WO2016030704A1

WO2016030704A1 - Solid form of intermediate of ticagrelor

Info

Publication number: WO2016030704A1
Application number: PCT/GB2015/052521
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Geena Malhotra; Manjinder Singh Phull; Maruti Ghagare
Original assignee: Cipla Limited; COTTRILL, Emily
Priority date: 2014-08-30
Filing date: 2015-09-01
Publication date: 2016-03-03

Abstract

A process for the preparation of a solid form of a compound of formula (VII) (Formula (VII)) comprises coupling(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid of Formula (VI) with (2-[[(3a R,4S,6R,6aS)-6-[7-chloro-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]-1-ethanol) of formula (V) in the presence of a suitable base and a first a suitable solvent at a suitable temperature to form 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]-1- ethanol of formula (VI)I; and isolating the compound of formula (VII) using a second suitable solvent so as to produce the compound of formula (VII) in solid form. A process for preparing Ticagrelor of formula (I) or a salt thereof (Formula (I)) comprises the conversion of a compound of formula (VII) in a solid form either as free base or as an acid addition salts thereof, into a compound of formula (I).

Description

SOLID FORM OF INTERMEDIATE OF TICAGRELOR

FIELD OF INVENTION:

The present invention relates to a solid form of intermediate of ticagrelor and a commercially viable and industrially advantageous process for the preparation of ticagrelor.

BACKGROUND OF INVENTION:

Ticagrelor chemically is (1 S,2S,3R,5S)-3-[7-{(1 R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino}-5- propylthio-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol, and has the following chemical structure:

Ticagrelor is currently marketed in Europe under the trade name BRILIQUE™. Ticagrelor is an antagonist of the P2Y₁₂ receptor. It is a platelet aggregation inhibitor. It is indicated for the treatment of thrombosis, angina, ischemic heart diseases, and coronary artery diseases.

U.S. Patent Nos. 6,251 ,910 discloses a variety of triazolo [4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds act as P_2T (P2Y_ADP or P2T_Ac) receptor antagonists and they are indicated for use in therapy as inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation and anti-thrombotic agents.

EP1299390B (hereinafter referred to as the '390 patent) discloses the process for the preparation of ticagrelor which comprises condensing 4,6-Dichloro-2-(propylthio)pyrimidin-5-amine and 2- [[(3aft,4S,6ft,6aS)-6-amino -2,2-dimethyltetrahydro-3a - -cyclopenta[d][1 ,3]-dioxol-4-yl]oxy]-1 - ethanol. L-tartaric acid salt in presence of triethyl amine at 120-125°C for 30 hours in an autoclave to form 2-[[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino] -2,2- dimethyltetrahydro-3a --cyclopenta-[d][1 ,3]-dioxol-4-yl]oxy]-1-ethanol as brown-red viscous oil. The above formed brown-red viscous oil compound is cyclized in aqueous acetic acid below 7°C to form (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-c/]pyrimidin-3-yl] -2,2- dimethyltetrahydro-3a --cyclopenta[d][1 ,3]-dioxol-4-yl]oxy]-1-ethanol as red-brown viscous oil. This is condensed with trans-(1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanaminium ((2R)-2-hydroxy-2- phenylethanoate (also known as (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) in presence of triethylamine in acetonitrile at 20-25°C for 13 hours to form 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-

1- ethanol as red oil. This is treated with aqueous HCI in methanol at 20°C for 24 hours to form ticagrelor. Recrystallized from ethyl acetate and iso-octane.

The process for the preparation of ticagrelor disclosed in '390 patent requires longer reaction time (30 hours), condensation reaction is conducted in an autoclave under pressure and wherein all the intermediates are isolated in oil form which is difficult to handle, store and to purify .

International Patent Application Publication Nos. WO2010030224 A1 , WO2012085665 A2, WO2012138981 A2 and WO2013037942 A1 and many other applications disclose processes for preparing ticagrelor.

International Patent Application Publication No. WO2014102830 discloses the process for the preparation of ticagrelor by condensation of 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro- 3aH-cyclopenta[d][1 ,3]-dioxol-4-yl]oxy}-1-ethanol with 4,6-dichloro-2-(propylthio)-5-pyrimidinamine to give 2-[[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino] -2,2- dimethyltetrahydro-3a --cyclopenta[d][1 ,3]-dioxol-4-yl]oxy]-1-ethanol which underwent cyclocondensation followed by amidation with trans-(1 R,2S)-2-(3,4-difluorophenyl) cyclopropanamine (2R)-2-hydroxy-2-phenylethanoate to give 2-({(3aR,4S,6R,6aS)-6-[7-{[(1 R,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)-1 -ethanol as an oil having purity 94% which after deprotection gave ticagrelor. Ticagrelor obtained by the processes described in the prior art results in unacceptable amounts of impurities along with ticagrelor thus affecting the final purity of the product. These processes also involve intermediate preparation and their isolation at various stages. It is revealed from the prior art processes that most of the intermediates involved are isolated at various stages of the process in the form of oil. Purification of such oils may be difficult and would result in the impurities getting carried forward in the subsequent steps thus affecting the purity of final compound.

