WO2014155389A2

WO2014155389A2 - Process for preparation of ticagrelor

Info

Publication number: WO2014155389A2
Application number: PCT/IN2014/000165
Authority: WO
Inventors: Navin G. BHATT; Samir Naik; Ajay Kumar Sharma; Mahendra CHORAGHE; Shekhar Bhaskar Bhirud
Original assignee: Glenmark Pharmaceuticals Ltd
Current assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2013-03-25
Filing date: 2014-03-14
Publication date: 2014-10-02
Anticipated expiration: 2015-09-25
Also published as: WO2014155389A3; IN2013MU01111A

Abstract

The present invention relates to a process for the preparation of ticagrelor and pharmaceutically acceptable salts thereof.

Description

PROCESS FOR PREPARATION OF TICAGRELOR

PRIORITY

[0001] This application claims the benefit of Indian Provisional Application 1 1 1 l/MUM/2013 filed on March 25, 2013, entitled "PROCESS FOR PREPARATION OF TICAGRELOR", the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

[0002] The present invention relates to a process for the preparation of ticagrelor and pharmaceutically acceptable salts thereof.

Description of the Related Art

[0003] Ticagrelor, also known as (15,2S,3^,5≤ -3-[7-{[(l ?,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopentane-l,2-diol, is represented by the structure of formula I.

I

[0004] 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 brand name BRILINTA® in the United States (approved in July 201 1) and under the brand name BRILIQUE® and POSSIA® in Europe (approved in December 2010).

[0005] United States Patent No. 6525060 discloses ticagrelor and its salts.

[0006] The object of the present invention is to provide a process for the preparation of ticagrelor via novel intermediate compounds. SUMMARY OF THE INVENTION

[0007] The present invention provides process for the preparation of ticagrelor, a compound of formula I,

J

and pharmaceutically acceptable salts thereof, the process comprising:

(a) condensing a compound of formula VII or its salt thereof,

VII

with a compound of formula X,

to give a compound of form

(b) optionally, converting the compound of formula VI to its salts thereof,

(c) reducing the compound of formula VI or its salt thereof to give a compound of formula V,

(d) optionally, converting the compound of formula V to its salts thereof,

(e) cyclizing the compound of formula V or its salt thereof to give a compound of formula IV, .

(f) condensing the compound of formula IV with a compound of formula XI or its salt thereof,

to give a compound of formula III,

(g) deprotecting the compound of formula III to give the compound of formula I.

[0008] In another embodiment, the present invention provides a compound of formula VI or a salt thereof.

[0009] In another embodiment, the present invention provides use of compound of formula III, IV, V, VI or VII or its salt thereof in the preparation of ticagrelor or salt thereof.

[0010] In another em a compound of formula II.

II _

[0011] In another embodiment, the present invention provides use of compound of formula II in the preparation of ticagrelor or salt thereof.

[0012] In another embodiment, the present invention provides a process for the purification of ticagrelor, the process comprising:

(a) dissolving tigacrelor in aromatic hydrocarbons, or a mixture of aromatic hydrocarbons with ketones or esters to form a solution,

(b) removing the solvent from the solution obtained in (a).

BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is a characteristic XRPD of ticagrelor in amorphous form as obtained in Example 1 1.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention provides process for the preparation of ticagrelor, a compound of formula I,

and pharmaceutically acceptable salts thereof, the process comprising:

(a) condensing a compound reof,

VII

with a compound of formula X,

to give a compound of form la VI,

(b) optionally, converting the compound of formula VI to its salts thereof,

(d) optionally, converting the compound of formula V to its salts thereof,

(e) cyclizing the compound of formula V or its salt thereof to give a compound of formula IV,

(f) condensing, the compound of formula IV with- a compound of fofrriuia XI or its salt thereof,

to give a compound of formula III,

(g) deprotecting the compound of formula III to give the compound of formula I.

[0015] In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C.

[0016] In (a) of the process for the preparation of the compound of formula I, the compound of formula VII, or its salt thereof is condensed with the compound of formula X to give the compound of formula VI.

[0017] The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4- dimethylaminopyridine, l ,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7- ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is diisopropylethylamine, sodium bicarbonate.

[0018] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof. Preferably the solvent selected is tetrahydrofuran.

[0019] In (b) of the process for the preparation of the compound of formula I, the compound of formula VI is converted to its salt thereof.

