DESC:FIELD OF INVENTION:

The present invention relates to a novel process for the preparation of Ticagrelor intermediate.

BACKGROUND OF THE INVENTION:

U.S. Patent Nos. 6,251,910 and 6,525,060 disclose a variety of triazolo[4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. Among them, Ticagrelor, [l S-(la,2a,3P(lS*,2R*),5P)]-3-[7-[2-(3,4- difluorophenyl)cyclo propyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl)- 5-(2-hydroxyethoxy)-cyclopentane-l,2-diol, acts as Adenosine uptake inhibitor, Platelet aggregation inhibitor, P2Y12 purinoceptor antagonist and Coagulation inhibitor. It is indicated for the treatment of thrombosis, angina, Ischemic heart diseases and coronary artery diseases. Ticagrelor is represented by the following structural formula I:

Various processes for the preparation of ticagrelor, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282 and 2008/0214812; and European Patent Nos. EP0996621 and EP1135391 and PCT Publication Nos. WO2008/018823 and WO2010/030224, WO2012/138981.

However in the above all process for the preparation of Ticagrelor it contains so many reaction steps and therefore to maintain chirality & purity is difficult in such long reaction.

Therefore, there is a need to develop an improved and commercially viable process of preparing pure Ticagrelor which is suitable for large-scale preparation, in lesser reaction time, in terms of simplicity, purity and yield of the product. Employing intermediates of the present invention in the process for the preparation of Ticagrelor, overcomes the drawbacks of the prior art and may be prepared and subsequently converted to Ticagrelor in high yield and purity.

OBJECT OF THE INVENTION

In one general object there is provided a novel process for the preparation of Ticagrelor intermediate of formula (f).

In another aspect present invention provides a process for preparation of Ticagrelor comprising reaction of compound of formula (d) with [(1R, 2S)-2-(3,4-difluorophenyl) cyclopropanamine] to obtain compound of formula (e)

Formula (d) Formula (e)

In another aspect present invention provides a process for preparation of Ticagrelor comprising reducing compound of formula (e) to obtain compound of formula (f).

Formula (e) Formula (f)

Yet another object of the present invention is to use the compound of formula (a), (b), (c), (d), (e) and (f) for the preparation of Ticagrelor.

DETAILED DESCRIPTION OF THE INVENTION:

An embodiment of the present invention provides a novel process for the preparation of Ticagrelor intermediate.

In another embodiment of the present invention provides a novel process for the preparation of compound of formula (f), comprising:

Formula (f)
a) reacting of compound of formula (a) with 4,6-dichloro-5-nitro-2 (propylthio)pyrimidine to obtain compound of formula(b).

Formula (a) Formula (b)

b) reducing compound of formual (b) to obtain compound of formula (c).

Formula (c)
c) Cyclizing compound of formula (c) to obtain compound of formula (d).

Formula (d)
d) reacting compound of formula (d) with [(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine] to obatain compound of formula (e)

Formula (e)
e) reducing compound of formula (e) to obtain compound of formula (f).

Yet, another embodiment of the present invention is a novel intermediates of compound of formula (a), (b), (c), (d), (e) and (f) and their use in preparation of Ticagrelor.

The main embodiment of the present invention is to provide a novel process for preparing Ticagrelor intermediate, which can be shown by scheme-I.

Scheme-I

The object of the invention will be explained in a more detailed way by means of the following examples, which however do not have any influence on the scope of the invention defined in the claims.

Examples
Example-1: Preparation of ethyl {[(1S, 4R)-4-{[6-chloro-5-nitro-2-(propylsulfanyl) pyrimidin-4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate

To a cooled solution of tetrahydrofuran (50 mL) and [4,6-dichloro-5-nitro-2-(propylsulfanyl) pyrimidine] (21.49 g, 0.08 moles) was added previously prepared solution of [ethyl {[(1S,4R)-4-aminocyclopent-2-en-1-yl]oxy}acetate] (10.0 g, 0.053 moles), Sodium carbonate (14.17 g, 0.133 moles) and water (50 mL). Stirred the reaction mixture for 2-3 hours at 0-5°C. Product was extracted by Ethyl acetate followed by distillation to give [ethyl {[(1S, 4R)-4-{[6-chloro-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate] (17.0 g, 75.0%).