Considering the prior art limitations and the possible difficulties involved in the isolation and purification of the intermediate and final product, there is a need to develop a technically feasible and industrially applicable process for preparation of ticagrelor, which involves the isolation of intermediate in a form which can be easily handled and further processed as required to yield the final product which has a high purity and higher yield.

OBJECTIVE OF THE INVENTION:

The object of the present invention is to provide a solid form of ticagrelor intermediate 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]- 1-ethanol of Formula VII.

Formula VII

Another object of the present invention is to provide an improved process for the preparation of the compound of Formula VII, such that the compound of formula VII is produced in a solid form, either as a free base or as an acid addition salt.

Yet another object of the present invention is to provide a further conversion of solid intermediate of Formula VII into ticagrelor, such that ticagrelor is produced with high purity and yield.

Yet another object of the present invention is to provide an improved process for preparation of ticagrelor of formula I. SUMMARY OF THE INVENTION:

In one aspect, the invention provides a solid form of an intermediate, 2-[[(3aR,4S,6R,6aS)-6-[7- [[(1 R,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]-1-ethanol of Formula VII. The intermediate of solid form can be either the free base of the compound of formula VII, or an acid addition salt of the compound of formula VII. The solid intermediate in free base form is preferably characterized by a melting point of from 92°C to 94°C. If the solid form of the intermediate of formula VII is in the form of an acid addition salt, the acid addition salt is preferably a fumarate salt or succinate salt.

In another aspect of the present invention, there is provided a process for the preparation of a solid form of the compound of Formula VII either as free base or as an acid addition salt. The solid form of the compound of formula VII can be further used in a process for preparing ticagrelor with increased purity and yield compared to synthetic processes previously known in the art. It has also been found that a solid form of the compound of formula VII has reduced amounts of diastereomeric impurities compared with forms known in the art.

Preferably, the process comprises coupling(1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)- Mandelic acid of Formula VI with (2-[[(3afi,4S,6fi,6aS)-6-[7-chloro-5-(propylthio)-3H-1 ,2,3- triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a - -cyclopenta[d[[1 ,3]dioxol-4-yl]oxy]-1- ethanol) of formula V in the presence of a suitable base and a first a suitable solvent at a suitable temperature to form 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1 -ethanol of formula VII; and

isolating the compound of formula VII using a third suitable solvent so as to produce the compound of formula VII in solid form.

In yet another aspect of the present invention, there is provided a process for the preparation of ticagrelor or a salt thereof comprising the conversion of a compound of formula VII in a solid form either as free base or as an acid addition salts thereof, into a compound of formula I. Preferably, the solid form of the compound of formula VII is prepared by the process of the present invention for preparing the compound of formula VII.

The improved process involves the use of the pure intermediate of the compound fo formula VII which is isolated in solid form with a high purity and yield. Said process eliminates laborious workup and extensive purifications. Hence, the process is simple, easy and user friendly.

DETAILED DESCRIPTION OF THE INVENTION:

2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]- 1-ethanol (Formula VII) as shown below, is the key intermediate in the preparation of ticagrelor. Prior art processes have only been able to produce this intermediate along with various impurities in the form of an oil. The inventors of the present invention have provided a process that enables this intermediate to be advantageously produced in a purer, solid form either as the free base or as an acid addition salt thereof.

Formula VII

A route of synthesis for the preparation of Ticagrelor can be represented as shown in below:

Formula V

Formula VII Formula I

Scheme-I Steps I is carried out as per the methods known in the art.

In the process of the present invention, step III is carried out to synthesise the compound of formula VII. In step III, (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid of Formula VI is coupled with (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3 --1 ,2,3-triazolo[4,5-d] pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a --cyclopenta[d[[1 ,3]dioxol-4-yl]oxy]-1 -ethanol) of formula V in the presence of a suitable base and a first suitable solvent at a suitable temperature to form 2- [[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1- ethanol of formula VII; and

The isolated intermediate of ticagrelor (Formula VII) is in the solid form and has high yield, high purity and high stability. Preferably, this solid form is the free base and is characterised by a melting point in the range of from about 92.0 to 94.0°C. Preferably, the free base solid of the compound of formula VII is characterised by a differential scanning calorimetry spectrum substantially as defined in figure 3.