[0020] The salts of the compound of formula VI may be prepared by reacting the compound of formula VI with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid. For example, such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.

[0021] In (c) of the process for the preparation of the compound of formula I, the compound of formula VI, or its salt thereof is reduced to give the compound of formula V.

[0022] A suitable reducing agent includes, but is not limited to sodium dithionite, zinc/acetic acid, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, transition metal borohydride/transition metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably, the reducing agent selected is zinc/acetic acid or reduction by catalytic hydrogenation using palladium catalyst.

[0023] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is acetic acid, methanol.

[0024] In (d) of the process for the preparation of the compound of formula I, the compound of formula V is converted to its salt thereof.

[0025] The salts of the compound of formula V may be prepared by reacting the compound of formula V with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid. For example, such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.

[0026] In (e) of the process for the preparation of the compound of formula I, the compound of formula V, or its salt thereof is cyclized to give the compound of formula IV.

[0027] The reaction may be carried out in the presence of alkali metal nitrite such as sodium nitrite, potassium nitrite and the like; alkaline earth metal nitrite such as calcium nitrite and the like. Preferably, sodium nitrite is used.

[0028] The reaction may be carried out in the presence of an acid. A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid. Preferably, the acid selected is acetic acid. [0029] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1 -butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; hydrocarbons such as toluene, xylene and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is acetic acid-water mixture.

[0030] In one embodiment, the present invention provides a process for the preparation of the compound of formula I wherein the product of step (c) is not isolated.

[0031] In (f) of the process for the preparation of the compound of formula I, the compound of formula IV is condensed with the compound of formula XI, or its salt thereof to give the compound of formula III.

[0032] The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is diisopropylethylamine.

[0033] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof. Preferably the solvent selected is dimethyl formamide, tetrahydrofuran.

[0034] In (g) of the process for the preparation of the compound of formula I, the compound of formula III is deprotected to give the compound of formula I.

[0035] A suitable deprotecting reagent is selected from an acid or a base.

[0036] A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. Preferably, the acid selected is hydrochloric acid.

[0037] A suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, , caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium hydroxide.

[0038] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran, methanol, methanol-water mixture.

[0039] The compound of formula VII is obtained by the process comprising:

(a) acetylating a compound of formula IX,

to give a compound of formula VIII

(b) deprotecting the compound of formula VIII to give the compound of formula VII, (c) optionally converting the compound of formula VII to its salt thereof.

[0040] In (a) of the process for the preparation of the compound of formula VII, the compound of formula IX is acetylated to give the compound of formula VIII.

[0041] The acetylating agent includes, but is not limited to acetyl chloride, acetic anhydride.

[0042] The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, 7V,JV-diisopropylethylamine; ammonia, pyridine, piperidine, 4- dimethylaminopyridine, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]undec-7- ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is triethylamine.

[0043] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to haloalkanes such as dichloromethane, chloroform and the like; ethers such as dimethyl ^'ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; N-Methyl-2- pyrrolidone; or mixtures thereof. Preferably the solvent selected is dichloromethane.

[0044] In (b) of the process for the preparation of the compound of formula VII, the compound of formula VIII is deprotected to give the compound of formula VII.

[0045] The deprotection reaction may be carried out by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably the compound of formula VIII is deprotected to give the compound of formula VII by catalytic hydrogenation using palladium on carbon catalyst.

[0046] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert- butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is methanol.

[0047] In (c) of the process for the preparation of the compound of formula VII, the compound of formula VII is converted to its salt thereof.

[0048] The compound of formula VII may be purified by preparing its salt. The salts of the compound of formula VII may be prepared by reacting the compound of formula VII with an acid, where the acid may be an aqueous, anhydrous or gaseous form, for example, an aqueous acid or solvent containing an acid or a gas containing an acid. For example, such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. Preferably, the acid is tartaric acid.

[0049] The present invention provides a compound of formula VI or a salt thereof.

[0050] The present invention provides use of compound of formula III, IV, V, VI or its salt thereof in the preparation of ticagrelor or salt thereof.

[0051] The present invention provides a compound of formula II.

Π

[0052] The present invention provides use of compound of formula II in the preparation of ticagrelor or salt thereof.

[0053] The present invention provides a process for the preparation of ticagrelor, a compound of formula I, and pharmaceutically acceptable salts thereof, the process comprising treating a compound of formula II with a deprotecting reagent.

