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WO2016038520A1 - Processes for the preparation of ticagrelor and its intermediates - Google Patents

Processes for the preparation of ticagrelor and its intermediates Download PDF

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Publication number
WO2016038520A1
WO2016038520A1 PCT/IB2015/056774 IB2015056774W WO2016038520A1 WO 2016038520 A1 WO2016038520 A1 WO 2016038520A1 IB 2015056774 W IB2015056774 W IB 2015056774W WO 2016038520 A1 WO2016038520 A1 WO 2016038520A1
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WIPO (PCT)
Prior art keywords
formula
compound
process according
group
ticagrelor
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PCT/IB2015/056774
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French (fr)
Inventor
Nagaraju GOTTUMUKKALA
Anil SAINI
Mahavir Singh Khanna
Mohan Prasad
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Publication of WO2016038520A1 publication Critical patent/WO2016038520A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides a process for the preparation of ticagrelor.
  • the present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula Via, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.
  • Ticagrelor chemically ( ⁇ S,2S,3R,5S)-3-[7- ⁇ [( ⁇ R,2S)-2-(3,4- difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H- [ 1 ,2,3] -triazolo [4,5 - ⁇ f]pyrimidin-3 - yl]-5-(2-hydroxyethox )cyclopentane-l,2-diol, is represented by Formula I.
  • Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction).
  • ACS acute coronary syndrome
  • the present invention provides a process for the preparation of ticagrelor.
  • the present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula Via, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.
  • the processes of the present invention involve environmentally friendly and easy- to-handle reagents and simpler processes for the isolation of the intermediates with significantly improved yields.
  • a first aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • X is Li, Na, or K
  • L is -S0 2 CH 3 , -S0 2 C 6 H 4 (4-CH 3 ), or -S0 2 C 6 H 4 (4-N0 2 );
  • a second aspect of the present invention provides a process for the preparation of a compound of Formula IV,
  • a third aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • a fourth aspect of the present invention provides a process for the preparation of a compound of Formula V,
  • a fiftli aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • a sixth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
  • a seventh aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • X is Li, Na, or K
  • An eighth aspect of the present invention provides a process for the preparation of a compound of Formula VII, H,CO
  • X is Li, Na, or K
  • a ninth aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • X is Li, Na, or K
  • a tenth aspect of the present invention provides a process for the preparation of a compound of Fonnula VIII,
  • L is -S0 2 CH 3 , -SC ⁇ CeH ⁇ -CHs), or -S0 2 C 6 H4(4-N0 2 )
  • An eleventh aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • L is -S0 2 CH 3 . -S0 2 C 6 H 4 (4-CH 3 ), or -SC ⁇ CeH ⁇ -NOz); and b) converting the compound of Formula VIII into ticagrelor of Fonnula I.
  • a twelfth aspect of the present invention provides a process for the preparation of a compound of Formula X, H 3 CO
  • L is -S0 2 CH 3 , -SC ⁇ CeH ⁇ -CHs), or -S0 2 C 6 H4(4-N0 2 )
  • a thirteenth aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
  • L is -S0 2 CH 3 , -S0 2 C 6 H4(4-CH 3 ), or -S0 2 C 6 H 4 (4-N0 2 ) with a compound of Formula IX or a salt thereof
  • a fourteenth as ect of the present invention provides a compound of Formula IV.
  • a fifteenth aspect of the present invention provides a compound of Formula V.
  • a sixteenth aspect of the present invention provides a compound of Formula VI.
  • a seventeenth aspect of the present invention provides a compound of Formula
  • X is Li, Na, or K.
  • An eighteenth aspect of the present invention provides a compound of Formula
  • a nineteenth aspect of the present invention provides a compound of Formula VIII
  • a twentieth aspect of the present invention provides use of a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula Via, a compound of Formula VII, or a compound of Formula VIII for the preparation of ticagrelor of Formula I.
  • the compound of Formula II and the compound of Formula III are prepared according to the methods as described herein.
  • the compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in the presence of a base in a solvent.
  • the base is selected from the group consisting of hydroxides, carbonates, and bicarbonates of alkali metals.
  • hydroxides, carbonates, and bicarbonates of alkali metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
  • the solvent is selected from the group consisting of water, alcohols, ethers, hydrocarbons, halogenated hydrocarbons, ketones, and mixtures thereof.
  • alcohols examples include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • hydrocarbons examples include «-hexane, «-heptane, cyclohexane, toluene, and xylene.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • ketones include acetone and methyl ethyl ketone.
  • reaction of the compound of Formula II with the compound of Formula III is carried out for about 5 hours to about 40 hours, preferably for about 5 hours to about 20 hours.
  • reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 25°C to about 80°C, preferably of about 40°C to about 70°C.
  • the compound of Formula IV may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula IV may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula IV is hydrogenated in the presence of a hydrogenation agent to obtain the compound of Formula V in a solvent.
  • the hydrogenation agent is selected from the group consisting of
  • the solvent is selected from the group consisting of alcohols, ketones, and mixtures thereof.
  • alcohols examples include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • the hydrogenation is carried out at a hydrogen pressure, for example, of about 1.5 kg per cm 2 to about 4.5 kg per cm 2 , preferably of about 3 kg per cm 2 to about 4 kg per cm 2 .
  • the hydrogenation of the compound of Formula IV is carried out at a temperature of about 15°C to about 50°C, preferably of about 25°C to about 35°C.
  • the hydrogenation of the compound of Formula IV is carried out for about 10 hours to about 25 hours, preferably for about 12 hours to about 20 hours.
  • the solution containing the compound of Formula V may be used as such for the next step.
  • the compound of Formula V may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula V may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula V is cyclized with an alkali metal nitrite to obtain the compound of Formula VI in the presence of an acid in a solvent.
  • the alkali metal nitrite is selected from the group consisting of sodium nitrite and potassium nitrite.
  • the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
  • the solvent is selected from the group consisting of water, alcohols, ethers, and mixtures thereof.
  • alcohols examples include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • the cyclization of the compound of Formula V with the alkali metal nitrite is carried out for about 1 hour to about 5 hours, preferably for about 2 hours to about 3 hours.
  • the cyclization of the compound of Formula V with the alkali metal nitrite is carried out at a temperature of about 0°C to about 20°C, preferably of about 0°C to about 10°C.
  • the compound of Formula VI is optionally isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VI is optionally purified through the formation of a compound of Formula Via using an alkali metal hydroxide in a solvent.
  • the alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the solvent is selected from the group consisting of methanol, ethanol, «-propanol, isopropanol, «-butanol, and ethyl acetate.
  • the purification of the compound of Formula VI is carried out for about 15 minutes to about 2 hours, preferably for about 20 minutes to about 1 hour.
  • the purification of the compound of Formula VI is carried out at a temperature of about 25 °C to about 70°C, preferably of about 40°C to about 65 °C.
  • the compound of Formula Via may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula Via may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula Via is optionally converted into the compound of Formula VI in the presence of an acid in a solvent.
  • the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
  • the solvent is selected from the group consisting of water, alcohols, halogenated hydrocarbons, and mixtures thereof.
  • alcohols examples include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • the conversion of the compound of Formula Via is carried out for about 2 minutes to about 1 hour, preferably for about 10 minutes to about 30 minutes.
  • the conversion of the compound of Formula Via is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 35°C.
  • the compound of Formula VI may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VI is esterified with methanol and 2,2- dimethoxypropane to obtain the compound of Formula VII in the presence of an acid.
  • Methanol is used as a solvent as well as a reagent.
  • the acid is selected from the group consisting of p-toluene sulphonic acid, methane sulfonic acid, sulfuric acid, and hydrochloric acid.
  • the esterification of the compound of Formula VI with methanol and 2,2- dimethoxypropane is carried out for about 12 hours to about 30 hours, preferably for about 15 hours to about 25 hours.
  • the esterification of the compound of Formula VI with methanol and 2,2- dimethoxypropane is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 45°C.
  • the compound of Formula VII may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the hydroxyl moiety of compound of Formula VII is O-protected with a protecting agent to obtain the compound of Formula VIII in the presence of a base and a catalyst in a solvent.
  • the protecting agent is selected from the group consisting of methanesulphonyl chloride, p-toluenesulphonyl chloride, and p-nitrobenzenesulphonyl chloride.
  • the base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
  • the preferred catalyst used is 4-dimethylaminopyridine.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • the O-protection of the compound of Formula VII with the protecting agent is carried out for about 30 minutes to about 6 hours, preferably for about 1 hour to about 4 hours.