Furthermore, the solid form of the isolated intermediate (Formula VII) of the present invention can be easily handled and further processed and converted to ticagrelor having high purity and higher yield.

The suitable base may comprise, but is not limited to, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal alkoxide, ammonia, an organic amine, or any combination thereof. Preferably, the suitable base comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; sodium methoxide, potassium tert-butoxide; sodium carbonate, potassium carbonate, calcium carbonate; sodium bicarbonate, potassium bicarbonate, calcium carbonate; ammonia, tertiary amine (such as a tri (C1 -6 alkyl) amine), diisopropylamine, dimethyl amine, diisopropylethylamine, diisopropylmethylamine, pyridine, piperidine, morpholine and N-methyl piperidine, or any combination thereof. Preferably, the suitable base comprises an organic amine such as N,N- diisopropylethylamine. The suitable first solvent may comprise, but is not limited to an organic solvent. Preferably, the organic solvent comprises a to C₁₀ aliphatic alcohol, a to C₁₀ alkane, a halogenated hydrocarbon, an alkyl nitrile, an alkyl ketone, an alkyl sulphoxide, an alkyl amide, or any combination thereof. More preferably, the organic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH₂CI₂), C C₄ alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, alkane solvents such as pentane, hexane, heptane, or any combination thereof.

Step-Ill reaction is carried out at a temperature in the range of 0^°C to 150°C, preferably 20 to 30°C, more preferably at 25^°C to 30°C.

After completion of the coupling step of the reaction, the reaction mixture of step III is preferably quenched in water and then extracted in a second suitable organic solvent. The third suitable organic solvent preferably comprises water, an ether, an ester, a halogenated hydrocarbon, a ketone, an aromatic and aliphatic hydrocarbon, or any combination thereof. More preferably, the second suitable organic solvent comprises tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, acetone, toluene, xylene, cyclohexane, heptane or combinations thereof.

The organic layer is then optionally washed with aqueous acid, optionally followed by basic solution. Preferably, the basic solution comprises an organic base such as triethylamine (TEA) or diisopropylethylamine (DIPEA), or an inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K₂C0₃), sodium carbonate (Na₂C0₃); or any combination thereof. The organic layer of the second suitable solvent is then preferably distilled, for example, by heating under reduced pressure so as to evaporate the solvent. The obtained residue of formula VII is then admixed with the third suitable solvent; before the compound of formula VII in solid form is isolated from the third suitable solvent. Optionally, the compound of formula VII can be isolated as an acid addition salt.

The third suitable solvent is preferably a non polar solvent. Examples of nonpolar solvents comprise to C₁₀ aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, or any combination thereof. Preferably, the non polar solvent comprises hexane, n-heptane, pentane, octane; cyclopentane, cyclohexane; dichloromethane, chloroform; benzene, toluene, or combinations thereof.

Preferably, the coupling reaction between the compound of formula VI with the compound of formula V is carried out for a time period of from 1 to 4 hours.

Preferably, the coupling reaction between the compound of formula VI with the compound of formula V is carried out at atmospheric pressure and does not require the use of an autoclave.

Preferably, the step of mixing the residue of the compound of formula VII with the third suitable solvent comprises stirring the third suitable solvent and compound of formula VII for a time period of from 15 minutes to 6 hours, before isolation of the solid form of the compound of formula VII. The solid form of the compound of formula VII prepared by the process of the invention described above, can be further converted to an acid addition salt of the compound of formula VII. The acid addition salt of the compound of formula VII is also in a solid form.

Preferably, this process comprises reacting the solid compound of formula VII with an acid in a suitable solvent for a time period of preferably from 15 minutes to an hour. Preferably, the reaction is carried out at a temperature of from 60°C to 80°C. Preferably, the suitable solvent is a C1 to C₆ aliphatic alcohol such as isopropanol.

The acid employed for preparation of a salt of compound of formula VII preferably comprises but is not limited to organic acids, such as fumaric acid, succinic acid, oxalic acid, formic acid, acetic acid, and combinations thereof; or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and combinations thereof.

The salts of compounds of formula VII are preferably fumarate and succinate salts.

The fumarate salt of compound of formula VII is characterized by XRD as provided in Figure 1 . Thus, the present invention provides the fumarate salt of a compound of formula VII with an XRD pattern substantially as shown in figure 1. The succinate salt of compound of formula VII can be characterized by XRD as provided in Figure 2. Thus, the present invention provides the succinate salt of a compound of formula VII with an XRD pattern substantially as shown in figure 2.