Example-2: Preparation of [ethyl {[(1S,4R)-4-{[5-amino-6-chloro-2-(propylsulfanyl) pyrimidin -4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate]:

Iron powder (20.09, 0.359 moles) was added to a solution of [ethyl {[(1S, 4R)-4-{[6-chloro-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate] (15 g, 0.035 moles) in acetic acid (150 mL) at 20-30°C. Stirred the reaction mixture up to completion of the reaction. Filtered iron salts through hyflo followed by distillation of acetic acid. Water was Charged and product was extracted with ethyl acetate followed by distillation to give [ethyl {[(1S,4R)-4-{[5-amino-6-chloro-2-(propylsulfanyl)pyrimidin-4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate] (12.0 g, 86%).

Example-3: Preparation of [ethyl ({(1S,4R)-4-[7 -chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate ]:

Isoamylnitrite (5.45g, 0.046 moles) and Acetonitrile (60 mL) was added to a stirred solution of [ethyl {[(1S,4R)-4-{[5-amino-6-chloro-2-(propylsulfanyl)pyrimidin-4-yl]amino}cyclopent-2-en-1-yl]oxy}acetate (12.0 g, 0.031 moles) at 20-30°C. Stirred the reaction mixture up to completion of the reaction at 65-75°C followed by distillation to give [ethyl ({(1S,4R)-4-[7 -chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate ] (10.0 g, 81%).

Example-4: Preparation of [ethyl ({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate ] -formula(e):

To a stirred solution of [ethyl ({(1S,4R)-4-[7 -chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate ] (10.0 g, 0.025 moles) in dichloromethane was added [(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine] (8.43g, 0.026 moles) ,diisopropylethylamine (12.96 g, 0.10 moles) at 20-30°C. Stirred the reaction mixture for 12 hours. Water was Charged and product was extracted with dichloromethane followed by distillation to give [ethyl ({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate](10.0 g, 71%)

Example-5: Preparation of [({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyl-ethoxy)cyclopent-2-en-1-yl}]:-formula(f):

Lithium borohydride (1.1 g, 0.04 moles) was added to a stirred solution of [ethyl ({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopent-2-en-1-yl}oxy)acetate ](10.0 g, 0.018 moles) in tetrahydrofuran (15 mL). The reaction mixture was Stirred for 3-4 hrs at 20-30°C followed by quenching the reaction mass using acetic acid (10 mL). Water was Charged and product was extracted with ethyl acetate followed by distillation of solvent to give [({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyl-ethoxy)cyclopent-2-en-1-yl}]- (7.5 g, 86%).

Example-6: Preparation of Ticagrelor [({(1S,2S,3R,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyl-ethoxy)cyclopentane – 1,2-diol}]

To a solution of [({(1S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino-chloro-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyl-ethoxy)cyclopent-2-en-1-yl}](7.5 g, 0.015 moles) in acetone (33.8 mL) and water (27.45 mL) ,N-methyl Morpholine N-oxide (3.77 g, 0.03 moles) and osmium tetroxide (0.039 g) was added at 20-25°C. Stir the reaction mixture for 24 hours at 20-25°C. Reaction mixture was quenched with sodium thiosulfate followed by distillation of acetone yielding crude residue which was crystallized from ethyl acetate and cyclohexane to give pure Ticagrelor (5.62 g, 70%).

,CLAIMS:WE CLAIM:

1. A novel process for the preparation of compound of formula (f), comprising:

Formula (f)
a) reacting of compound of formula (a) with 4,6-dichloro-5-nitro-2 (propylthio)pyrimidine to obtain compound of formula(b);

Formula (a) Formula (b)

b) reducing compound of formual (b) to obtain compound of formula (c);

Formula (c)
c) Cyclizing compound of formula (c) to obtain compound of formula (d);

Formula (d)
d) reacting compound of formula (d) with [(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine] to obatain compound of formula (e);

Formula (e)
e) reducing compound of formula (e) to obtain compound of formula (f).

Formula (f)
2. A process for preparation of Ticagrelor comprising reaction of compound of formula (d) with [(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine] to obtain compound of formula (e)

Formula (d) Formula (e)

3. A process for preparation of Ticagrelor comprising reducing compound of formula (e) to obtain compound of formula (f).

Formula (e) Formula (f)

4. Use of the compound of formula (a), (b), (c), (d), (e) and (f) for the preparation of ticagrelor.