  • the O-protection of the compound of Formula VII with the protecting agent is carried out at a temperature of about - 15°C to about 20°C, preferably of about -10°C to about 10°C.
  • the solution containing the compound of Formula VIII may be used as such for the next step.
  • the compound of Formula VIII may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula VIII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula VIII is coupled with the compound of Formula IX or a salt thereof to obtain the compound of Formula X in the presence of a base in a solvent.
  • the base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1 ,2-dichloroethane .
  • the coupling of the compound of Formula VIII with the compound of Formula IX or a salt thereof is carried out for about 15 minutes to about 3 hours, preferably for about 30 minutes to about 2 hours.
  • the coupling of the compound of Formula VIII with the compound of Formula IX is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 35°C.
  • the compound of Formula X may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula X may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula X is reduced with a reducing agent to obtain the compound of Formula XI in a solvent.
  • the reducing agent is selected from the group consisting of lithium borohydride, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride.
  • the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
  • ethers examples include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, and 1,2-dichloroethane.
  • the reduction of the compound of Formula X with the reducing agent is carried out for about 10 hours to about 30 hours, preferably for about 12 hours to about 25 hours.
  • the reduction of the compound of Formula X with the reducing agent is carried out at a temperature of about 20°C to about 40°C, preferably for about 20°C to about 35°C.
  • the compound of Formula XI may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the compound of Formula XI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • the compound of Formula XI is deprotected in the presence of the deprotecting agent to obtain ticagrelor of Formula I by following the methods provided in the art, for example, PCT Publication Nos. WO 00/34283 and WO 01/92263. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
  • the NMR spectrum was recorded using a Bruker ® Avance III (400 MHz) NMR spectrometer.
  • Mass spectrum was recorded using a MASS (API 2000) LC/MS/MS system, AB Sciex ® QTRAP ® LC/MS/MS system.
  • Methanesulfonyl chloride (59.42 g) was added to a precooled mixture of 5-nitro-2- (propylsulfanyl)pyrimidin-4,6-diol (100 g), triethyl amine (56.9 g), and 4- dimethylaminopyridine (1 g) in dichloromethane (600 mL) at 10°C to 15°C. The reaction mixture was stirred for 2 hours at 10°C to 20°C. Aqueous hydrochloric acid (IN, 600 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes at 20°C to 30°C to obtain a solid. The solid was filtered, then washed with aqueous hydrochloric acid (IN, 600 mL) and dichloromethane (600 mL), and then dried under vacuum at 30°C to 35°C for 6 hours to obtain the title compound.
  • aqueous hydrochloric acid (IN, 600 mL) and dich
  • the organic layer was separated, and a solution of sodium hydroxide (52.1 g) in deionized water (800 mL) was added over a period of 15 minutes at 30°C to 35°C.
  • the reaction mixture was stirred for 16 hours at 30°C to 35°C.
  • the aqueous layer was separated and washed with dichloromethane (2 x 400 mL).
  • the aqueous layer was acidified with acetic acid until the pH was 4.5 to 5.0.
  • the resulting mixture was extracted with
  • the reaction mixture was heated to 60°C to 65°C, and then stirred for 5 hours.
  • the mixture was cooled to 25°C to 30°C, and then washed with dichloromethane (500 mL).
  • the layers were separated, and the aqueous layer was acidified with aqueous hydrochloric acid (IN, 600 mL).
  • the aqueous layer was cooled to 0°C to 5°C, and then stirred for 16 hours to obtain a solid.
  • the solid was filtered, and then washed with deionized water (100 mL) to afford a wet cake.
  • the wet cake was washed with dichloromethane (300 mL), and the material was dried under vacuum at 30°C to 35°C for 4 hours to obtain the title compound.
  • Example 3 in methanol (320 mL).
  • the reaction mixture was hydrogenated at hydrogen pressure of 3.5 kg per cm 2 for 16 hours at 25°C to 30°C.
  • the reaction mixture was filtered, and then washed with methanol (80 mL).
  • Methanolic solution (56.25 mL) was distilled off under reduced pressure to dryness to afford a crude material.
  • the crude material was purified with ethyl acetate (30 mL). The rest of the methanolic solution was used as such for the next step.
  • Aqueous hydrochloric acid (IN, 350 mL) was added to the methanolic solution of
  • Example 6 Preparation of disodium ( ⁇ (3ai?.4 ⁇ , .6j?.6aS)-2.2-dimethyl-6-r7-oxido-5- (propylsulfanyl)-3H-ri.2.31triazolor4.5- lpyrimidin-3-ylltetrahvdro-3aH- cvclopentaM IT.31dioxol-4-yl ⁇ oxy)acetate (Formula Via, when X is Na)
  • Example 7 Preparation of methyl ( ⁇ (33 ⁇ .4 ⁇ .6 ⁇ .63 ⁇ )-6- ⁇ 7-1 ⁇ -5-( ⁇ 8 ⁇ 1 ⁇ 3 ⁇ 1)-3 ⁇ ri.2.31triazolor4.5- ⁇ ilpyrimidin-3-yll-2.2-dimethyltetrahvdro-3aH- cvclopentak/llT.31dioxol-4-yl ⁇ oxy)acetate (Formula VII)
  • Acetic acid (0.5 mL) was added to a solution of disodium ( ⁇ (3ai?,45 * ,6i?,6aS)-2,2- dimethyl-6-[7-oxido-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-ii]pyrimidin-3- yl]tetrahydro-3aH-cyclopenta[ ⁇ f][l,3]dioxol-4-yl ⁇ oxy)acetate (1 g, Formula Via, when X is Na, as obtained from Example 6) in dichloromethane (6 mL), followed by the addition of deionized water (6 mL). The reaction mixture was stirred for 15 minutes at 25°C to 30°C. The layers were separated. Dichloromethane was distilled off completely to obtain a residue.
  • the organic layer was washed with aqueous sodium bicarbonate solution (10 %, 7.5 mL), followed by brine solution (9 g sodium chloride in 7.5 mL deionized water).
  • the organic layer was distilled off completely under vacuum at 25 °C to 30°C to obtain a crude material.
  • the crude material was then purified with a mixture of ethyl acetate (1 mL) and hexanes (5 mL) to obtain the title compound.
  • 2,2-Dimethoxy propane (36 mL) was added to the residue, and then the reaction mixture was stirred for 16 hours at 25°C to 30°C.
  • the solvent was recovered under vacuum at 25°C to 30°C to obtain a residue.
  • the residue was dissolved in dichloromethane (108 mL).
  • the organic layer was washed with aqueous sodium bicarbonate solution (10%, 136 mL), followed by brine solution (9 g sodium chloride in 136 mL deionized water).
  • the organic layer was distilled off completely under vacuum at 25 °C to 30°C to obtain a crude material.
  • the crude material was purified with a mixture of ethyl acetate (18 mL) and hexanes (90 mL) to obtain the title compound.
  • Example 8 Preparation of methyl ⁇ r(3ai?.4 ⁇ , .6j?.6aS)-2.2-dimethyl-6- ⁇ 7- r(methylsulfonyl)oxyl -5 -(propylsulfanyl)-3H- ⁇ 1.2.31triazolo r4.5- ⁇ flpyrimidin-3 - yl ⁇ tetrahvdro-3aH-cvclopentaMri.31dioxol-4-ylloxy ⁇ acetate (Formula VIII. when L is - SQ 2 CF )
  • Triethyl amine (4.75 mL) and 4-dimethylaminopyridine (0.5 g) were added to a solution of methyl ( ⁇ (3aR,45',6i?,6aS)-6-[7-hydroxy-5-(propylsulfanyl)-3H- [l,2,3]triazolo[4,5-£/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH- cyclopenta[ ⁇ f] [l,3]dioxol-4-yl ⁇ oxy)acetate (10 g, Formula VII as obtained from Example 7) in dichloromethane (100 mL). The reaction mixture was cooled to -5 °C to 0°C.
