Description:FIELD OF THE INVENTION
The present application provides an impurity controlled process for the preparation of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine is a potential intermediate for the preparation of Ticagrelor in high yields and purity, which is suitable for manufacturing in commercial scale.

BACKGROUND OF THE INVENTION
Ticagrelor is a platelet aggregation inhibitor is chemically known as (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and having the following chemical structure.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation.

Several processes have been discussed in the literature for the preparation of Ticagrelor and their pharmaceutically acceptable salts, which are disclosed in US6525060, US 7067663, US7250419, W02000/034283, WO2008018823 and W02010030224.

Patent application WO99/05143 discloses for the first time triazole[4,5- d]pyrimidine derivatives as P2T receptor antagonists, including among others ticagrelor, as well as a process for its preparation. This process is based on the incorporation of an amino group to the triazole[4,5-d]pyrimidine ring previously formed and subsequent transformation of the substituents of the lateral chains. The triazole[4,5-d]pyrimidine ring can be prepared by a diazotization reaction of a free amino group of a pyrimidine compound. The amino group is derived from a nitro group which is reduced using a metal catalyst.

Several synthetic methods have been reported in the literature to prepare 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine of formula (I)

Patent application WO2001/92263 discloses a preparation process for ticagrelor based on the preparation of the compound 4,6-dichloro-2-(propylthio)pyrimidin5-amine by hydrogenolisis of a diazo compound. The disadvantage of the process is usage of Platinum reagents which are costly and formation of deschloro impurities are observed and not convenient to manufacture in industrial scale.

WO2005095358 discloses the below process to prepare intermediate compound of formula (I) as shown below. The disadvantage of the process is usage of Platinum and vanadium catalysts reagents for amine formation which are costly and formation of deschloro impurities are observed and not convenient to manufacture in industrial scale.

WO2014/023681 discloses the below process to prepare intermediate compound of formula (I) as per the following synthetic scheme. As the overall yield are very low, the process is not viable for commercial scale production.

WO2011036479 particularly discloses the below nitro to amine reduction process using Platinum/ ammonium orthomolybdate/Phosphorous acid catalyst, which is commercially not a viable catalyst to produce the required intermediate in industrial manufacturing scale.

WO2011101740A1 discloses the below process to prepare 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (nitro compound of ticagrelor intermediate).

WO2012138981 and WO2013060837 discloses the nitro to amine reduction process by using Iron (Fe)/acetic acid in presence of as protic solvents like ethanol, methanol, and isopropanol. The disadvantages are formation of deschloro and hydroxy impurities and the obtained yields in both patents are 90% and 73% respectively.

2434/CHE/2014 disclosed the below process to prepare compound of formula (I), uses NiCl2 and NaBH4 for nitro reduction, which is not suitable for commercial scale production.

The main disadvantages of the all the above processes which consists of nitro to amine reduction are low yielding and formation of below shown deschloro and hydroxy impurities.

, , and
Nitro reduction plays an important role in the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine with single maximum controlled impurity levels of NMT 0.1. Therefore, still there is need for the development of commercially viable, impurity controlled and cost-effective process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine a Ticagelor intermediate compound of formula (I).

SUMMARY OF THE INVENTION
The present invention provides an impurity-controlled process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine a Ticagelor intermediate compound of formula (I).

In an aspect of the present application provides an impurity controlled process for preparation of compound formula (I)

which comprises
a) reacting thio urea with diethyl malonate in presence of sodium methoxide and methanol gives sodium thiobarbiturate compound of formula (II);

Formula (II)
b) sodium thiobarbiturate compound of formula (II) on alkylation with n-propyl bromide in presence of sodium hydroxide and TBAB gives 2-(ethylthio)pyrimidine-4,6-diol compound of formula (III);

