DESC:FIELD OF THE INVENTION
The field of the invention relates to an improved process for preparation of ticagrelor and intermediates thereof. In particular, the invention relates to an improved process for preparation of condensed-nitro compound of Formula (V) and protected-triazole compound of Formula (II). Further the invention relates to a novel dimeric impurity and a process for its preparation.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Ticagrelor is a P2Y12 platelet inhibitor of compound of Formula (I) indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. Ticagrelor is marketed as BRILINTA® in USA and as BRILIQUE® in the Europe by AstraZeneca as oral tablets of 90 mg.

(I)
U.S. 7,250,419 B2 discloses ticagrelor specifically and processes for its preparation.
U.S. 6,251,910 B1, 6,525,060 B1 and 7,250,419 B2 and U.S. 2012/165348 A1, all disclose process for preparation of ticagrelor and analogous compounds and intermediates.
U.S. 2012/101274 A1 (the US ‘274 A1) discloses a process for preparation of ticagrelor of Formula (I) comprising reacting an oxalate or dibenzoyl-L-tartrate salt of cyclopentylamine compound of Formula (VII) with 4,6-dichloro-2-propylthio-pyrimidine-5-amine to get condensed-amino compound of Formula (IV) which is converted to triazole compound of Formula (III) by treatment with NaNO2 and acetic acid in toluene. The said process of further comprises preparation of ticagrelor of Formula (I) by treating protected-triazole compound of Formula (II) with concentrated aq. HCl in methanol.
U.S. 2012/0301458 A1 (the US ‘458 A1) discloses a process for preparation of ticagrelor of Formula (I) comprising reacting cyclopentylamine compound of Formula (II) as free base with dichloropyrimidine compound of Formula (VI) to get condensed-nitro compound of Formula (V), which is further converted to condensed-amino compound of Formula (IV) by treatment with iron powder and acetic acid in water/ethanol which is converted to triazole compound of Formula (III) by treatment with NaNO2 and acetic acid in toluene. The said process further comprises preparation of ticagrelor of Formula (I) by treating protected-triazole compound of Formula (II) with dilute aq. HCl in methanol.
WO 2012/085665 A2 discloses a process for preparation of ticagrelor of Formula (I) via a carbamate intermediate compound of Formula (A).

(A)
The reference article Bioorg. Med. Chem. Lett. 2007, 17(21), 6013-6018 discloses a process for preparation of ticagrelor of Formula (I) comprising reacting cyclopentyl amino compound of Formula (VII) as free base with 4,6-dichloro-2-propylthio-pyrimidine-5-amine to prepare condensed-amino compound of Formula (IV) and further reaction with isoamylnitrite to prepare triazole compound of Formula (III). The said process further comprises preparation of ticagrelor of Formula (I) by treating protected-triazole compound of Formula (II) with trifluoroacetic acid in water.
The reference article Bioorg. Med. Chem. Lett. 2012, 22(11), 3598-3602 also discloses a process for preparation of ticagrelor of Formula (I) comprising reacting cyclopentylamine compound of Formula (VII) as free base with 4,6-dichloro-2-propylthio-pyrimidine-5-amine to prepare condensed-amino compound of Formula (IV) . The said process further comprises preparation of ticagrelor of Formula (I) by treating protected compound of Formula (II) with concentrated HCl acid in methanol. The reference article also discloses process for preparation of starting materials and difluoro compound of Formula (VIII) for preparation of ticagrelor of Formula I.
WO 2011/101740 A1 and WO 2012/139455 A1 disclose processes for preparation of dichloropyrimidine compound of Formula (VI) and cyclopentylamine compound of Formula (VII) respectively.
Though there are processes disclosed for the preparation of ticagrelor of Formula (I), there is still a need in the art for process for preparation of intermediates with better yield and lower levels of impurities thereby obtaining ticagrelor with higher overall yield and purity.
The inventors of the present invention have found that during the reaction of a cyclopentylamine compound of Formula (VII) and dichloropyridine compound of Formula (VI) to obtain condensed-nitro compound of Formula (V), a dimer compound of Formula (A) is generated as an impurity and the levels of which are required to be controlled. There is provided an improved process for the preparation condensed-nitro compound of Formula (V), a crystalline protected-triazole compound of Formula (II) and thereby process for preparation of ticagrelor of Formula (I).
SUMMARY OF THE INVENTION
In one general aspect, there is provided a process for the preparation of condensed-nitro compound of Formula (V) substantially free from dimer impurity (A),

