JP2016523868A - Preparation method of ticagrelol - Google Patents

Abstract

The present invention discloses a process for the preparation of ticagrelor (Ticagrelor, I), wherein 5-amino-1,4-disubstituted-1,2,3-triazole (II) and a sulfur-containing cyclizing agent (III) are cyclic To give 9-substituted-2-thio-6-oxy-8-azapurine (IV), and intermediate (IV) to halogenated propane (V) to give 9-substituted-2-sulfhydryl The group propane-6-oxy-8-azapurine (VI) is obtained, the intermediate (VI) is salified and trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (VII) To form a 9-substituted-6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII), intermediate (VIII) removes the acetonylidene protecting group and ticagrelol (I ). The preparation method is simple in process, economical and ecological, has high chemical and chiral purity, and provides a new preparation route for mass production of ticagrelol.

Description

  The present invention belongs to the field of organic synthesis route design and raw material medicine and intermediate preparation technology, and particularly relates to a method for preparing ticagrelol.

Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant researched and developed by AstraZeneca Co., Ltd. It is also an anti-drug, has a significant inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of acute coronary syndrome. The drug appeared in the European Union and the United States in 2010 and 2011 with the permission of the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA), respectively, and the trade name is Brinta. The imported drug, ticagrelol tablets, appeared in China with the permission of the Chinese National Food Supervision Administration (SFDA) in 2012, and the Chinese trade name is Bryrinta.
Since ticagrelol is a drug with a chemical classification different from that of thienopyridines, the Chinese name “tikagrel” was changed to “ticagrelor”.

The chemical name of ticagrelol represented by the following chemical formula 1 is (1S, 2S, 3R, 5S) -3- [7-[(1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine group] -5- (sulfhydryl group propane) -3H- [1,2,3] triazole [4,5-d] pyrimidinyl-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol is there.

The synthetic route and preparation method of ticagrelol has already been reported a lot, and after analyzing the already disclosed synthetic route and preparation method, the route is different, but the process is roughly the following three intermediates A (formula A), It was discovered that ticagrelol could be prepared by different chemical reactions of B (Chemical Formula B) and C (Chemical Formula C), different reaction sequences, and different linking methods.

The synthesis route of WO97 / 03084, WO99 / 05142, WO2000 / 34283 and WO2012 / 13881 is represented by the chemical formula D.

The main difference between the synthetic route of WO2001 / 36421, WO2001 / 36438, WO2001 / 92263 and WO2011 / 017108 is that the above-mentioned route is completed, as shown in Chemical Formula E, the introduction of 2-ethanol functional group in the five-membered ring is first completed First, the nitro group in the pyrimidinyl ring is reduced to produce an amino group. In addition, in WO2012 / 139455 and CN10267321, in order to consider a sub-reaction in which the 2-ethanol functional group may occur in the subsequent reaction, the hydroxyl group should be protected first, followed by further amine substitution reaction, and finally further deprotection. Produces ticagrelol.

In WO2012 / 172426, as shown in Formula F, the methyl acetate functional group is first retained in the five-membered ring to complete the link of the three intermediates, and finally the ester group is reduced to an alcohol.

WO2013 / 037942, WO2012 / 085665 and EP2570405 describe a method of condensing another kind of intermediate B with a pyrimidinyl ring, as shown in Chemical Formula G, and the selectivity of the condensation reaction by amino protection in cyclopropylamine. Is increasing.

In CN102311437, as shown in Chemical Formula H, another idea for the method of linking the five-membered ring (intermediate C) and the pyrimidinyl ring benzotriazole (intermediate A) is submitted, and the hydroxyl group in the five-membered ring And the nitrogen atom in the triazole are combined under the action of triphenylphosphine and diethyl azodicarboxylate. However, the position of the bond is relatively difficult to control due to the fragrance of the triazole ring.