  • Example 9 Preparation of methyl ( ⁇ (3aft4£6R.6a-3V6-r7- ⁇ rqR.2S)-2-(3.4- difluorophenvDcvclopropyll amino ⁇ -5-(propylsulfanyl)-3H-r 1.2.31triazolo ⁇ 4.5- lpyrimidin-3-yll-2.2-dimethyltetrahvdro-3aH-cvclopentaMri.31dioxol-4-yl ⁇ oxy)acetate (Formula X)
  • Triethyl amine (4.45 g) and (7i?,2 ⁇ S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride (Formula IX, 4.76 g) were added to methyl ⁇ [(3ai?,45 * ,6i?,6aS)-2,2- dimethyl-6- ⁇ 7-[(methylsulfonyl)oxy]-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- £/]pyrimidin-3-yl ⁇ tetrahydro-3aH-cyclopenta[ii][l,3]dioxol-4-yl]oxy ⁇ acetate solution (Formula VIII as obtained from Example 8, when L is -SO 2 CH 3 ) at 25°C to 30°C.
  • the reaction mixture was stirred for 1 hour at 25 °C to 30°C.
  • the organic layer was washed with hydrochloric acid (IN, 55 mL), followed by washing with aqueous sodium bicarbonate solution (5 g in 50 mL deionized water).
  • the solvent was distilled off completely under vacuum at 35°C to obtain the title compound.
  • Example 10 Preparation of 2-( ⁇ (3ai?.4 ⁇ .6j?.6aS -6-r7- ⁇ r(li?.2 ⁇ )-2-(3.4- difluorophenvDcvclopropyll amino ⁇ -5-(propylsulfanyl)-3H-r 1.2.31triazolo ⁇ 4.5- ⁇ f]pyrimidin-3-yl]-2.2-dimethyltetrahydro
  • Lithium borohydride (60% in tetrahydrofuran, 15 mL) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to 20°C to 25 °C, and then stirred for 16 hours. The reaction mixture was cooled to 0°C to 5°C, and quenched slowly with deionized water (60 mL). The reaction mixture was extracted with ethyl acetate (60 mL) and re-extracted with ethyl acetate (20 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (5 g in 50 mL deionized water). The solvent was distilled off completely to obtain a solid material. The solid material was crystallized with a mixture of methyl tert butyl ether (10 mL) and cyclohexane (60 mL) to afford the title compound.
  • Example 1 1 Preparation of ( ⁇ S.2S3R.5S)-3- ⁇ 7-i ⁇ ( ⁇ R.2S)-2-(3.4- difluorophenvDcvclopropyll amino ⁇ -5-(propylthio)-3H- ⁇ 1.2.31 -triazolo ⁇ 4.5 - lpyrimidin-3 - yl]-5-(2-hydroxyethoxy)cyclopentane-1.2-diol (Formula I )
  • the reaction mixture was heated to 35°C to 40°C.
  • the reaction mixture was stirred for 16 hours at 35°C to 40°C.
  • Methanol was distilled off completely under vacuum at 30°C to 35°C to obtain a residue.
  • the residue was extracted with dichloromethane (36 mL).
  • the organic layer was washed with aqueous hydrochloric acid (IN, 30 mL) followed by washing with aqueous sodium bicarbonate solution (3 g in 30 mL) and deionized water (30 mL).
  • the organic layer was distilled off to dryness to obtain a crude material.
  • the crude material was purified with acetonitrile (30 mL) to afford the title compound.

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Abstract

The present invention provides a process for the preparation of ticagrelor. The present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula VIa, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.

Description

PROCESSES FOR THE PREPARATION OF TICAGRELOR AND ITS
INTERMEDIATES
Field of the Invention
The present invention provides a process for the preparation of ticagrelor. The present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula Via, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.
Background of the Invention
Ticagrelor, chemically (\S,2S,3R,5S)-3-[7-{[(\R,2S)-2-(3,4- difluorophenyl)cyclopropyl] amino } -5-(propylthio)-3H- [ 1 ,2,3] -triazolo [4,5 -<f]pyrimidin-3 - yl]-5-(2-hydroxyethox )cyclopentane-l,2-diol, is represented by Formula I.
Figure imgf000002_0001
Formula I
Ticagrelor is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction).
PCT Publication Nos. WO 00/34283, WO 01/92263, WO 2010/030224, WO 2011/017108, WO 2012/138981, WO 2012/139455, WO 2013/037942, WO 2013/092900, WO 2013/060837, WO 2013/150495, WO 2014/036823, WO 2014/086291, and WO 2014/102830; Chinese Patent Nos. CN 102311437, CN 102675321, CN 103288837, CN 103304567, CN 103360396, CN 103524429, CN 103588712, and CN 103709167; and Indian Patent Application Nos. 1029/MUM/2012, 2802/MUM/2012, and
3197/MUM/2012 disclose various processes for the preparation of ticagrelor. Summary of the Invention
The present invention provides a process for the preparation of ticagrelor. The present invention further provides compounds of Formula IV, Formula V, Formula VI, Formula Via, Formula VII, and Formula VIII, processes for their preparation, and their use for the preparation of ticagrelor.
The processes of the present invention involve environmentally friendly and easy- to-handle reagents and simpler processes for the isolation of the intermediates with significantly improved yields.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000003_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000003_0002
Formula II with a compound of Formula III
Figure imgf000004_0001
Formula III
to obtain a compound of Formula IV;
Figure imgf000004_0002
Formula IV
b) hydrogenating the compound of Formula IV in the presence of a hvdrogenation agent to obtain a compound of Formula V;
Figure imgf000004_0003
Formula V
c) cyclizing the compound of Formula V with an alkali metal nitrite to obtain a compound of Formula VI;
Figure imgf000005_0001
Formula VI
d) optionally purifying the compound of Formula VI through the formation of a compound of Formula Via
Figure imgf000005_0002
Formula Via
wherein X is Li, Na, or K;
e) optionally converting the compound of Formula Via into the compound of Formula VI;
f) esterifying the compound of Formula VI or the compound of Formula Via with methanol and 2,2-dimethoxypropane to obtain a compound of Formula VII;
Figure imgf000005_0003
Formula VII
g) O-protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII
Figure imgf000006_0001
Formula VIII
wherein L is -S02CH3, -S02C6H4(4-CH3), or -S02C6H4(4-N02);
h) coupling the compound of Formula VIII with a compound of Formula IX or a salt thereof
Figure imgf000006_0002
Formula IX
to obtain a compound of Formula X;
Figure imgf000006_0003
Formula X
i) reducing the compound of Formula X with a reducing agent to obtain a
compound of Formula XI; and
Figure imgf000006_0004
Formula XI j) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain ticagrelor of Formula I.
A second aspect of the present invention provides a process for the preparation of a compound of Formula IV,
Figure imgf000007_0001
Formula IV
wherein the process comprises reacting a compound of Formula II
Figure imgf000007_0002
Formula II
with a compound of Formula III
Figure imgf000007_0003
Formula III
to obtain the compound of Formula IV.
A third aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000008_0001
Formula I
wherein the process comprises:
a) reacting a compound of Formula II
Figure imgf000008_0002
Formula II
a compound of Formula III
Figure imgf000008_0003
Formula III
to obtain a compound of Formula IV; and
Figure imgf000008_0004
Formula IV
b) converting the compound of Formula IV into ticagrelor of Formula I.
A fourth aspect of the present invention provides a process for the preparation of a compound of Formula V,
Figure imgf000009_0001
Formula V
wherein the process comprises hydrogenating a compound of Formula IV
Figure imgf000009_0002
Formula IV
in the presence of a hydrogenation agent to obtain the compound of Formula V.
A fiftli aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000009_0003
Formula I
wherein the process comprises:
a) hydrogenating a compound of Formula IV
Figure imgf000010_0001
Formula IV
in the presence of a hydrogenation agent to obtain a compound of Formula V; and
Figure imgf000010_0002
Formula V
b) converting the compound of Formula V into ticagrelor of Formula I.
A sixth aspect of the present invention provides a process for the preparation of a compound of Formula VI,
Figure imgf000010_0003
Formula VI
wherein the process comprises:
a) cyclizing a compound of Formula V
Figure imgf000011_0001
Formula V
with an alkali metal nitrite to obtain a compound of Formula VI; and b) optionally purifying the compound of Formula VI through the formation of a compound of Formula Via
Figure imgf000011_0002
Formula Via
wherein X is Li, Na.
A seventh aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000011_0003
Formula I
wherein the process comprises:
a) cyclizing a compound of Formula V
Figure imgf000012_0001
Formula V
alkali metal nitrite to obtain a compound of Formula VI;
Figure imgf000012_0002
Formula VI
b) optionally purifying the compound of Formula VI through the formation of a compound of Formula Via
Figure imgf000012_0003
Formula Via
wherein X is Li, Na, or K;
c) optionally converting the compound of Formula Via into the compound of Formula VI; and
d) converting the compound of Formula VI or the compound of Formula Via into ticagrelor of Formula I.
