) of the process above, the compound of formula XIII is optionally protected with a suitable N-protecting group known in the art, by standard techniques. The N-protecting groups may be selected from but are not limited to carbobenzyloxy chloride (CBZ-C1, benzyl chloroformate), tert-butyl carbonate (BOC), benzyl bromide, p-nitro benzyl bromide. The compound of formula XIII or the N-protected compound is reacted with an alkyl halo ester. The term "alkyl" refers to C1-6 alkyl which includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl. The term halo refers to chlorine, bromine or iodine. The alkyl halo ester includes but not limited to ethyl chloro acetate, ethyl bromo acetate. Preferably compound of formula XIII is reacted with ethyl bromo acetate to obtain compound of formula VI.

The above process further includes splitting off when necessary the N-protecting groups in the compounds obtained.
In an embodiment the compound of formula VI thus obtained can be converted to compound of formula VII and finally to ticagrelor as described herein above.
In one embodiment, the present invention provides compounds of formula XII or its N-protected derivative, compound of formula XIII or its N-protected derivative.

In one embodiment, the present invention provides a process for the preparation of ticagrelor represented schematically in scheme 4


In one embodiment, the present invention provides a process for the preparation of ticagrelor represented schematically in scheme 5.


In the above scheme 5, R may be selected from the group consisting of but are not limited to carbobenzyloxy (CBZ), tert-butyloxy (BOC), benzyl, p-nitrobenzyl. Preferablly, R may be benzyl.

In one embodiment, the present invention provides a process for the preparation of ticagrelor, the process comprising: (a) converting compound of formula V to its N-protected derivative,

(b) reacting the N-protected compound of formula V with compound of formula II to give compound of formula Xlla,


(d) reducing compound of formula XIHa to give the compound of formula XIV,
(c) reacting the compound of formula XIIa with compound of formula I to give compound of formula XIIIa,



(f) converting compound of formula XV to compound of formula XVI,

(e) cyclizing compound of formula XIV to give compound of formula XV
(g) deprotecting compound of formula XVI to give ticagrelor.
In (g) of the process for the preparation of ticagrelor, the compound of formula XVI is deprotected to give ticagrelor, the process comprising: (i) deprotecting compound of formula XVI to give compound of formula XVII,


(ii) deprotecting compound of formula XVII to give ticagrelor.

In (g) of the process for the preparation of ticagrelor, the compound of formula XVI is deprotected to give ticagrelor, the process comprising: (i) deprotecting compound of formula XVI to give compound of formula DC,

(ii) deprotecting compound of formula IX to give ticagrelor.


The present invention provides the processes for the preparation of ticagrelor by any of the
schemes herein disclosed may be further crystallized to obtain crystalline form or an amorphous
form.
The examples that follow are provided to enable one skilled in the art to practice the invention
and are merely illustrative of the invention. The examples should not be read as limiting the scope
of the invention as defined in the features and advantages.

EXAMPLES
EXAMPLE 1 Preparation of trans-(lR,2S)-N-benzyl-2-(3,4-dinuorophenyl) cyclopropanamine
A mixture of trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride (l.Og) and triethylamine (1 .0g) in dimethylformamide (l0mL) was stirred for about 15min to about 20min at about 25°C to about 30°C and benzyl bromide (0.9lg) was added to it. The reaction mixture was stirred at about 25°C to about 30°C. After completion of reaction, water (20mL) and dichloromethane (20mL) was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with 20% sodium chloride solution (20mL), concentrated and degassed to give the title compound.
EXAMPLE 2 Preparation of trans-(1R,2S)HV-benzyl-2-P(3,4-difluorophenyl) cyclopropanamine
A mixture of trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropylamine hydrochloride (l.Og), 3N sodium hydroxide solution (lOmL) and methanol (lOmL) was stirred for about lOmin. Benzaldehyde (0.77g) and sodium borohydride (0.92g) was added to the reaction mixture in about lOmin to about 15min maintaining the temperature at about 25°C to about 30°C. After completion of reaction, water (20mL) and dichloromethane (20mL) was added to the reaction mixture and the pH was adjusted to about 6 to about 7 by adding 1:1 hydrochloric acid solution. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound.
EXAMPLE 3 Preparation of N-benzyl-6-chloro-N-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]-5-nitro-2-(propyIsulfanyl)pyrimidin-4-amine
A mixture of trans-(1R-2S)-N-benzyl-2-(3,4-difluorophenyl) cyclopropanamine (l.Og), 4,6-dichIoro-5-nitro-2-(propylsulfanyl)pyrimidine (l.Og) and tetrahydrofuran (lOmL) was cooled to about -5°C. Sodium bis(trimethylsilyl)amide (2mL) was slowly added to the reaction mixture in about lOmin to about 15min maintaining the temperature below about 5°C. After completion of the reaction, dichloromethane (20mL) and water (20mL) was added to the reaction mixture and the pH was adjusted to about 6.5 to about 7 by adding dilute hydrochloric acid solution. The two layers were separated and the organic layer was washed with water, concentrated under reduced pressure and degassed to give the title compound.

EXAMPLE 4 Preparation of (3aR,45,6R,6aS)-6-{[6-{benzyl[(lR,2S)-2-(3,4-difluorophenyl)
cyclopropyl]amino}-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]amino}-2,2-
dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol
A mixture of N-benzyI-6-chloro-N-[(lR,2S)-2-(3,4-difluorophenyI)cyclopropyl]-5-nitro-2-(propylsulfanyl)pyrimidin-4-amine (1,0g), (3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol (0.55g), diisopropylethylamine (I.0mL) and dimethylformamide (l0mL) was stirred at about 25°C to about 30°C for about 3h to about 4h. After completion of the reaction, water and dichloromethane was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water, concentrated and degassed to give the title compound.
EXAMPLE 5 Preparation of (3aR,4S,6R,6aS)-6-[7-{benzyl[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol
To a mixture of (3aR,4S,6R,6aS)-6-{[6-{benzyl[(lR,2S)-2-(3,4-difiuorophenyl) cyclopropyl]amino}-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol (l.Og) and methanol (lOmL) cooled to about 0°C, Zn dust (1 .0g) was added. Ammonium chloride (0.8g dissolved in 5mL water) was slowly added in about 15min maintaining the temperature below about 5°C to the reaction mixture. The reaction mixture was stirred for about 60min. Water (20mL) and toluene was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water, cooled to about 10°C and a mixture acetic acid (2mL) and water (lOmL) was added to it. To the reaction mixture, sodium nitrite (0,45g) dissolved in water (5mL) was slowly added in about l0min to about 15min maintaining the temperature below about 20°C. After completion of reaction, water (lOmL) was added and the pH was adjusted to about 7 to about 8 by adding sodium carbonate. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound.
EXAMPLE 6 Preparation of N-benzyl-3-{(3a5,4R,6S,6aR)-6-[2-(benzyloxy)ethoxy]-2,2-
difluethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-N-[(1R,2S)-2-(3,4-
difluorophenyl)cyclopropyl]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine
To a mixture of (3aR,4S,6R,6aS)-6-[7-{benzyl[(lR,2S)-2-(3,4-difluorophenyl) amino}-5-(propylsulfanyl)-3H-[l,2,3]triazoIo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-ol (l.Og), potassium carbonate (0.5g) and dimethylformamide (IOmL) at about 25°C to about 30°C, was added [(2-bromoethoxy)methyl]benzene (0.53g) and the

reaction mixture was stirred at about 30°C to about 40°C for about 6h to about 8h. After completion of reaction, dichloromethane (lOmL) was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water, concentrated and degassed to give the title compound.
EXAMPLE 7 Preparation of (1S,2S,3R,5S)-3-(7-{[(lR,2S)-2-(3,4-dinuorophenyl)
cycIopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-
hydroxyethoxy)cyclopentane-l,2-diol
To a mixture of N-benzyl-3-{(3aS,4R,6S,6aR)-6-[2-(benzyIoxy)ethoxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yl}-N-[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]-5-(propylsulfanyi)-3H-[l,2,3]triazoIo[4,5-d]pyrimidin-7-amine (l.0g), acetic acid (l.OmL) and ethanol (20mL) was added 10% palladium on carbon (0.2g). The reaction mixture was hydrogenated under about 5kg hydrogen pressure at about 60°C for about 5h to about 6h. The reaction mixture was filtered and the filtrate was concentrated and degassed to give a residue. The residue was dissolved in methanol (lOmL). The mixture was cooled to about 10°C and concentrated hydrochloric acid was added to it. The mixture was stirred for about 1 h to about 2h and concentrated under vacuum to give a residue. Water was added to the residue and the pH was adjusted to about 7 to about 8 by adding sodium carbonate. Dichloromethane was added to the mixture. The mixture was stirred and the two layers were separated. The organic layer was washed with water, concentrated and degassed to give ticagrelor which was further purified by column chromatography using dichloromethane and acetone.
EXAMPLE 8 Preparation of (lS,2S,3R,5S)-3-[7-{benzyl[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylsulfanyI)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-[2-(benzy loxy)ethoxy ] cyclopentane-1,2-d iol
To a mixture of N-benzyl-3-{(3aS,4R,6S',6aR)-6-[2-(benzyloxy)ethoxy]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l)3]dioxo]-4-yl}-N-[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-amine (l.Og) and methanol (lOmL) cooled to about 10°C, was added concentrated hydrochloric acid (lOmL) and the temperature of the reaction mixture was maintained below about 20°C. The reaction mixture was stirred for about lh to about 2h. The reaction mixture was concentrated under vacuum and water and dichloromethane was added to it and the pH was adjusted to about 7 to about 8 by adding sodium carbonate. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound.

EXAMPLE 9 Preparation of (lS,2S,5S)-3-(7-{[(lR,2S)-2-(3,4-difluorophenyl)
cyclopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-
hydroxyethoxy)cyclopentane-l,2-diol
To a mixture of (1S,2S,3R,5S)-3-[7-{benzyI[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyI)-3H-[I)2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-[2-(ben2yloxy)ethoxy] cyclopentane-l,2-diol (l.Og), acetic acid (l.OmL) and ethanol (20mL) was added 10% palladium on carbon (0.2g). The reaction mixture was hydrogenated under about 5kg hydrogen pressure at about 60°C. The reaction mixture was filtered and the filtrate was concentrated and degassed to give ticagrelor which was further purified by column chromatography using dichloromethane and acetone as eluent.

WE CLAIM
1. A process for preparing ticagrelor, compound of formula A, comprising:

a) reducing a compound of formula VII to obtain a compound of formula VIII,

wherein R is H or a suitable N-protecting group,
b) cyclizing compound of formula VIII to obtain a compound of formula IX; and

c) hydrolyzing the compound of formula IX to obtain Ticagrelor.

2. Use of intermediate compounds VII or VIII in the preparation of ticagrelor or salts thereof.