  In addition, CN103130726, CN102250097, WO2011 / 101740, US2011 / 071290, WO2010 / 03224, WO2007 / 093368, and WO2005 / 095358 studied the preparation method of ticagrelol pyrimidinyl ring (intermediate A), and WO2012 / 001531 , WO2011 / 132083, CN1431992, CN13334816, CN1014954444, CN101495422, CN102796007, CN102249929, etc., studied the preparation method of ticagrelol three-membered ring (intermediate B), and WO2010 / 030224, US2010 / 0669408 and CN10265978roll, etc. The focus was on the synthesis and preparation of the ring (intermediate C).

  As mentioned above, the literature of preparation of ticagrelol already disclosed so far has been carried out all around the preparation, protection, linking and reaction of three important intermediates (A, B and C). The ability to prepare ticagrelol more easily and economically and ecologically by finding new intermediates and synthetic routes is very important for the economic technological development of the raw materials.

  The object of the present invention is to overcome the deficiencies of the prior art, and to provide an improved preparation method of ticagrelol based on the synthesis philosophy of green chemistry. The preparation method is simple, economical and ecological, and is advantageous for mass production of the pharmaceutical products. And the development of economic technology of the raw material drug can be promoted.

In order to achieve the above object, the technical solution provided by the present invention is a method for preparing ticagrelol (I) represented by the following chemical formula 1,
In the preparation method, as shown in the following chemical formula I, a 5-amino-1,4-disubstituent-1,2,3-triazole (II) and a sulfur-containing cyclizing agent (III) are cyclized. To give 9-substituted-2-thio-6-oxy-8-azapurine (IV), and 9-substituted-2-thio-6-oxy-8-azapurine (IV) and halogenated propane (V). Substitution reaction is performed to obtain 9-substituted-2-sulfhydryl group propane-6-oxy-8-azapurine (VI), and 9-substituted-2-sulfhydryl group propane-6-oxy-8-azapurine (VI) is chlorinated. And 9-substituted-6-amino-substituted-2-sulfhydryl group propane by amination reaction with trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (VII) Produces -8-azapurine (VIII) and 9-substitution 6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII) comprising removing acetonylidene protecting group to obtain ticagrelol (I), wherein the 9-substituted-2-sulfhydryl group propane- 6-Oxy-8-azapurine (VI) is directly condensed with the trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (VII) to form the 9-substituted-6-amino. The substitution-2-sulfhydryl group propane-8-azapurine (VIII) may be produced.

In addition, the present invention further provides the following attached technical solutions:
The raw material 5-amino-1,4-disubstituent-1,2,3-triazole is represented by the following formula (II):
R is hydrogen (H), alkyl acetate ester (—CH ₂ COOR ₁ ) or 2-alkoxyethyl (—CH ₂ CH ₂ OR ₂ ),
R ₃ is a formamide group (—CONH ₂ ), a carboxy group (—COOH), a cyano group (—CN), or an alkyl formate group (—COOR ₄ ).

The substituent groups R ₁ and R _{4 in the} 5-amino-1,4-di substituent-1,2,3-triazole (II) are independently methyl, ethyl, propyl, butyl, allyl, phenyl group, substituted phenyl Selected from the group, benzyl group or substituted benzyl group, wherein the substituent group R ₂ is hydrogen (H), an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms and 2 to 6 carbon atoms An alkyne group, a benzyl group or a substituted benzyl group, a trimethylsilyl group, a triphenylmethyl group or a substituted triphenylmethyl group, a tetrahydrofuran group, a substituted tetrahydrofuran group or an alkoxycarbonyl group.

  The sulfur-containing cyclizing agent (III) is carbon disulfide, potassium thiocyanate, thiocyanic acid, isothiocyanate, thiocarbonyl chloride, thiourea or substituted thiourea, preferably isothiocyanate or thiocarbonyl chloride.

  The alkali accelerator used in the cyclization reaction is sodium, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, triethylammonium, Pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] -nonane-5-alkenyl, 1,8 -Diazabicyclo [5.4.0] -undec-7-alkenyl or 1,4-diazabicyclo [2.2.2] capryl (DABCO), preferably potassium hydroxide or potassium t-butoxide.

