A PROCESS FOR THE PREPARATION OF CANGRELOR AND INTERMEDIATES THEREOF
FIELD OF THE INVENTION
The present invention relates to a process for preparation of Cangrelor or its pharmaceutically acceptable salts and intermediates thereof.
BACKGROUND OF THE INVENTION
Cangrelor is chemically known as ([dichloro-[[[(2JR,3'S'34^J5/?)-3)4-dihydroxy-S-te^-methylsulfanylethylamino^-CS.S^-trifluoropropylsulfanylJpurin^-ylloxolan -2-yl]methoxy-hydroxyphosphoryl]oxyhydroxyphosphoryl]methylJphosphonic acid, tetrasodium salt (I).
Cangrelor has been approved by US FDA as Cangrelor tetrasodium salt under the brand name KENGREAL®. It is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein Ilb/IIIa inhibitor.
The patent US 572129 describes cangrelor or its pharmaceutically acceptable salts and its process for preparation.
Ingall et al, Journal of Medicinal Chemistry, 42, 213-220, 1999 describes a process for preparation of cangrelor and its intermediates.

The process for preparation of cangrelor and its intermediates available in the prior arts associated with formation of impurities, low yield and require chromatographic techniques for purification and/or isolation. Therefore, there is a need in the art to prepare highly pure cangrelor and its intermediates using industrially and economically viable process.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides a process for preparation of compound of formula (II) comprising;
a) N-giycosytation of 2,6-dihalo purine having compound of formula (1) with D-ribofuranose of compound of formula (2) to obtain a compound of formula (3)
b) 6-amination of compound of formula (3) by reacting it with 2-aminoethyl methyl sulfide or its salts to obtain a compound of formula (4)
t3> (4)
c) thionation of compound of formula (4) to obtain thiol compound of formula (5) and

d) thioalkylation of thiol compound of formula (5) with compound of formula (6) to obtain a compound of formula (II).
Another embodiment of the invention provides a process for preparation of compound of formula (II) comprising;-
a) amination of 2,6-dihalopurine (1) using 2-aminoethyl methyl sulfide to obtain a compound of formula (7)
(1) (?)
b) thionation of compound of formula (7) to obtain thiol compound of formula (8)
c) thioalkylation of compound of formula (8) to obtain compound of formula (9)
d) N-glycosylation of compound of formula (9) to obtain a compound of formula (10) and

e) O-deprotection of compound of formula (10) to obtain a compound of formula (II)
Still another embodiment of the invention provides a process for preparation of cangrelor or its pharmaceuticaliy acceptable salts using the compound of formula (II) obtained from the processes described herein.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention provides a process for preparation of compound of formula (II) comprising;
a) N-glycosylation of 2,6-dihalo purine having compound of formula (1) with D-ribofuranose of compound of formula (2) to obtain a compound of formula (3)
b) 6-amination of compound of formula (3) by reacting it with 2-aminoethyl methyl sulfide or its salts to obtain a compound of formula (4)

c) thionation of compound of formula (4) to obtain thiol compound of formula (5)and
d) thioalkylation of thiol compound of formula (5) with compound of formula (6) to obtain a compound of formula (II).
2, 6-dihalo purine is synthesized by reacting xanthine with phosphoryl halide compounds. The phosphoryl halide is selected from phosphoryl chloride, phosphoryl bromide and phosphoryl iodide. Further, 2,6-dihalo purine can be synthesized by any methods known in the prior arts.
N-Glycosylation of 2,6-dihalopurine of compound of formula (1) with D-ribofuranose of compound of formula (2) is carried out in the presence of base, silylating agents and solvent. D-ribofuranose comprises optional protection of hydroxy! group; preferably protected D-ribofuranose. The "P" represents the hydroxyl protecting group which is selected from acetyl, benzoyl and the like and

independently present in the compound. The base is selected from organic base such
as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine,
diisopropylethylamine, morpholine, N-methyl morpholine, 1,4-
diazabicyclo[2.2.2]octane (DABCO) and the like; preferably DBU. Silylating agent is selected from N,0-Bis(trimethylsilyl)trifluoroacetamide (BSTFA), Trimethylsilyl chloride (TMSCI), Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like; preferably TMSOTf.
The solvent used in the N-glycosylation is selected from polar aprotic solvent such as acetone, acetonitrile, N,N-dimethy! formamide, N, N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane and the like or the mixture thereof; preferably acetonitrile. The reaction is carried out in the temperature range between 20°C and 90°C; preferably 40-80°C. The glycosylation is carried out in the presence of catalytic amount of lewis acid selected from triflic acid, acetic acid, aluminium trichloride (AIC^), boron trichloride (BC13), ferric chloride (FeCb), boron trifluoride (BF3), boron trifluoride etherate (BF3OEt2), zinc chloride (ZnCl2), aluminum bromide and aluminum chloride THF complex; preferably triflic acid.
6-amination of compound of formula (3) is carried out using 2-aminoethyl methyl sulfide or its salt in the presence of base and solvent. The salt is selected from acid addition salt such as HCI, HBr and the like. The base is selected from organic base such as l,8-Diazabicyclo[5.4.0)undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methyl morpholine and 1,4-diazabicyclo[2.2.2]octane (DABCO); preferably triethylamine.
The solvent is selected from polar solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, isoamylalcohol, ethylene glycol, water and the like; acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, I, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane

