DESC:Field of invention:

The present invention relates to an improved process for the preparation of Ticagrelor.

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, [lS-(la,2a,3P(lS*,2R*),5P)]-3-[7-[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-l,2-diol, 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 enantiomer 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.
However in the above all process for the preparation of Ticagrelor results in law yield and therefore it is difficult for industrial application.

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.

Summary of the invention:

In one general aspect there is provided an improved process for the preparation of Ticagrelor.
In one aspect of present invention provides a process which comprise reacting compound of formula (A) or a salt thereof with a compound of formula (B) or a salt thereof, in presence of base and solvent to form a compound of formula (C) .

Suitable bases that can be employed include, but are not limited to: inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, N-methyl Morpholine N-oxide, DABCO (1,4-diazabicyclo[2.2.2]octane) and the like. In a preferred embodiment, diisopropylethylamine has been employed as suitable base.

Suitable solvents that can be employed include, but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n- butanol, isoamylalcohol, ethylene glycol, water, polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, nitriles, such as acetonitrile, dimethylsulfolane, dioxane, cyclohexanone and diglyme and the like, and any mixtures of two or more thereof. In a preferred embodiment, sulfolane is employed as a suitable solvent.
Mixtures of polar protic and polar aprotic solvent can also be employed.

In another aspect compound of formula (C) is cyclized into compound of formula (D) in presence of oxalic acid dihydrate and sodium nitrite in presence of suitable solvent.

Suitable solvent that can be employed include, polar aprotic solvent like dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, dimethylacetamide and the like. In a preferred embodiment, tetrahydrofuran is employed as a suitable solvent.

Detailed Description of the Invention:

An embodiment of the present invention provides an improved process for the preparation of Ticagrelor.

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

Scheme-I

Other main embodiment of the present invention is to synthesis of compound of formula-C or its pharmaceutical salts thereof by reaction between compound of formula-A or its pharmaceutical acceptable salts thereof with compound of formula-B or its pharmaceutical acceptable salts thereof in presence of suitable base and suitable solvent.

Suitable bases that can be employed include, but are not limited to: inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, and the like; and organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, N-methyl Morpholine N-oxide, DABCO (1,4-diazabicyclo[2.2.2]octane) and the like. In a preferred embodiment, diisopropylethylamine has been employed.

Suitable solvents that can be employed include, but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamylalcohol, ethylene glycol, water, polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, nitriles, such as acetonitrile, dimethylsulfolane, dioxane, cyclohexanone and diglyme and the like, and any mixtures of two or more thereof. In a preferred embodiment, sulfolane is employed as a solvent.
Mixtures of polar protic and polar aprotic solvent can also be employed.

A suitable salt of compound of Formula-A employed is a salt of a mineral or organic acid. Suitable mineral acids for salt formation include hydrochloric, hydrobromic, hydroiodic, nitric, and sulphuric acid. Suitable organic acids include organic achiral acids such as acetic, trifluoroacetic, oxalic, succinic acid, formic acid and p-toluenesulphonic acids, and organic chiral acids such as L-tartaric acid, dibenzoyl-L-tartaric acid, and di-p-toluoyl-L-tartaric acid. Preferably, organic acid is employed and more preferably, L-tartaric acid is used.

Other embodiment of our present invention is isolation of compound of formula-C and crystallization of compound of formula-C by use of solvent cyclohexane and water.

Other embodiment of our present invention is to synthesize of compound of formula-D by cyclization of compound of formula-C in presence of suitable organic acids, sodium nitrite and suitable organic solvents.

Suitable organic acids that can be employed include, but are not limited to lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid. In a preferred embodiment, oxalic acid is employed as a suitable organic acid.

Suitable solvent that can be employed include, polar aprotic solvent like dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, dimethylacetamide and the like. In a preferred embodiment, tetrahydrofuran is employed as a suitable solvent.

In other embodiment of our invention is purification of ticagrelor by use of solvent ethylacetate and cyclohexane.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

Examples:
Example-1: Preparartion 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: [Formula: (C)]

Charged Sulfolane (100 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 (100 g) [Formula (A)], 4,6-dichloro-2-(propylsulfonyl)-5-pyrimidinamine [Formula (B)] (81 g) and diisopropylethylamine (175.9 g) in RBF at ambient temperature. The reaction mass was heated at 103±2°C for 7-8 hrs. After completion of the reaction charged water (1000 mL) and methyl t-butyl ether (500 mL) into the reaction mixture and stirred it for 30 min. Organic layer which contains product was separated. Aqueous layer was extracted 2-3 times by methyl t-butyl ether and combined the organic layer. Combined organic layer was washed with aqueous acetic acid (500 mL). Organic layer was separated and distilled out solvent under vacuum. Charged cyclohexane (1000 mL) and water (500 mL) and stirred the reaction mass for 6-7 hrs. Filtered the material and washed the wet cake with cyclohexane (200 mL). The material was dried under vacuum.

Example-2: preparation of preparation of [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]]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy] ethanol. [Formula (E)]

Charged THF (500 mL), [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 (100 gm) and oxalic acid dihydrate (32.24 g) in to RBF and then stirred the reaction mixture for 15 min. Then, Solution of Sodium nitrite (17.65 gm) prepared in water (10.0 mL) was added into the reaction mixture. Stirred it for 15 minutes at 10±5°C and then heated the reaction mixture to 40±5°C for 90 minutes. After completion of the reaction filtered the undissolved salt and washed it with methylene chloride (500 mL). Charged filtrate into RBF and aqueous sodium bicarbonate solution was added (500 mL) to adjust pH of the reaction mass to 7.0 to 8.0. Stirred it for 30 minutes and then separated out upper organic layer. Charged (1R-trans)-2-(3,4-difluorophenyl)-cyclopropanamine tartrate salt (74.31 g), DIPEA (150.03 g) into the above organic layer and stirred the reaction for 4-5 hrs. After completion of the reaction charged water (100 mL) and stirred it for 30 minutes. Upper organic layer was separated and washed it with 5% aqueous acetic acid solution (500 mL). Organic layer was collected and again wash it with aq. Sodium bicarbonate solution (500 mL). Organic layer was separated out and charged charcoal (10 g) to the org. layer and stirred the reaction mixture for 30 minutes. Filtered the reaction mixture through hyflo bed and washed the bed with methylene chloride (100 mL). Distilled out solvent under vacuum at 47±3°°C. Charged Ethyl acetate (100 mL) and n-heptane (150 mL) into residual mass and charged seed crystal of formula-E into it. Stirred it for 1-2 hrs at 47±3°C. Cooled the reaction mixture to 2±3°C. Filtered out the material and dried it.

Example-3: preparation of Ticagrelor

Charged [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]]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy] ethanol (100 g) and methanol (500 mL) in RBF. Cooled the reaction mass to -2±3°C. Conc. HCl (108.28 ml) was added into the reaction mass at -2±3°C. Stirred it for 1-2 hrs at 2±3°C. After completion of the reaction charged methyl t-butyl ether (500 mL) into the reaction mass. Then, aqueous sodium hydroxide solution (985.8 mL) was added to the reaction mass to adjust pH in between 8-9. Organic layer was collected and aqueous layer was extracted 2-3 times by methyl t-butyl ether (500 mL). Combined the organic layer. Into the organic layer charcoal (10 g) was added and heated the reaction mixture to 40±5°C for 30 min. Reaction mixture was filtered through hyflo-bed. Solid product was collected into it ethylacetate (680 mL) was added and heated to 67±3°C. Cyclohexane (900 mL) was added into it and stirred the reaction mixture for 1 hrs. The reaction mixture was cooled to 27±3°C and was filtered through hyflo bed. Solid product was collected and was dried under vacuum.

,CLAIMS:1. An improved process for the preparation of Ticagrelor compound of formula –I or pharmaceutical acceptable salt thereof

comprising,
a. reacting compound of formula-A or salt thereof with compound of formula-B or salt thereof, in presence of suitable organic base and sulfolane to form compound of formula-C or salt thereof.

b. cyclization of a compound of Formula-C or its salts in presence of sodium nitrite, oxalic acid dihydrate in presence of THF solvent to from compound of formula-D or its pharmaceutical acceptable salts.

c. reaction of compound of formula-D with (1R-trans)-2-(3,4-difluorophenyl)-cyclopropanamine tartrate salt in presence of diisopropylethylamine and methylene chloride to form compound of formula-E.

d. deprotection of compound of formula-E to form Compound of formula-I.

2. An improved process for the preparation of Ticagrelor or pharmaceutical acceptable salt thereof comprising,

a. reacting compound of formula-A or salt thereof with compound of formula-B or salt thereof, in presence of suitable organic base and sulfolane to form compound of formula-C or salt thereof.

b. converting compound of formula-C or a pharmaceutical salt thereof to compound of formula-I or a pharmaceutical acceptable salt thereof.

3. The process of preparation of Ticagrelor according to claim 2, further comprising,
a. isolation and purification of compound of formula-C by use of solvent cyclohexane and water.
b. cyclization of compound of formula-C to form compound of formula-D.
c. reaction of compound of formula-D with (1R-trans)-2-(3,4-difluorophenyl)-cyclopropanamine tartrate salt in presence of diisopropylethylamine and methylene chloride to form compound of formula-E.

d. deprotection of compound of formula-E in presence of mineral acid like conc. HCl and alcoholic solvent like methanol to form compound of formula-I
e. purification of Ticagrelor by means of crystallization is done by use of solvent ethyl acetate and cyclohexane.

4. The process according to claim 2, wherein compound of formula-A is present in the form of L-tartrate salt.

5. The process according to claim 2, wherein organic suitable base is selected from morpholine, triethylamine, diisopropylethylamine, N-methyl Morpholine, N-methyl Morpholine N-oxide, DABCO (1,4-diazabicyclo[2.2.2]octane) or mixtures thereof.

6. The process for the preparation of Ticagrelor of formula-I, comprising,


a. cyclization of a compound of Formula-C or its salts in presence of sodium nitrite, oxalic acid dihydrate in presence of THF solvent to from compound of formula-D or its pharmaceutical acceptable salts.

b. converting compound of formula-D or a pharmaceutical salt thereof to compound of formula-I or a pharmaceutical acceptable salt thereof.

7. The process of preparation of Ticagrelor according to claim 6, further comprising,
a. reaction of compound of formula-D with (1R-trans)-2-(3,4-difluorophenyl)-cyclopropanamine tartrate salt in presence of diisopropylethylamine and methylene chloride to form compound of formula-E.

b. deprotection of compound of formula-E in presence of mineral acid like conc. HCl and alcoholic solvent like methanol to form compound of formula-I
c. purification of ticagrelor by means of crystallization is done by use of solvent ethylacetate and cyclohexane.