  The solvent for the cyclization reaction is methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, dimethyl sulfoxide, tetrahydrofuran, 1,2-dioxane, acetonitrile, acetone, pyridine, diphenyl ether or N, N-dimethylformamide. Dimethyl sulfoxide or ethanol is preferred.

  Halogen in the raw material halogenated propane is chloro, bromo or iodo, preferably bromo or iodo.

  The acid acceptor for the substitution reaction is potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, trimethylamine or pyridine, with potassium carbonate, potassium hydroxide or pyridine being preferred.

  The solvent for the substitution reaction is methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, dimethyl sulfoxide, tetrahydrofuran, 1,2-dioxane, acetonitrile or N, N-dimethylformamide, acetonitrile or N, N-dimethylformamide. Is preferred.

  The chlorinating agent for the chlorination reaction is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, sulfuryl chloride, benzoyl chloride, phthaloyl chloride, dichloroneb or thionyl chloride, preferably thionyl chloride or phosphorus oxychloride.

  The condensing agent for the condensation reaction is N, N-dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), N, N′-diisopropylcarbodiimide (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole- N, N, N ′, N′-tetramethyluronium tetrafluoroborate (TBTU), O- (7-azabenzotriazole) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate Salt (HATU), benzotriazole-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate ( BOP) and benzotriazole-N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HB) U) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro phosphate (BOP) is preferred.

  The alkali accelerator for the condensation reaction is triethylammonium (TEA), pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine. (DIEA) 1,5-diazabicyclo [4.3.0] -nonane-5-alkenyl (DBN), 1,8-diazabicyclo [5.4.0] -undec-7-alkenyl (DBU) or 1, 4-diazabicyclo [2.2.2] capryl (DABCO), 1,8-diazabicyclo [5.4.0] -undec-7-alkenyl (DBU) or 1,5-diazabicyclo [4.3.0]. ] -Nonane-5-alkenyl (DBN) or 1,4-diazabicyclo [2.2.2] capryl (DABCO) is preferred.

  The solvent for the condensation reaction is toluene, xylene, acetate ester, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N, N-dimethylformamide or acetonitrile, and acetonitrile is preferred.

  The preparation method of ticagrelol according to the present invention makes the preparation process comfortable, convenient, economical and eco-friendly with a new intermediate and a new synthetic route, and has high product yield and product purity. In particular, the direct condensation reaction is suitable for mass production by omitting the chlorination process and avoiding the use of hazardous materials such as phosphorus oxychloride.

  In the following, the technical solutions of the present invention will be described in more detail in a non-regulatory manner according to a plurality of preferred embodiments.

Example 1 (cyclization):
1- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolan-4-oxy] ethanol] -6-yl]- Add 5-amino-4-formamide group-1,2,3-triazole (II) (3.27 g, 10 mmol), potassium carbonate (4.14 g, 30 mmol), 2 mL of water and 50 mL of dichloromethane, and bring the temperature to 0 ° C. The solution is gradually dropped and a solution of thiocarbonyl (III) chloride (3.45 g, 30 mmol) in 25 mL of dichloromethane is added dropwise and reacted for 2 h. The reaction solution is poured into ice water to suppress the reaction, and the organic phase is separated. The aqueous phase is extracted twice with dichloromethane, combined with the organic phase, dried and the solvent is removed under reduced pressure. The crude product was recrystallized with acetic ester to give a white solid 9- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4 -Oxy] ethanol] -6-yl] -2-thio-6-oxy-8-azapurine (IV) 3.14 g, 85.1% yield.

Example 2 (Substitution):
9- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolan-4-oxy] ethanol] -6-yl]- 2-thio-6-oxy-8-azapurine (IV) (1.85 g, 5 mmol), potassium hydroxide solution (0.1 M, 10 mL) and 25 mL of acetonitrile were added, and bromopropane (V) (1.53 g) was added at room temperature. , 12.5 mmol) in acetonitrile is added dropwise. The reaction is allowed to stir at room temperature for 15 h. The solvent is recovered under reduced pressure and the residue is extracted three times with dichloromethane, combined with the organic phase, dried and distilled under reduced pressure to give an oil 9- [3aR- (3aα, 4α, 6α, 6aα)-[[2 , 2-Dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4-oxy] ethanol] -6-yl] -2-sulfhydryl group propane-6-oxy-8-azapurine (VI) 1.83 g The yield is 89.1%.