(V) (A)
the process comprising;
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC; and

(b) obtaining the condensed-nitro compound of Formula (V) substantially free from dimer impurity (A) by removal of solvent.
In another general aspect, there is provided a process for the preparation of crystalline protected-triazole compound of Formula (II),

(II)
the process comprising:
(a) reducing a condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(b) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula (III),
(c) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base to obtain protected-triazole compound (II) in a solution in one or more organic solvents,
(d) optionally, removing the organic solvent completely or partially from the solution of step c) to obtain a residue; and
(e) treating the solution of step c) or the residue of step d) with an anti-solvent to obtain the crystalline protected-triazole compound of Formula (II).
In another general aspect, there is provided a process for the preparation of ticagrelor of Formula (I),

(I)
the process comprising:
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC to a obtain condensed-nitro compound of Formula (V),
(b) reducing the condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(c) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula (III),
(d) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base to obtain a protected-triazole compound (II); and
(e) deprotecting the protected-triazole compound of Formula (II) with a deprotecting agent to obtain the ticagrelor of Formula (I).
In another general aspect, there is provided a compound of Formula (A) which is an impurity for ticagrelor.

(A)
In another general aspect, there is provided a process for the preparation of dimer impurity of Formula (A), the process comprising reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine Compound VII to obtain the dimer impurity of Formula (A).
In another general aspect, there is provided a compound of Formula (B) which is an impurity for ticagrelor.

(B)
In another general aspect, there is provided a process for the preparation of amino impurity of Formula (B), the process comprising:
(a) reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine compound of Formula (VII) or acid addition salt thereof to obtain a compound of Formula (A); and
(b) reducing the compound of Formula (A) with a reducing agent to obtain the amino impurity of Formula (B).
In another general aspect, there is provided a method of analysis of ticagrelor for detecting the presence of dimer impurity of Formula (A) and amino impurity of Formula (B).
BRIEF DESCRIPTION OF THE FIGURES AND DRAWINGS
FIG.1: Discloses the 1H-NMR spectrum of dimer compound of Formula (A).
FIG.2: Discloses the 13C-NMR spectrum of dimer compound of Formula (A).
FIG.3: Discloses the 1H-NMR spectrum of protected-triazole compound of Formula (II).
FIG.4: Discloses the 13C-NMR spectrum of protected-triazole compound of Formula (II).
FIG.5: Discloses the FTIR spectrum protected-triazole compound of Formula (II).
FIG.6: Discloses the Differential Scanning calorimetry (DSC) of protected-triazole compound of Formula (II).
DETAILED DESCRIPTION OF THE INVENTION
The “cyclopentylamine compound” herein means the compound 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol.
The “dichloropyrimidine compound” herein means the compound 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.
The “condensed-nitro compound” herein means the compound 2-(((3aR,4S,6R,6aS)-6-((6-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol.
The “condensed-amino compound” herein means the compound 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol.
The “triazole compound” herein means the compound 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-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol.
The “difluoro compound” herein means the compound (1R,2S)-2-(3,4-difluorophenyl) cyclopropanamine.
The “protected triazole compound” herein means the compound 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-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol.
All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “general”, “substantially” are to be construed as modifying a term or value such that it is not an absolute.
Optionally, the solution, prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
In general, the removal of solvent may be done by technique, which includes, for example, filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
In one general aspect, there is provided a process for the preparation of condensed-nitro compound of Formula (V) substantially free from dimer impurity (A),

(V) (A)
the process comprising;
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC; and

