DESC:Technical Field of the invention:
The present invention relates to an improved and cost effective process for preparation of Ticagrelor in good yield and purity. The invention further relates to novel Polymorphic Form of Ticagrelor and its process for preparation thereof.

Background of the invention:
Ticagrelor chemically known as (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Di fluoro phenyl) cyclo propyl amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy ethoxy) cyclopentane-1,2-diol is a platelet aggregation inhibitor having the following structural formula;

Ticagrelor is indicated for the treatment or prevention of thrombotic actions such as stroke, acute coronary syndrome or myocardial infections, heart attack, other coronary and arterial disorders. It is marketed by Astra Zeneca under the trade name Brilinta in USA and Russia, Brilique and Possia in Europe.

The synthetic process for Ticagrelor is reported in WO00034283 by AstraZeneca. Five to six known synthetic process variants are described in said basic patent application WO’283. The improved processes for preparation of Ticagrelor are provided in WO01/92263 and WO10/ 030224 respectively derived from the originator Astra Zeneca.
Other Patent/Patent Applications which describe the synthesis of Ticagrelor or its related salts, enantiomers are described in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and European Patent Nos. EP0996621, EP1135391, EP2570405, EP2586773 and PCT published documents viz. WO2011017108, WO2012138981, WO2013150495 and WO2014102830.

The synthesis of Ticagrelor as described in the basic patent application no. WO00034283 is shown in Scheme 1 below:

As per the scheme, 4, 6-dichloro-5-nitro-2- (propylthio)-pyrimidine (CLIN) and 3aR- (3aa, 4a, 6a, 6aa)- 6-Amino-tetrahydro-2,2-dimethyl- 4H-cyclopenta-1,3dioxol-4-ol (AMAL) are reacted together in presence of diisopropylethylamine to obtain 3aR- (3aa, 4a, 6a, 6aa)-6- 6-Chloro-5-nitro-2- (propylthio)-pyrimidin-4-yl amino]tetrahydro-2,2-dimethyl4H-cyclopenta-1, 3-dioxol-4-ol (AMALCIN) which is reduced with Fe/AcOH to amino compound [3aR-(3aa,4a,6a,6aa)]-6-[[5-Amino-6-Chloro-2-(propylthio)-pyrimidin-4- yl amino-tetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-ol (AMALCINA). AMALCINA with isopentyl nitrite (iAmONO) produced 3aR- (3aa, 4a, 6a, 6aa)-6- 7-Chloro-5- (propylthio)-3H-1,2, 3-triazolo[4,5-d]pyrimidin-3-yl-tetrahydro-2,2-dimethyl4H-cyclopenta-1,3-dioxol-4-ol (CLTAM) which was treated with ammonia to form 3aR- (3aa, 4a, 6a, 6aa)-6- 7-Amino-5- (propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-ol (ATAM). The side chain was introduced by reacting ATAM with n-butyl lithium and methyl2-((( trifluoromethyl)sulfonyl)oxy)acetate to 3aR- (3aa, 4a, 6a, 6aa)]-[[6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclo penta-1, 3-dioxol-4-ol oxy] acetic acid, methyl ester (MATAM). Reacting MATAM with iAmONO and CHBr3 gave [3aR-(3aa,4a,6a,6aa)]-[[6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidin-3-yl-tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol] oxy] acetic acid, methyl ester (BRTAME). Nucleophilic substitution of bromine in BRTAME with CPA in the presence of iPr2NEt produced 3aR- [3aa,4a,6a(1R*,2S*),6aa]]-[[6-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]5-(propyl thio)-3H-1,2,3-triazolo [4,5-d]-pyrimidin-3-yl]-tetrahydro-2, 2-dimethyl-4Hcyclopenta-1,3-dioxol-4-yl oxy] acetic acid, methyl ester (CPATAME ) which was reduced using DIBAL-H to give 3aR-[3aa,4a,6a(1R*,2S*),6aa]]-2-[6-[[7-[2-(3,4-Difluorophenyl) cyclopropyl amino-5- (propylthio)-3H-1,2,3-triazolo 4, 5-d pyrimidin-3-yl-tetrahydro2,2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl] oxy]-ethanol (CPATAMA). Finally, deprotection of the diol group using trifluoroacetic acid yielded Ticagrelor. The process described is lengthy, uses toxic chemicals such as CHBr3, triflic anhydride and methyl 2-((( trifluoromethyl)sulfonyl)oxy)acetate.