Example 3 (chlorination / amination):
9- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolan-4-oxy] ethanol] -6-yl]- 2-sulfhydryl group propane-6-oxy-8-azapurine (VI) (1.95 g, 5 mmol), 7.5 mL of phosphorus oxychloride was added, stirring was started, and the temperature was lowered to below 0 ° C. 3.5 mL of 2,6-dimethylpyridine is added dropwise. The temperature is gradually raised to 100 ° C., and the reaction is performed by stirring for 9 hours while maintaining the temperature. Phosphorus oxychloride is recovered under reduced pressure, and the residue is cooled to room temperature, and then the reaction is suppressed with ice water. Extract three times with dichloromethane, combine with the organic phase, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, dissolve the resulting oil in 25 mL of acetonitrile and transfer to a reaction flask, trans- (1R, 2S ) -2- (3,4-difluorophenyl) cyclopropylamine (VII) (1.0 gram, 6 mmol) and 1.5 mL of pyridine were allowed to react with stirring for 12 h while maintaining at room temperature, measured by TLC. To complete the reaction. Concentrate under reduced pressure, add acetate and water to the residue and adjust the pH to 4 with dilute acid. The organic phase is separated and the aqueous phase is extracted 3 times with acetate. Combined with the organic phase, the organic phase was washed sequentially with purified water and brine, dried, distilled under reduced pressure to recover the solvent, and oily 9- [3aR- (3aα, 4α, 6α, 6aα)-[[ 2,2-Dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4-oxy] ethanol] -6-yl] -6-[[(1R, 2S) -2- (3,4-difluorophenyl) Cyclopropyl] amino] -2-sulfhydryl group propane-8-azapurine (or: 2-[[(3aR, 4S, 6R, 6aS) -6- [7-[[(1R, 2S) -2- (3, 4-difluorophenyl) cyclopropyl] amino] -5-sulfhydryl group propane-3H- [1,2,3] triazo [4,5-d] pyrimidinyl-3-yl] -2,2-dimethyl-tetrahydro-3aH -Cyclopenta [d] [1,3] -dioxolan-4-yl] oxy] -1-ethanol (VIII) 2.20 g, the yield is 78.3%.

Example 4 (condensation):
Under the protection of nitrogen gas, 9- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4-oxy] ethanol was added to the reaction flask. ] -6-yl] -2-sulfhydryl group propane-6-oxy-8-azapurine (VI) (1.95 g, 5 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate ( BOP) (3.32 g, 7.5 mmol) and 25 mL of acetonitrile are added. Under stirring, 1,8-diazabicyclo [5.4.0] -11- 7-ene (DBU) (1.14 g, 7.5 mmol) is added dropwise, and the mixture is reacted at room temperature for 12 hours. The temperature is raised to 60 ° C. and the reaction is continued for 12 h. Remove the solvent under reduced pressure, dissolve by adding 100 mL of acetic ester and wash with 20 mL of 2M sodium hydroxide, separate the organic phase, dry, concentrate under reduced pressure and dissolve the residue in 50 mL tetrahydrofuran. , Trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (VII) (1.0 g, 6 mmol) and sodium hydride (0.16 g, 6.5 mmol) are added and the temperature is increased. Raise to 50 ° C., stir to react for 5 h, observe completion of reaction by TLC. The reaction is suppressed with saturated saline and the pH is adjusted to 4-5 with dilute acid. Concentrate under reduced pressure, add acetate and water to the residue, separate the organic phase and extract the aqueous phase three times with acetate. According to the organic phase, washed with purified water and brine successively, dried, distilled under reduced pressure to recover the solvent, oily 9- [3aR- (3aα, 4α, 6α, 6aα)-[[2, 2-Dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4-oxy] ethanol] -6-yl] -6-[[(1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl ] Amino] -2-sulfhydryl group propane-8-azapurine (or: 2-[[(3aR, 4S, 6R, 6aS) -6- [7-[[(1R, 2S) -2- (3,4- Difluorophenyl) cyclopropyl] amino] -5-sulfhydryl group propane-3H- [1,2,3] triazo [4,5-d] pyrimidinyl-3-yl] -2,2-dimethyl-tetrahydro-3aH-cyclopenta [d] [1,3] -Dioxolan-4-yl] oxy] -1-ethanol)) Give III) 2.35 g, yield of 83.6%.