& the like or the mixture thereof; preferably alcohol. The amination reaction is carried out in the temperature range between 20-90°C; preferably 40-80°C.
Thionation reaction of compound of formula (4) is carried out using alkali metal hydrosulfide in the presence of solvent. Alkali metal hydrosulfide is selected from sodium or potassium hydrosulfide and the like; preferably sodium hydrosulfide. The solvent is selected from polar protic solvent or aprotic solvent or mixture thereof. The protic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isoamylalcohol, ethylene glycol, water and the like. The polar aprotic solvent is selected from acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane & the like; preferably N,N-dimethyl formamide. The reaction is carried in the temperature range between 20-140°C; preferably 40-120°C.
The thionation reaction comprises addition of additives selected from sodium iodide, potassium iodide, tetrabutyl ammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), lithium chloride, lithium iodide and the like; preferably sodium iodide.
The thioalkylation of compound of formula (5) is carried out using 1,1,1,-trifluoro-3-halopropoane (6) in the presence of base and solvent. The base is selected from inorganic bases such as metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide and the like; metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate and the like; metal alkoxide such as sodium methoxide, sodium terMmtoxide, potassium terf-butoxide and the like; metal hydride such as lithium hydride, sodium hydride, potassium hydride, calcium hydride and the like; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organ lithium compound such as methyl lithium, n-butyl lithium, /erf-butyl lithium or the like; an alkaline earth metal

amide or alkali earth metal amide such as lithium amide, sodium amide, lithium diisopropyl amide, sodium hexamethyl disilazide or the like; preferably sodium hydroxide and organic base such as 3,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, l,4-diazabicyclo[2.2.2]octane (DABCO) and the like; preferably DBU.
The solvent is selected from polar protic solvent or aprotic solvent or mixture thereof. The protic solvent is selected from methanol, ethanol, propanol, isopropanol, n- butanol, isoamylalcohol, ethylene glycol, water and the like or mixture thereof. The polar aprotic solvent is selected from acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane & the like. The reaction is carried in the temperature range between 20-140°C; preferably 40-123°C.
The present invention provides a process wherein the compounds of formula (3), (4), (5) & (II) are may be isolated or without isolation (in-situ process) the compounds are subjected to further reaction. Isolation may be carried out by extraction, evaporation, precipitation, column purification and the like.
The present invention provides the compound of formula (II) having purity >99%; preferably >99.5%; more preferably >99.9%.
Another embodiment of the invention provides a process for preparation of compound of formula (II) comprising;
a) amination of 2,6-dihalopurine of compound of formula (1) by reacting it with 2-aminoethyl methyl sulfide or its salt to obtain a compound of formula (7)

b) thionation of compound of formula (7) using alkali thiosulfide to obtain thiol compound of formula (8)
c) thioalkylation of compound of formula (8) to obtain compound of formula (9)
d) N-glycosylation of compound of formula (9) to obtain a compound of formula (10) and
e) O-deprotection of compound of formula (10) to obtain a compound of formula (II)
2, 6-dihalo purine of formula (1) is synthesized by reacting xanthine with phosphoryl halide compounds. The phosphoryl halide is selected from phosphoryl chloride, phosphoryl bromide and phosphoryl iodide. Further, 2,6-dihalo purine can be synthesized by any methods known in the prior arts.

The amination of 2,6-dihalopurine of compound of formula (1) by using 2-aminoethyl methyl sulfide or its salt is carried out in the presence of base and solvent. The salt is selected from acid addition salt such as HC1, HBr and the like. The base is selected from organic base such as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine and 1,4-diazabicyclo[2.2.2]octane (DABCO); preferably diisopropylethylamine.
The solvent is selected from polar solvent such as methanol, ethanol, propanol, isopropanol, n- butanol, isoamylalcohol, ethylene glycol, water and the like; acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane & the like or the mixture thereof. The amination reaction is carried out in the temperature range between 20-90°C; preferably 40-80°C.
The present invention provides the compound of formula (7) having purity >99%; preferably >99.5%; more preferably >99.9%.
Thionation of compound of formula (7) is carried out using alkali metal hydrosulfide in the presence of solvent. Alkali metal hydrosulfide is selected from sodium or potassium hydrosulfide and the like; preferably sodium hydrosulfide. The solvent is selected from polar protic solvent or aprotic solvent or mixture thereof. The polar protic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol, isoamylalcohol, ethylene glycol, water and the like. The polar aprotic solvent is selected from acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane & the like; preferably N.N-dimethylformamide. The reaction is carried in the temperature range between 20-140°C; preferably 40-123°C.

The thionation reaction comprises optional addition of of additives selected from potassium iodide, tetrabutyl ammonium iodide (TBAI), tetrabutylammonium bromide (TBAB), sodium iodide, lithium chloride, lithium iodide and the like.
The process of the present invention mentioned in step (b) controls the formation of the below S-S dimer impurity well within the acceptable limit.
1H-NMR (DMSO-d6, 400 MHz,): 5H 7.96 (2H, s, H3&H3'), 3.55(4H, s,H8&H8'), 2.56 (4H, S.H9&H9'), 1.98 (6H, s H10&H10'), 12.93 (2H, s, H4&H4'), 7.96 (1H, s, H7&H7'), HRMS (ESI) calcd for C16H20N10S4: 480.07552 (fM+H]+), found; 481.08319 ([M+H]+). IR (KBr, cm-1): 3441.01 (-1MH s), 1620.21 (C=N, s), 628.79 (C-S, s).
The present invention provides the compound of formula (8) having purity >99%; preferably >99.5%; more preferably >99.9%.
The thioalkylation of compound of formula (8) is carried out using 1,1,1,-trifluoro-3-halopropoane (6) in the presence of base and solvent. The base is selected from inorganic base such as metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide and the like; metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; metal alkoxide such as sodium methoxide, sodium /er/-butoxide, potassium /erMxitoxide and the like; metal hydride such as lithium hydride, sodium hydride, potassium hydride, calcium hydride and the like; organ lithium compound such as methyl lithium, n-butyl lithium, ter/-butyl lithium or the like; an alkaline earth metal amide or alkali earth meta! amide such as lithium amide, sodium amide, lithium diisopropyl amide, sodium hexamethyl disilazide or the like; preferably sodium

hydroxide and organic base such as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methyl morpholine, l,4-diazabicyclo[2.2.2]octane (DABCO) and the like; preferably DBU.
The solvent is selected from polar protic solvent or aprotic solvent or mixture thereof. The protic solvent is selected from methanol, ethanol, propanol, isopropanol, n- butanol, isoamylalcohol, ethylene glycol, water and the like. The polar aprotic solvent is selected from acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane & the like; preferably methanol. The reaction is carried in the temperature range between 20-l40°C; preferably 40-123°C.
The process of the present invention mentioned in step (c) controls the formation of the below sulfoxide impurity well within the acceptable limit.
1H-NMR (DMSO-d6, 400 MHz,): 8H 7.99 (2H, s, H8&H 10), 12.83( IH, s,H9), 3.82 (2H, br s,Hl 1), 2.90-2.96 (1H, m, H12a), 3.08-3.15 (1H, m, H12b), 2.58 (3H, s, H13), 3.24 (2H, t s,H 15), 2.65-2.77 (2H, m, H16), HRMS (ESI) calcd for C11H14F3N50S2: 353.0591, found; 354.0664 [M+H]+. IR (KBr, cm-1): 1039.63 (S=0, s), 1620.21 (C=N, s), 628.79 (C-S, s).
The present invention provides the compound of formula (9) having purity >99%; preferably >99.5%; more preferably >99.9%.
N-Glycosylation of compound of formula (9) with D-ribofuranose of compound of formula (2) is carried out in the presence of, silylating agents and solvent. D-ribofuranose comprises optional protection of hydroxyl group; preferably protected D-ribofuranose. The "P" represents the hydroxyl protecting group which is

selected from acetyl, benzoyl and the like and independently present in the compound. Further, the N-glycosylation optionally involves use of base. The base is selected from organic base such as l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methyi morpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like. Silylating agent is selected from N,0-Bis(trimethylsilyl)trifluoroacetamide (BSTFA), Trimethylsilyl chloride (TMSCI), Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the like; preferably BSTFA.
The solvent used in the N-glycosylation is selected from polar aprotic solvent such as acetone, acetonitrile, N,N-dimethyl formamide, N, N-dimethyl acetamide, dimethyl sulfoxide, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran(THF), 1,4-dioxane and the like or the mixture thereof; preferably acetonitrile. The reaction is carried out in the temperature range between 20°C and 90°C; preferably 40-80°C. The glycosylation is carried out in the presence of catalytic amount of lewis acid selected from triflic acid, acetic acid, aluminium trichloride (AICI3), boron trichloride (BCI3), ferric chloride (FeCI3), boron trifluoride (BF3), boron trifluoride etherate (BFjOEt2), zinc chloride (ZnCl2), aluminum bromide and aluminum chloride THF complex; preferably triflic acid.
The present invention provides the compound of formula (10) having purity >99%; preferably >99.5%; more preferably >99.9%.
O-deprotection of compound of formula (10) is carried out in the presence of base in solvent. "P" represents the O-protecting group and independently selected from acetyl, benzoyl and the like. The base is selected from metal hydroxide such as sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide and the like; metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate and the like; preferably sodium hydroxide. The solvent is selected from polar protic solvent such as methanol, ethanol, propanol,

isopropanol, n- butanol, isoamylalcohol, ethylene glycol, water and the like; preferably water.
The process of the present invention mentioned in step (e) controls the formation of the below sulfoxide impurity well within the acceptable limit.
1H-NMR (DMSO-d6, 400 MHz,): 5H 8.27 (1H, s, H8), 8.22 (1H, br s, H10), 3.80-3.93 (3H, m, H11& H20), 2.90-2.96 (1H, m, H12a), 3.08-3.15 (IH, m, H12b), 2.58 (3H, s, H13), 3.28 (2H, t, H14), 2.66-2.78 (2H, m, H15), 5.82 (IH, d, J= 6.0 Hz, HI7), 4.53-4.58 (IH, m, H18) 4.08-4.13(lH, m, H19), 3.60-3.66(IH, m, H2Ja), 3.50-3.56 (IH, m, H21b), 5.05 (IH, t, J= 5.2&6.0HZ, H22) 5.17 (IH, d, J= 4.8Hz, H23), 5.42 (IH, d, J= 6.0Hz, H24) LC-MS calcd for C16H22F3N505S2: 485.49, found; 486.2 [M+H]+. IR (KBr, cm-1): 1055.06 (S=0, s), 1624.06 (ON, s), 628.79 (C-S, s).
The present invention provides the compound of formula (II) having purity >99%; preferably >99.5%; more preferably >99.9%.
The present invention provides a process wherein the compounds of formula (3), (4), (5) & (II) are may be isolated or without isolation (in-situ process) the compounds are subjected to further reaction. Isolation may be carried out by extraction, evaporation, filtration and the like.
Another embodiment of the present invention provides a process for the preparation of cangrelor or its pharmaceutically acceptable salt comprising
a) reacting a compound of formula (II) with phosphorous oxychloride, trialkyl phosphate to obtain compound of formula (III) or its salt,

b) reacting a compound of formula (III) with
(dihalo)methylenebis(phosphonic acid) to obtain Cangrelor (1) or its
pharmaceutically acceptable salts and
i
The reaction of compound of formula (II) is carried out with phosphorous oxychloride and trialkyl phosphate. The trialkyl phosphate is selected from trimethyl phosphate, triethyl phosphate and the like; preferably triethyl phosphate. The compound of formula (111) is isolated or purified by treating the free acid with suitable base selected from ammonium hydroxide, Ammonium bicarbonate, Triethylammonium bicarbonate, Sodium bicarbonate, Potassium bicarbonate, calcium carbonate and the like; preferably ammonium hydroxide. The salt of compound of formula (III) is selected from ammonium salt, sodium salt, potassium salt, calcium salt and the like.
The reaction of compound of formula (III) or its salt with (dichloro)methylenebis(phosphonic acid) is carried out in the presence of base, coupling agent and solvent. The base is selected from organic base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, n-tributylamine,

diisopropylethylamine, morpholine, N-methyl morpholine, 1,4-
diazabicyclo[2.2.2]octane (DABCO) and the like; preferably n-tributylamine. The coupling agent is selected from 1,1'- Carbonyldiimidazole (CD1), Dicyclohexylcarbodiimide (DCC) and the like. The solvent is selected from polar aprotic solvent such as acetone, acetonitrile, N,N-dimethyl formamide, N,N-dimethy] acetamide, dimethyl sulfoxide, dichIoromethane, 1, 2-dichloroethane, tetrahydrofuran (THF), 1,4-dioxane and the like or the mixture thereof; preferably N,N-dimethylformamide. The crude cangrelor or its pharmaceutically acceptable salts is purified using chromatography or other conventional techniques known in the art.
The pharmaceutical ly acceptable salts of cangrelor is selected from amine salt such as ammonia, ethanolamine, diethanolamine and the like; alkali metal salt such as sodium, potassium and the like; Cangrelor or its pharmaceutically acceptable salts obtained in the present process is isolated by extraction, evaporation, precipitation and any other methods known in the prior arts; preferably precipitation. The presents process also includes lyophilization to obtained the cangrelor(III) or its pharmaceutically acceptable salts. The lyophilization process involves use of solvents such as acetone, water, methanol, ethano), isopropanol and the like or mixture thereof.
The present invention provides cangrelor (I) or its pharmaceutically acceptable salts having purity >99%; preferably >99.5%; more preferably >99.9%.
The present invention provides a pharmaceutical composition comprising cangrelor or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients wherein the cangrelor or its pharmaceutically acceptable salt is prepared using the present invention.
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 application in any manner.
Example-1: (2R, 3R, 4R, 5R)-2-((benzoyloxy) methyl)-5-(2, 6-dichloro-9H-purin-9-yl) tetra-hydrofuran-3,4-diyl dibenzoate2, 6-dichIoro-9H-purine
2,6-dichloropurine (50g, 0.2645 mol) and l-0-acetyl-2,3,5-tri-0-benzoyl-[3-D-ribofuranose (146.7 g, 0.291 mol) were added in acetonitrile (500 ml) at 25°C. DBU (118.4 mL, 0.7936 mol) was added to the reaction mass followed by drop wise addition of trimethylsilyl trifuoromethylsulfonate (191.52 mL, 1.058 mol) over a period of 30 minutes under argon atmosphere. The reaction temperature was raised to 70-80°C and was stirred at same temperature for about 4 hours. The reaction mixture was then diluted with dichloromethane (1000 mL) and washed with saturated sodium bicarbonate solution (2000 mL) followed by brine solution (1000 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The resultant solid obtained was purified by DMSO: water (100 mL: 1000 mL) to obtain the title compound.
'H-NMR (CDC13J 300 MHz,): 5H 4.73 (1H, dd, H5', J= 12.0 & 3.6 Hz), 4.88 (1H, dd, H5", J= 12.3 & 3.6 Hz,), 6.12-6.20 (2H, m, H1' & H2'), 6.48 (1H, d, H4'} J = 6.0 Hz), 4.91-4.96 (1H, m, H3'), 8.30 (1H, s, H8), 7.35-8.08 (I5H, m, phenyl ring protons). HRMS (ESI) calcd for C31H22CI2N4O7: 655.07632 ([M+Na]4), found; 655.07653 ([M+Na]*). 1R (KBr, cm'1): 1728.29 (C=0 of benzoate), 2925.17 & 2956.04 (CH). Yield: 150 g; HPLC purity: 98.6 %; M.P: 82-85°C.
Exarnple-2:(2R,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(2-chloro-6-((2-(methylthio)ethyl)-amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyldibenzoate
A mixture of glucosylated 2,6-dichlorpurine (40 g, 0.0631 mol), (methylthio)ethan-l-amine (11.28 g, 0.088 mol) in ethanol (1 Lit.), triethylamine (26.62 mL, 0.1894 mol) was added at 25°C followed by the temperature was raised to 70-75°C for about 4 hours. The reaction mixture was cooled to 0°C. The resultant

solid obtained was filtered and washed with cold ethanol (200 mL) and dried to obtain the title compound.
'H-NMR (CDCI3, 300 MHz,): 5H 3.83 (2H, brs, HI"), 2.79 (2H, t, H2"), 2.14 (3H, s, H3"), 5.06-5.07 (IH.m.Hl'), 6.16 (1H, t, H2',J= 5.4 Hz), 5.99 (1H, t, H3", J= 5.1 Hz), 6.85 (lH,d,H4', 7=5.4 Hz), 4.65 (IH, dd, H5', J= 12.0 & 3.3 Hz), 4.77 (1H, dd, H5', J = 12.6 & 2.4 Hz), 7.29-8.15 (I6H, m, phenyl ring protons & H8). HRMS (ESI) calcd for C34H31CIN5O7S: 688.16327 ([M+H]*), found; 688.16319 [M+H]4). IR (KBr, cm1): 3372.68 (NH), 1728.29 (C=0 of benzoate), 2919.39 & 2954.11 (CH).
Yield: 37.36g; HPLC purity: 97.99 %; M.P: 79-82°C
Example-3:(2R,3S,4R,5R)-2-(hydroxymethyl)-5-(2-mercapto-6-((2-(methylthio)ethyl)-amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol
To a stirred solution of (2R,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(2-chloro-6-((2-(methylthio)ethyl)-amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diyl dibenzoate (35 g, 0.05086 mol), in N,N-dimethyl formamide (525 mL), 60% sodium hydrogen sulphide hydrate (22.58 g, 0.3051 moi) was added followed by Nal (3.81 g, 0.0254 mol) at 25°C. The resultant reaction mixture was heated to 120°C for about 62 hours. The reaction mixture was concentrated and poured into water (875 mL). The precipitated salts were filtered off and the filtrate was washed with dichloromethane (525 mL). The layers were separated and the pH of the aqueous layer was adjusted to 4.5 using acetic acid. The solid obtained was filtered and washed with water (350 mL). The resultant solid obtained was recrystalized from 10 % aqueous ethanol (525 mL) and dried under reduced pressure to obtain the title compound.
!H-NMR (DMSO-^6, 300 MHz,): 5H 2.12 (3H, s, H3"), 2.72 (2H, t, H2"), 3.65-3.67 (2H, m, HI"), 8.00 (IH, s, H8), 3.41 (IH, dd, H5'a, J= 5.1 & 11.7 Hz), 3.50 (IH, dd, H5'b, J= 3.9 & 11.7 Hz), 3.95 (IH, t, HI', J = 5.1 Hz), 4.02 (IH, t, H2',y= 4.8 Hz) 3.78 (IH, t, H3', J= 4.5 Hz), 5.92 (IH, d, H4', J = 4.2 Hz). HRMS (ESI) calcd for

C|3H2oN504S2: 374.09567 ([M+H]4), found; 374.09695 ([M+H]4). IR (KBr, cm1): 3365. 93 (-0H), 3305.17 (NH), 2924.21 & 2956.04 (CH), 1618.35 & ! 596.16 (C=N).
Yield: 17g; HPLC purity: 99.52 %; M.P: 139-14TC
ExampIe-4: (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl) amino)-2-((3,3,3-trinuoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol
To a stirred solution of (2R)3S,4R,5R)-2-(hydroxymethyl)-5-(2-mercapto-6-((2-(methylthio)ethyl)-amino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol (20 g, 0.0536 mol), in methanol: water (360 mL: 120 mL), 1M sodium hydroxide solution (132 mL) was added at 25°C. The resultant solution was cooled to 0°C followed by 1,1,1-trifluoro-3-iodopropane (9.14 mL, 0.0803 mol) was added slowly at 0°C. The reaction mixture was warmed to 28°C and stirred at 9 hours. The reaction mass was concentrated, the solid was filtered and washed with cold methanol (40 mL) to obtain the title compound.
lH NMR: (DMSO-^6, 300 MHz): 2.10 (3H, s, SCH3), 2.65-2.81 (4H, m, CH2S & CF3-CH2-C//2-S-), 3.28 (2H,1, CF3-CH2), 3.63-3.67 (3H, brs,NCH2& C-5'Ha), 3.51-3.58 (1H, C-5'Hb), 3.93-3.94 (1H, brs, C-3'H) 4.12-4.13 (IH, brs.C-4'H), 4.55-4.59 (1H, brs.C-2'H), 5.09 (1H, brs, C-5'H), 5.21 (IH, d, -OH), 5.46 (IH, d, -OH), 5.82 (IH, d, -OH), 8.28 (IH, s, imidazole CH), 8.15 (IH, brs, NH). ; HRMS (ESI) calcd for C|6H23F3N504S2: 470.11436 ([M+H]4), found; 470.11606 ([M+H]4). IR (KBr, cm-'): 3339. 89 (-OH), 3270.43 (NH), 2928.07 & 2980.15 (CH), 1623.17 & 1584.59 (ON). Yield: 24g; HPLC purity: 99.61%; M.P: 175-177°C
Example-5: 2-Chloro-N-(2-(methylthio)ethyl)-9H-purin-6-amine
To a solution of 2-(methylthio)ethan-l -amine hydrochloride (67.48 g, moles) in isopropyl alcohol (750 mL), 2,6-dichloropurine (50 g) was added under nitrogen atmosphere at 25°C D1PEA (182.24 mL, 4.0 eq) was added to the reaction mixture and the temperature was raised to 70-75°C and stirred for 6-7 hours. The reaction mixture was cooled to 0-5°C and stirred at the same temperature for about 1 hour.

The solid was filtered and washed with cold n-butanol/ isopropyl alcohol (150 mL) to obtain the title compound.
i
!H NMR: (DMSO-<4, 300 MHz): 2.12 (3H, s, SCH3), 2.73 (2H, d, CH2S, J = 6.6 Hz), 3.69 (2H, brs, NCH2), 8.15 (IH, s, imidazole CH), 8.23 (IH, brs, NH), 13.02 (1H, brs, imidazole NH). I3C NMR (DMSO-d6, 75 MHz): 14.53 (S-CH3), 32.43 (CH2-S-), 39.08 (N-CH2), 139.65 (CH-N=), 152.88(C), 154.91 (C).
Yield: 62.5 g; HPLC purity: 99.8%; M.P: 214-216°C.
Example-6: 6-((2-(Methylthio)ethyl)amino)-9Jfir"-purine-2-thiol
The compound 2-Chloro-N-(2-(methylthio)ethyl)-9H-purin-6-amine 40 g (0.16 moles) obtained from the above procedure was taken in N,N-dimethylformamide (500 mL) at 25°C. Sodium Iodide (Nal) (12.3g, 0.08 moles) followed by 60% sodium hydrogen sulphide (200 g, 2.70 moles) were added to the reaction mixture then heated to 120-125°C for 24 hours. The reaction mixture was cooled to room temperature and filtered the solid which was treated with water (320 mL) and filtered. The filtrate was washed with dichloromethane (800 mL). The layers ,-were separated and the aqueous layer pH was adjusted to 4.0 - 4.5 by using acetic ■acid. The obtained solid was filtered and dried.
The dried solid (45 g) was taken in water (320 mL) and pH of the solution was adjusted to 10-11 using aqueous ammonia solution and filtered. The pH of the filtrate was adjusted to 4 using acetic acid. The precipitate obtained was cooled to 0°C and stirred for one hour then filtered and washed with methanol (200 mL) to obtain the title compound. Yield: 76%; HPLC purity: 99.0%; M.P: 277°C
'H NMR: (DMSO-dfi, 300 MHz): 2.13 (3H, s, SCH3), 2.73 (2H, d, CH2S, J = 6.6 Hz), 3.61 (2H, m, NCH2), 7.97 (IH, s, imidazole CH), 8.05 (IH, brs, NH), 12.60 (IH, brs, imidazole NH). I3C NMR (DMSO-d6, 75 MHz): 14.58 (S-CH3), 32.63 (CH2-S-), 39.03 (N-CH2), 139.63 (CH-N=), 149.57 (C).

Example-7: N-(2-(methylthio)ethyl)-2-((3,3,3-trinuoropropyl)thio)-9//-purin-6-amine
To the stirred solution of 6-((2-(Methylthio)ethyl)amino)-9H-purine-2-thiol (30 g, moles) in mixture of watenmethanol (60 mL:168 mL), aqueous 1M sodium hydroxide solution (520 mL) was added and the reaction mixture was cooled to 2-8°C. l,l,l-trifluoro-3-iodopropane (11.5 g, 0.50 moles) was added to the reaction mixture then the temperature was raised to 28°C and stirred for about 9 hours. The reaction mass was concentrated to obtain the solid which was washed with water (300 mL) to obtain the title compound. Yield: 37 g; HPLC purity: 99.8%; MP: 256°C
'H NMR: (DMSO-4,, 300 MHz): 2.11 (3H, s, SCH3), 2.64-2.80 (4H, m, CH2S & CF3-CH2-C//2-S-), 3.24 (2H, t, CF3-CH2), 3.64 (2H, brs, NCH2), 8.00 (1H, s, imidazole CH), 7.88 (1H, brs, NH), 12.76 (1H, brs, NH, imidazole). ,3C NMR (DMSO-d6l 75 MHz): 14.52 (S-CH3), 22.59 (S-CH2), 32.69 (CH2-S-), 39.39 (N-CH2), 33.52, 33.87, 34.24, 34.60 (CF3-CH2), 138.34 (CH-N=), 116.04 (C), 121.18, 124.86, 128.54, 132.25 (CF3), 151.07(C), 153.54(C), 161.84(C).
Example-8:(2/?,35,4JR,5J?)-2-((benzoyloxy)methyl)-5-(6-((2-
(methylthio)ethyl)amino)-2-((3,3,3-trinuoro-propyl)thio)-9/f-purin-9-
yl)tetrahydrofuran-3,4-diyldibenzoate
BSTFA (64.12 g, 0.24 moles) was added to the mixture of N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-6-amine (28 g, 0.08 moles) in acetonitrile (400 mL) at 25"C. The reaction mixture was heated to 70°C for 1 hour. Trifilic acid (2.52 g, 0.016 mole) was added followed by (2S,3rt,4/?,5/?)-2-acetoxy-5-((benzoyloxy)methyl)-tetrahydrofuran-3,4-diyl dibenzoate (41.88 g, 0.08mole) was added to the reaction mixture under dilution with acetonitrile (280mL) and the reaction mixture was continued to stirred at 70°C for four hours. The reaction mixture was cooled to 25°C followed by aqueous sodium bicarbonate solution (140 mL) and dichloromethane (280 mL) were added. The organic layer was separated and

concentrated to obtain the title compound which was purified through a column of chromatography using silica by 5% MeOH: dichloromethane to obtain a title compound. Yield: 56 g; HPLC purity: 99.2%; M.P: 65-68°C
'H NMR: (DMSO-<4, 300 MHz): 2.11 (3H, s, SCH3), 2.69-2.74 (4H, m, CH2S & CF3-CH2-C//3-S-), 3.26-3.28 (2H, m, CF3-CH2), 3.65-3.67 (2H, m, NCH2), 4.66 (IH, d,C-5'Ha,J = 12.0 & 5.1 Hz), 4.76 (IH, C-5'Hb, J = 12.3 & 4.0 Hz), 4.86-4.88 (1H, m, C-3'H) 6.18 (1H, t, C-4'H, J = 5.4 Hz), 6.44 (1H, t, C-2'H, J = 5.1 Hz), 6.51 (1H, t, C-5'H, J = 4.0 Hz), 7.43-7.96 (15H, m, phenyl ring protons), 8.31 (IH, s, imidazole CH), 8.23 (IH, brs, NH). ,3C NMR (DMSO-d6j 75 MHz): 14.52 (S-CH3), 22.70 (S-CH2), 32.53 (CH2-S-), 39.39 (N-CH2), 33.67, 34.04 (CF3-CH2), 63.84 (C-5'), 71.25 (C-l'), 73.67 (C-2'), 79.48 (C-3'), 86.63 (C-4'), 138.98 (CH-N=), 117.42 (C), 121.24, 124.92, 128.60, 128.71, 128.74, 129.12, 129.17, 129.33, 133.47, 133.87, 133.99, 138.99 (aromatic CH), 132.28 (CF3), 128.28 (C), 128.53 (C), 149.58 (C), 150.80(C), 153.94(C), 163.31, 164.45, 164.65, 165.40 (C=0).
Example-9: (2/f,31S,,4/f,5/?)-2-(hydroxymethyl)-5-(6-((2-(methy[thio)ethyi)amino)-2-((3,3,3-trifluoropropyl)thio)-9W-purin-9-yI)tetrahydrofuran-3,4-diol
(2R,3S)4R,5R)-2-((benzoyloxy)methyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoro-propyl)thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diyl dibenzoate (14.0 g, 0.017 moles) was treated with IN NaOH in MeOH (110 mL) at 25°C. The temperature of the reaction mixture was raised to 65°C for 3 hours. The reaction mass was concentrated. Water (140 mL) was added to the crude compound and pH is adjusted to 6.0 using acetic acid. The precipitated compound obtained was filtered and washed with water (140 mL) to obtain the title compound.
Yield: 7.0 g; HPLC purity: 99.2%; M.P: 175-177°C
lH NMR: (DMSO-4,, 300 MHz): 2.10 (3H, s, SCH3), 2.65-2.81 (4H, m, CH2S & CF3-CH2-C#2-S-), 3.28 (2H, t, CF3-CH2), 3.63-3.67 (3H, brs, NCH2& C-5'Ha), 3.51-3.58 (IH, C-5'Hb), 3.93-3.94 (IH, brs, C-3'H) 4.12-4.13 (IH, brs, C-4'H), 4.55-4.59

(IH, brs, C-2'H), 5.09 (IH, brs, C-5'H), 5.21 (IH, d, -OH), 5.46 (IH, d} -OH), 5.82 (1H, d, -OH), 8.28 (IH, s, imidazole CH), 8.15 (IH, brs, NH). !3C NMR (DMSO-d6, 75 MHz): 14.63 (S-CHj), 22.90 (S-CH2), 32.77 (CH2-S-), 39.07 (N-CH2), 33.16, 33.53, 33.88, 34.25 (CF3-CH2), 61.62 (C-5'), 70.57 (C-T), 73.58 (C-2'), 85.71 (C-3'), 87. 51 (C-4*), '38.95 (CH-N=), 117.56 (C), 121.24, 124.92, 128.60, 132.28 (CF3), 149.58.07 (C), 154.03 (C), 162.57 (C).
Example-10: (((2S,3S,4R,5R)-3,4-dihydroxy-5-(6-((2-(methylthio)ethyl)amino)-2-
((3^,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-2-
yl)methyl)phosphonate
Phosphorus oxychloride (0.8 mL) was added to a solution of (2R,3SJ4R,5R)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yt)tetrahydrofuran-3,4-diol (0.5 g) in triethyl phosphate (24 mL) at 25°C then cooled to 0 °C and stirred for four hours. The reaction mass was poured into ice-water (100 mL) containing 5% Ammonium bicarbonate (100 mL) and stirred for 10 minutes. Methyl tertiary butyl ether (MTBE) (200 mL) was added and the layers were separated. The aqueous layer was loaded to a column of Dowex 50Wx8 (H* form). The column was washed with deionized water upto pH 6. Further the product was eluted with 2M ammonium hydroxide. The product containing fractions were collected, combined and freeze-dried to obtain the tile compound as ammonium salt.
Yield: 0.5 g; HPLC purity: 99.7%
Exa m pie-11: (D ich loro((((((2R,3S,4R,5R)-3,4-d i hyd roxy-S-(6-((2-(methylthioJethylJaminoJ-Z-tp^-trifluoropropyOthio^H-purin^-yl)tetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)-oxy)(hydroxy)phosphoryl)methyI)phosphonic acid tetra sodium
An equimolar mixture of (((2S,3S,4R,5R)-3,4-dihydroxy-5-(6-((2-(methylthioJethyOaminoJ^-^^^-trifluoropropyOthioJ^H-purin^-yl)tetrahydrofuran-2-yl)methyl)phosphonate (200 mg) and tri-«-butylamine (0.07 g)

in pyridine (20 mL) was evaporated to dryness under reduced pressure at 35°C followed by anhydrous DMF (20 mL) was added then evaporated to dryness under reduced pressure at 35°C. The residue was dissolved in anhydrous DMF (10 mL), and carbonyldiimidazole (0.28 g,) was added arid stirred for 4 hours at 25°C. Methanol (0.11 mL) was added and stirred for 30 minutes. A solution of the mono(tri-«-butylammonium) salt of dich!oromethylenebis(phosphonic acid) (0.89 g) in anhydrous DMF (15 mL) was added and stirred at 25°C for 18 hours, then filtered, and evaporated to dryness under reduced pressure. The crude product was purified by ion-exchange chromatography using DEAE-Sephadex and 0-0.01 M ammonium bicarbonate solution as eluent. The product containing fractions were combined and freeze dried to obtain the product as ammonium salt.
To the solution of the ammonium salt (100 mg) in methanol (5 mL), 1M sodium iodide solution in acetone (5 mL) was added at 0°C. The precipitated solid was centrifuged and dried. The dried compound was dissolved in water (5 mL) and lyophilized to obtain the title compound.

Claim:
I. A process for preparation of compound of formula (II) comprising;
a) amination of 2,6-dihalopurine of compound of formula (1) by reacting
it with 2-aminoethyl methyl sulfide or its salt to obtain a compound of formula (7)
b) thionation of compound of formula (7) using alkali metal thiosulfide to obtain thiol compound of formula (8)
c) thioalkylation of compound of formula (8) to obtain compound of formula (9)

d) N-glycosylation of compound of formula (9) to obtain a compound of formula (10) and
e) O-deprotection of compound of formula (10) to obtain a compound of
formula (11)
2. The process according to claim 1, wherein the base in step (a) comprises organic base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), diethylamine, triethylamine, diisopropylethylamine, morpholine, N-methyl morpholine and l,4-diazabicyclo[2.2.2]octane (DABCO).
3. The process according to claim 1, wherein the alkalimetal sulfide in step (b) is selected from sodium hydrosulfide and potassium hydrosulfide.
4. The process according to claim 1, wherein the compound of formula (6) in step-c is lJJj-trifluoro-S-iodopropoane.
5. The process according to claim I, wherein the protecting group (P) of compound of formula (2) in step (d) is independently selected from acetyl and benzoyl.
6. The process according to claim 1, wherein the base in step (e) is selected from metal hydroxide, metal carbonate and metal bicarbonate.

7. A process for preparation of compound of formula (II) comprising;
a) N-g!ycosylation of 2,6-dihalo purine having compound of formula (1) with D-ribofuranose of compound of formula (2) to obtain a compound of formula (3)
b) 6-amination of compound of formula (3) by reacting it with 2-aminoethyl methyl sulfide or its salts to obtain a compound of formula (4)
c) thionation of compound of formula (4) to obtain thiol compound of formula (5) and

d) thioalkylation of thiol compound of formula (5) with compound of formula (6) to obtain a compound of formula (II).
8. The process according to claim 1, wherein the protecting group (P) of compound of formula (2) in step (a) is independently selected from acetyl and benzoyl.
9. The process according to claim 1 & 2, wherein the process further comprising converting the compound of formula (II) to cangrelor or its pharmaceutically acceptable salts.
10. A process for the preparation of cangrelor (1) or its pharmaceutically acceptable salt wherein the process is as described herein.