The present invention also provides a process for preparing Ticagrelor of formula I or a salt thereof

comprising the conversion of a compound of formula VII in a solid form either as free base or as an acid addition salts thereof, into a compound of formula I.

Preferably, the process comprises deprotection of 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1-ethanol of formula VII using a suitable acid in a suitable solvent to obtain ticagrelor of formula I. Preferably, the solid form of the compound of formula VII is prepared according to the process of the invention for preparing the solid form of the compound of formula VII as discussed above.

Suitable acids employed in step IV for deprotection preferably comprises but is not limited to an inorganic acid such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid; an organic acid such as acetic acid, trifluoro acetic acid; or any combination thereof.

Suitable solvents employed in step IV may comprise but are not limited to water, alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol; ketones such as acetone; esters such as ethyl acetate; ethers such as tetrahydrofuan; aliphatic and alicyclic hydrocarbons such as hexane, heptane, cyclohexane; halogenated hydrocarbons such as methylene dichloride, chloroform; aromatic hydrocarbons such as toluene or xylene; nitriles such as acetonitrile; polar aprotic solvents; organic acids such as acetic acid; and any mixtures or combinations thereof. Preferably, the suitable solvent comprises a mixture of water and isopropanol. The solid form of the compound of formula VII used in the process of preparing Ticagrelor can be the free base form, or an acid addition salt thereof. Preferable acid addition salts comprise the hydrochloride, sulphate, hydrobromide, phosphate, lactate, malonate, oxalate, succinate or fumarate salts. Most preferably, the acid addition salt is the fumarate or succinate salt of the compound of formula VII.

Preferably, the reaction is carried out for a time period of from 1 hours to 3 hours. Preferably, the reaction is carried out at room temperature.

The process of the invention for the preparation of ticagrelor may also comprise converting ticagrelor into therapeutically useful medicaments.

The compound 2-[[(3a ?,4S,6 ?,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-2,2- dimethyltetrahydro-3a --cyclopenta-[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol) of formula IV in step II can be cyclized with an alkali metal nitrate or with an organic nitrite in a suitable solvent at a suitable temperature to obtain (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3 --1 ,2,3-triazolo[4,5-d] pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a --cyclopenta-[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol) of formula V .

The alkali nitrates and nitrites preferred for use in the present invention are those having potassium, sodium, cesium, or rubidium as the alkali component; or organic nitrite such as tert butyl nitrite, n-butyl nitrite, amyl nitrite, iso-amyl nitrite; or combinations thereof.

Suitable solvents may comprise organic solvents such as dimethylformamide (DMF); dimethylsulfoxide (DMSO); methylene chloride (DCM or CH₂CI₂); C C₄ alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol; esters such as ethyl acetate; nitriles such as acetonitrile; ketones such as acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK); alkane solvents such as pentane, hexane, heptane, sulfolane ionic liquid, ethylene glycol, hexamethylphosphoramide (HMPA), and combinations thereof.

The compound of formula V may be prepared and isolated prior to the reaction with the compound of formula VI in the process of the present invention. Alternatively, the compound of formula V may be prepared in situ from the reaction of a compound of formula IV and an alkali metal nitrate or organic nitrite such that the compound of formula VII in a solid form is prepared from the compound of formula IV without isolation of any intermediates.

The compound 2-[[(3a ?,4S,6 ?,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]-2,2- dimethyl tetrahydro-3a4 --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol of formula IV may be prepared by condensing 5-amino-4,6-dichloro-2-(propylthio)pyrimidine of formula II with 2-[[(3a ?, 4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol, L- tartaric acid salt of formula III in presence of a suitable base and catalyst in a suitable solvent at a suitable temperature.

Alternatively, the reaction is carried out in the absence of a catalyst.

The base may comprise an organic base such as ammonia; secondary and tertiary amines such as a tri (C1-6 alkyl) amines;, diisopropylamine, dimethyl amine, diisopropylethylamine, diisopropylmethylamine; aromatic amines such as pyridine, and morpholine; piperidine, and N- methyl piperidine, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; alkoxides such as sodium methoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate, calcium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, calcium bicarbonate; and combinations thereof.

Suitable solvents comprise but are not limited to organic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulfolane, hexamethylphosphoramide (HMPA), methylene chloride (DCM or CH₂CI₂), C C₄ alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, alkane solvents such as pentane, hexane, heptane and combinations thereof.