[0054] A suitable deprotecting reagent is selected from an acid or a base.¹

[0055] A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. Preferably, the acid selected is hydrochloric acid.

[0056] A suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium ^'methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium hydroxide.

[0057] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran, methanol-water mixture.

[0058] The compound of formula II is obtained by deprotecting the compound of formula III to give the compound of formula II.

[0059] The deprotection reaction may be carried out in the presence of an acid. A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. Preferably, the acid selected is hydrochloric acid. [0060] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol ai d the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof., Preferably the solvent selected is methanol-water mixture.

[0061] The present invention provides a process for the preparation of ticagrelor, a compound of formula I, and pharmaceutically acceptable salts thereof, the process comprising treating a c tecting reagent.

Ilia

wherein R_\ and R₂ are protecting groups selected from the group consisting of Cj.₆ alkyl, C_3-8 cycloalkyl, trialkylsilyl, acyl, or Rj and R₂ together with the atoms to which they are attached form an alkylidene ring such as methylidene or isopropylidene ring, or Rj and R₂ can form an alkoxymethylidene ring such as ethoxymethylidene.

[0062] The term "C_1-6 alkyl" includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl. The term "C_3-8 cycloalkyl" includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term "trialkylsilyl" includes groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldimethylsilyl. The term "acyl" includes groups such as acetyl, optionally substituted benzoyl, pivaloyl. The term "optionally substituted benzoyl" means benzoyl which is optionally substituted with halo or nitro group wherein halo includes CI, Br, I.

[0063] A suitable deprotecting reagent is selected from an acid or a base.

[0064] A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid. [0065] A suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l ,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide.

[0066] In one embodiment, the present invention provides a process for the preparation' of ticagrelor or salt thereof, the process comprising:

(a) deprotecting the compound of formula III to give a compound of formula XII,

(b) deprotecting the compound of formula XII to give ticagrelor,

(c) and optionally, converting to pharmaceutically acceptable salts thereof.

[0067] In (a) of the process for the preparation of ticagrelor, the compound of formula III is deprotected to give the compound of formula XII.

[0068] A suitable deprotecting reagent includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert- butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l ,4-diazabicyclo[2.2.2]octane, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium hydroxide.

[0069] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1 -pentanol, 1 -octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran.

[0070] In (b) of the process for the preparation of ticagrelor, the compound of formula XII is deprotected to give ticagrelor.

[0071] A suitable deprotecting reagent includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. Preferably, the deprotecting reagent selected is hydrochloric acid.

[0072] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, 1-pentanol, 1 -octanol and the like; ethers such as tetrahydrofuran, ^'dioxane and the like; esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; water or mixtures thereof. Preferably the solvent selected is methanol.

[0073] The present invention provides a process for the purification of ticagrelor, the process comprising: (a) dissolving tigacrelor in aromatic hydrocarbons, or a mixture of aromatic hydrocarbons with ketones or esters to form a solution,

(b) removing the solvent from the solution obtained in (a).

[0074] In (a) of the process for the purification of ticagrelor, tigacrelor is dissolved in aromatic hydrocarbons, or a mixture of aromatic hydrocarbons with ketones or esters to form a solution.

[0075] The aromatic hydrocarbons used for dissolving ticagrelor include, but are not limited to toluene, xylene, chlorobenzene and the like; ketones include, but are not limited to acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters include, but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like.

[0076] In one embodiment, ticagrelor is dissolved in toluene to form a solution.

[0077] In one embodiment, ticagrelor is dissolved in toluene-methyl isobutyl ketone mixture to form a solution.

[0078] In one embodiment, ticagrelor is dissolved in toluene-isopropyl acetate mixture to form a solution.

[0079] In (b) of the process for the purification of ticagrelor, the solvent is removed from the solution obtained in (a).

[0080] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid.

[0081] In one embodiment, ticagrelor is obtained in a purity of at least 99%, as determined by high performance liquid chromatography.

[0082] In one embodiment, ticagrelor obtained is substantially free of compound of formula XII.

[0083] In the present application, the term "substantially free" means the compound of formula XII is less than 0.10% w/w with respect to ticagrelor, as determined by high performance liquid chromatography (HPLC).

[0084] In one embodiment, ticagrelor obtained is substantially free of one or more of compounds of formula XII, A or B.