The process described in WO01/92263 is depicted in Scheme 2 below:

According to the process of Scheme 2, the free amino group of 3aR- (3aa, 4a, 6a, 6aa)- 6-amino-tetrahydro-2,2-dimethyl- 4H-cyclopenta-1,3dioxol-4-ol (AMAL) is blocked using CbzCl and a side chain is introduced to produce [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6-amino-2, 2-dimethyl-tetrahydro-4H- cyclopenta-1, 3-dioxol-4-yl] oxy]-ethanol (alternatively named: 2-f [ (3aR, 4S, 6R, 6aS)-6amino-2, 2-dimethyltetrahydro-3aH-cyclopenta [d] [1, 3]-dioxol-4-yl] oxy}-1-ethanol) (AMALA) in first three steps. AMALA is then reacted with 4, 6-dichloro-2- (propylsulfanyl)-5-pyrimidinamine (CLINA) in presence of triethylamine to form [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [ [5-amino-6-chloro-2- (propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol (AMALCINAA). The triazole ring is further introduced by reacting AMALCINAA with NaNO2/AcOH to give [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [7-chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyriinidin-3-yl] tetrahydro-2,2-dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol (CLTAM). The chloro group in CLTAM is substituted using trans- (lR, 2S)-2- (3, 4-Difluorophenyl) cyclopropanaminium (2R)-2-hydroxy-2phenylethanoate to give {3aR- [3aa, 4a, 6a (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2, 2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol (CPATAMA) which on deprotection yields Ticagrelor. The process described in WO’263 is still lengthy and involves protection and deprotection steps.

WO 11/017108 by Auspex Pharmaceuticals discloses synthesis of Ticagrelor as shown in Scheme 3 below:

The intermediate Ethyl 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH- cyclopenta[d][1,3]dioxol-4-yloxy)acetate (AMALE) is obtained by deprotection of ethyl 2-((3aR,4S,6R,6aS)-6-(benzyloxycarbonyl)-2,2-dimethyl-tetrahydro-3aH-cyclo penta [d] [l,3] dioxol-4-yloxy) acetate (ZAMALE) using H2/Pd-C which is further reduced to 2-((3aR,4S,6R.6aS)-6-amino-2.2-dimethyl-tetrahvdro-3aH-cyclopenta[dl[l,31dioxol-4-yloxy) ethanol (AMALA) using LiAlH4. The process disclosed in WO’108 is lengthy and employs corrosive chemicals such as LiAlH4.

Further, WO0192262 has reported the Polymorphic Forms I to IV of Ticagrelor. The process for preparing Polymorph I, comprises obtaining a few seed crystals of Polymorph I from the slow crystal growth of Polymorph I from a melt of Polymorph II, and using this to seed a reaction mixture comprising of the compound of formula (I), and a suitable mixed solvent system such as methanol/water. The process for preparing Polymorph II comprises crystallisation in a suitable solvent such as ethyl acetate. Preparation of Polymorph III comprises crystallisation in a suitable solvent such as an alcohol, for example ethanol or isopropyl alcohol (IPA), in particular seeding with crystals of Polymorph III or slurrying a compound of formula (I) in a suitable solvent such as IPA. Polymorph IV is obtained by crystallisation from a suitable solvent such as acetonitrile, in particular seeding with crystals of Polymorph IV or a period of slurrying a compound of formula (I) in a suitable solvent such as acetonitrile.

The major drawback in the prior art processes for preparation of Ticagrelor is that the synthetic procedures are lengthy, cumbersome, require large amount of reagents and solvents and excess work ups.

The present inventors therefore felt a need to provide a process which is short, industrially feasible and economically improved. To meet the objectives, the present invention provides optimized reaction conditions and optimal use of reagents and avoiding hazardous chemicals. The process according to the present invention increases the efficiency of the reaction and results in product with high purity and improved yield.

The present inventors accidentally explored a novel Polymorphic Form of Ticagrelor which is one of the preferred embodiment of the present invention.

Summary of the invention
With the objective to provide a process for synthesis of Ticagrelor which is industrially and economically viable over the prior art processes, the present invention in its preferred aspect discloses an improved and cost effective process for synthesis of Ticagrelor comprising the steps of:

(i) Condensing 4,6-Dichloro-2-propyl thiopyrimidine-5-amine with 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol, L-tartaric acid salt in presence of cesium carbonate to obtain [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [ [5-amino-6-chloro-2- (propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol followed by purification using non-polar solvent;
(ii) Reacting compound of step (i) with sodium nitrite and acetic acid in DCM as solvent to obtain [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [7-chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol and the organic layer is taken as such without isolation;

(iii) Reacting organic layer of step (ii) with (1R,2S)-2-(3,4difluorophenyl) cyclopropyl amine HCl in presence of potassium carbonate to obtain{3aR- [3aa, 4a, 6aa (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol followed by purification using non-polar solvent; and

(iv) Deprotecting compound of step (iii) in methanol using sulfuric acid to obtain crude Ticagrelor.

The crude Ticagrelor is further crystallized from isobutyl acetate alone or in combination with aliphatic or aromatic hydrocarbon to obtain pure crystallized Ticagrelor Polymorph Form II.

In another aspect, the present invention provides a novel polymorphic Form of Ticagrelor, which is herein after referred as Form-V, characterized by PXRD pattern as shown in Fig 1, TGA in Fig 2 and DSC as shown in Fig 3 and to the process for preparation thereof.

Description of figures
Fig 1 depict the PXRD of Ticagrelor Polymorph Form-V
Fig 2 depict the TGA of Ticagrelor Polymorph Form-V
Fig 3 depict the DSC of Ticagrelor Polymorph Form-V
Fig 4 depict the PXRD of Ticagrelor Polymorph Form-II

Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention relates to a cost effective and industrially feasible process for preparation of Ticagrelor employing optimized reagents and reaction conditions.

In an embodiment of the present process, step 1 comprises condensation of 4,6-Dichloro-2-propylthio-pyrimidine-5-amine with 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol,L-tartaric acid salt. The reaction can be performed in presence of inorganic base selected from alkali or alkaline earth metal carbonates; preferably the reaction is carried using cesium carbonate. The concentration of cesium carbonate can be varied in the range of 1 to 2 mol equivalence. The temperature of the reaction is maintained in the range of 50-110°C for a period of 6 to 24 hrs. After completion of the reaction, the reaction mixture is filtered and the solid is washed with water. The obtained solid is further stirred with about 5 to 15 volumes of non-polar solvent selected from aliphatic or aromatic hydrocarbon such as n-hexane, iso-hexane, n-heptane, iso-heptane, toluene or the like either alone or in combination to obtain a slurry. The temperature is maintained at either r.t or the reaction mixture is heated to about 80-90°C. This is followed by filtration, washing with a non-polar solvent, drying to obtain crude product [3aR- (3aa, 4a, 6a, 6aa)]-2-[6-[5-amino-6-chloro-2-(propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol.

Step 2 of the present process comprises adding [3aR- (3aa, 4a, 6a, 6aa)]-2-[6-[5-amino-6-chloro-2-(propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol of step 1, acetic acid and DCM to the RB flask. This is followed by drop wise addition of sodium nitrite in water for a period of about 10 min at 25-30°C and stirred for about 3 hours to obtain the compound [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [7-chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyriinidin-3-yl] tetrahydro-2,2-dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol. The organic layer is separated and the aqueous layer is extracted further using DCM as solvent. The combined organic layers are washed with water and the organic layer is taken for further reaction without isolation.

According to process step 3, to the organic layer of step 2 is added (1R,2S)-2-(3,4difluorophenyl) cyclopropylamine. HCl and stirred for about 10-20 minutes. Added inorganic base selected from alkali or alkaline earth metal carbonates; preferably potassium carbonate in the concentration ranging from 1 mol% to 3 mol% and stirring for about 4 to 5 hours to obtain the compound {3aR- [3aa, 4a, 6a (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol. The solid is filtered out and the filtrate is washed with water. The organic layer is separated and concentrated on rotavapor. To the crude product obtained is added non-polar solvent selected from aliphatic or aromatic solvent such as n-hexane, iso-hexane, n-heptane, iso-heptane, toluene or the like either alone or in combination; followed by filtration to obtain the pure product.

Step 4 of the process comprises adding pure {3aR- [3aa, 4a, 6a (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol of step 3 and methanol to the RB flask and stirring for about 10 mins. This is followed by addition of 1 to 2 volumes of sulphuric acid at a temperature ranging from 0°C to r.t. and stirring for about 6-7 hours. pH of the reaction mixture is adjusted to 7-7.5 using 5 to 40% of aqueous solution of base selected from NaOH, KOH, carbonates or bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like. The solid obtained is filtered and dried to obtain crude Ticagrelor.

The crude Ticagrelor is crystallized in isobutyl acetate either alone or in combination with non-polar solvents selected from aliphatic or aromatic hydrocarbons at a temperature ranging from room temperature to 80°C to yield crystalline Ticagrelor. The solvent for crystallization preferably is isobutyl acetate and toluene.

Accordingly, in one embodiment crude Ticagrelor is heated with isobutyl acetate using 2 volumes to 6 volumes, preferably 3 volumes, to a temperature in the range of 70-80°C for about an hour. The reaction mass is cooled to room temperature and filtered to obtain pure crystalline Ticagrelor Polymorph, Form-II as shown in Fig.4.

In another aspect, crude Ticagrelor is heated with isobutyl acetate using 2 volumes to 6 volumes, preferably 3 volumes, in combination with non-polar solvent selected from aliphatic or aromatic solvent such as n-hexane, iso-hexane, n-heptane, iso-heptane, toluene or the like; preferably toluene, using 4 volumes to 12 volumes, preferably 6 volumes, at a temperature in the range of 70-80°C for about an hour. The reaction mass is cooled to room temperature and filtered to obtain pure crystalline Ticagrelor Polymorph II as shown in Fig.4

In another preferred embodiment, the present invention discloses a novel Polymorph of Ticagrelor Form V, which is characterised by X-ray powder diffraction peaks at 5.5° (±0.2°), 5.7° (±0.2°), 6.9° (±0.2°), 11.1° (±0.2°), 12.5° (±0.2°), 13.9° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), 18.9° (±0.2°), 21.3° (±0.2°), 22.7° (±0.2°) 2? as shown in Fig 1. The DSC curve of novel polymorph Form V exhibits an endotherm at 133.9°C and an exotherm at 315.6°C as shown in Fig 3; the TGA analysis indicate that Polymorph Form V loses about 99.9% volatiles at 305°C as shown in Fig 2.

In another embodiment, the process for preparation of novel Polymorph Form V of Ticagrelor comprises dissolving Ticagrelor in acetone at a temperature ranging from ambient temperature to about 60°C and precipitating the product using anti-solvent such as water or lower alcohols such as methanol or ethanol either alone or mixture thereof at a temperature ranging from ambient temperature to about 80°C, preferably at ambient temperature. The anti-solvent is preferably water.