Suitable catalysts comprise metal halides, quaternary ammonium halides and quaternary phosphonium halides. Preferred catalysts include sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, tetraethyl ammonium chloride, tetraethyl ammonium bromide, tetraethyl ammonium iodide, tetrabutyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, methyltrioctylammonium chloride (aliquot 336), tetraethylphosphonium chloride, tetraethylphosphonium bromide and tetraethylphosphonium iodide, crown ethers, linear ethers, heterocyclic ammonium salts, phosphonium salts like hexa decyl tributyl phosphonium salt, 1 ,8-Diazabicyclo[5.4.0]undec-7-ene, 1 ,5-Diazabicyclo(4.3.0)non-5-ene, dimethylamino pyrimidine and the like.

The reaction is carried out at a temperature in the range of 0°C to 200°C, preferably 95 to 1 15°C.

Thus, the present invention also provides processes for the preparation of the compounds of formula IV and formula V.

Preferably, the present invention provides a multi-step synthesis of ticagrelor, the compound of formula I from the compounds of formula II and formula III. The compounds of formula II and II I are reacted to form the compound of formula IV, which can be converted into the compound of formula V, which can be converted into the compound of formula VII via reaction with the compound of formula VI, before the compound of formula VII is converted to the compound of formula I.

Preferably, all of the reactions are done at atmospheric pressure. Preferably, none of the reactions require the use of an autoclave.

Brief Description of accompanying drawings

Figures 1 a and 1 b are X-ray powder diffractograms (XRD) of fumarate salt of compound of formula VII.

Figure 2a and 2b are X-ray powder diffractograms (XRD) of succinate salt of compound of formula VII.

Figure 3 is a differential scanning calorimetry (DSC) spectrum of the solid free base form of the compound of formula VII.

The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in any way.

Examples:

Example 1 : Preparation of compound of Formula IV To a reaction flask 24 g (0.06533moles) 2-[[(3aft,4S,6ft,6aS)-6-amino -2,2-dimethyltetrahydro- 3aH-cyclopenta[d][1 ,3]dioxol-4-yl]oxy]-1-ethanol, L-tartaric acid in 40 ml sulfolane, 40 ml (0.296moles) of Ν,Ν-diisopropylethylamine and 2 g of tetra butyl ammonium iodide were charged and the reaction mixture was stirred for 20-25 minutes 10 g (0.04199moles) of 5-amino-4,6- dichloro-2-(propylthio)pyrimidine in 10 ml sulfolane was charged and the reaction mixture was heated to 95°C to 105°C for 3-4 hours. The reaction mixture was quenched with 150 ml water at 10-15°C and stirred for 3 hours at 20-25°C. The product obtained was filtered and washed with water and then dried under vacuum at 50-55°C for 12 hours.

Yield = 15 g. (Efficiency - 85.27%, HPLC - 99%).

Example 2: Preparation of compound of Formula IV

45.8 g of 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl] oxy]-1 -ethanol, L-tartaric acid in 125 ml of sulfolane was charged to the reaction flask followed by addition of 100 ml of Ν,Ν-diisopropylethylamine and the reaction mixture was stirred for 10-15 minutes. 25 g of 5-amino-4,6-dichloro-2-(propylthio)pyrimidine was charged and the reaction mixture was heated to 105°C to 1 10°C for 16-18 hours. The reaction mixture was quenched with 375 ml of water at 25-30°C. The pH of the reaction mass was adjusted to 6.5 to 7.5 using glacial acetic acid and stirred for 2 hours. The obtained product was filtered and washed with water. Dried the material under vacuum at 55-60°C.

Yield = 40 g (Efficiency - 91 %, HPLC - 98%).

Example 3: Preparation of compound of Formula V

To a reaction mixture of 1 1 gm (0.02630moles) 2-[[(3afi,4S,6fi,6aS)-6-[[5-amino-6-chloro-2- (propylthio)-4-pyrimidinyl]amino]-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]1- ethanol of formula IV, 44 ml isopropyl alcohol was charged, followed by drowise addition of 5.3 ml of isoamyl nitrite in 1 1 ml isopropyl alcohol at 25°C to 30°C for 2 to 3 hours. The reaction mixture was concentrated under reduced pressure and to the residue 1 10ml water and 1 10ml ethyl acetate were added and stirred for 5 minutes. The organic layer was separated and washed with 50 ml 1 N HCI followed by 50 ml water followed by 100ml 5% sodium bicarbonate solution, the organic layer was separated and concentrated under vacuum to obtain oil.