[0085] The present invention provides ticagrelor wherein the compound of formula XII is present to an extent of less than 0.10% w/w relative to the amount of ticagrelor, obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:

Reagents, Solvents and Standards: Water (Milli Q or equivalent), Acetonitrile (HPLC grade), Methanol (HPLC grade), Sodium perchlorate monohydrate (AR grade), Perchloric acid (70%) (AR grade)

Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software. Column: Hypersil BDS CI 8, 250 X 4.6mm, 5μ; Column temperature: 40°C

Sample cooler temperature: 25°C

Mobile Phase A: Buffer: Methanol (85: 15, v/v); Buffer: 0.02M Sodium perchlorate monohydrate in water. Adjust pH to 2.5 with diluted Perchloric acid.

Mobile Phase B: Methanol: Acetonitrile (85: 15, v/v)

Diluent: Water: Acetonitrile (50: 50, v/v)

Flow Rate: 1.OmL/minute

Detection: UV 210nm and 255nm

Injection Volume: 20μί

The retention time of ticagrelor is about 35.0 minutes under these conditions.

Relative retention time for compound of formula XII is about is about 1.24 with respect to ticagrelor.

[0086] In one embodiment, ticagrelor is obtained in a chiral purity of at least 99.9%, as determined by high performance liquid chromatography.

[0087] The present invention provides pure amorphous ticagrelor and a process thereof.

[0088] The present invention provides amorphous form of ticagrelor having an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.

[0089] The X-Ray powder diffraction can be measured by an X-ray powder diffractometer equipped with a Cu-anode (λ=Τ .54 Angstrom), X-ray source operated at

45 kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50° 2Θ; step width=0.017°; and measuring time per step=5 sec.

[0090] The present invention provides a process for the preparation of ticagrelor i amorphous form, comprising the steps of: (a) dissolving ticagrelor in a solvent to form a solution,

(b) removing the solvent from the solution obtained in (a).

[0091] A suitable solvent includes but is not limited to haloalkanes such as dichloromethane, chloroform and the like; alcohols such as methanol, ethanol, 1- propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, hexane, heptane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; or mixtures thereof. Preferably, the solvent selected is dichloromethane, dichloromethane-methanol mixture.

[0092] In one preferred embodiment, ticagrelor is dissolved in dichloromethane at about 40°C to form a solution.

[0093] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably solvent was removed by concentrating the solution under vacuum to give amorphous ticagrelor.

[0094] The present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:

(a) dissolving a solvate of ticagrelor in a solvent to form a solution; and

(b) removing the solvent from the solution obtained in (a).

[0095] In (a) of the process for the preparation of ticagrelor in amorphous form, a solvate of ticagrelor is dissolved in a solvent to form a solution.

[0096] The solvate of ticagrelor includes solvate with water, methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, or dimethyl sulfoxide. [0097] The solvent used for dissolution of the solvate of ticagrelor includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert- butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.

[0098] Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0099] In (b) of the process for the preparation of ticagrelor in amorphous form, the solvent is removed from the solution obtained in (a).

[0100] Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably solvent was removed by concentrating the solution under vacuum to give amorphous ticagrelor.

[0101] The present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:

(a) dissolving a salt of ticagrelor in a solvent to form a solution; and

(b) removing the solvent from the solution obtained in (a).

[0102] In (a) of the process for the preparation of ticagrelor in amorphous form, a salt of ticagrelor is dissolved in a solvent to form a solution.

[0103] The salt of ticagrelor includes salt with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like.

[0104] The solvent used for dissolution of the salt of ticagrelor includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1- pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, tert- butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene and the like; haloalkanes such as methylene dichloride, ethylene dichloride, chloroform and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.

[0105] Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 3 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.

[0106] In (b) of the process for the preparation of ticagrelor in amorphous form, the solvent is removed from the solution obtained in (a).

[0107] Removal of solvent may be accomplished as discussed supra.

[0108] The isolated ticagrelor may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 20 hours, or longer.

[0109] 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

[0110] EXAMPLE 1 Preparation of 2-{[(3aR,4S,6R,6aS)-6-

{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-hexahydrocyclopenta[d] [l,3]dioxoM- yl]oxy}ethyl acetate, compound of formula VIII

A mixture of benzyl [(3a5,4i?,65',6ai?)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l ,3]dioxol-4-yl]carbamate, compound of formula IX (5g) and triethylamine (2.9g) in dichloromethane (50mL) was stirred at about room temperature. The reaction mixture was cooled to about G°C to about 5°C. Acetyl chloride (1.7g) was added to the reaction mixture in about 15min to about 30min maintaining the temperature at about below 5°C. The reaction mixture was further stirred for about lh to about 2h at about 0°C to about 5°C. After completion of reaction, water 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, concentrated and degassed to give the title compound.