(b) obtaining the condensed-nitro compound of Formula (V) substantially free from dimer impurity (A) by removal of solvent.
In general, the process parameters include reacting tartrate salt of a cyclopentylamine compound of Formula (VII) with a base in water to obtain a cyclopentylamine free base solution in water which is added to a solution of a dichloropyrimidine compound of Formula (VI) in an organic solvent at less than 20°C, preferably at less than 10°C or more preferably at less than 5°C.
In general, the organic solvent comprises one or more of water, methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, diethylether, methyl-t-butyl ether, di-iso-propyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, butyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon Tetrachloride, dioxane, acetonitrile, dimethylsulfoxide, pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene and petroleum ether. In particular THF, acetone, IPA or ethyl acetate may be used.
When the reaction was performed at above 20°C, particularly at 25-30°C, the dimer impurity (A) was the only major product obtained and measured by HPLC as more than 80%; when the same is repeated at below 20°C, level of the dimer impurity (A) was found below 10%; and further at 0-5°C the level of dimer impurity (A) was found 6-7% when measured by HPLC in the condensed-nitro compound of Formula (V).
The low level of the dimer impurity (A) in condensed-nitro compound of Formula (V) is obtained by treating the reaction mixture or the organic layer of it with an adsorbent, e.g. silica. The adsorbent treated organic layer may be used in further reaction, if required, or it may be distilled off to obtain condensed-nitro compound of Formula (V) substantially free from dimer impurity (A). The process as described in the US ‘458 A1 provides the condensed-nitro compound of Formula (V) in 45% yield and is silent about the dimer impurity (A) whereas the process of the present invention provides condensed-nitro compound of Formula (V) in 80-86% yield with 6-7% dimer impurity (A).
In another general aspect, there is provided a process for the preparation of crystalline protected-triazole compound of Formula (II),

(II)
the process comprising:
(a) reducing a condensed-nitro compound of Formula (V) with a reducing agent to obtain condensed-amino compound of Formula (IV),
(b) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula III,
(c) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base obtain a protected-triazole compound (II) in a solution in one or more organic solvents,
(d) optionally, removing the organic solvent completely or partially from the solution of step c) to obtain a residue; and
(e) treating the solution of step c) or the residue of step d) with an anti-solvent to obtain the crystalline protected-triazole compound of Formula (II).
In general, the reducing agent of step (a) comprises one or more of H2(g) Pd/C, Raney Ni, Fe in acidic media, sodium hydrosulfite, Tin(II) chloride and Zinc. In particular Fe in acetic acid may be used.
In general, the process parameters include reducing a condensed-nitro compound of Formula (V) with Fe/Acetic acid in an organic solvent to obtain a condensed-amino compound of Formula (IV). In general, the organic solvent comprises one or more of methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol, dioxane, acetonitrile and dimethylsulfoxide. In particular methanol may be used.
In general, the base of step (c) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, cesium carbonate, triethylamine, diisopropyl ethyl amine, diethylamine, pyridine and piperidine. The mixture of two bases may be considered as the scope of the invention. In particular potassium carbonate may be used.
In general, the process parameters include reacting a triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in presence of K2CO3 in an organic solvent to obtain a protected-triazole compound (II) in a solution in one or more organic solvents. In general, the organic solvent comprises water, methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol, pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene, petroleum ether, chloroform, diethyl ether, ethyl acetate, butyl acetate, methylenedichloride, ethylene dichloride, carbontetrachloride, dioxane, acetonitrile and dimethylsulfoxide. In particular mixture of toluene and water may be used.
In general, the anti-solvent of step (e) comprises one or more of pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene, petroleum ether, chloroform, diethyl ether, ethyl acetate, butyl acetate, methylenedichloride, ethylene dichloride and carbontetrachloride. In particular, cyclohexane may be used.
In another general aspect, there is provided a process for the preparation of crystalline protected-triazole compound of Formula (II),

(II)
the process comprising:
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC to obtain a condensed-nitro compound of Formula (V),
(b) reducing the condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(c) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula III,
(d) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in presence of a base obtain a protected-triazole compound (II) in a solution in one or more organic solvents,
(e) optionally, removing the organic solvent completely or partially from the solution of step d) to obtain a residue; and
(f) treating the solution of step d) or the residue of step e) with an anti-solvent to obtain the crystalline protected-triazole compound of Formula (II).
In another general aspect, there is provided a crystalline protected-triazole compound of Formula (II). The crystalline protected-triazole compound of Formula (II) may be characterized by differential scanning calorimetry by melting onset temperature 86±5°C and peak at 92±5°C.
In another general aspect, there is provided a process for the preparation of ticagrelor of Formula (I),