Yield = 1 1.3 g (efficiency - 100%, HPLC - 98%). Example 4: Preparation of compound of Formula VII

8.44 g (0.02626 moles) of (1 fi,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) of Formula VI in 25ml dimethyl sulfoxide and 14ml (0.08036moles) Ν,Ν-diisopropylethylamine were charged and stirred for 15 minutes followed by addition of solution of 1 1.3 g 2-[[(3a ?,4S,6 ?,6aS)- 6-[7-chloro-5-(propylthio)-3H-1 ,2,3-triazolo[4,5-c/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a -- cyclopenta-[d][1 ,3]dioxol-4-yl]oxy]-1 -ethanol) formula V dissolved in 15 ml dimethyl sulfoxide at room temperature for 2-3 hours. The reaction mixture was quenched with 100ml water at 10-15°C and extracted two times each with 50 ml ethyl acetate. The organic layer was washed two times each with 25ml 1 N HCI solution followed by 25ml water followed by 50ml 5% sodium bicarbonate solution. The organic layer was separated and distilled under reduced vacuum at 40°C to obtain residue. The residue was stirred with 30ml heptane for 4-5 hours at 25°C to 30°C, filtered and dried under vacuum at 50°C to 55°C for 12 hours to obtain compound of formula VII.

Yield =12.4 g (efficiency -84%, HPLC -99%)

Example 5 : Preparation of compound of Formula VII

To a reaction mixture of 25 g of 2-[[(3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)-4- pyrimidinyl]amino]-2,2-dimethyltetrahydro-3a --cyclopenta[d][1 ,3]dioxol-4-yl]oxy]1-ethanol of formula IV, 125 ml isopropyl alcohol were charged, followed by dropwise addition of 20 ml of isoamyl nitrite at 20°C to 30^°C. The reaction mass was stirred to complete the reaction.

To this reaction mass, 18.9 g of (1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid) of Formula VI was added and stirred for 10 minutes followed by addition of14ml (0.08036moles) Ν,Ν-diisopropylethylamine and stirred for 1 to 2 hours. N,N-diisopropylethylamine was charged and stirred. Isopropyl alcohol was distilled. Water and toluene were charged to the reaction mass. The reaction mass extracted with toluene. Toluene then distilled out and replaced with cyclohexane and stirred. The seed was added followed by addition of n-heptane and stirred at 20 to 30°C. Solid obtained was filtered and dried under vacuum

Yield = 28 g (Efficiency - 83%, HPLC -99.0%).

Example 6: Preparation of compound of Formula I

To a reaction mixture of 7.7 g (0.01368 moles) 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1-ethanol of formula VII in 15 ml methanol, 15 ml concentrated hydrochloric acid was charged and the reaction mixture was stirred at room temperature for 2-3 hours. The reaction mixture was cooled to 0°C to 5°C and neutralized with 30 ml aqueous ammonia and extracted two times with 25 ml ethyl acetate, ethyl acetate layers were combined and washed with 25 ml water. Ethyl acetate layer was distilled under reduced pressure at 40°C. Ticagrelor was isolated from 20% acetone in heptane mixture and dried under vacuum at 45°C to 50°C.

Yield = 5.36g (Efficiency - 75%, HPLC -99.4%).

Example 7 : preparation of compound of Formula I

50 ml Distilled water and 75 ml concentration HCI were charged to the reaction flask followed by 25 g of 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino]-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]-1-ethanol of formula VII and stirred for 10 to 15 minutes at 20-30°C. 75 ml of isopropyl alcohol was added and again stirred for 1 hour. The reaction mass was filtered, washed with isopropyl alcohol and cooled to 5 to 10°C. To the filtrate liquid ammonia, water were added and stirred till solid precipitated. The temperature was raised to 20 to 30°C and stirred for 2 hours. The solid obtained was washed with water and dried.

Yield = 21 g (Efficiency - 91 %, HPLC -99.0%).

Example 8: Purification of compound of Formula I

To 4.9 (0.00937 moles) g of crude ticagrelor, charged 25ml heptane and 14.8 ml ethyl acetate and heated to 75°C. Cooled to room temperature. Solid was filtered and washed with 10ml of 20% ethyl acetate in heptane. The solid was dried to obtain purified ticagrelor.

Yield = 4.1 g (Efficiency -84%, HPLC - 99.8%)

Example 9 : Purification of compound of Formula I

To 21 g of crude ticagrelor, 168 ml of toluene and 42 ml of acetone were charged and heated to 50-55°C. The reaction mixture was cooled to room temperature. The solid obtained was filtered and washed with 42 ml of toluene. The solid was dried to obtain purified ticagrelor.

Yield = 18g (Efficiency -85%, HPLC - 99.6%) Example 10 : Preparation of compound of Formula VII fumarate salt

4g (0.007109moles) of formula VII was charged in 25ml isopropanol followed by addition of 1.6gm (0.01379moles) of fumaric acid and the reaction mixture was heated to 70-75°C for 30 minutes. The mixture was cooled to room temperature, filtered, dried under reduced pressure at 50-55°C to obtain Formula VII fumarate salt.