[0111] EXAMPLE 2 Preparation of 2-{[(3aR,4S,6R,6a5)-6-amino-2,2-dimethyl- hexahydrocyclopenta[d] [l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula VII

To the mixture of 2-{ [(3ai?,45^,,6i?,6aS)-6-[(benzyloxy)carbonyl]amino}-2,2-dimethyl- hexahydrocyclopenta[d][l ,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula VIII (5g) and 10% Pd/C (0.5g) in methanol (l OOmL) was applied hydrogen pressure (5kg) for about 2h to about 4h. After completion of reaction, the reaction mixture was filtered over Hyflo bed. The filtrate was concentrated and degassed to give 3.5g of the title compound. 1H NMR (300 MHz in DMSO-d₆): δ 4.62 (dd, lH), 4.589 (dd, lH), 4.125 (s,2H), 3.97 (t,2H), 3.88 (m, lH), 3.654 (t,2H), 3.41 (m, lH), 2.18 (m, lH), 2.019 (s,3H), 1.91 (s, l H), 1.36 (s,3H), 1.23 (S,3H)

[0112] EXAMPLE 3 Preparation of compound of formula VI

A mixture of 2-{[(3a ?,45,6i?,6aiS)-6-amino-2,2-dimethyl-hexahydrocyclopenta[d][l ,3] dioxol-4-yl]oxy}ethyl acetate, compound of formula VII (l g) and diisopropylethylamine (2.5mL) in tetrahydrofuran (25mL) was stirred for about 30min to about lh. To a solution of 4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine, compound of formula X (2g) in tetrahydrofuran (20mL) was added the above reaction mixture in about 30min to about lh. The reaction mixture was stirred for about lh to about 2h and concentrated to give an oily residue. Ethyl acetate and water was added to the above residue. 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 which was further purified by column chromatography using hexane-ethyl acetate.

[0113] EXAMPLE 4 Preparation of 2-{[(3aR,4S,6R,6aS)-6-[7-chloro-5- (propylsulfanyl)-3H- [1 ,2,3] triazolo [4,5-d] py rimidin-3-y 1] -2,2-dimethyI- hexahydrocyclopenta[d][l,3] dioxol-4-yl]oxy} ethyl acetate, compound of formula IV To a mixture of compound of formula VI (lg) and acetic acid (lOmL) cooled to about 15°C to about 20°C was added Zn dust (2g) in about 15min maintaining the temperature at about below 20°C. The reaction mixture was stirred for about 30min to about lh at about 15°C to about 20°C. Water (20mL) and toluene (20mL) was added to the reaction mixture. The reaction mixture was stirred for about 5min and the two layers were separated. The organic layer was washed with water. The organic layer was cooled to about 10°C and a mixture of acetic acid (2mL) and water (lOmL) was added to it. Sodium nitrite (0.45g) dissolved in water (5mL) was slowly added to the reaction mixture in about lOmin to about 15min maintaining the temperature at about below 20°C. After completion of reaction, water was added to the reaction mixture 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 0.7g of the title compound.

[0114] EXAMPLE 5 Preparation of 2-{[(3aR,4S,6R,6aS)-6-(7-{[(lR,2S)-2-(3,4- difiuoro phenyl)cyclopropyI]amino}-5-(propyIsulfanyl)-3H-[l,2,3]triazolo[4,5- d] py rimidin-3-yI)-2,2-dimethyl-hexahy drocyclopenta [d] [1 ,3] dioxol-4-yl] oxy} ethyl acetate, compound of formula III

A mixture of 2-{[(3a/?,45,6i?,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-3-yl]-2,2-dimethyl-hexahydrocyclopenta[d][l ,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula IV (lg), (li?,2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride, compound of formula XI (0.6g), diisopropyl ethyl amine (2mL) and dimethyl formamide (lOmL) was stirred at about room temperature for about lh to about 2h. After completion of reaction, ethyl acetate and water 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.