An eighth aspect of the present invention provides a process for the preparation of a compound of Formula VII, H,CO
°X C°h
Formula VII
wherein the process comprises esterifving a compound of Formula VI
Figure imgf000013_0001
Formula VI
or a compound of Formula Via
Figure imgf000013_0002
Formula Via
wherein X is Li, Na, or K
with methanol and 2,2-dimethoxypropane to obtain the compound of Formula VII.
A ninth aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000014_0001
Formula I
wherein the process comprises:
a) esterifying a compound of Formula VI
Figure imgf000014_0002
Formula VI
or a compound of Formula Via
Figure imgf000014_0003
Formula Via
wherein X is Li, Na, or K
with methanol and 2,2-dimethoxypropane to obtain a compound of Formula VII; and
Figure imgf000015_0001
Formula VII
b) converting the compound of Fonnula VII into ticagrelor of Formula I.
A tenth aspect of the present invention provides a process for the preparation of a compound of Fonnula VIII,
Figure imgf000015_0002
Formula VIII
wherein L is -S02CH3, -SC^CeH^-CHs), or -S02C6H4(4-N02)
comprising O-protecting a compound of Formula VII
Figure imgf000015_0003
Formula VII
with a protecting agent to obtain the compound of Formula VIII.
An eleventh aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000016_0001
Formula I
wherein the process comprises:
a) O-protecting a compound of Formula VII
Figure imgf000016_0002
Formula VII
a protecting agent to obtain a compound of Formula VIII
Figure imgf000016_0003
Formula VIII
wherein L is -S02CH3. -S02C6H4 (4-CH3), or -SC^CeH^-NOz); and b) converting the compound of Formula VIII into ticagrelor of Fonnula I.
A twelfth aspect of the present invention provides a process for the preparation of a compound of Formula X, H3CO
Figure imgf000017_0001
Formula X
wherein the process comprises coupling a compound of Formula VIII
Figure imgf000017_0002
Formula VIII
wherein L is -S02CH3, -SC^CeH^-CHs), or -S02C6H4(4-N02)
with a compound of Formula IX or a salt thereof
Figure imgf000017_0003
Formula IX
to obtain the compound of Formula X.
A thirteenth aspect of the present invention provides a process for the preparation of ticagrelor of Formula I,
Figure imgf000018_0001
Formula I
wherein the process comprises:
a) coupling a compound of Formula VIII
Figure imgf000018_0002
Formula VIII
wherein L is -S02CH3, -S02C6H4(4-CH3), or -S02C6H4(4-N02) with a compound of Formula IX or a salt thereof
Figure imgf000018_0003
Formula IX
to obtain a compound of Formula X; and
Figure imgf000018_0004
Formula X b) converting the compound of Formula X into ticagrelor of Formula I.
A fourteenth as ect of the present invention provides a compound of Formula IV.
Figure imgf000019_0001
Formula IV
A fifteenth aspect of the present invention provides a compound of Formula V.
Figure imgf000019_0002
Formula V
A sixteenth aspect of the present invention provides a compound of Formula VI.
Figure imgf000019_0003
Formula VI
A seventeenth aspect of the present invention provides a compound of Formula
Figure imgf000020_0001
Formula Via
wherein X is Li, Na, or K.
An eighteenth aspect of the present invention provides a compound of Formula
VII.
Figure imgf000020_0002
Formula VII
A nineteenth aspect of the present invention provides a compound of Formula VIII
Figure imgf000020_0003
Formula VIII
wherein L is -S02CH3,
Figure imgf000020_0004
A twentieth aspect of the present invention provides use of a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula Via, a compound of Formula VII, or a compound of Formula VIII for the preparation of ticagrelor of Formula I. The compound of Formula II and the compound of Formula III are prepared according to the methods as described herein.
The compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in the presence of a base in a solvent.
The base is selected from the group consisting of hydroxides, carbonates, and bicarbonates of alkali metals.
Examples of hydroxides, carbonates, and bicarbonates of alkali metals include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate.
The solvent is selected from the group consisting of water, alcohols, ethers, hydrocarbons, halogenated hydrocarbons, ketones, and mixtures thereof.
Examples of alcohols include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of hydrocarbons include «-hexane, «-heptane, cyclohexane, toluene, and xylene.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
Examples of ketones include acetone and methyl ethyl ketone.
The reaction of the compound of Formula II with the compound of Formula III is carried out for about 5 hours to about 40 hours, preferably for about 5 hours to about 20 hours.
The reaction of the compound of Formula II with the compound of Formula III is carried out at a temperature of about 25°C to about 80°C, preferably of about 40°C to about 70°C.
The compound of Formula IV may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula IV may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula IV is hydrogenated in the presence of a hydrogenation agent to obtain the compound of Formula V in a solvent.
The hydrogenation agent is selected from the group consisting of
palladium/carbon, platinum oxide, and Raney nickel.
The solvent is selected from the group consisting of alcohols, ketones, and mixtures thereof.
Examples of alcohols include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
Examples of ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
The hydrogenation is carried out at a hydrogen pressure, for example, of about 1.5 kg per cm2 to about 4.5 kg per cm2, preferably of about 3 kg per cm2 to about 4 kg per cm2.
The hydrogenation of the compound of Formula IV is carried out at a temperature of about 15°C to about 50°C, preferably of about 25°C to about 35°C.
The hydrogenation of the compound of Formula IV is carried out for about 10 hours to about 25 hours, preferably for about 12 hours to about 20 hours.
The solution containing the compound of Formula V may be used as such for the next step.
The compound of Formula V may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula V may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula V is cyclized with an alkali metal nitrite to obtain the compound of Formula VI in the presence of an acid in a solvent. The alkali metal nitrite is selected from the group consisting of sodium nitrite and potassium nitrite.
The acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
The solvent is selected from the group consisting of water, alcohols, ethers, and mixtures thereof.
Examples of alcohols include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
The cyclization of the compound of Formula V with the alkali metal nitrite is carried out for about 1 hour to about 5 hours, preferably for about 2 hours to about 3 hours.
The cyclization of the compound of Formula V with the alkali metal nitrite is carried out at a temperature of about 0°C to about 20°C, preferably of about 0°C to about 10°C.
The compound of Formula VI is optionally isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VI is optionally purified through the formation of a compound of Formula Via using an alkali metal hydroxide in a solvent.
The alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
The solvent is selected from the group consisting of methanol, ethanol, «-propanol, isopropanol, «-butanol, and ethyl acetate.
The purification of the compound of Formula VI is carried out for about 15 minutes to about 2 hours, preferably for about 20 minutes to about 1 hour. The purification of the compound of Formula VI is carried out at a temperature of about 25 °C to about 70°C, preferably of about 40°C to about 65 °C.
The compound of Formula Via may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula Via may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula Via is optionally converted into the compound of Formula VI in the presence of an acid in a solvent.
The acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
The solvent is selected from the group consisting of water, alcohols, halogenated hydrocarbons, and mixtures thereof.
Examples of alcohols include methanol, ethanol, «-propanol, isopropanol, n- butanol, isobutanol, and fert-butanol.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The conversion of the compound of Formula Via is carried out for about 2 minutes to about 1 hour, preferably for about 10 minutes to about 30 minutes.
The conversion of the compound of Formula Via is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 35°C.
The compound of Formula VI may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula VI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VI is esterified with methanol and 2,2- dimethoxypropane to obtain the compound of Formula VII in the presence of an acid. Methanol is used as a solvent as well as a reagent.
The acid is selected from the group consisting of p-toluene sulphonic acid, methane sulfonic acid, sulfuric acid, and hydrochloric acid.
The esterification of the compound of Formula VI with methanol and 2,2- dimethoxypropane is carried out for about 12 hours to about 30 hours, preferably for about 15 hours to about 25 hours.
The esterification of the compound of Formula VI with methanol and 2,2- dimethoxypropane is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 45°C.
The compound of Formula VII may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula VII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The hydroxyl moiety of compound of Formula VII is O-protected with a protecting agent to obtain the compound of Formula VIII in the presence of a base and a catalyst in a solvent.
The protecting agent is selected from the group consisting of methanesulphonyl chloride, p-toluenesulphonyl chloride, and p-nitrobenzenesulphonyl chloride.
The base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
The preferred catalyst used is 4-dimethylaminopyridine.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane . The O-protection of the compound of Formula VII with the protecting agent is carried out for about 30 minutes to about 6 hours, preferably for about 1 hour to about 4 hours.