Formula (III)
c) reacting 2-(ethylthio)pyrimidine-4,6-diol compound of formula (III) with fuming nitric acid and acetic acid gives 5-nitro-2-(propylthio)pyrimidine-4,6-diol compound of formula (IV);

Formula (IV)
d) reacting compound of formula (IV) with POCl3 in presence of bases like triethylamine or diisopropyl ethylamine and solvents like toluene gives 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine compound of formula (V);

Formula (V)
a) compound of formula (V) undergoes reduction in presence of iron (Fe), acetic acid and in solvents like combination of hydrocarbon non polar solvents and protic solvents at an appropriate temperature gives amine compound of formula (I); wherein the hydrocarbon non polar solvents are selected from benzene, cyclohexane, hexane, toluene, xylene, MTBE and protic solvents are selected from methanol, ethanol or isoproponol

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the present invention particularly describes impurity controlled process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine a Ticagelor intermediate compound of formula (I).

In one embodiment the following scheme- 1 describe the process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine compound of formula (I).

Scheme 1
In one embodiment stage (a) of the present process involves reacting thiourea with diethylmalonate in presence bases like metal alkoxides in a suitable solvent gives sodium salt of thio barbiturate compound of formula (II); wherein the metal alkoxide bases are selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the suitable solvents are selected from methanol, ethanol, isopropanol, tert-butanol or mixture thereof.

In another embodiment stage (b) of the present process involves alkylation of sodium salt of thio barbiturate with propyl halides in presence of a suitable base, a phase transfer catalyst gives 2-(ethylthio)pyrimidine-4,6-diol compound of formula (III); wherein propyl halides are selected from n-propyl bromide, n-propyl chloride, or n-propyl iodide; wherein the phase transfer catalysts are selected from TBAB, TBAHS or TBAI.

In another embodiment stage (c) of the present process involves nitration of compound of formula (III) in presence of fuming nitric acid and acetic acid gives at a temperature of 5-10 0C gives 5-nitro-2-(propylthio)pyrimidine-4,6-diol compound of formula (IV);

In another embodiment stage (d) of the present process involves chlorination of compound of formula (IV) with POCl3 in presence of a base and in suitable solvent gives chloro compound of formula (IV); wherein the suitable base is selected from TEA, DIPEA or N, N dimethyl aniline or N, N ethyl aniline and the solvents are selected from Toluene, acetonitrile, cyclohexane etc.

In another embodiment stage (e) of the present process involves reduction of compound of formula (V) with a suitable reducing agent and presence of a solvent gives amine compound of formula (I); wherein the suitable reducing agent is selected from Iron (Fe) in acetic acid, sodium dithionate, Pd/C, Pt/C etc and the suitable solvent is selected from combination of hydrocarbon nonpolar solvents and protic solvents. Nonpolar hydrocarbon solvents are selected from a) benzene, cyclohexane, hexane, toluene, xylene, MTBE, and protic solvents are selected from methanol, ethanol, or isopropanol. Most preferable reducing agent is Iron (Fe) in acetic acid and the most preferable solvent is the combination of toluene and ethanol.

In another embodiment the present invention provides an impurity-controlled conversion of nitro to amine i.e., compound of formula (IV) to compound of formula (I) wherein single maximum impurities are controlled at a level of not more than 0.1
In another embodiment the present invention provides a process to control the below mentioned impurities at level of not more than 0.1.
and
The below summarized table provides prior art reaction conditions, solvents and yields obtained in the process for the preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine to 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine.

# Patent Reaction conditions Solvents used Yield Drawbacks/
Disadvantages
1 WO2005095358 Pt/Vanadium hydrogen MTBE NA Costly reagents
2 WO2012138981 Fe/ Acetic acid Methanol 95% Formation of impurities
3 WO2013060837 Fe/ Acetic acid No solvent 73% Low yield and impurities formation
4 CN103923020 Pd/H2 Ethanol 90% Low yield and impurity formation
5 2434/CHE/2014 NiCl2/ NaBH4 Methanol 80% Costly reagents and low yielding

The obtained level of the impurities are shown below in the process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine from 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by using the reducing reagents like Fe/Acetic acid and the solvents like methanol and ethanol. The level of impurities impacts the purity of ticagrelor and difficult to produce the intermediate compound of formula (I) in tonnage levels.