[0115] EXAMPLE 6 Preparation of 2-{[(lS,2S,3S,4R)-4-(7-{[(lR,2S)-2-(3,4-difluoro phenyl) cycIopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin- 3-yl)-2,3-dihydroxycyclopentyl]oxy}ethyl acetate, compound of formula II

A mixture of 2-{[(3ai?,4₁S,6 ?,6a5)-6-(7-{[(li?,25)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (lg), methanol (lOmL) and hydrochloric acid (2.5mL) was stirred at about 5°C to about 10°C for about lh to about 1.5h. After completion of reaction, the reaction mixture was concentrated. Water (lOmL) and ethyl acetate (lOmL) was added to the reaction mixture and the pH was adjusted to about 7 to about 8 by adding sodium bicarbonate. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound.

[0116] EXAMPLE 7 Preparation of ticagrelor

A mixture of 2-{[(15,25,35,4i?)-4-(7-{[(li?,2S')-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,3- dihydroxycyclopentyljoxy} ethyl acetate, compound of formula II (lgm), tetrahydrofuran (lOmL) and 30% aqueous sodium hydroxide (lOmL) was stirred at about 50°C to about 55°C for about 2h to about 6h. After completion of reaction, the reaction mixture was concentrated. 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 ticagrelor.

[0117] EXAMPLE 8 Preparation of ticagrelor

A mixture of 2-{[(3ai?,4S,6 ?,6a5)-6-(7-{[(l^,25 -2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (lg), methanol (lOmL) and hydrochloric acid (5mL) was stirred at about 5°C to about 10°C for about 2h to about 4h. After completion of reaction, the reaction mixture was concentrated. Water (lOmL) and ethyl acetate (lOmL) was added to the reaction mixture and the pH was adjusted to about 7 to about 8 by adding sodium bicarbonate. The two layers were separated and the/ organic layer was washed with water, concentrated and

degassed to give ticagrelor which was further purified by column chromatography using

dichloromethane-acetone.

[0118] EXAMPLE 9 Preparation of 2-{[(3aR,4S,6R,6aS)-6-(7-{[(lR,2S)-2-(3,4- difluoro phenyI)cyclopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazoIo[4,5- d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxpl-4-yl]joxy}ethan- l-o I, compound of formula XII

A mixture of 2-{[(3ai?,4S,6_J/?,6aS)-6-(7-{[(l ?,2S)-2-(3,4-difluorophenyl)cyclopropyl]

amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l ,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III

(lg), tetrahydrofuran (lOmL) and 30% aqueous sodium hydroxide (lOmL) was stirred at

about 50°C to about 55°C for about 2h to about 6h. After completion of reaction, the

reaction mixture was concentrated. 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.

[0119] EXAMPLE 10 Preparation of ticagrelor

To a mixture of 2-{[(3a_JR,4₁S,6_J ?,6aS)-6-(7-{[(l^,2S)-2-(3,4-difluorophenyl)cyclopropyl]

amino} -5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethan-l-ol, compound of formula XII (2g)

and methanol (20mL) cooled to about 10°C, concentrated hydrochloric acid (l OmL) was

added maintaining the temperature at about below 20°C. The reaction mixture was stirred

for about lh to about 2h. After completion of reaction, the reaction mixture was

concentrated. Water and dichloromethane was added to the reaction mixture 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 ticagrelor which was further purified by column chromatography using

dichloromethane-acetone.

[0120] EXAMPLE 11 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (lOOmL) was stirred at about 40°C to get

a clear solution. The reaction mixture was concentrated and degassed to give amorphous

ticagrelor.

I - 28

I [0121] EXAMPLE 12 Preparation of tartrate salt of 2-{[(3aR,4S,6i?,6aS)-6-amino- 2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yI]oxy}ethyl acetate, tartrate salt of compound of formula VII

To the mixture of 2-{[(3a/?,45',6i?,6a5 -6-[(benzyloxy)carbonyl]amino}-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula VIII (5g), D-(-)-tartaric acid (2.34g) and 10% Pd/C (0.5g) in methanol (lOOmL) was applied hydrogen pressure (5kg/cm²) for about 2h to about 4h at about 20°C to about 25°C. After completion of reaction, the reaction mixture was filtered over Hyflo bed. The filtrate was concentrated and degassed. To the obtained residue, ethyl acetate is added and the mixture was stirred for about lh. The solid obtained was filtered and washed with ethyl acetate to give the title compound. Yield: 5g