The quantity of acetone used in the process is in the range of three to ten volumes, preferably about 3 volumes. The quantity of the anti-solvent is used in the range of five to twenty five volumes, preferably about ten volumes.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the invention. The examples included herein are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Examples:
Example 1:
Preparation of [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [ [5-amino-6-chloro-2- (propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol.
4,6-Dichloro-2-propyl thio-pyrimidine-5-amine (10 g, 0.041 moles), water 50 mL, 2-{[( 3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl] oxy}-1-ethanol,L-tartaric acid salt (16.97 g, 0.046 moles) and cesium carbonate (13.35 g 0.041 moles) were taken in RB flask at 20-25°C and temperature was increased to 100°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was filtered and the solid was washed with 50 mL of water. The solid was further stirred with 100 mL (2 vol) of heptane, filtered and the filter cake was washed with 50 mL of heptane and dried at 25-30°C for 2hr to obtain 16.2 g of product with 92% yield and HPLC purity 99%.

Example 2:
Preparation of [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [7-chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyriinidin-3-yl] tetrahydro-2,2-dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol.
The material of example 1(16 g, 0.038 moles), 160 mL (3.2 vol) of DCM and acetic acid (6.87 g, 0.11 moles) were taken in RB flask. Sodium nitrite solution (2.9 g, 0.042 moles) in 32 mL of water was added drop wise over a period of 10 min at 25-30°C and stirred for 2½ hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction, the organic layer was separated and aqueous layer was extracted with 32 mL of DCM. Combined organic layer was washed twice with 80 mL of water. The organic layer was taken for next step without isolation.

Example 3:
Preparation of 3aR- [3aa, 4a, 6aa (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol
The organic layer from example 2 and (1R, 2S)-2-(3,4diflurophenyl) cyclopropylamine HCl (7.85 g, 0.038 moles) were taken in 2L 3N RB flask and stirred for 10 mins. To this potassium carbonate (15.83 g, 0.11 moles) was added and stirred for 4½hr. The progress of the reaction was monitored by HPLC. After completion of the reaction solid was filtered off and the filtrate was washed with 80 mL water. Organic layer was separated and concentrated on rotavapor. To the crude product 160 mL of Heptane was added. Obtained solid was collected by filtration. 18.3 g of the product was obtained with 85% yield. HPLC purity: 99.3%.

Example 4:
Preparation of crude Ticagrelor
The material (18.3 g, 0.032 moles) of example 3 and Methanol (91.5 mL) were taken in 2L 3N RB flask and stirred for 10 mins. 27.45 mL of sulfuric acid was added to the reaction mixture at 0°C and stirred for 6-8hr. pH of the reaction mixture was adjusted to 7-7.5 with 20% NaOH solution. The solid so formed was filtered and dried to yield 16.1g of crude Ticagrelor Purity 99%.

Example 5:
Purification of crude Ticagrelor using Isobutyl acetate
Crude Ticagrelor (16g; 0.0306moles) obtained in example 4 was added in a reaction flask containing isobutyl acetate (3 vol) and heated to 70-75°C for 1 hour with stirring. The reaction mass was cooled to room temperature and filtered to obtain crystalline Ticagrelor Polymorph Form-II.

Example 6:
Purification of crude Ticagrelor using Isobutyl acetate and Toluene
The crude Ticagrelor (16g, 0.0306 moles) was added to Isobutyl acetate (3vol.) and heated to 70-75°C for 1hr. The reaction mass was cooled and Toluene (6 vol.) was further added. The solid formed was filtered to obtain pure crystalline Ticagrelor with Polymorph Form-II.