(I)
the process comprising: deprotecting a protected-triazole compound of Formula (II) with a deprotecting agent comprising one or more of a sulfonic acid or an acidic resin or a lewis acid to obtain the ticagrelor of Formula (I).
When the acid reagents as described in prior art, i.e., HCl, HBr, aq. acetic acid; are used for the deprotection of 1,2-diol compound, i.e. the compound of Formula II, strict control of the reaction parameters like pH of the medium and reaction time becomes extremely crucial for high region- and/or stereoselectivity. Any negligence in these reaction parameters leads to over hydrolysis and/or formation of diastereoisomers up to 5-7% which requires subsequent multiple crystallization/ purification or chiral chromatography which diminished yield and is, at the same time, not viable for industrial manufacturing.
This problem is solved by the process of present invention using a sulfonic acid or an acidic resin or a lewis acid.
In general, there is provided a process for the preparation of ticagrelor of Formula (I), the process comprising reacting a protected-triazole compound of Formula (II) and an acidic resin to obtain the ticagrelor of Formula (I).
In general, there is provided a process for the preparation of ticagrelor of Formula (I), the process comprising reacting a protected-triazole compound of Formula (II) and a sulfonic acid to obtain the ticagrelor of Formula (I).
In general, there is provided a process for the preparation of ticagrelor of Formula (I), the process comprising reacting a protected-triazole compound of Formula (II) and a lewis acid to obtain the ticagrelor of Formula (I).
In general, the sulfonic acid comprises methane sulfonic acid, p-toluene sulfonic acid or benzene sulfonic acid. In particular, p-toluene sulfonic acid may be used.
In general, the lewis acid comprises ZrCl4, InCl3, CdSO4, CoCl2 or hydrated forms thereof. In particular, ZrCl4, CdSO4.8H2O, CoCl2.2H2O and InCl3 may be used.
In general, the acidic resin comprises Amberlite or Amberlyst Resins. In particular, Amberlite IR-120 H may be used.
In general, the process parameters include reacting a protected triazole compound with p-toluene sulfonic acid or Amberlite IR-120 or CoCl2.2H2O in an organic solvent followed by addition of water to obtain ticagrelor of Formula (I).
In general, the organic solvent comprises one or more of dioxane, acetonitrile, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, tetrahydrofuran, diethyl ether, water or any combination thereof. In particular mixture of methanol and water is used.
In another general aspect, there is provided a process for the preparation of ticagrelor of Formula (I),

(I)
the process comprising:
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC to obtain a condensed-nitro compound of Formula (V),
(b) reducing the condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(c) cyclizing a condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula III,
(d) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base to obtain protected-triazole compound (II); and
(e) deprotecting the protected-triazole compound of Formula (II) with a deprotecting agent to obtain ticagrelor of Formula (I).
In general, the solvent of step a), reducing agent of step b) and base of step d) may be selected as per embodiments described herein above for the process for preparation of condensed-nitro compound of Formula (V) substantially free from dimer impurity (A) and crystalline protected-triazole compound of Formula (II).
In general, the deprotecting agent comprises one or more of HCl, H2SO4, acetic acid, trifluoroacetic acid, ZrCl4, InCl3, CdSO4, CoCl2, t-butyl hydroperoxide, methane sulfonic acid, p-toluene sulfonic acid, tetrakis(3,5-trifluoro methylphenyl)borate (NaBArF4)and an acidic resin (Amberlite).
In particular a sulphonic acid, or an acidic resin or a lewis acid as defined herein above may be used.
In general, the ticagrelor of Formula (I), the condensed-nitro compound of Formula (V) or the protected-triazole compound of Formula (II) may further be converted to a salt or polymorphic form thereof.
In general, there is provided the synthesis of condensed-nitro compound of Formula (V) substantially free from dimer impurity (A), crystalline protected-triazole compound of Formula (II) and ticagrelor of Formula (I) substantially as shown in Scheme-1.

Scheme-1

In another general aspect, there is provided a compound of Formula (A) which is an impurity for ticagrelor.

(A)

In another general aspect, there is provided a process for the preparation of dimer impurity of Formula (A), the process comprising reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine compound of Formula (VII) to obtain the dimer impurity of Formula (A).
In general, the process parameters include reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine compound of Formula (VII) in THF-water mixture.
In another general aspect, there is provided a compound of Formula (B) which is an impurity for ticagrelor.

(B)
In another general aspect, there is provided a process for the preparation of amino impurity of Formula (B), the process comprising:
(a) reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine compound of Formula (VII) or acid addition salt thereof to obtain a compound of Formula (A); and
(b) reducing the compound of Formula (A) with a reducing agent to obtain the amino impurity of Formula (B).
In general, the reducing agent of step (b) comprises one or more of H2(g) Pd/C, Raney Ni, Fe in acidic media, sodium hydrosulfite, Tin(II) chloride and Zinc. In particular Fe in acetic acid may be used.
In general, the process parameters include reducing the compound of Formula (A) with Fe/Acetic acid in methanol to obtain amino impurity of Formula (B).
In another general aspect, there is provided a method of analysis of ticagrelor for detecting the presence of dimer impurity of Formula (A) and amino impurity of Formula (B).
The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention.

EXAMPLES
Example-1:
Preparation of condensed-nitro compound of Formula (V)
Tartrate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)oxy)ethanol (VII) (20 g) and water (60 mL) were cooled to 0-5°C and a solution of sodium bicarbonate (15.6 g) in water (170 mL) was added and stirred at 0-5°C to prepare solution A. 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (VI) (36.5 g) and tetrahydrofuran (200 mL) were cooled to 0-5°C and solution A was added and stirred at 0-5°C. After completion of reaction the reaction mass was settled and the organic layer was separated. Silica (120 g) and ethyl acetate (20 mL) were added to the organic layer and the solvent was then distilled out completely at reduced pressure. Hexane (200 mL) and ethyl acetate (10 mL) were added to the residue stirred, filtered and washed with 5% ethyl acetate in hexane (4 X 100 mL). The filtrate was distilled off to get 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)-pyrimidine-4-ylamino)-2,2-dimethyl-tetrahdro-3aH-cyclopenta[d][1,3]dioxo-4-yloxy)ethanol (V). (Yield 80-86%, Purity: 87% to 90% by HPLC, Dimer Impurity A 6-7%)
Example-2:
Preparation of condensed-nitro compound of Formula (V)
Tartrate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)oxy)ethanol (VII) (20 g) and water (60 mL) were cooled to 0-5°C and a solution of sodium bicarbonate (15.6 g) in water (170 mL) was added and stirred at 0-5°C to prepare solution A. 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (VI) (36.5 g) and Acetone (200 mL) were cooled to 0-5°C and solution A was added and stirred at 0-5°C. After completion of reaction ethyl acetate (200 mL) was added to the reaction mass, stirred, settled and the organic layer was separated. Silica (120 g) was added to the organic layer and the solvent was then distilled out completely at reduced pressure. Hexane (200 mL) and ethyl acetate (10 mL) were added to the residue stirred, filtered and washed with 5% ethyl acetate in hexane (4 X 100 mL). The filtrate was distilled off to get 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)-pyrimidine-4-ylamino)-2,2-dimethyl-tetrahdro-3aH-cyclopenta[d][1,3]dioxo-4-yloxy)ethanol (V). (Purity: 85% by HPLC)

Example-3:
Preparation of condensed-nitro compound of Formula (V)
Tartrate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)oxy)ethanol (VII) (20 g) and water (60 mL) were cooled to 0-5°C and a solution of sodium bicarbonate (15.6 g) in water (170 mL) was added and stirred at 0-5°C to prepare solution A. 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (VI) (36.5 g) and Ethyl acetate (200 mL) were cooled to 0-5°C and solution A was added and stirred at 0-5°C. After completion of reaction the reaction mass was settled and the organic layer was separated. Silica (120 g) was added to the organic layer and the solvent was then distilled out completely at reduced pressure. Hexane (200 mL) and ethyl acetate (10 mL) were added to the residue stirred, filtered and washed with 5% ethyl acetate in hexane (4 X 100 mL). The filtrate was distilled off to get 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)-pyrimidine-4-ylamino)-2,2-dimethyl-tetrahdro-3aH-cyclopenta[d][1,3] dioxo-4-yloxy)ethanol (V). (Purity: 93% by HPLC)

Example-4:
Preparation of condensed-nitro compound of Formula (V)
Tartrate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)oxy)ethanol (VII) (20 g) and water (60 mL) were cooled to 0-5°C and a solution of sodium bicarbonate (15.6 g) in water (170 mL) was added and stirred at 0-5°C to prepare solution A. 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (VI) (36.5 g) and isopropanol (200 mL) were cooled to 0-5°C and solution A was added and stirred at 0-5°C. After completion of reaction the reaction mass was extracted with ethyl acetate (200 mL + 100 mL). Silica (120 g) was added to the combined ethyl acetate layer and the solvent was then distilled out completely at reduced pressure. Hexane (200 mL) and ethyl acetate (10 mL) were added to the residue stirred, filtered and washed with 5% ethyl acetate in hexane (4 X 100 mL). The filtrate was distilled off to get 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)-pyrimidine-4-ylamino)-2,2-dimethyl-tetrahdro-3aH-cyclopenta[d][1,3]dioxo-4-yloxy)ethan-ol (V). (Purity: 85% by HPLC)

Example-5:
Preparation of condensed-amino compound of Formula (IV)
2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidine-4-ylamino)-2,2-dimeth-yl-tetrahdro-3aH-cyclopenta[d][1,3]dioxo-4-yloxy)ethanol (V) (20 g), methanol (200 mL), acetic acid (20 mL) and iron powder (12.5 g) were stirred at 20-25°C. After completion of reaction toluene (200 mL) and water (100 mL) were added to the reaction mixture, stirred and layers were separated. The aqueous layer was extracted with toluene (3 X 60 mL). The combined toluene layer was washed with saturated sodium chloride solution and after giving carbon treatment the solvent was removed by distillation at reduced pressure. n-Butyl acetate was added to the residue and stirred at 60-65°C, n-heptane (198 mL) was added slowly at 60-65°C, stirred and cooled to 0-5°C. The solid was filtered, washed with mixture of n-butyl acetate and n-heptane and dried to get 2-((3aR,4S,6R,6aS)-6-(5-Amino-6-chkoro-2-(propylthio)pyrimidine-4-ylamino)-2,2-dimeth-yl-tetrahydro-3aH-cyclo-penta[d][1,3]dioxo -4-yloxy)ethanol (IV).

Example-6:
Preparation of triazole compound of Formula (III)
2-((3aR,4S,6R,6aS)-6-(5-Amino-6-chkoro-2-(propylthio)pyrimidine-4-ylamino)-2,2-dimeth-yl-tetrahydro-3aH-cyclopenta[d][1,3]dioxo-4-yloxy)ethanol (IV) (20 g), acetic acid (100 mL) and water (10 mL) were cooled to 0-5°C and solution of NaNO2 (3.3 g) in water (40 mL) was added slowly and stirred at 0-5°C. After the reaction completion, 40% K2CO3 solution (140 mL) was added slowly to the reaction mixture, stirred, settled and the layers were separated. The organic layer was washed with saturated sodium chloride solution, given charcoal treatment and distilled off at reduced pressure 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-3aH-cyclopen-ta[d][1,3]dioxol-4-yl)oxy)ethanol (III).

Example-7:
Preparation of crystalline protected-triazole compound of Formula II
2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopen-ta[d][1,3]dioxol-4-yl)oxy)ethanol (III) (20 g), (1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride (9.6 g), toluene (100 mL), water (60 mL) and K2CO3 (16 g) were stirred at 20-25°C till reaction complied. Toluene (100 mL) was added to the reaction mixture, stirred, settled and layers were separated. The organic layer was successively washed with aqueous acetic acid, water and saturated sodium chloride solution and then given carbon treatment. The organic layer was then distilled off at reduced pressure. Cyclohexane (120 mL) was added to the residue and stirred till maximum solid is obtained, filter and wash with cyclohexane to get 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propyl-thio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (II) as crystalline solid (TGA: onset - 86.37°C, peak – 92.75°C, Purity: >99% by HPLC).

