Claims:WE CLAIM:

1. An improved process for the preparation of Ticagrelor, comprising the steps of;

a) 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / water to obtain 2-(((3aR,4S,6R,6aS)-6-((5- amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv),

b) The compound of formula (xiv) undergoes cyclisation in presence of NaNO2 to obtain 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxo-4-yl)oxy)ethan-1-ol (xv),

c) The compound of formula (xv) is reacted with (1R,2S)-2-(3,4-difluorophenyl) cyclopropane amine hydrochloride salt (xiiib) in presence of base / solvent to obtain 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,2]triazolo[4,5 -d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol -4-yl)oxy)ethan-1-ol (xii),

d) The compound of formula (xii) is deprotected in presence of acid to obtain Ticagrelor.

2. The process as claimed in claim 1, wherein the solvent is selected from ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dichloride, ethylene dichloride, dimethyl amino formamide, tetrahydrofuran, toluene, benzene and xylene or mixtures thereof.

3. The process as claimed in claim 1, wherein the base is selected from methyl amine, triethyl amine, pyridine, phenyl amine, ammonia, tertiary butyl amine.

4. The process as claimed in claim 1, wherein the acid is selected from, Trifluoro acetic acid, acetic acid, hydrochloric acid, methyl sulphonic acid.

5. A process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate and solvent.

, Description:
The present invention relates to an improved, commercially viable, industrially advantageous and cost effective process for the preparation of Ticagrelor with good yield and purity.

BACKGROUND OF THE INVENTION

Ticagrelor is a platelet aggregation inhibitor. 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.

Ticagrelor is a reversible allosteric antagonist of P2Y12. This prevents ADP binding to the P2Y12 receptor. Because it is not a prodrug, it may be of use to patients who are poor metabolizers as they may not receive as much benefit from a prodrug. Plasma concentrations of ticagrelor are higher in the elderly, women, patients of Asian ethnicity, and those with hepatic impairment. Plasma concentrations are decreased in patients with darker skin and those with severe renal impairment. Japenese patients have 40% higher plasma concentrations than Caucasian patients. This difference decreases to 20% when corrections for body weight are made. Ticagrelor has not been tested in severe hepatic impairment.

Ticagrelor chemically known as (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluoro phenyl) cyclopropyl 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 Ticagrelor;

Ticagrelor
Ticagrelor is reported in WO 00034283 by AstraZeneca. The synthetic process for Ticagrelor is reported in WO00034283. Five to six known synthetic process variants are described in said basic patent application WO’283. The compound of formula (ii) is reacted wit the compound of formula (iii) in presence of DIPEA to obtain the compound of formula (iv). The compound of formula (iv) is reduced with Fe / AcOH to obtain the compound of formula (v). the compound of formula (v) converts into the compound of formula (vi) in presence of i-AmONO. The compound of formula (vi) is reacted with NH3 to obtain the compound of formula (vii). The compound of formula (vii) is reacted with ester compound in presence of BuLi to obtain the compound of formula (viii). The compound of formula (viii) undergoes bromination to obtain the compound of formula (ix). The compound of formula (ix) is reacted with the compound of formula (xiii) in presence DIPEA to obtain the compound of formula (x). the compound of formula (x) deprotected with DIBAL-H to obtain the compound of formula (xii). The compound of formula (xii) converts into Ticagrelor in presence of CF3CO2H.

The above process is schematically shown as below:

WO 01/92263 discloses process for the preparation of Ticagrelor, which comprises the compound of formula (xvi) is reacted with the compound of formula (xi) in presence of TEA to obtain the compound of formula (xiv). The compound of formula (xiv) undergoes cyclisation in presence of NaNO2 / AcOH to obtain the compound of formula (xv). The compound of formula (xv) is reacted with CPA (xiii) in presence of TEA to get the compound of formula (xii). The compound of formula (xii) converts into Ticagrelor in presence of HCl.

The above process is schematically shown as below:

WO 11/017108 of Auspex pharmaceuticals discloses a process for the preparation of Ticagrelor (I), which comprises the compound of formula (ii) is reacted with the compound of formula (xi) to obtain the compound of formula (xvii). The compound of formula (xvii) undergoes reduction in presence of Fe / AcOH to obtain the compound of formula (xiv). The compound of formula (xiv) undergoes cycliation in presence of NaNO2 / AcOH to obtain the compound of formula (XV). The compound of formula (XV) is reacted with CPA (xiii) in presence of DIPEA to obtain the compound of formula (xii). The compound of formula (xii) converts into Ticagrelor in presence of HCl.

The above process is schematically shown as below:

IN 8073/CHENP/2014 of Dr.Reddy’s discloses a process for the preparation of Ticagrelor, which comprises, the compound of formula (xvi) is reacted with the compound of formula (xia) in presence of sodium bicarbonate / water / toluene or sodium bicarbonate / isoamyl alcohol / toluene to obtain the compound of formula (xiv). The compound of formula (xiv) converts into the compound of formula (xv) in presence of NaNO2 / HCl and water. The compound of formula (xv) is reacted with the compound of CPA mandelate salt (xiiia) in presence of EtOAc / 20% NaOH soln and DIPEA to obtain the compound of formula (xii). The compound of formula (xii) converts into Ticagrelor in presence of hydrochloric acid.