Yield= 3.9g. (Efficiency = 80.91 , HPLC-99.38%)

Example 11 : Preparation of compound of Formula VII succinate salt.

4.5g (0.007998moles) of formula VII was charged in 25ml isopropanol followed by addition of 1.8g (0.01524moles) of succinic acid and the reaction mixture was heated to 70-75°C for 30 minutes. The mixture was cooled to room temperature, filtered, dried under reduced pressure at 50-55°C to obtain Formula VII succinate salt.

Yield= 4.0g. (Efficiency = 81.05, HPLC-99.45%)

Claims

1. A process for the pre aration of a solid form of a compound of formula VII,

which process comprises coupling(1 ?,2S)-2-(3,4-difluorophenyl)cyclopropanamine (R)-Mandelic acid of Formula VI with (2-[[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3 --1 ,2,3-triazolo[4,5-d] pyrimidin-3-yl]-2,2-dimethyltetrahydro-3a --cyclopenta[d[[1 ,3]dioxol-4-yl]oxy]-1 -ethanol) of formula V in the presence of a suitable base and a first a suitable solvent at a suitable temperature to form 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1- ethanol of formula VII; and

2. A process according to claim 1 , wherein the suitable base comprises an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal alkoxide, ammonia, an organic amine, or any combination thereof.

3. A process according to claim 2, wherein the suitable base comprises sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide; sodium methoxide, potassium tert-butoxide; sodium carbonate, potassium carbonate, calcium carbonate; sodium bicarbonate, potassium bicarbonate, calcium carbonate; ammonia, tertiary amine (such as a tri (C1-6 alkyl) amine), diisopropylamine, dimethyl amine, diisopropylethylamine, diisopropylmethylamine, pyridine, piperidine, morpholine and N-methyl piperidine, or any combination thereof.

4. A process according to any one of claims 1 to 3, wherein the first suitable solvent comprises an organic solvent, optionally selected from a C-_\ to C₁₀ aliphatic alcohol, a C-_\ to C₁₀ alkane, a halogenated hydrocarbon, an alkyi nitrile, an alkyi ketone, an alkyi sulphoxide, an alkyi amide, or any combination thereof.

5. A process according to any one of claims 1 to 4, wherein the first suitable solvent is selected from the group comprising of dimethylformamide (DMF), dimethylsulfoxide (DMSO), methylene chloride (DCM or CH₂CI₂), methanol, ethanol, isopropanol, isobutanol, n-butanol, ethyl acetate, acetonitrile, acetone, pentane, hexane, heptane, or any combination thereof.

6. A process according to any one of claims 1 to 5, wherein the reaction is carried out at a temperature in the range of 0^°C to 150°C, preferably 20 to 30°C, and more preferably from 25^°C to 30°C.

7. A process according to any one of claims 1 to 6, wherein the suitable third solvent used for isolation of the solid comprises one or more non-polar solvents, optionally selected from a C-_\ to C₁₀ aliphatic or aromatic hydrocarbon, a halogenated hydrocarbon, or any combination thereof.

8. A process according to any one of claim 7, wherein the suitable non-polar solvent comprises hexane, n-heptane, pentane, octane; cyclopentane, cyclohexane; dichloromethane, chloroform; benzene, toluene, or combinations thereof.

9. A process according to any preceding claim, further comprising extracting the compound of formula VII from the first suitable solvent with a second suitable solvent, prior to the isolation step with the third suitable solvent.

10. A process according to claim 9, wherein the second suitable solvent comprises water, an ether, an ester, a halogenated hydrocarbon, a ketone, an aliphatic and aromatic hydrocarbon, or any combination thereof.

1 1. A process according to 9 or 10, wherein the suitable second solvent used for the extraction comprises tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, acetone, toluene, xylene, cyclohexane, hexane, heptane or combinations thereof.

12. A process according to any one of claims 9 to 1 1 , further comprising quenching the reaction mixture with water prior to the step of extracting the compound of formula (VII) with the second suitable solvent.

13. A process according to any one of claim 9 to 12, wherein after the step of extracting the compound of formula (VII) in the second suitable solvent, the second suitable solvent is washed with aqueous acid; optionally followed by washing with basic solution.

14. A process according to claim 13, wherein the basic solution comprises an organic base such as triethylamine (TEA) or diisopropylethylamine (DIPEA), or an inorganic base, such as sodium hydroxide (NaOH), potassium hydroxide (KOH) or potassium carbonate (K₂C0₃), sodium carbonate (Na₂C0₃); or any combination thereof.