Example-8:
Preparation of Ticagrelor
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-3aH-cyclopenta[d][1,3]di-oxol-4-yl)oxy)ethanol (II) (20 g), methanol (180 mL), water (20 mL) and p-toluene sulphonic acid (1.35 g) were stirred at 55-60°C. The reaction was cooled to 25-35°C after completion, water (60 ml) was added and the reaction mass was stirred at 25-35°C till maximum solid is obtained. The mass was cooled further to 0-5°C, filtered and washed with methanol-water mixture to get Ticagrelor. (Yield: 85-90%, Purity: >98% by HPLC).

Example-9:
Preparation of Ticagrelor
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-3aH-cyclopenta[d][1,3]di-oxol-4-yl)oxy)ethanol (II) (1 g), ethanol (10 mL), water (0.5 mL) and Amberlite IR-120H acidic resin (0.4 g) were stirred at 55-60°C. The reaction was cooled to 25-35°C after completion and filtered. Solvent was completely removed from the filtrate at reduced pressure to get a residue. N-Heptane (10 mL) was added to the residue and stirred till complete solidification. The mass was filtered and washed with n-heptane to get Ticagrelor (Yield: 75-80%, Purity: >98% by HPLC).

Example-10:
Preparation of Ticagrelor
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-3aH-cyclopenta[d][1,3]di-oxol-4-yl)oxy)ethanol (II) (1 g), acetonitrile (10 mL) and CoCl2.2H2O (0.1 g) were stirred at 55-60°C. The reaction was cooled to 25-35°C after completion and filtered. Solvent was completely removed from the filtrate at reduced pressure to get a residue. N-Heptane (10 mL) was added to the residue and stirred till complete solidification. The mass was filtered and washed with n-heptane to get Ticagrelor (Yield: 85-90%, Purity: >98% by HPLC).

Example-11:
Purification of Ticagrelor
Ticagrelor (16 g) and n-butyl acetate (96 mL) were stirred at 55-60°C and filtered to remove particulate matter. n-heptane (56 ml) was added slowly to the filtrate at 55-60°C and stirred. The mass was cooled to 25-35°C, stirred, filtered and washed with mixture of n-butyl acetate and n-heptane and dried to get Ticagrelor (Purity: >99.5% by HPLC).

Example-12:
Preparation of dimer impurity of Formula (A)
Tartrate salt of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d]-[1,3]dioxol-4-yl)oxy)ethanol (VII) (20 g) and water (60 mL) were cooled to 0-5°C and a solution of sodium bicarbonate (15.6 g) in water (170 mL) was added and stirred at 0-5°C to prepare solution A. 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (VI) (7.3 g) and tetrahydrofuran (200 mL) were cooled to 0-5°C and solution A was added and stirred at 0-5°C. After completion of reaction the reaction mass was settled and the organic layer was separated. The organic layer was distilled off to get the titled compound (Purity: 87% to 90% by HPLC).

Example-13:
Preparation of amino impurity of Formula (B)
Compound A (20 g), methanol (200 mL), acetic acid (20 mL) and iron powder (8.9 g) were stirred at 20-25°C. After completion of reaction toluene (200 mL) and water (100 mL) were added to the reaction mixture, stirred and layers were separated. The aqueous layer was extracted with toluene (3 X 50 mL). The combined toluene layer was washed with saturated sodium chloride solution and after giving carbon treatment the solvent was removed by distillation at reduced pressure. n-Butyl acetate was added to the residue and stirred at 60-65°C, n-heptane (198 mL) was added slowly at 60-65°C, stirred and cooled to 0-5°C. The solid was filtered, washed with mixture of n-butyl acetate and n-heptane and dried to get the title compound. (Purity 85% to 90% by HPLC).