The O-protection of the compound of Formula VII with the protecting agent is carried out at a temperature of about - 15°C to about 20°C, preferably of about -10°C to about 10°C.
The solution containing the compound of Formula VIII may be used as such for the next step.
The compound of Formula VIII may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula VIII may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula VIII is coupled with the compound of Formula IX or a salt thereof to obtain the compound of Formula X in the presence of a base in a solvent.
The base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1 ,2-dichloroethane .
The coupling of the compound of Formula VIII with the compound of Formula IX or a salt thereof is carried out for about 15 minutes to about 3 hours, preferably for about 30 minutes to about 2 hours.
The coupling of the compound of Formula VIII with the compound of Formula IX is carried out at a temperature of about 15°C to about 60°C, preferably of about 20°C to about 35°C. The compound of Formula X may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula X may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula X is reduced with a reducing agent to obtain the compound of Formula XI in a solvent.
The reducing agent is selected from the group consisting of lithium borohydride, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride.
The solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
Examples of ethers include diethyl ether, 1,4-dioxane, and tetrahydrofuran.
Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
The reduction of the compound of Formula X with the reducing agent is carried out for about 10 hours to about 30 hours, preferably for about 12 hours to about 25 hours.
The reduction of the compound of Formula X with the reducing agent is carried out at a temperature of about 20°C to about 40°C, preferably for about 20°C to about 35°C.
The compound of Formula XI may optionally be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The compound of Formula XI may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
The compound of Formula XI is deprotected in the presence of the deprotecting agent to obtain ticagrelor of Formula I by following the methods provided in the art, for example, PCT Publication Nos. WO 00/34283 and WO 01/92263. While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Methods
The NMR spectrum was recorded using a Bruker® Avance III (400 MHz) NMR spectrometer.
The Mass spectrum was recorded using a MASS (API 2000) LC/MS/MS system, AB Sciex® QTRAP® LC/MS/MS system.
Examples
Example 1 : Preparation of 6-hvdroxy-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl methane sulfonate (Formula II)
Methanesulfonyl chloride (59.42 g) was added to a precooled mixture of 5-nitro-2- (propylsulfanyl)pyrimidin-4,6-diol (100 g), triethyl amine (56.9 g), and 4- dimethylaminopyridine (1 g) in dichloromethane (600 mL) at 10°C to 15°C. The reaction mixture was stirred for 2 hours at 10°C to 20°C. Aqueous hydrochloric acid (IN, 600 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes at 20°C to 30°C to obtain a solid. The solid was filtered, then washed with aqueous hydrochloric acid (IN, 600 mL) and dichloromethane (600 mL), and then dried under vacuum at 30°C to 35°C for 6 hours to obtain the title compound.
Yield: 58 g
Example 2: Preparation of {[(3ai?.4^'.6j?.6aS -6-amino-2.2-dimethyltetrahydro-3aH- cvclopentak/UT.31dioxol-4-ylloxy}acetic acid (Formula III)
Step a): Preparation of {[(3a/?,4 ,6i?,6a^-6-{[(benzyloxy)carbonyl]amino}-2,2- dimethyltetrahydro-3aH-cyclopenta[i/| [l,3]dioxol-4-yl]oxy}acetic acid
A solution of benzyl [(3aS',4i?,65',6ai?)-6-hydroxy-2,2-dimethyltetrahydro-3aH- cyclopenta[<f] [l,3]dioxol-4-yl]carbamate (200 g) in N,N-dimethylformamide (400 mL) was added to a suspension of sodium hydride (60% in oil, 31.3 g) in N,N- dimethylformamide (400 mL) at -15°C to -10°C over a period of 45 minutes. The reaction mixture was stirred for 1 hour at -15°C to -10°C, and then cooled to -25°C to -20°C. A solution of ethyl bromoacetate (163 g) in NN-dimethylformamide (400 mL) was added to the reaction mixture at -25 °C to -20°C over a period of 1.5 hours. The reaction mixture was stirred for 1 hour at -25 °C to -20°C. Acetic acid (20 mL) was added to the reaction mixture, followed by the addition of deionized water (1.6 L) and toluene (800 mL). The organic layer was separated, and the aqueous layer was extracted with toluene (2 x 300 mL). The combined organic layers were washed with deionized water (3 x 1.6 L). The organic layer was separated, and a solution of sodium hydroxide (52.1 g) in deionized water (800 mL) was added over a period of 15 minutes at 30°C to 35°C. The reaction mixture was stirred for 16 hours at 30°C to 35°C. The aqueous layer was separated and washed with dichloromethane (2 x 400 mL). The aqueous layer was acidified with acetic acid until the pH was 4.5 to 5.0. The resulting mixture was extracted with
dichloromethane (800 mL), followed by extraction with dichloromethane (400 mL). The combined organic layers were washed with deionized water (2 x 600 mL). The organic layer was recovered under vacuum to obtain a crude product. The crude product was crystalized with ethyl acetate (200 mL) and hexanes (1200 mL) to afford the title compound.
Yield: 163 g
Step b): Preparation of {[(3a/?, £,6i?,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[i/| [l,3]dioxol-4-yl]oxy}acetic acid (Formula III)
{[(3ai?,4^,6i?,6aS)-6-{[(benzyloxy)carbonyl]amino}-2,2-dimethyltetrahydro-3aH- cyclopenta[<f] [l,3]dioxol-4-yl]oxy}acetic acid (100 g, obtained from step a) was dissolved in methanol (400 mL). Palladium/carbon (10 g) was added to the mixture, and then the reaction mixture was hydrogenated for 5 hours at hydrogen pressure of 2.5 kg per cm2 at 25 °C to 30°C. The reaction mass was filtered, and then washed with methanol (200 mL). Methanol was distilled off under vacuum. Deionized water (500 mL) was added and the solution was used as such for the next step.
Example 3: Preparation of { [(33^.4^.6^.63^)-6-{[6^νάΓθχν-5-ηίΐΓθ-2- (propylsulfanyl)pyrimidin-4-yl]amino}-2.2-dimethyltetrahydro-3aH- cyclopenta[<f] [1.3]dioxol-4-yl]oxy}acetic acid (Formula IV)
A solution of {[(3ai?,45',6i?,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[<f][l,3]dioxol-4-yl]oxy}acetic acid (Formula III as obtained from Example 2) in deionized water (500 mL) and 6-hydroxy-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl methane sulfonate (84.7 g, Formula II as obtained from Example 1) were added to deionized water (500 mL), followed by the lot wise addition of sodium bicarbonate (71.33 g). The reaction mixture was heated to 60°C to 65°C, and then stirred for 5 hours. The mixture was cooled to 25°C to 30°C, and then washed with dichloromethane (500 mL). The layers were separated, and the aqueous layer was acidified with aqueous hydrochloric acid (IN, 600 mL). The aqueous layer was cooled to 0°C to 5°C, and then stirred for 16 hours to obtain a solid. The solid was filtered, and then washed with deionized water (100 mL) to afford a wet cake. The wet cake was washed with dichloromethane (300 mL), and the material was dried under vacuum at 30°C to 35°C for 4 hours to obtain the title compound.
Yield: 65 g
¾ NMR (de-DMSO, 400 MHz): δ 0.96 - 0.99 (3H, m), 1.21 (3H, s), 1.35 (3H, s), 1.65- 1.74 (2H, m), 2-2.03 (1H, m), 2.17-2.23 (1H, m), 3-3.25 (2H, m), 4.05 (1H, s), 4.2 (2H, s), 4.55-4.65 (2H, m), 4.67 (1H, m), 9.73-9.75 (1H, m), 12.7 (2H,s).
Mass (m/z): 445.2 [m+l] +
Figure imgf000030_0001
(propylsulfanyl)pyrimidin-4-yllamino}-2.2-dimethyltetrahydro-3aH- cyclopenta[<f] [1.3]dioxol-4-yl]oxy}acetic acid (Formula V)
Palladium/carbon (4 g) was added to a solution of {[(3ai?,45*,6i?,6aS)-6-{[6- hydroxy-5-nitro-2-(propylsulfanyl)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH- cyclopenta[<f] [l,3]dioxol-4-yl]oxy}acetic acid (40 g, Formula IV as obtained from
Example 3) in methanol (320 mL). The reaction mixture was hydrogenated at hydrogen pressure of 3.5 kg per cm2 for 16 hours at 25°C to 30°C. The reaction mixture was filtered, and then washed with methanol (80 mL). Methanolic solution (56.25 mL) was distilled off under reduced pressure to dryness to afford a crude material. The crude material was purified with ethyl acetate (30 mL). The rest of the methanolic solution was used as such for the next step.