S. No Impurity structure Percentage
1
0.9%
2
0.24%
3
0.33%

In another embodiment the present invention provides an impurity controlled process for the preparation of 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine from 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by using the reducing reagents like Fe/Acetic acid and the solvents like combination of toluene- methanol, toluene-ethanol and toluene- isopropanol. The controlled level of impurities is shown below.
S. No Impurity structure Percentage
1
0.02%
2
0.02%
3
0.02%

In another embodiment the present invention summarized in below provides impurity controlled and high yielding reaction conditions and solvents used for the conversion of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine to 4, 6-Dichloro-2-(propyithio)pyrimidin-5-amine.
# Reaction conditions Solvents used Yield Advantages
1 Fe/ Acetic acid Ethanol and Toluene combination 97% High yielding and Impurities are controlled at a level of single maximum impurity NMT < 0.1%

In another embodiment the below are the abbreviations are used in the specification.
HCl- Hydrochloric acid, NaOH- Sodium Hydroxide, MTBE- Methyl tertiary butyl ether, TEA- Triethyl amine, DIPEA- Diisopropyl ethyl amine, NiCl2- Nickel Chloride, NaBH4- Sodium borohydride, POCl3- Phophorous oxychloride, TBAB- Tetrabutyl ammonium bromide, TBAHS- tetrabutyl ammonium hydrogen sulphate, TBAI- tetrabutyl ammonium iodide, Pd/C- Palladium on carbon, Pt/C- Platinum on carbon, Na2SO4- Sodium sulphate, NMT- not more than, HPLC- High performance liquid chromatography.

EXAMPLES
Example 1
Preparation of 2-(ethylthio)pyrimidine-4,6-diol

To a solution of Thiourea (100 g, 1.0 eq) in methanol (500 mL) was added Diethyl malonate (358 g,1.7 eq) at 25-35°C. Then Slowly 30% Sodium methoxide solution (108 g, 1.7 eq) at 45-50°C for a period of 1-2 hrs. The temperature of the reaction mass was raised to 55-60 0C and maintained at the same temperature for 1-2 hrs. After the completion of the reaction the reaction mass was cooled to 0 -5 0C, then filtered and washed the solid with methanol. The dried material was transferred into another reactor and water (300 mL) was added to the reactor and cooled to 10-150C. Sodium hydroxide (85 g, 3.5 eq) was added to the reaction and maintain the reaction mass at the same temperature for 15-20 min. Then TBAB and n-propyl bromide (93 g,1.2 eq) were added to the reaction mass at same temperature. The temperature of the reaction mass was raised to 50-55 0C and maintained at the same temperature for 5 hrs. Water was added to the reaction mass at 25-30 0C and stir for 30 min. The pH of the reaction mass was adjusted to 4.0 to 5.0 with Con.HCl at 25-30°C. Stir the reaction mass at the same temperature for 2 hrs. The reaction mass was filtered and dried to obtain the desired product. Yield: 230.0gm (95.8%), Purity By HPLC: 97.7%.
Example 2:
Preparation of 5-nitro-2-(propylthio)pyrimidine-4,6-diol

In a reactor acetic acid (350 mL) was charged and cooled to 15 – 20 0C. Then fuming nitric acid (120g, 1.5 eq) was added below 20 0C, the reaction mass stirred at same temperature for 15-20 min. To the reaction mass 2-(ethylthio)pyrimidine-4,6-diol (100 g, 1 eq) was added at 10-20 0C. The reaction was maintained at 30-35°C for 60-90 min. After the completion of the reaction water was added to the reaction mass at maintained at 350C for 2 hrs. The reaction mass was filtered to obtain the desired product. Yield: 112.0gm (92.8%), Purity By HPLC: 99.3%.
Example 3:
Preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine

To a solution of 5-nitro-2-(propylthio)pyrimidine-4,6-diol (100 g, 1.0 eq) in toluene (1000 mL) was added Phosphorous oxychloride (243 g, 3.3 eq) under nitrogen atmosphere at 10- 150C. Then at the same temperature slowly N, N-Diisopropylethylamine (167 g, 3.0 eq) was added. The reaction mass was heated to 70 – 75 0C and maintained for 12 hrs at the same temperature. After completion of the reaction the solvent was completely distilled off under reduced pressure. The reaction mass was cooled to 5-10 0C and water was added to the reaction mass at the same temperature. To the reaction mass toluene (500 mL) was added at the same temperature. The organic layer was separated dried over Na2SO4 concentrated under vacuum to obtain the desired product. Yield: 110.0gm (95.3%), HPLC purity:98.9%.
Example 4:
Preparation of 4,6-dichloro-2-(propylthio)pyrimidin-5-amine

To the reactor Acetic acid (300.0ml) and Ethanol (50.0ml) were added at 25 – 35 0C. To the solution 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (100 g,1.0 eq) was added at the same temperature. To the reaction mass toluene (500 mL) was added and Iron (Fe) powder (85 g) was added lot wise. The temperature of the reaction mass raised to 60 – 65 0C and maintained at the same temperature for 5 hrs. After completion of the reaction the reaction mass was filtered over celite bed to remove the undissolved material. The filtrate was distilled off completely. To the reaction mass HCl solution was added below 30 0C. Toluene (300 mL) was added to the reaction mass, the organic layer was separated, sodium bicarbonate solution was added to the organic layer. The organic layer separated and dried over Na2SO4 and concentrated under vacuum to provide the crude material. The crude material was triturated with hexane (300 mL) to obtain the pure material. Yield: 86.0 g (97.0%) and Purity by HPLC:99.91%.
 
, Claims:1. A process for the preparation of compound of formula (I)

which comprises
b) reacting thio urea with diethyl malonate in presence of sodium methoxide and methanol gives sodium thiobarbiturate compound of formula (II);

Formula (II)
c) sodium thiobarbiturate compound of formula (II) on alkylation with n-propyl bromide in presence of sodium hydroxide and TBAB gives 2-(ethylthio)pyrimidine-4,6-diol compound of formula (III);

Formula (III)
d) reacting 2-(ethylthio)pyrimidine-4,6-diol compound of formula (III) with fuming nitric acid and acetic acid gives 5-nitro-2-(propylthio)pyrimidine-4,6-diol compound of formula (IV);

Formula (IV)
e) reacting compound of formula (IV) with POCl3 in presence of bases like triethylamine or diisopropyl ethylamine and solvents like toluene gives 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine compound of formula (V);

Formula (V)
f) compound of formula (V) undergoes reduction in presence of iron (Fe), acetic acid and in solvents like combination of toluene and protic solvents at an appropriate temperature gives amine compound of formula (I); wherein the protic solvents are selected from methanol, ethanol or isopropanol.
g) optionally purifying compound of formula (I).
2. A process for the preparation of compound of formula (I)

wherein
a) compound of formula (V) undergoes reduction in presence of iron (Fe), acetic acid and in solvents like combination of hydrocarbon nonpolar solvents and protic solvents gives amine compound of formula (I); wherein the hydrocarbon nonpolar solvents are selected from benzene, cyclohexane, hexane, toluene, xylene, MTBE, and protic solvents are selected from methanol, ethanol, or isopropanol.

Formula (V)
3. The process as claimed in claim 2, compound of formula (V) undergoes reduction in presence of iron (Fe), acetic acid and in solvents like combination of toluene and ethanol.