The above process is schematically shown as below:

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. Therefore there remains a need to prepare Ticagrelor and it’s intermediates of good purity and yield where total synthesis time is short and overcoming the drawbacks presented by the processes described in the art.

In view of the foregoing, the present inventors have result of extensive studies, the efficiency is extremely only for the process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5- amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethanol from 4,6-dichloro-2-(propylthio)pyrimidin-5-amine is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt in presence of sodium carbonate (Na2CO3) / H2O / EtOAc (or) sodium carbonate (Na2CO3) / alcohol solvent.

In order to evaluate eco-friendly, industrial feasible process for preparation of Ticagrelor (I). our inventors surprisingly found with the use of sodium carbonate (Na2CO3) / H2O / EtOAc (or) sodium carbonate (Na2CO3) / alcohol solvent in the condensation reaction with advantages of low consumption of solvents with good yield and purity.

None of the above prior-art processes teaches nor suggests the use of sodium carbonate (Na2CO3) / H2O / EtOAc (or) sodium carbonate (Na2CO3) / alcohol solvent in the condensation reaction.

SUMMARY OF THE INVENTION

The present invention relates to an improved, commercially viable, industrially advantageous and cost effective process for the preparation of Ticagrelor with good yield and purity.

In one aspect of the present invention, provides an process for the preparation of Ticagrelor, comprising the steps of;

a) 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate (Na2CO3) / water to obtain 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclo penta[d][1,3]dioxol-4-yl)oxy) ethanol (xiv).

b) The compound of formula (xiv) undergoes cyclisation in presence of NaNO2 to obtain 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxo-4-yl)oxy)ethan-1-ol (xv).

c) The compound of formula (xv) is reacted with (1R,2S)-2-(3,4-difluorophenyl) cyclopropane amine hydrochloride salt (xiiib) in presence of base / solvent to obtain 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,2]triazolo[4,5 -d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol (xii).

d) The compound of formula (xii) is deprotected in presence of acid to obtain Ticagrelor.

In another aspect of the present invention provides an process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv) which comprises, 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / water.

In another aspect of the present invention provides an process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / solvent.


DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved, commercially viable, industrially advantageous and cost effective process for the preparation of Ticagrelor with good yield and purity.

In one embodiment of the present invention, provides an process for the preparation of Ticagrelor (I), comprising the steps of;

a) 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / water to obtain 2-(((3aR,4S,6R,6aS)-6-((5- amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv).

b) The compound of formula (xiv) undergoes cyclisation in presence of NaNO2 to obtain 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxo-4-yl)oxy)ethan-1-ol (xv).

c) The compound of formula (xv) is reacted with (1R,2S)-2-(3,4-difluorophenyl) cyclopropane amine hydrochloride salt (xiiib) in presence of base / solvent to obtain 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,2]triazolo[4,5 -d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol -4-yl)oxy)ethan-1-ol (xii).

d) The compound of formula (xii) is deprotected in presence of acid to obtain Ticagrelor.

According to the embodiment of the present invention process for the preparation of Ticagrelor which comprises, 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / water to obtain 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv). The compound of formula (xiv) undergoes cyclisation in presence of sodium nitrate to obtain 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxo-4-yl)oxy)ethan-1-ol (xv). The compound of formula (xv) is reacted with (1R,2S)-2-(3,4-difluorophenyl) cyclopropane amine hydrochloride salt (xiiib) in presence of triethyl amine / acetic acid and ethyl acetate to obtain 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,2]triazolo[4,5-d]pyrimidi n-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol (xii). The compound of formula (xii) is deprotected in presence of hydrochloric acid to obtain Ticagrelor.

In an embodiment of the present invention provides, wherein the solvent is selected from ethanol, methanol, isopropyl alcohol, ethyl acetate, water, acetic acid, cyclohexane, methylene dichloride, ethylene dichloride, dimethyl amino formamide, tetrahydrofuran, toluene, benzene and xylene or mixtures thereof.

In an another embodiment of the present invention provides, wherein the base is selected from methyl amine, triethyl amine, pyridine, phenyl amine, ammonia, tertiary butyl amine.

I an embodiment of the present invention provide, wherein the acid is selected from, Trifluoro acetic acid, acetic acid, hydrochloric acid, methyl sulphonic acid.

Another embodiment of the present invention provides an process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / water.

In another aspect of the present invention provides an process for the preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro -3aH-cyclopenta [d][1,3]dioxol-4-yl)oxy) ethanol (xiv) which comprises, 4,6-dichloro-2-(propylthio) pyrimidin-5-amine (xvi) is reacted with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethanol L-tartaric acid salt (xia) in presence of sodium carbonate / solvent.
The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention