DR. REDDY’S LABORATORIES LIMITED [IN/IN]; 8-2-337, Road No. 3, Banjara hills, Hyderabad, Telangana Hyderabad 500034 (IN)
DAHANUKAR, Vilas; (IN).
ELATI, Ravi Ram Chandrasekhar; (IN).
ORUGANTI, Srinivas; (IN).
RAPOLU, Rajesh Kumar; (IN).
KURELLA, Sreenivasulu; (IN)
The drug compound having the adopted name “ticagrelor” has chemical names: [1 S-(1 α,2α,3β(1 S*,2R*),5p)]-3-[7-[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; or (1 S,2S,3fl,5S)-3-[7-{[(1 fl,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H 1 ,2,3]-triazolo[4,5-c/|pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclope ed by Formula I.
Formula I
Ticagrelor is the active ingredient in the commercially available BRILINTA® tablets for oral administration.
Ticagrelor and related compounds are disclosed in International Patent Application Publication Nos. WO 00/34283 and WO 99/05143 as pharmaceutically active Ρ2τ (which are now usually referred to as P2Y12) receptor antagonists. Such antagonists can be used, inter alia, as inhibitors of platelet activation, aggregation, or degranulation. International Patent Application Publication Nos. WO 01 /92263 and WO 2010/030224 A1 , WO 2012085665 A2, WO 2012138981 A2 and WO 2013037942 A1 disclose processes for preparing ticagrelor.
The processes for the preparation of traizolo [4,5-d] pyrimidine derivatives preferably Ticagrelor and related compounds, described in the above mentioned prior art suffer from disadvantages since the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions under pressure and high temperature, longer reaction times, tedious work up procedures and multiple crystallizations or isolation steps, column chromatographic purifications and thus resulting in low overall yields of the product. Ticagrelor obtained by the processes described in the prior art does not have satisfactory purity and unacceptable amounts of impurities are formed along with Ticagrelor at various stages of the processes that are difficult to purify and thus get carried forward in the subsequent steps thus affecting the purity of final compound. Thus, there remains a need to prepare compounds of Formula I of high purity and in good yield while overcoming the drawbacks presented by the previously described processes.
Formula V Formula V”
In a preferred embodiment, present application provide compounds of Formula IV with specific groups i.e. compounds of Formula IV and Formula IV”,
Formula IV Formula IV”
In a preferred embodiment, present application provides a compound of Formula II with specific groups i.e. compounds of Formula ΙΓ and Formula II”,
Formula ΙΓ Formula II”
In a preferred embodiment, present application provides a compound of Formula l la with specific grou
Formula lla
Formula VII’ Formula VII”
In a preferred embodiment, present application provides compounds of Formula Vila with specific groups i.e. compounds of Formula Vila’ and Formula “,
Formula Vila’ Formula Vila”
G.V. Prasad, chairman, Dr Reddy’s Laboratories
EXAMPLES
EXAMPLE 1 : Preparation of 2-bromo-N,N-diphenylacetamide (FORMULA Vile).
A flask is charged with Ν,Ν-diphenyl amine (25 g) and dichloromethane (350 mL) under nitrogen atmosphere. The reaction mixture is cooled to 0°C followed by addition of solution of triethyl amine (20.7 mL) and bromoacetyl chloride (38.72 mL) in dichloromethane (181 mL). The mixture is cooled to room temperature and then stirred for about 16 hours. The completion of the reaction is monitored by TLC. The reaction mixture is diluted with dichloromethane (250 mL) and then washed with 0.5N aqueous hydrochloric acid solution (3×150 mL), brine (100 mL). The organic layer is separated and subjected to distillation under vacuum at 45°C. The obtained compound is recrystallized from hexane (250 mL) and methanol (100 mL) to afford the title compound.
EXAMPLE 2: Preparation of benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (FORMULA Vila).
A flask is charged with sodium hydride (2.85 mL, 60% dispersion in oil) and dimethyl formamide (10 mL) under nitrogen atmosphere. The reaction mixture is then cooled to -30°C followed by addition of a solution of benzyl
((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (20 g) in dimethyl formamide (40 mL). The mixture is stirred at -30°C for about 45 minutes, then a solution of 2-bromo-N,N-diphenylacetamide (22.65 g) in dimethyl formamide (60 mL) is added at the same temperature. The reaction mixture is allowed to attain room temperature and stirred at the same for 3 hours and completion of the reaction is monitored by TLC. The reaction mixture is quenched with ice-cold water (200 mL) and extracted with ethyl acetate (3×150 mL). The organic layer is combined and washed with water (3×100 mL), brine (100 mL) and then organic layer is then subjected to complete distillation under vacuum at 45°C. The crude so obtained is treated with MTBE (150 mL) and stirred at room temperature for overnight followed by filtration of obtained solid to afford the title compound.
EXAMPLE 3: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula VII)
A flask is charged with benzyl ((3aS,4R,6S,6aR)-6-(2-(diphenylamino)-2-oxoethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (15 g), ethanol (300 mL), 10% Pd/C (1.5 g) and ammonium formate (5.49 g). The reaction mixture is stirred at 80°C for 8 hours and completion of the reaction is monitored by TLC. Then reaction mixture is cooled to room temperature and filtered through celite bed, bed is washed with ethyl acetate (100 mL). The filtrate is subjected to complete distillation under vacuum at 45°C. Then ethanol (120 mL), L-tartaric acid (4.88 g) is added to the crude compound and mixture is stirred for 4 hours at room temperature. To the mixture, MTBE (300 mL) is added at the same temperature. The solvent is distilled under vacuum at 35°C to afford the gummy solid. Then MTBE (100 mL) is added to the gummy solid and mixture is stirred for 10-12 hours. The solid obtained is filtered and washed with MTBE (50 mL). The solid obtained is dissolved in water and sodium bicarbonate solution (200 mL) is added, desired compound is extracted in ethyl acetate (100 mL). The solvent is subjected to distillation (upto 40%) followed by addition of hexane (150 mL) and ethyl acetate (20 mL). The mixture is stirred at -10°C, then solid is recovered followed by drying under vacuum at 40°C. The crude compound is purified by column chromatography using methanol and dichloromethane (5:95) to afford the title compound.
EXAMPLE 4: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]
[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula V)
A flask is charged with 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.5 g),
2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (10.39 g), sodium bicarbonate (9.13 g) and water. The mixture is stirred at 95-100°C for 15-20 hours till completion of the reaction (as monitored by TLC). Then water (20 mL) and ethyl acetate (25 mL) are added at room temperature. The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined and washed with brine solution (2×25 mL). The organic layer is subjected to complete distillation under vacuum at 40-45°C. The obtained crude compound is purified by column chromatography using ethyl acetate and hexane (30:70) to afford the title compound.
EXAMPLE 5: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (6 g), acetic acid (30 mL) and water (6 mL). The mixture is cooled to 0 to -5°C followed by addition of addition of sodium nitrite solution (768 mg in 6 mL of water). The mixture is stirred for 1 hour at the same temperature and then mixture is allowed to attain room temperature, and further stirred for 1 hour. The completion of the reaction is monitored by TLC and then toluene (60 mL) is added. The layers are separated, organic layer is washed with saturated solution of potassium carbonate and subsequently organic layer is dried with sodium sulphate and used for next reaction.
EXAMPLE 6: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin- 3- yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula II)
A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (3.25 g), diisopropylethyl amine (6.1 mL), toluene (60 mL) and stirred for 30 minutes at room temperature. Then slowly, toluene layer containing 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (60 mL) is added over a period of 10 minutes. The reaction mixture is stirred at room temperature for overnight and completion of the reaction is monitored by TLC. The reaction mixture is diluted with water (60 mL), layers are separated and aqueous layer is extracted with toluene (2×30 mL). The combined organic layers are washed with brine (60 mL) and then subjected to complete distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using ethyl acetate and hexane (80:20).
EXAMPLE 7: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (3 g), THF (90 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (940 mg) is added over a period of 10 minutes and mixture is stirred at 0°C for 1 hour. The reaction mixture is then stirred at room temperature for 5 hours and progress of the reaction is monitored by TLC. Then mixture is cooled to 0-5°C and quenched with ice cold water (100 mL) and then diluted with ethyl acetate (30 mL). The layers are separated and organic layer after drying is used for next step.
EXAMPLE 8: Preparation of Ticagrelor (Formula I)
A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (1 10 mL) and 2% hydrochloric acid solution (75 mL). The reaction mixture is stirred at room temperature for 48 hours and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (50 mL), layers are separated. The organic layer is sequentially washed with water (50 mL), brine solution (50 mL) followed by complete distillation under vacuum at 45°C. The crude compound is dissolved in ethyl acetate (12 mL) and then hexane (50 mL) is added. The mixture is stirred for 2 hours followed by isolation of solid by filtration. The obtained solid is dissolved in ethyl acetate (12 mL) and treated with charcoal followed by filtration. The filtrate is subjected to complete distillation and obtained solid is purified by column chromatography using ethyl acetate:hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.
EXAMPLE 9: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol (Formula lib)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (3 mL) and cooled to 0-5°C followed by addition of Vitride (0.04 mL) at 0-5°C over a period of 5 minutes. The mixture is stirred at same temperature for 1 hour and progress of the reaction is monitored by TLC. Additional amount of Vitride (0.13 mL) is added to the mixture and stirred for additional 6 hours. After completion of reaction, reaction mixture is cooled to 0-5°C and quenched with saturated sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer is subjected to complete distillation under reduced pressure and obtained material is purified by column chromatography using ethyl acetate: hexane (1 :1 ) and methanohdichloromethane (5:95) to afford the title compound.
EXAMPLE 10: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)acetaldehyde (Formula lib’)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (100 mg), THF (5 mL) and mixture is cooled to 0°C. Then portion wise, Lithium aluminium hydride (15 mg) is added over a period of 1 0
minutes and mixture is stirred at 0°C for 1 hour. The progress of the reaction is monitored by TLC. After completion of the reaction, mixture is quenched with ice cold water (5 mL) and diluted with ethyl acetate (10 mL). The layers are separated and organic layer after drying is subjected to complete distillation followed by purification using preparative TLC using 40% ethyl acetate in hexane to afford the title compound.
EXAMPLE 11 : Preparation of 2-bromo-1 -morpholinoethan-1 -one
A flask is charged with bromoacetyl bromide (25 mL), dichloromethane (500 mL) and mixture is stirred under nitrogen atmosphere. The reaction mixture is cooled to -25°C followed by slow addition of morpholine (72.7 mL in 500 mL of DCM) at the same temperature over a period of 30 minutes. The reaction mixture is stirred at -25°C for 15 minutes, then allowed to attain room temperature at which it is further stirred for 4 hours. The completion of the reaction is monitored by TLC and reaction mixture is sequentially washed with water (2×250 mL) and brine solution (2×100 mL). The organic solvent is subjected to distillation to afford the title compound.
EXAMPLE 12: Preparation of benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (Formula Vila”)
A flask is charged with sodium hydride (60%, 4.29 g), DMF (90 mL) and cooled to -30°C. Then, benzyl ((3aS,4R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate (30 g) is added to the reaction mixture at the same temperature over a period of 25 minutes and mixture is stirred at -30°C for 1 hour. Then 2-bromo-1 -morpholinoethan-1 -one (24.36 g) is added to the reaction mixture at -30°C over a period of 20 minutes and temperature is raised to room temperature. The mixture is stirred at RT for 1 hour. The progress of the reaction is monitored by TLC and after completion, the reaction mixture is quenched with ice cold water followed by extraction with ethyl acetate. The organic layer is separated and subjected to distillation to afford the title compound.
EXAMPLE 13: Preparation of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula VII”)
A flask is charged with benzyl ((3aS,4R,6S,6aR)-2,2-dimethyl-6-(2-morpholino-2-oxoethoxy)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)carbamate, ethanol (1 0 g), ammonium formate (4.35 g) and 10% Pd/C (1 g). The reaction mixture is heated to 80°C and then stirred for 2 hours. The progress of the reaction is monitored by TLC and after completion of the reaction, mixture is cooled to room temperature, filtered and washed with ethyl acetate (100 mL). The filtrate is distilled under reduced pressure and obtained compound is purified by column chromatography using methanol-DCM (5:95) to afford the title compound.
EXAMPLE 14: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2- (propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]
[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula V”)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (8 g), water (24 mL) and stirred for 10 minutes. Then sodium bicarbonate (8.9 g), 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (6.3 g) and water (24 mL) is added and mixture is heated to 95-100°C at which point it is stirred for 15 hours. The progress of the reaction is monitored by TLC and on completion reaction mixture is cooled to room temperature followed by addition of water (24 mL) and ethyl acetate (40 mL). The layers are separated and aqueous layer is extracted with ethyl acetate (20 mL). The organic layers are combined, washed with brine solution (2×40 mL) and subjected to distillation under vacuum at 45°C to afford the title compound.