Yield: 3.5 g
¾ NMR (de-DMSO, 400 MHz): δ 0.95 (3H, m), 1.2 (3H, s), 1.34 (3H, s), 1.62-1.68 (2H, m), 1.81-1.85 (1H, d), 2.14-2.2 (1H, m), 2.97-3.12 (2H, m), 3.9 (2H, s), 4.02-4.16 (3H, m), 4.29 (2H, s), 4.44-4.46 (1H, m), 4.53 (2H, m), 6.15 (lH,s). Mass (m/z): 415.2 [m+l] +
Example 5: Preparation of ({(3^.4^.6^.63^)-6-Γ7-1ινάΓθχν-5-(ρΓορνΐ8η1ί3ην1)-3^ ri.2.31triazolor4.5- lpyrimidin-3-yll-2.2-dimethyltetrahvdro-3aH- cvclopentak/HT.31dioxol-4-yl}oxy)acetic acid (Formula VI)
Aqueous hydrochloric acid (IN, 350 mL) was added to the methanolic solution of
{ [(3aR,4S,6R,6aS)-6- { [5 -amino-6-hydroxy-2-(propylsulfanyl)pyrimidin-4-yl] amino } -2,2- dimethyltetrahydro-3aH-cyclopenta[£/][l,3]dioxol-4-yl]oxy}acetic acid (380 mL, Formula V obtained from Example 4) at 0°C to 5°C. A solution of sodium nitrite (10.85 g) in deionized water (35 mL) was slowly added to the mixture. The mixture was stirred for 2 hours at 0°C to 5°C. Deionized water (175 mL) and dichloromethane (210 mL) were added to the reaction mixture, and then the reaction mixture was stirred for 10 minutes. The layers were separated, and the aqueous layer was extracted with dichloromethane (120 mL). The combined organic layers were washed with brine solution (10 g sodium chloride in 175 mL deionized water ). The organic layer was concentrated under vacuum to dryness at 30°C to 35°C to afford the title compound.
Yield: 30 g
¾ NMR (de-DMSO, 400 MHz): δ 0.97 (3H, m), 1.27 (3H, s), 1.47 (3H, s), 1.71-1.77 (3H, m), 2.5-2.78 (2H, m), 3.1-3.3 (2H, m), 3.5-3.65 (2H, m), 4.0-4.2 (3H, m), 4.7 (1H, m), 5.62 (1H, m), 5.21 (1H, m), 12.6-12.9 (2H, 2s).
Mass (m/z): 426.3 [m+1] +
Example 6: Preparation of disodium ({(3ai?.4^,.6j?.6aS)-2.2-dimethyl-6-r7-oxido-5- (propylsulfanyl)-3H-ri.2.31triazolor4.5- lpyrimidin-3-ylltetrahvdro-3aH- cvclopentaM IT.31dioxol-4-yl}oxy)acetate (Formula Via, when X is Na)
({(3ai?,4^,6i?,6aS)-6-[7-hydroxy-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- ]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[ii][l,3]dioxol-4-yl}oxy)acetic acid (1 g, Formula VI as obtained from Example 5) was dissolved in methanol (2 mL) at 25°C to 30°C. Sodium hydroxide (98 mg) was added to the solution. Methanol was distilled off completely to obtain a residue. The residue was dried under vacuum for 30 minutes. Ethyl acetate (6 mL) was added to the residue and stirred for 2 hours to obtain a solid. The solid was filtered, then washed with ethyl acetate (2 mL), and then dried under vacuum at 25°C to 30°C for 6 hours to obtain the title compound. Yield: 0.6 g
¾ NMR (de-DMSO, 400 MHz): δ 0.97 (3H, s), 1.25 (3H, s), 1.47 (3H, s), 1.6-1.7 (2H, m), 2.5-2.51 (1H, m), 3.01-3.05 (2H, m), 3.8-3.9 (3H, m), 3.9-4.1 (1H, m), 4.66-4.68 (1H, m), 4.8-4.9 (1H, m), 5.11-5.13 (1H, m).
Figure imgf000032_0001
Example 7: Preparation of methyl ({(33^.4^.6^.63^)-6-Γ7-1ινάΓθχν-5-(ρΓορνΐ8η1ί3ην1)-3^ ri.2.31triazolor4.5-<ilpyrimidin-3-yll-2.2-dimethyltetrahvdro-3aH- cvclopentak/llT.31dioxol-4-yl}oxy)acetate (Formula VII)
Method A
Step a): Preparation of ({(3afl,4£,6i?,6a^-6-[7-hydroxy-5-(propylsulfanyl)-3H- [1 ,2,3] triazolo [4,5-i/] pyrimidin-3-yl] -2,2-dimethyltetrahydro-3aH- cyclopenta[i/| [l,3]dioxol-4-yl}oxy)acetic acid (Formula VI)
Acetic acid (0.5 mL) was added to a solution of disodium ({(3ai?,45*,6i?,6aS)-2,2- dimethyl-6-[7-oxido-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-ii]pyrimidin-3- yl]tetrahydro-3aH-cyclopenta[<f][l,3]dioxol-4-yl}oxy)acetate (1 g, Formula Via, when X is Na, as obtained from Example 6) in dichloromethane (6 mL), followed by the addition of deionized water (6 mL). The reaction mixture was stirred for 15 minutes at 25°C to 30°C. The layers were separated. Dichloromethane was distilled off completely to obtain a residue.
Step b): Preparation of methyl ({(3a/?,4 ,6i?,6aS)-6-[7-hydroxy-5-(propylsulfanyl)- 3H- [1 ,2,3] triazolo [4,5-i/] pyrimidin-3-yl] -2,2-dimethyltetr ahydro-3aH- cyclopenta[i/] [l,3]dioxol-4-yl}oxy)acetate (Formula VII)
Methanol (4 mL) was added to the residue obtained from step a), followed by the addition of p-toluenesulphonic acid (0.1 g). The reaction mixture was stirred for 4 hours at 35°C to 40°C. Methanol was distilled off completely under vacuum to obtain a residue. 2,2-Dimethoxy propane (2 mL) was added to the residue, and then the reaction mixture was stirred for 16 hours at 25°C to 30°C. The solvent was recovered under vacuum at 25°C to 30°C to obtain a residue. The residue was dissolved in dichloromethane (6 mL). The organic layer was washed with aqueous sodium bicarbonate solution (10 %, 7.5 mL), followed by brine solution (9 g sodium chloride in 7.5 mL deionized water). The organic layer was distilled off completely under vacuum at 25 °C to 30°C to obtain a crude material. The crude material was then purified with a mixture of ethyl acetate (1 mL) and hexanes (5 mL) to obtain the title compound.
Method B
p-Toluenesulphonic acid (1.8 g) was added to a solution of ({(3aR,4S,6R,6aS)-6- [7-hydroxy-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-£/]pyrimidin-3-yl]-2,2- dimethyltetrahydro-3aH-cyclopenta[£/][l,3]dioxol-4-yl}oxy)acetic acid (18 g, Formula VI as obtained from Example 5) in methanol (72 mL). The reaction mixture was heated to 35°C to 40°C for 4 hours. The methanol was distilled off completely under vacuum to obtain a residue. 2,2-Dimethoxy propane (36 mL) was added to the residue, and then the reaction mixture was stirred for 16 hours at 25°C to 30°C. The solvent was recovered under vacuum at 25°C to 30°C to obtain a residue. The residue was dissolved in dichloromethane (108 mL). The organic layer was washed with aqueous sodium bicarbonate solution (10%, 136 mL), followed by brine solution (9 g sodium chloride in 136 mL deionized water). The organic layer was distilled off completely under vacuum at 25 °C to 30°C to obtain a crude material. The crude material was purified with a mixture of ethyl acetate (18 mL) and hexanes (90 mL) to obtain the title compound.
Yield: 18 g
¾ NMR (de-DMSO, 400 MHz): δ 0.99 (3H, s), 1.27 (3H, s), 1.47 (3H, s), 1.71-1.76 (2H, m), 2.50-2.72 (2H, m), 3.13-3.23 (2H, m), 3.63 (3H, s), 4-4.2 (3H, m), 4.7-4.73 (1H, m), 5-5.03 (1H, m), 5.19-5.22 (1H, m), 12.9 (1H, s).