,CLAIMS:We Claim:

1. A process for the preparation of ticagrelor of Formula (I), the process comprising:
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC to a obtain condensed-nitro compound of Formula (V),
(b) reducing the condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(c) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula (III),
(d) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base to obtain a protected-triazole compound (II); and
(e) deprotecting the protected-triazole compound of Formula (II) with a deprotecting agent to obtain the ticagrelor of Formula (I).
2. The process as claimed in claim 1, wherein the organic solvent comprises one or more of water, acetone, methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, t-butanol methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, diethylether, methyl-t-butyl ether, di-iso-propyl ether, N,N-dimethylformamide, N,N-dimethylacetamide , ethyl acetate, butyl acetate, dichloromethane , 1,2-dichloroethane, chloroform, carbon Tetrachloride, dioxane, acetonitrile, dimethylsulfoxide, , pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene and petroleum ether.
3. The process as claimed in claim 1, wherein the reducing agent comprises one or more of H2(g) Pd/C, Raney Ni, Fe in acidic media, sodium hydrosulfite, Tin(II) chloride and Zinc.
4. The process as claimed in claim 1, wherein the deprotecting agent comprises one or more of HCl, H2SO4, acetic acid, trifluoroacetic acid, ZrCl4, InCl3, CdSO4, CoCl2, t-butyl hydroperoxide, methane sulfonic acid, p-toluene sulfonic acid, tetrakis(3,5-trifluoromethylphenyl)borate (NaBArF4) and an acidic resin (Amberlite).
5. The process as claimed in claim 1, wherein the process further comprises purifying the ticagrelor compound of Formula (I).
6. A process for the preparation of ticagrelor of Formula (I) comprising: deprotecting a protected-triazole compound of Formula (II) with a deprotecting agent comprising one or more of a sulfonic acid or an acidic resin or a lewis acid to obtain the ticagrelor of Formula (I).
7. A process for the preparation of crystalline protected-triazole compound of Formula (II), the process comprising:
(a) reducing a condensed-nitro compound of Formula (V) with a reducing agent to obtain a condensed-amino compound of Formula (IV),
(b) cyclizing the condensed-amino compound of Formula (IV) in the presence of sodium nitrite and acetic acid at less than 10ºC to obtain a triazole compound of Formula (III),
(c) reacting the triazole compound of Formula (III) with a difluoro compound of Formula (VIII) or its acid addition salt in the presence of a base to obtain protected-triazole compound (II) in a solution in one or more organic solvents,
(d) optionally, removing the organic solvent completely or partially from the solution of step c) to obtain a residue; and
(e) treating the solution of step c) or the residue of step d) with an anti-solvent to obtain the crystalline protected-triazole compound of Formula (II).
8. The process as claimed in claim 7, wherein the organic solvent comprises one or more of pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene, petroleum ether, chloroform, diethyl ether, ethyl acetate, butyl acetate, methylenedichloride, ethylene dichloride, carbontetrachloride, dioxane, acetonitrile, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and water.
9. The process as claimed in claim 7, wherein the anti-solvent comprises one or more of pentane, hexane, n-heptane, octane, cyclohexane, benzene, toluene, mix-xylene, m-xylene, o-xylene, p-xylene, petroleum ether, chloroform, diethyl ether, ethyl acetate, butyl acetate, methylenedichloride, ethylene dichloride, carbontetrachloride or any combination thereof.
10. A process for the preparation of condensed-nitro compound of Formula (V) substantially free from dimer impurity (A), the process comprising:
(a) reacting a cyclopentylamine compound of Formula (VII) with a dichloropyrimidine compound of Formula (VI) in one or more organic solvents at less than 20ºC; and
(b) obtaining the condensed-nitro compound of Formula (V) substantially free from dimer impurity (A) by removal of solvent.
11. The process as claimed in claim 12, wherein the cyclopentylamine compound of Formula (VII) and the dichloropyrimidine compound of Formula (VI) are reacted at less than 5°C.
12. A compound of Formula (A)

(A)
13. A process for the preparation of dimer impurity Compound of Formula (A), the process comprising reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine Compound VII to obtain the dimer impurity of Formula (A).
14. A compound of Formula (B)

(B)
15. A process for the preparation of amino impurity Compound of Formula (B), the process comprising:
(a) reacting a dichloropyrimidine compound of Formula (VI) with less than 1 mole eq. of a cyclopentylamine compound of Formula (VII) or acid addition salt thereof to obtain a compound of Formula (A); and
(b) reducing the compound of Formula (A) with a reducing agent to obtain the amino impurity of Formula (B).

Dated this 22nd day of September 2014.

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