Example 5 (hydrolytic deprotection):
At room temperature, 9- [3aR- (3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxolane-4-oxy] ethanol] -6 was added to the reaction flask. -Yl] -6-[[(1R, 2S) -2- (3,4-difluorophenyl) cyclopropyl] amino] -2-sulfhydryl group propane-8-azapurine (VIII) (1.41 g, 2.5 mmol The solution is dissolved in 20 mL methanol, hydrochloric acid (3N, 10 mL) is added, and the mixture is stirred at room temperature for 24 h to be reacted. Adjust the pH to 7.0-7.5 with 30% sodium hydroxide solution. Concentrate under reduced pressure to remove methanol, extract the remaining aqueous phase three times with acetic ester, combine with the organic phase, dry, distill under reduced pressure to recover the solvent, and obtain the crude product as acetate and normal. Recrystallization from hexane yields 0.85 g of white solid ticagrelol (I), yield 65.4%.

  It should be pointed out that the preferred embodiment has been used only to illustrate the technical concept and features of the present invention, and its purpose is to enable those skilled in the art to understand and implement the present invention. That is not to limit the protection scope of the present invention. All equivalent changes and modifications made based on the substance of the present invention should be included in the protection scope of the present invention.

Claims (15)

In the preparation method of ticagrelol (I) represented by the following chemical formula 1,
In the preparation method, 9-substituted-2-thio is obtained by cyclization reaction of 5-amino-1,4-disubstituted-1,2,3-triazole (II) and sulfur-containing cyclizing agent (III). -6-oxy-8-azapurine (IV) was obtained, and 9-substituted-2-thio-6-oxy-8-azapurine (IV) was substituted with halogenated propane (V) to give 9-substituted-2 A sulfhydryl group propane-6-oxy-8-azapurine (VI) is obtained, the 9-substituted-2-sulfhydryl group propane-6-oxy-8-azapurine (VI) is subjected to a chlorination reaction and trans- (1R, 2S ) -2- (3,4-difluorophenyl) cyclopropylamine (VII) to generate an amination reaction to produce 9-substituted-6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII) 9-substituted-6-amino-substituted-2-sulfate Process for the preparation of Chikagureroru (I) which hydryl groups propane-8- azapurine (VIII) comprises the step of obtaining a Chikagureroru (I) by disengaging the Asetoniriden protecting group, characterized in that.   The 9-substituted-2-sulfhydryl group propane-6-oxy-8-azapurine (VI) is directly condensed with the trans- (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine (VII) The method for preparing ticagrelol (I) according to claim 1, wherein a reaction is carried out to produce the 9-substituted-6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII). The chemical formula of the 5-amino-1,4-disubstituent-1,2,3-triazole is represented by the following formula (II):
Wherein R is hydrogen (H), alkyl acetate (—CH ₂ COOR ₁ ) or 2-alkoxyethyl (—CH ₂ CH ₂ OR ₂ ),
The R ₃ is a formamide group (-CONH ₂ ), a carboxy group (-COOH), a cyano group (-CN), or an alkyl formate group (-COOR ₄ ), according to claim 1 or 2, Preparation method of ticagrelol (I). The substituent groups R ₁ and R _{4 in the} 5-amino-1,4-di substituent-1,2,3-triazole (II) are independently methyl, ethyl, propyl, butyl, allyl, phenyl group, substituted phenyl Selected from the group, benzyl group or substituted benzyl group, wherein the substituent group R ₂ is hydrogen (H), an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms and 2 to 6 carbon atoms It is an alkyne group, benzyl group or substituted benzyl group, trimethylsilyl group, triphenylmethyl group or substituted triphenylmethyl group, tetrahydrofuran group, substituted tetrahydrofuran group or alkoxycarbonyl group, Preparation method of I).   