Example 7:
Preparation of Ticagrelor Polymorph Form V
Ticagrelor was dissolved in three volumes acetone at ambient temperature and the product was precipitated by adding 10 volumes of water and the mixture was stirred for 2hr. The precipitate was filtered and dried. The product was obtained with 90% yield. It was characterized by, PXRD and DSC which confirmed that substantially pure Polymorph Form V has been formed.
X-ray powder diffraction peaks at 5.5° (±0.2°), 5.7° (±0.2°), 6.9° (±0.2°), 11.1° (±0.2°), 12.5° (±0.2°), 13.9° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), 18.9° (±0.2°), 21.3° (±0.2°), 22.7° (±0.2°) 2? as shown in Fig 1.

Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
,CLAIMS:We Claim;

1. An improved and cost effective process for synthesis of Ticagrelor consisting of;

(i) Condensing 4,6-Dichloro-2-propyl thiopyrimidine-5-amine with 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclo penta [d] [1,3] -dioxol-4-yl]oxy}-1-ethanol, L-tartaric acid salt in presence of inorganic base selected from alkali or alkaline earth metal carbonates to obtain [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [ [5-amino-6-chloro-2- (propylthio)-4- pyrimidinyl] amino] tetrahydro-2,2-dimethyl-3aH-cyclopenta [d] [1,3] dioxol-4yl] oxy] ethanol and purifying;

(ii) Reacting compound of step (i) with sodium nitrite and acetic acid in DCM to obtain [3aR- (3aa, 4a, 6a, 6aa)]-2- [ [6- [7-chloro-5- (propylthio)-3- [1, 2,3] triazolo [4,5-d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-3aHcyclopenta [d] [1, 3] dioxol-4-yl] oxy] ethanol and the organic layer is taken as such without isolation;

(iii) Reacting organic layer of step (ii) with (1R,2S)-2-(3,4difluorophenyl) cyclopropyl amine HCl in presence of potassium carbonate to obtain{3aR- [3aa, 4a, 6aa (lR*, 2S*), 6aa]}-2- [6- ( {7- [2- (3, 4-difluorophenyI) cyclopropyl] amino-5- (propylthio)-3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl} tetrahydro-2,2dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl) oxy] ethanol followed by purification; and

(iv) Deprotecting compound of step (iii) using sulphuric acid in methanol to obtain crude Ticagrelor and purifying.

2. The improved and cost effective process according to claim 1, comprising crystallizing crude Ticagrelor in a solvent system comprising isobutyl acetate alone or in combination with aliphatic or aromatic hydrocarbon to obtain Ticagrelor Form- II

3. The improved and cost effective process according to claim 2, wherein the solvent system comprises isobutyl acetate and toluene.

4. The improved and cost effective process according to claim 1, wherein the inorganic base in step (i) is cesium carbonate.

5. The improved and cost effective process according to claim 4, wherein cesium carbonate used is in the range of 1 to 2 mol equivalence.

6. The improved and cost effective process according to claim 1, wherein the temperature in step (i) is in the range of 50-110?C.

7. The improved and cost effective process according to claim 1, wherein potassium carbonate in step (ii) is 1 mol to 3 mol%.

8. Novel Ticagrelor Polymorphic Form V characterized by an X-ray powder diffraction pattern having peaks at 5.5° (±0.2°), 5.7° (±0.2°), 6.9° (±0.2°), 11.1° (±0.2°), 12.5° (±0.2°), 13.9° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), 18.9° (±0.2°), 21.3° (±0.2°), 22.7° (±0.2°) 2?.

9. The novel Ticagrelor Polymorphic Form V according to claim 8, characterised by DSC having an endotherm at 133.9°C and an exotherm at 315.6°C.

10. The process for preparation of Ticagrelor Polymorphic Form V characterized according to claim 8 and 9, comprising;
(i) dissolving pure crystalline Ticagrelor in acetone; and
(ii) precipitating the Polymorphic Form V using anti-solvent such as water or lower alcohols alone or mixtures thereof.

11. The process according to claim 10, wherein acetone is used in an amount of 3-10 volumes and anti-solvent in an amount 5-25 volumes.