15. A process according to any one of claims 9 to 14, further comprising distilling the second suitable solvent to produce a residue of the compound of formula VII; and admixing the residue of the compound of formula VII with the third suitable solvent; before isolating the compound of formula VII from the third suitable solvent.

16. A process according to any any preceding claim, wherein the step of coupling the compound of formula VI with the compound of formula V is carried out for a time period of from 1 to 4 hours.

17. A process according to any preceding claim, wherein the step of isolating the compound of formula VII comprises mixing a residue of the compound of formula VII with the third suitable solvent for a time period of from 15 minutes to 6 hours.

18. A process according to any one of claims 1 to 17, wherein the process is carried out at atmospheric pressure.

19. A process according to any one of claims 1 to 18, wherein the process is not carried out in an autoclave.

20. A process according to any preceding claim, further comprising converting the solid form of the compound of formula VII into an acid addition salt thereof.

21. A process according to claim 20, wherein the acid addition salt is an organic acid addition salt such as a fumarate salt, succinate salt, oxalate salt, formate salt or acetate salt; or an inorganic acid addition salt such as a hydrochloride salt, hydrobromide salt, sulphate salt, or phosphoric acid salt.

22. A process according to claim 20 or 21 , wherein the process comprises reacting the solid compound of formula VII with an acid in a suitable solvent for a time period of from 15 minutes to an hour.

23. A process according to any one of claims 20 to 22, wherein the reaction is carried out at a temperature of from 60°C to 80°C.

24. A process according to any one of claims 20 to 23, wherein the suitable solvent is a C1 to C₆ aliphatic alcohol such as isopropanol.

25. A process according to any preceding claim, wherein the compound of formula V is prepared in situ from the reaction of a compound of formula IV and an alkali metal nitrate or organic nitrite such that the compound of formula VII in a solid form is prepared from the compound of formula IV without isolation of any intermediates.

26. A process for prepari

27. A process according to claim 26, wherein the compound of formula VII is prepared according to a process according to any one of claims 1 to 25.

28. A process according to claim 26 or 27, wherein compound of formula VII is treated with a suitable acid in a suitable solvent to obtain tica relor of formula I.

Formula VII

29. A process according to claim 28, wherein the suitable acid employed comprises an inorganic acid such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid; an organic acid such as acetic acid, trifluoro acetic acid; or any combination thereof.

30. A process according to claim 28 or 29, wherein the suitable solvent comprises water, alcohols such as methanol, ethanol, isopropanol, isobutanol, n-butanol; ketones such as acetone; esters such as ethyl acetate; ethers such as tetrahydrofuan; aliphatic and alicyclic hydrocarbons such as hexane, heptane, cyclohexane; halogenated hydrocarbons such as methylene dichloride, chloroform; aromatic hydrocarbons such as toluene or xylene; nitriles such as acetonitrile; polar aprotic solvents; organic acids such as acetic acid; and any mixtures or combinations thereof.

31. A process according to any one of claims 28 to 30, wherein the suitable solvent comprises water and isopropanol.

32. A process according to any one of claims 26 to 31 , wherein the solid form of the compound of formula VII is in the form of an acid addition salt selected from hydrochloride, sulphate, hydrobromide, phosphate, lactate, malonate, oxalate, succinate or fumarate.

33. A process according to any one of claims 26 to 32, wherein the reaction is carried out for a time period of from 1.5 hours to 3.5 hours, optionally at room temperature.

34. A process according to any one of claims 25 to 33, wherein the total time taken for the preparation of Ticagrelor of formula I from the compounds of formula V and VI is less than 30 hours, less than 25 hours, less than 20 hours, or less than 15 hours.

35. A process according to any one of claims 25 to 33, wherein the process further comprises converting Ticagrelor, the compound of formula I into a medicament.

36. A solid form of 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1 R,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]-1-ethanol of Formula VII either as free base or as an acid addition salt thereof.

Formula VII

37. A solid form as a free base according to claim 36, characterised by a melting point of from about 92.0 to 94.0°C.

38. A solid form as a free base according to claim 36 or 37, characterised by the DSC spectrum shown in figure 3.

39 A solid form of the compound of formula VII according to claim 36, wherein the compound of formula VI is in the form of a succinate salt.

40. A solid form of the compound of formula VII according to claim 39, wherein the succinate salt of the compound of formula VII is characterised by the XRD spectrum of figure 2.

41. A solid form of the compound of formula VII according to claim 36 wherein the compound of formula VII is in the form of a fumarate salt.

42. A solid form of the compound of formula VII according to claim 41 , wherein the fumarate salt of the compound of formula VII is characterised by the XRD spectrum of figure 1.