[0122] EXAMPLE 13 Preparation of compound of formula VI

A mixture of tartrate salt of 2-{[(3ai?,4S,67?,6aS)-6-amino-2,2-dimethyl- hexahydrocyclopenta[d][l,3] dioxol-4-yl]oxy} ethyl acetate, tartrate salt of compound of formula VII (lg) and sodium bicarbonate (0.52g) in water (lOmL) was stirred for about 30min to about lh. To a solution of 4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine, compound of formula X (0.82g) in tetrahydrofuran (lOmL) was added the above reaction mixture in about 30min to about lh. The reaction mixture was stirred for about lh to about 2h and concentrated to give an oily residue. Ethyl acetate and water was added to the above residue. 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.

Ή NMR (300 MHz in DMSO-d₆): 58.47 (d,lH), 4.6 (m,2H), 4.15 (d,2H), 3.95 (d,lH), 3.74 (t,2H), 3.11 (m,3H), 2.009 (s,3H), 1.93 (dd,lH), 1.88 (dd,lH), 1.75 (m,2H), 1.366 (s,3H), 1.21 (S,3H), 0.987(t,3H)

[0123] EXAMPLE 14 Preparation of 2-{[(3aR,4S,6R,6aS)-6-[7-chloro-5- (propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl- hexahydrocyclopenta[d][l,3] dioxol-4-yl]oxy} ethyl acetate, compound of formula IV To a mixture of compound of formula VI (lg), 10% Pd/C (0.175g) and methanol (lOmL) was applied hydrogen pressure (5kg/cm²) for about 2h to about 4h at 15°C to about 20°C. After completion of reaction, the reaction mixture was filtered over Hyflo bed. The filtrate was concentrated and degassed to give compound of formula V.

Ή NMR (300 MHz in CDCl₃-d₆): 65.827 (d,lH), 5.628 (s,lH), 4.515 (t,2H), 4.281 (d,lH), 4.229 (d,2H), 3.85 (s,lH), 3.76(d,2H), 3.65 (d,lH), 3.06 (m,lH), 2.976 (m,lH), 2.256 (m,lH), 2.033 (s,3H), 1.825-1.70 (m,3H), 1.385 (s,3H), 1.216 (s,3H), 0.975(s,3H) Toluene (20mL) was added to the above residue and the mixture was cooled to about 10°C. A mixture of acetic acid (2mL) and water (lOmL) was added to it. Sodium nitrite (0.45g) dissolved in water (5mL) was slowly added to the reaction mixture in about l Omih to about 15min maintaining the temperature at about below 10°C. After completion of reaction, water was added to the reaction mixture. The two layers were separated and the organic layer was washed with water, concentrated and degassed to give the title compound which was purified by column chromatography using hexane and ethyl acetate.

Yield: 0.5g

Ή NMR (300 MHz in DMSO-d₆): 65.39-5.35 (m,lH), 5.21-5.17 (m,lH), 4.72 (d,lH), 4.03 (t,lH), 3.96 (t,2H), 3.64 (m,lH), 3.55(m,lH), 3.18 (t,2H), 2.69 (m,2H), 1.96 (s,3H), 1.74 (m,2H), 1.48 (s,3H), 1.28 (s,3H), 1.019 (t,3H)

[0124] EXAMPLE 15 Preparation of 2-{[(3aR,4S,6R,6a5)-6-(7-{[(lR,25)-2-(3,4- difluoro phenyI)cyclopropyl]amino}-5-(propyIsuIfanyl)-3H-[l,2,3]tHazolo[4,5- d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III

A mixture of 2-{[(3ai?,4S',6/?,6a5)-6-[7-chloro-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-3-yl]-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula IV (lg), (li?,25 -2-(3,4-difluorophenyl)cyclopropanamine hydrochloride, compound of formula XI (0.6g), diisopropyl ethyl amine (2mL) and THF (lOmL) was stirred at about room temperature for about lh to about 2h. After completion of reaction, the reaction mixture was concentrated under vacuum. Ethyl acetate and water was added to the obtained residue. 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. - ^' , Ή NMR (300 MHz in DMSO-d₆): 67.36 (d,lH), 7.28 (s,lH), 7.14-7.03 (m,2H), 5.47- 5.44 (d,lH), 5.12-5.1 1 (d,lH), 4.76-4.74 (m,lH), 4.15(m,2H), 3.73-3.60 (m,4H), 2.98- 2.81(m,2H), 2.63 (d,lH), 2.29-2.09 (m,lH), 2.07-2.05(s,3H), 2.00(m,lH), 1.73-1.33 (m,4H), 1.34 (s,3H), 1.28 (s,3H), 1.008 (t,3H)

