FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – NOVEL PROCESS FOR THE PREPARATION OF
TICAGRELOR
2. Applicant(s)
(a) NAME : ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which is to be
preformed :

Cross Reference to Related Applications:
This application claims the benefit of priority to Indian provisional application Nos. 2693/MUM/2012, filed on September 17, 2012; and 3147/MUM/2012, filed on October 30, 2012; which is incorporated herein by reference in their entirety.
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.
In the preparation of ticagrelor, (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol, alternatively named as [3aR- (3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol, of formula II: is a key starting material.

Various processes for syntheses of free amine or hydrochloride salt of substituted cyclopentanoloamine derivatives are apparently disclosed in U.S. Patent No. 6,525,060; PCT Publication No. WO99/05142; Synthetic communications 31(2001) 18, 2849-2854; Tetrahedron, 1997, 53, 3347; Helv. Chim. Acta, 1983, 66, 1915; Tetrahedron, 1997, 53, 3347; and Tetrahedron Lett., 2000, 41, 9537.
According to U.S. Patent No. 6,525,060 (hereinafter referred to as the '060 patent), the [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l ,3- dioxol-4-ol of formula II is prepared by a process as depicted in scheme 1.


PCT Publication No. WO 2010/022121 (hereinafter referred to as the ' 121 application) describes a process for the preparation of [3aR-(3aa,4a,6a,6aa)]-6-amino- tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol.

U.S. Patent No.7,067,663; and PCT Publication Nos. WO2009/064249 and WO2010/030224 disclose L-tartrate, dibenzoyl-L-tartrate and oxalate salts of substituted cyclopentanoloamine derivatives.
According to the ‘60 patent, ticagrelor is prepared using [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol hydrochloride salt.
The processes for the preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol of formula II described in the above mentioned prior

art have the following disadvantages and limitations:
a) long reaction times, low yields and low purities of the products;
b) the time required for the oxidation reaction is 4 days, which is industrially not feasible;
c) the processes involve the use of excess amounts of osmium tetroxide, which is an expensive and hazardous reagent, in the oxidation reaction (d) the processes involve the use of expensive column chromatographic purifications; methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible; and e) the overall processes generate a large quantity of chemical waste which is difficult to treat.
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.
In another object of the present invention is to provide novel intermediates; compound of formula (d), compound of formula (e), compound of formula (h), compound of formula (g) and compound of formula (j)


Yet another object of the present invention is to use compound of formula (d), compound of formula (e), compound of formula (h), compound of formula (g) and compound of formula (j) 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.
One embodiment of the present invention is to provide process for the preparation of cyclopentanoloamine derivative of formula IIa,

or an acid addition salt thereof; wherein R1 and R2 both represents hydrogen or a protecting group, or R1 and R2 together with the atoms to which they are attached form an alkylidine ring such as methylidene or isopropylidine ring; comprising:
a) reacting camphorsultam derivative of formula (b) with cyclopentadiene to get compound of formula (c)


b) oxidizing compound of formula (c) to get compound of formula (d)

c) protecting compound of formula (d) to get compound of formula (h)

formula (h)
d) hydrolysis of compound of formula (h) to get compound of formula (i)

e) reducing compound of formula (i) to get compound of formula (IIa).
Another embodiment of the present invention is to provide process for the preparation of cyclopentanoloamine derivative of formula IIa,


or an acid addition salt thereof; wherein R1 and R2 both represents hydrogen or a protecting group, or R1 and R2 together with the atoms to which they are attached form an alkylidine ring such as methylidene or isopropylidine ring; comprising:
a) reacting camphorsultam derivative of formula (b) with cyclopentadiene to
get compound of formula (c)

b) oxidizing compound of formula (c) to get compound of formula (d)

c) protecting compound of formula (d) to get compound of formula (h)

d) Reducing compound of formula (h) and then hydrolysis to get compound
of formula (j)


e) Hydrolysing compound of formula (j) to get compound of formula (IIa).
Further embodiment of the present invention is to provide novel intermediates; compound of formula (d), compound of formula (e), compound of formula (h), compound of formula (g) compound of formula (j)

Yet another embodiment of the present invention is to use compound of formula (d), compound of formula (e), compound of formula (h), compound of formula (g) and compound of formula (j) for the 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-1 and scheme-II

The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention.
Examples
Example-1:Preparation of compound formula (c):
To a cooled solution of THF (2.5 L) and Triphosgene (344.5 g, 1.16 moles) and camphor Sultam (250.0 g, 1.16 moles) was added triethylamine (352.5 g, 3.48 moles) at 0 to -5°C. Stirred the reaction mixture for 2-3 hours at 25-30°C. Aqueous solution of Hydroxyl amine (403.5 g) and potassium carbonate was added to the reaction mixture at 25-30°C. Stirred the reaction mixture for 1-2 hours at 25-30°C. Product extracted by MDC followed by distillation to give crude residue which dissolved in methanol and water. Added cyclopentadiene (268.2 g) and sodium metaperiodate (270.7 g) to reaction mass at 0-5°C. Stirred the reaction mixture up to completion of reaction at 0-5°C. Product extracted with ethyl acetate followed by distillation gives crude residue which is further crystallized with MTBE to get pure formula (c) (325.0 g, 82.0%).
Preparation of compound formula (d):
To a solution of formula- (c ) (265.0 g) in acetone (1.1 L) and water (31.8 mL) charged N-methyl morpholine N-oxide (385.8 g) and osmium tetroxide (398 mg) at 20-25°C. Stirred the reaction mixture up to completion of the reaction. Reaction mass quenched with sodium thiosulfate followed by distillation of acetone yields pure formula (d) (282.0 g, 96%).
Preparation of compound formula (e):
To a stirred solution of formula (d) (225.0 g) and acetone (1.1 L) was added p-toluene sulfonicacid and Dimethoxy propane (188.7 g). Stirred for 2-3 hrs at 25-30°C gives formula (e) (225.0 g, 91%).
Preparation of compound formula (f):
Lithium hydroxide (1.87 g, 2.3 eq) was added to a stirred solution of formula(e) (8.0 g, 1.9 mmol) in acetonitrile. Stirred the reaction mixture for 3-4 hrs at 40-45°C followed by distillation of acetonitrile yields formula (f) as a white solid (2.21 g, 66.67%).

Preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][l,3]-dioxol-4-ol ( formula II) :
To a stirred solution of formula(f) (10.0 g) in methanol was hydrogenated by using Pd/C and hydrogen gas pressure (3-4 kg/cm2) at 25-30°C gets crude material of formula II, which is further crystallized with hexane to get pure product (9.5 g, 95.0%).
Preparation of compound formula (g):
To a solution of formula (e) (10.0 g) in acetonitrile was hydrogenated with hydrogen gas pressure (5-6 kg/cm2) in presence of palladium carbon at 25-30°C for 24 hrs. Palladium catalyst was filtered through hyflo. Lithium hydroxide and water was added to filtrate and stirred for 2 hours at 55-60°C. After distillation of acetonitrile; cooled the reaction mass to 25-30°C. The precipitated product was obtained by filtration yields formula (g) (2.7 g, 56%)
Preparation of (3aR,4S,6R,6aS)-6-amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-ol (formula-II) :
To a stirred solution of formula (g) (2.5 g) and potassium tert butoxide in THF was heated to 60-65°C for 12-15 hrs. Cooled the reaction mixture to 25-30°C. Charged water and product extracted with ethyl acetate. Distilled off ethyl acetate under vacuum to get crude product. Crude residue crystallized in hexane. (2.08 g, Yield: 95%)

Claims We claim:
1. A process for the preparation of cyclopentanoloamine derivative of formula IIa,

or an acid addition salt thereof; wherein R1 and R2 both represents hydrogen or a protecting group, or R1 and R2 together with the atoms to which they are attached form an alkylidine ring such as methylidene or isopropylidine ring; comprising:
f) reacting camphorsultam derivative of formula (b) with cyclopentadiene to
get compound of formula (c)

g) oxidizing compound of formula (c) to get compound of formula (d)

h) protecting compound of formula (d) to get compound of formula (h)

i) hydrolysis of compound of formula (h) to get compound of formula (i)


j) reducing compound of formula (i) to get compound of formula (IIa).
2. A process for the preparation of cyclopentanoloamine derivative of formula IIa,

or an acid addition salt thereof; wherein R1 and R2 both represents hydrogen or a protecting group, or R1 and R2 together with the atoms to which they are attached form an alkylidine ring such as methylidene or isopropylidine ring; comprising:
a) reacting camphorsultam derivative of formula (b) with cyclopentadiene to
get compound of formula (c);

b) oxidizing compound of formula (c) to get compound of formula (d);

c) protecting compound of formula (d) to get compound of formula (h);


d) Reducing compound of formula (h) and then hydrolysis to get compound
of formula (j);

e) Hydrolysing compound of formula (j) to get compound of formula (IIa).
3. The intermediate compound of formula (d) and its use in preparation of
Ticagrelor.

4. The intermediate compound of formula (h) and its use in preparation of Ticagrelor.
5. The intermediate compound of formula (j) and its use in preparation of Ticagrelor.


6. Use of the substantially pure [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl- 4H-cyclopenta-l,3-dioxol-4-ol obtained by the process of claim 1 and 2 in the process for manufacture of ticagrelor or a pharmaceutically acceptable salt thereof.