Figure imgf000033_0001
Example 8: Preparation of methyl {r(3ai?.4^,.6j?.6aS)-2.2-dimethyl-6-{7- r(methylsulfonyl)oxyl -5 -(propylsulfanyl)-3H- Γ 1.2.31triazolo r4.5-<flpyrimidin-3 - yl}tetrahvdro-3aH-cvclopentaMri.31dioxol-4-ylloxy}acetate (Formula VIII. when L is - SQ2CF )
Triethyl amine (4.75 mL) and 4-dimethylaminopyridine (0.5 g) were added to a solution of methyl ({(3aR,45',6i?,6aS)-6-[7-hydroxy-5-(propylsulfanyl)-3H- [l,2,3]triazolo[4,5-£/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH- cyclopenta[<f] [l,3]dioxol-4-yl}oxy)acetate (10 g, Formula VII as obtained from Example 7) in dichloromethane (100 mL). The reaction mixture was cooled to -5 °C to 0°C. A solution of methanesulphonyl chloride (2.85 g) in dichloromethane (10 mL) was slowly added to the reaction mixture at -5°C to 0°C. The reaction mixture was stirred for 2 hours at -5°C to 0°C. The organic layer was washed with deionized water (100 inL) and used as such for the next step.
Example 9: Preparation of methyl ({(3aft4£6R.6a-3V6-r7-{rqR.2S)-2-(3.4- difluorophenvDcvclopropyll amino} -5-(propylsulfanyl)-3H-r 1.2.31triazolo Γ4.5- lpyrimidin-3-yll-2.2-dimethyltetrahvdro-3aH-cvclopentaMri.31dioxol-4-yl}oxy)acetate (Formula X)
Triethyl amine (4.45 g) and (7i?,2<S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride (Formula IX, 4.76 g) were added to methyl {[(3ai?,45*,6i?,6aS)-2,2- dimethyl-6-{7-[(methylsulfonyl)oxy]-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- £/]pyrimidin-3-yl}tetrahydro-3aH-cyclopenta[ii][l,3]dioxol-4-yl]oxy}acetate solution (Formula VIII as obtained from Example 8, when L is -SO2CH3) at 25°C to 30°C. The reaction mixture was stirred for 1 hour at 25 °C to 30°C. The organic layer was washed with hydrochloric acid (IN, 55 mL), followed by washing with aqueous sodium bicarbonate solution (5 g in 50 mL deionized water). The solvent was distilled off completely under vacuum at 35°C to obtain the title compound.
Yield: 12 g
Example 10: Preparation of 2-({(3ai?.4^.6j?.6aS -6-r7-{r(li?.2^)-2-(3.4- difluorophenvDcvclopropyll amino} -5-(propylsulfanyl)-3H-r 1.2.31triazolo Γ4.5- <f]pyrimidin-3-yl]-2.2-dimethyltetrahydro
(Formula XI)
A solution of methyl ({(3a/-,45,,6R,6a5)-6-[7-{[(lR,25)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5- £/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopenta[ii][l,3]dioxol-4-yl}oxy)acetate (10 g, Formula X as obtained from Example 9) in tetrahydrofuran (80 mL) was cooled to 0°C to 5°C. Lithium borohydride (60% in tetrahydrofuran, 15 mL) was added slowly under a nitrogen atmosphere. The resulting mixture was warmed to 20°C to 25 °C, and then stirred for 16 hours. The reaction mixture was cooled to 0°C to 5°C, and quenched slowly with deionized water (60 mL). The reaction mixture was extracted with ethyl acetate (60 mL) and re-extracted with ethyl acetate (20 mL). The combined organic layers were washed with aqueous sodium bicarbonate solution (5 g in 50 mL deionized water). The solvent was distilled off completely to obtain a solid material. The solid material was crystallized with a mixture of methyl tert butyl ether (10 mL) and cyclohexane (60 mL) to afford the title compound.
Yield: 8 g
Example 1 1 : Preparation of (\S.2S3R.5S)-3-\7-i \(\R.2S)-2-(3.4- difluorophenvDcvclopropyll amino } -5-(propylthio)-3H- Γ 1.2.31 -triazolo Γ4.5 - lpyrimidin-3 - yl]-5-(2-hydroxyethoxy)cyclopentane-1.2-diol (Formula I )
Hydrochloric acid (3N, 24 mL) was added to a solution of 2-({(3ai?,45*,6i?,6aS)-6- [7-{ [( li?,25)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylsulfanyl)-3H- [l,2,3]triazolo[4,5-£/]pyrimidin-3-yl]-2,2-dimethyltetrahydro-3aH- cyclopenta[<f] [l,3]dioxol-4-yl}oxy)ethanol (6 g, Formula XI as obtained from Example 10) in methanol (30 mL). The reaction mixture was heated to 35°C to 40°C. The reaction mixture was stirred for 16 hours at 35°C to 40°C. Methanol was distilled off completely under vacuum at 30°C to 35°C to obtain a residue. The residue was extracted with dichloromethane (36 mL). The organic layer was washed with aqueous hydrochloric acid (IN, 30 mL) followed by washing with aqueous sodium bicarbonate solution (3 g in 30 mL) and deionized water (30 mL). The organic layer was distilled off to dryness to obtain a crude material. The crude material was purified with acetonitrile (30 mL) to afford the title compound.
Yield: 4.16 g

Claims

We claim
1. A process for the reparation of ticagrelor of Formula I,
Figure imgf000036_0001
Formula I
wherein the process comprises
a) reacting a compound of Formula II
Figure imgf000036_0002
Formula II
with a compound of Formula III
Figure imgf000036_0003
Formula III
to obtain a compound of Formula IV;
Figure imgf000036_0004
Formula IV b) hydrogenating the compound of Formula IV in the presence of a hydrogenation agent to obtain a compound of Formula V;
Figure imgf000037_0001
Formula V
c) cyclizing the compound of Formula V with an alkali metal nitrite to obtain a compound of Formula VI;
Figure imgf000037_0002
Formula VI
d) optionally purifying the compound of Formula VI through the formation of a compound of Formula Via
Figure imgf000037_0003
Formula Via
wherein X is Li, Na, or K;
e) optionally converting the compound of Formula Via into the compound of Formula VI; f) esterifying the compound of Formula VI or the compound of Formula Via with methanol and 2,2-dimethoxypropane to obtain a compound of Formula VII;
Figure imgf000038_0001
Formula VII
g) O-protecting the compound of Formula VII with a protecting agent to obtain a compound of Formula VIII
Figure imgf000038_0002
Formula VIII
wherein L is -S02CH3, -SC^CeH^-CHs), or -S02C6H4(4-N02);
h) coupling the compound of Formula VIII with a compound of Formula IX or a salt thereof
Figure imgf000038_0003
Formula IX
to obtain a compound of Formula X;
Figure imgf000039_0001
Formula X
i) reducing the compound of Formula X with a reducing agent to obtain a compound of Formula XI; and
Figure imgf000039_0002
Formula XI
j) deprotecting the compound of Formula XI in the presence of a deprotecting agent to obtain ticagrelor of Formula I.
2. A process for the preparation of a compound of Formula IV,
Figure imgf000039_0003
Formula IV
wherein the process comprises reacting a compound of Formula II
Figure imgf000040_0001
Formula II
with a compound of Formula III
Figure imgf000040_0002
Formula III
to obtain the compound of Fonnula IV.
3. A process for the reparation of ticagrelor of Formula I,
Figure imgf000040_0003
Formula I
wherein the process comprises
a) reacting a compound of Formula II
Figure imgf000040_0004
Formula II
with a compound of Fonnula III o o
H3C CH3
Formula III
to obtain a compound of Formula IV; and
Figure imgf000041_0001
Formula IV
b) converting the compound of Formula IV into ticagrelor of Formula I. A process for the preparation of a compound of Formula V,
Figure imgf000041_0002
Formula V
wherein the process comprises hydrogenating a compound of Formula IV
Figure imgf000041_0003
Formula IV the presence of a hydrogenation agent to obtain the compound of Formula V.
A process for the preparation of ticagrelor of Formula I,
Figure imgf000042_0001
Formula I
wherein the process comprises
a) hydrogenating a compound of Formula IV
Figure imgf000042_0002
Formula IV
in the presence of a hydrogenation agent to obtain a compound of Formula V; and
Figure imgf000042_0003
Formula V
b) converting the compound of Formula V into ticagrelor of Fonnula I.