EXAMPLE 15: Preparation of 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] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula IV”)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]
[1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g), acetic acid (20 mL) and stirred under nitrogen atmosphere for 10 minutes. Then water (8 mL) is added and mixture is cooled to -5 to 0°C followed by slow addition of sodium nitrite (650 mg). The mixture is stirred at 0°C for 1 hour and progress of the reaction is monitored by TLC. After completion of the reaction, mixture is extracted with toluene (40 mL and 20 mL). The combined toluene layer is sequentially washed with potassium
carbonate solution (40 mL) and brine solution (2×20 mL) followed by distillation under vacuum to afford the desired compound.
EXAMPLE 16: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (Formula II”)
A flask is charged with (1 R,2S)-2-(3,4-difluorophenyl)cyclopropan-1 -amine mandelate (2.5 g) and toluene (20 mL) followed by drop-wise addition of diisopropylethylamine (4.7 mL), then mixture is stirred for 10 minutes at RT. Then toluene layer containing 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] dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (4 g in 55 mL) is added to the above mixture and reaction mass is stirred for 15 hours at room temperature. The progress of the reaction is monitored by TLC followed by addition of water (20 mL) on completion of reaction. The layers are separated, aqueous layer is extracted with toluene (20 mL). The organic layers are combined, washed with brine solution (2×20 mL) and then subjected to distillation under vacuum at 45°C to afford the crude compound. The crude compound is purified by column chromatography using hexane to afford the title compound.
EXAMPLE 17: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)ethan-1 -ol
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-1 -morpholinoethan-1 -one (1 g) in tetrahydrofuran (20 mL) and stirred under nitrogen atmosphere followed by addition of vitride (1 .53 mL) over a period of 10 minutes. The reaction mixture is stirred for 1 hour at room temperature and progress of the reaction is monitored by TLC. On completion, the mixture is quenched with sodium potassium tartrate (5 mL). The mixture is extracted with ethyl acetate (10 mL), then layers are separated and organic layer is subjected to distillation under vacuum at 45°C. The obtained material is dissolved in THF (20 mL) and slowly lithium aluminiumhydride (0.1 17 g) is added to the mixture at 0-5°C. Then mixture is stirred at room temperature for 1 hour and progress of the reaction is monitored by TLC. On completion of reaction, it is quenched with ice-cold water (20 mL) and extracted with ethyl acetate (15 mL). The layers are separated and organic layer is used for next step.
EXAMPLE 18: Preparation of Ticagrelor
A flask is charged with organic layer containing 2-(((3aR,4S,6R,6aS)-6-(7-(((1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1 ,2,3] triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy) ethan-1 -ol (30 mL) and 2% hydrochloric acid solution (30 mL). The reaction mixture is stirred at room temperature for overnight and progress of the reaction is monitored by TLC. Then the reaction mixture is diluted with ethyl acetate (20 mL), layers are separated. The organic layer is washed with brine solution (20 mL) followed by complete distillation under vacuum at 45°C. The crude compound is purified by column chromatography using ethyl acetate:hexane (7:10) and methanol :d ic h I oro methane (5:95) to afford the title compound.
EXAMPLE 19: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1 ,2,3]triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-4H-cyclopenta[d][1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (Formula IV)
A flask is charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d]
[1 ,3]dioxol-4-yl)oxy)-N,N-diphenylacetamide (5 g) and acetonitrile (50 mL) for clear solution. To this, isoamyl nitrite (1 .5 g) is added over a period of 5 minutes. The reaction mixture is maintained at room temperature for 5 hours and completion of the reaction is monitored by TLC. Then water (50 mL) and toluene (50 mL) are added and layers are separated. The aqueous layer is extracted with toluene (50 mL) and total organic layers are combined, subjected to distillation under vacuum to afford the title compound.
Anji Reddy
Mr G.V. Prasad, CEO, Dr. Reddy’s Labs
G V Prasad and Mr K. Satish Reddy
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NEW PATENT, TICAGRELOR, DR. REDDY’S LABORATORIES LIMITED, WO 2016001851