[0125] EXAMPLE 16 Preparation of ticagrelor

A mixture of 2-{[(3a ?,4S,6 ?,6aS)-6-(7-{[(li?,25')-2-(3,4-difluoroprienyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (lg), methanol (lOmL) and hydrochloric acid (2.5mL) was stirred at about 5°C to about 10°C for about 4h to about 5h. After completion of reaction, the reaction mixture was concentrated. Water and ethyl acetate was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water and sodium carbonate solution, concentrated and degassed to give ticagrelor. Ticagrelor obtained was dissolved in methyl isobutyl ketone (5mL) and toluene (lOmL) at about 70°C to about 75°C The solution was cooled to about 25°C and the solid obtained was filtered to give pure ticagrelor.

HPLC purity: >99.5%

Impurity XII with relative retention time (RRT) of 1.24: below detection limit, as determined by HPLC

[0126] EXAMPLE 17 Preparation of ticagrelor

A mixture of 2-{[(3ai?,45,6i?,6aS)-6-(7-{[(li?,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl- hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (lg), methanol (lOmL) and hydrochloric acid (2.5mL) was stirred at about 5°C to about 10°C for about 4h to about 5h. After completion of reaction, the reaction mixture was concentrated. Water and ethyl acetate was added to the reaction mixture. The reaction mixture was stirred and the two layers were separated. The organic layer was washed with water and sodium carbonate solution, concentrated and degassed to give ticagrelor. Ticagrelor obtained was dissolved in isopropyl acetate (5mL) and toluene (lOmL) at about 70°C to about 75°C The solution was cooled to about 25°C and the solid obtained was filtered to give pure ticagrelor. [0127] EXAMPLE 18 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum on rotavapour to give amorphous ticagrelor. i

[0128] EXAMPLE 19 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum with slow stirring to give amorphous ticagrelor.

[0129] EXAMPLE 20 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum. Cyclohexane (50mL) was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.

[0130] EXAMPLE 21 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum, n- Heptane (50mL) was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.

[0131] EXAMPLE 22 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum. Hexane (50mL) was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.

[0132] EXAMPLE 23 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum, n- Methyl tert-butyl ether (50mL) was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.

[0133] EXAMPLE 24 Preparation of amorphous ticagrelor

A mixture of ticagrelor (5g) in dichloromethane (50mL) and methanol (2.5ml) was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum, n- Diisopropyl ether (50mL) was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.

Claims

CLAIMS:

1. A process for the preparation of ticagrelor, a compound of formula I,

I

and pharmaceutically acceptable salts thereof, the process comprising:

(a) condensing a compound of formula VII or its salt thereof,

with a compound of formula X,

to give a compound of formula VI

(b) optionally, converting the compound of formula VI to its salts thereof,

(d) optionally, converting the compound of formula V to its salts thereof,

IV

XI

to give a compound of formula III,

(g) deprotecting the compound of formula III to give the compound of formula I.

2. The process of claim 1, wherein the deprotecting reagent is selected from an acid or a base.

3. The process of claim 2, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoro acetic acid.

4. The process of claim 2, wherein the base is selected from the group consisting of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkali metal hydride, alkali metal alcoholate, alkaline earth metal alcoholate.

5. The process of claim 1, wherein the compound of formula VII is obtained by the process comprising:

(a) acetylating a compound of formula IX

IX

to give a compound of formula VIII

VIII

6. A compound of formula VI or a salt thereof.

7. The use of compound of formula III, IV, V, VI or VII or its salt thereof in the preparation of ticagrelor or salt thereof.

8. A compound of formula II.

II

9. The use of compound of formula II in the preparation of ticagrelor or salt thereof.

10. A process for the purification of ticagrelor, the process comprising:

(b) removing the solvent from the solution obtained in (a).

1 1. The process of claim 10, wherein ticagrelor is obtained in a purity of at least 99%, as determined by high performance liquid chromatography.

12. The process of claim 10, wherein ticagrelor obtained is substantially free of compound of formula XII.

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