6. A process for the preparation of a compound of Formula VI,
Figure imgf000043_0001
Formula VI
wherein the process comprises
a) cyclizing a compound of Formula V
Figure imgf000043_0002
Formula V
with an alkali metal nitrite to obtain a compound of Formula VI; and b) optionally purifying the compound of Formula VI through the fonnation of a compound of Formula Via
Figure imgf000043_0003
Formula Via
wherein X is Li, Na, or K.
A process for the preparation of ticagrelor of Formula I,
Figure imgf000044_0001
Formula I
wherein the process comprises
a) cyclizing a compound of Formula V
Figure imgf000044_0002
Formula V
witli an alkali metal nitrite to obtain a compound of Formula VI;
Figure imgf000044_0003
Formula VI
b) optionally purifying tlie compound of Formula VI through the fonnation of a compound of Fonnula Via
Figure imgf000045_0001
Formula Via
wherein X is Li, Na, or K;
c) optionally converting the compound of Formula Via into the compound of Formula VI; and
d) converting the compound of Formula VI or the compound of Formula Via into ticagrelor of Formula I.
8. A process for the preparation of a compound of Formula VII,
Figure imgf000045_0002
Formula VII
wherein the process comprises esterifying a compound of Formula VI
Figure imgf000045_0003
Formula VI
or a compound of Formula Via
Figure imgf000046_0001
Formula Via
wherein X is Li, Na, or K
with methanol and 2,2-dimethoxypropane to obtain the compound of Formula VII.9. A process for the preparation of ticagrelor of Formula I,
Figure imgf000046_0002
Formula I
vherein the process comprises
a) esterifying a compound of Formula VI
Figure imgf000046_0003
Formula VI
or a compound of Formula Via
Figure imgf000047_0001
Formula Via
wherein X is Li, Na, or K
with methanol and 2,2-dimethoxypropane to obtain a compound of Formula VII; and
Figure imgf000047_0002
Formula VII
b) converting the compound of Formula VII into ticagrelor of Fonnula I. 10. A process for the preparation of a compound of Formula VIII,
Figure imgf000047_0003
Formula VIII
wherein L is -S02CH3,
Figure imgf000047_0004
comprising O-protecting a compound of Formula VII
Figure imgf000048_0001
Formula VII
with a protecting agent to obtain the compound of Fonnula VIII.
11. A process for the preparation of tica relor of Fonnula I,
Figure imgf000048_0002
Formula I
wherein the process comprises
a) O-protecting a compound of Fonnula VII
Figure imgf000048_0003
Formula VII
with a protecting agent to obtain a compound of Formula VIII H,co
Figure imgf000049_0001
Formula VIII
wherein L is -S02CH3, -S02C6H4(4-CH3), or -S02C6H4(4-N02); and b) converting the compound of Formula VIII into ticagrelor of Formula I.
12. A process for the preparation of a com ound of Formula X,
Figure imgf000049_0002
Formula X
wherein the process comprises coupling a compound of Formula VIII
Figure imgf000049_0003
Formula VIII
wherein L is -S02CH3, -S02C6H4(4-CH3), or -S02C6H4(4-N02)
with a compound of Formula IX or a salt thereof
Figure imgf000050_0001
Formula IX
to obtain the compound of Formula X.
13. A process for the reparation of ticagrelor of Formula I,
Figure imgf000050_0002
Formula I
wherein the process comprises
a) coupling a compound of Formula VIII
Figure imgf000050_0003
Formula VIII
wherein L is -S02CH3, -S02C6H4(4-CH3), or
Figure imgf000050_0004
with a compound of Formula IX or a salt thereof
Figure imgf000050_0005
Formula IX
to obtain a compound of Formula X; and
Figure imgf000051_0001
Formula X
b) converting the compound of Formula X into ticagrelor of Formula I.
14. The process according to claim 1, 2, or 3, wherein the compound of Formula II is reacted with the compound of Formula III to obtain the compound of Formula IV in the presence of a base in a solvent.
15. The process according to claim 14, wherein the base is selected from the group consisting of hydroxides, carbonates, and bicarbonates of alkali metals.
16. The process according to claim 14, wherein the solvent is selected from the group consisting of water, alcohols, ethers, hydrocarbons, halogenated hydrocarbons, ketones, and mixtures thereof.
17. The process according to claim 1, 4, or 5, wherein the compound of Formula IV is hydrogenated in the presence of a hydrogenation agent to obtain the compound of Formula V in a solvent.
18. The process according to claim 1, 4, or 5 wherein the hydrogenation agent is selected from the group consisting of palladium/carbon, platinum oxide, and Raney nickel. 19. The process according to claim 17, wherein the solvent is selected from the group consisting of alcohols, ketones, and mixtures thereof.
20. The process according to claim 1, 4, or 5, wherein the hydrogenation is carried out at a hydrogen pressure of about 1.5 kg per cm2 to about 4.5 kg per cm2.
21. The process according to claim 1 , 6, or 7, wherein the compound of Formula V is cyclized with an alkali metal nitrite to obtain the compound of Formula VI in the presence of an acid in a solvent.
22. The process according to claim 1, 6, or 7, wherein the alkali metal nitrite is selected from the group consisting of sodium nitrite and potassium nitrite.
23. The process according to claim 21, wherein the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
24. The process according to claim 21, wherein the solvent is selected from the group consisting of water, alcohols, ethers, and mixtures thereof.
25. The process according to claim 1, 6, or 7,wherein the compound of Formula VI is optionally purified through the formation of the compound of Formula Via using an alkali metal hydroxide in a solvent.
26. The process according to claim 25, wherein the alkali metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
27. The process according to claim 25, wherein the solvent is selected from the group consisting of methanol, ethanol, «-propanol, isopropanol, «-butanol, and ethyl acetate. 28. The process according to claim 1 or 7, wherein the compound of Formula Via is optionally converted into the compound of Formula VI in the presence of an acid in a solvent.
29. The process according to claim 28, wherein the acid is selected from the group consisting of formic acid, acetic acid, propionic acid, and hydrochloric acid.
30. The process according to claim 28, wherein the solvent is selected from the group consisting of water, alcohols, halogenated hydrocarbons, and mixtures thereof.
31. The process according to claim 1, 8, or 9, wherein the compound of Formula VI is esterified with methanol and 2,2-dimethoxypropane to obtain the compound of Formula VII in the presence of an acid.
32. The process according to claim 31, wherein the acid is selected from the group consisting of p-toluene sulphonic acid, methane sulfonic acid, sulfuric acid, and hydrochloric acid.
33. The process according to claim 1, 10, or 11, wherein the compound of Formula VII is O-protected with a protecting agent to obtain the compound of Formula VIII in the presence of a base and a catalyst in a solvent.
34. The process according to claim 1, 10, or 11, wherein the protecting agent is selected from the group consisting of methane sulphonyl chloride, p-toluenesulphonyl chloride, and p-nitrobenzenesulphonyl chloride.
35. The process according to claim 33, wherein the base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
36. The process according to claim 33, wherein the catalyst is 4- dimethylaminopyridine.
37. The process according to claim 33, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
38. The process according to claim 1, 12, or 13, wherein the compound of Formula VIII is coupled with the compound of Formula IX or a salt thereof to obtain the compound of Formula X in the presence of a base in a solvent.
39. The process according to claim 38, wherein the base is selected from the group consisting of triethyl amine, diisopropyl amine, and diisopropyl ethyl amine.
40. The process according to claim 38, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
41. The process according to claim 1 , wherein the compound of Formula X is reduced with a reducing agent to obtain the compound of Formula XI in a solvent.
42. The process according to claim 1, wherein the reducing agent is selected from the group consisting of lithium borohydride, lithium aluminum hydride, sodium borohydride, and diisobutylaluminum hydride.
43. The process according to claim 41, wherein the solvent is selected from the group consisting of ethers, halogenated hydrocarbons, and mixtures thereof.
44. A compound of Formula IV.
Figure imgf000053_0001
Formula IV compound of Formula V.
Figure imgf000054_0001
Formula V
46. A compound of Formula VI.
Figure imgf000054_0002
Formula VI
47. A compound of Formula Via
Figure imgf000054_0003
Formula Via wherein X is Li. Na, or K.
48. A compound of Formula VII.
Figure imgf000055_0001
Formula VII
49. A compound of Formula VIII
Figure imgf000055_0002
Formula VIII
wherein L is -S02CH3, -SC^CeH^-CH), or -S02C6H4(4-N02).
50. Use of a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula Via, a compound of Formula VII, or a compound of Formula VIII for the preparation of ticagrelor of Formula I .
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