3. The sulfur-containing cyclizing agent (III) is carbon disulfide, potassium isothiocyanate, isothiocyanate, isothiocyanate, thiocarbonyl chloride, thiourea or substituted thiourea, according to claim 1 or 2. Of the preparation of ticagrelol (I).   The alkali accelerator used in the cyclization reaction is sodium, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, potassium carbonate, potassium hydroxide, sodium hydroxide, triethylammonium, Pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0] -nonane-5-alkenyl, 1,8 It is -diazabicyclo [5.4.0] -undec-7-alkenyl or 1,4-diazabicyclo [2.2.2] capryl. 3. The ticagrelol (I) according to claim 1 or 2, Preparation method.   The solvent for the cyclization reaction is methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, dimethyl sulfoxide, tetrahydrofuran, 1,2-dioxane, acetonitrile, acetone, pyridine, diphenyl ether or N, N-dimethylformamide. The method for preparing ticagrelol (I) according to claim 1 or 2, wherein:   The method for preparing ticagrelol (I) according to claim 1 or 2, wherein the halogen in the halogenated propane is chloro, bromo or iodo.   The acid acceptor for the substitution reaction is potassium carbonate, potassium t-butoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, trimethylamine or pyridine, according to claim 1 or 2. Of the preparation of ticagrelol (I).   2. The solvent for the substitution reaction is methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, dimethyl sulfoxide, tetrahydrofuran, 1,2-dioxane, acetonitrile or N, N-dimethylformamide. Or the preparation method of ticagrelol (I) of 2.   The chlorinating agent for the chlorination reaction is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, sulfuryl chloride, benzoyl chloride, phthaloyl chloride, dichloroneb, or thionyl chloride. A method for preparing the ticagrelol (I) described.   The condensing agent for the condensation reaction is N, N-dicyclohexylcarbodiimide, carbonyldiimidazole, N, N′-diisopropylcarbodiimide, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ′, N′-tetramethyl. Uronium tetrafluoroborate, O- (7-azabenzotriazole) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, benzotriazole-N, N, N ′, N′— The method for preparing ticagrelol (I) according to claim 2, which is tetramethyluronium hexafluorophosphate or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.   The alkali accelerator for the condensation reaction is triethylammonium, pyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicyclo [4.3.0. ] -Nonane-5-alkenyl, 1,8-diazabicyclo [5.4.0] -undec-7-alkenyl or 1,4-diazabicyclo [2.2.2] capryl. 3. A method for preparing ticagrelol (I) according to 2.   The solvent for the condensation reaction is toluene, xylene, acetate ester, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N, N-dimethylformamide, or acetonitrile. ) Preparation method. In the preparation method of ticagrelol (I) represented by the following chemical formula 1,
In the above preparation method, 9-substituted-2-thio is obtained by cyclization of 5-amino-1,4-disubstituent-1,2,3-triazole (II) and sulfur-containing cyclizing agent (III). -6-oxy-8-azapurine (IV) was obtained, and 9-substituted-2-thio-6-oxy-8-azapurine (IV) was substituted with halogenated propane (V) to give 9-substituted-2 -Sulphhydryl group propane-6-oxy-8-azapurine (VI) can be produced, and 9-substituted-2-sulfhydryl group propane-6-oxy-8-azapurine (VI) and trans- (1R, 2S) -2 9-substituted-6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII) is formed by direct condensation reaction with-(3,4-difluorophenyl) cyclopropylamine (VII). The substituted-6-amino-substituted-2-sulfhydryl group propane-8-azapurine (VIII) removes the acetonylidene protecting group It comprises obtaining a Kagureroru (I), process for the preparation of Chikagureroru (I), wherein.