Preparation method of ticagrelor intermediate

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a ticagrelor intermediate, which comprises the following five steps: S1, preparing an intermediate II; s2, preparing an intermediate III; s3, preparing an intermediate IV; s4, preparing an intermediate V; and S5, preparing an intermediate VI. Compared with a multi-step and complex synthesis process in the prior art, the method has the advantages that the route of the ticagrelor key intermediate V is greatly shortened, the synthesis process of the intermediate V is simplified, the production efficiency and the yield are remarkably improved, the production period is shortened, the raw material consumption and the generation of byproducts are reduced, and the requirements of industrial production are met.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a ticagrelor intermediate. Background Art

[0002] Ticagrelor is a new type of platelet inhibitor of the cyclopentyltriazolopyrimidine class. Its chemical name is (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The molecular weight of Ticagrelor is 522.57, CAS number is 274693-27-5, and its structural formula is as follows: .

[0003] Ticagrelor is an antiplatelet drug originally developed by AstraZeneca. It can effectively inhibit platelet diseases caused by adenosine diphosphate. It is mainly used clinically to reduce the incidence of thrombotic cardiovascular events in patients with acute coronary syndrome and has broad application prospects. 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl]oxy]ethanol is the key intermediate V for the synthesis of Ticagrelor, and its structure is as follows: .

[0004] At present, there are relevant literature reports on the construction of intermediate V, most of which are obtained by multi-step reactions using cyclopentadiene and alanine as starting materials. For example, WO2011017108A reports that D-alanine is used as a raw material, and the key intermediate V is obtained by Boc protection, condensation reaction, oxidation reaction, Diels-Alder reaction, dihydroxylation reaction, acetone fork protection, sodium borohydride reduction, and palladium-carbon catalytic hydrogenation. The synthesis route is as follows: ; The synthesis route has a long process. The third step of oxidation uses expensive sodium periodate, and the iodine atom has a large molecular weight and is very expensive. The fourth step requires cyclopentadiene, which is a strong irritant to the skin and mucous membranes. In addition, the substrate induction effect of D-alanine is average, with an enantiomeric value of only about 40%, and multiple refinements are required to remove non-enantiomeric impurities. The seventh step reaction uses sodium borohydride, which is a strong irritant.

[0005] For example, WO9905143A reports that cyclopentadiene is used as a raw material, and the key intermediate V is obtained through epoxidation reaction, coupling reaction and other steps. The synthesis route is as follows: ; This synthetic route has long steps, cumbersome operations, and low overall yields. Although the raw materials are cheap and readily available, they have a pungent odor, and the first step epoxidation yield is low. The second step reaction requires a non-recyclable homogeneous palladium catalyst with a low yield. The product obtained is a racemate, and the cost of subsequent chiral resolution is very high. The selectivity of dihydroxylation is not high and purification is difficult.

[0006] There are also reports on the preparation of intermediate V in the prior art, such as patent application CN105481823A - a method for synthesizing a ticagrelor intermediate, which uses (1R, 4S)-4 (benzyloxy)-2-enylcyclopentanoic acid as a starting material, and obtains the target compound key intermediate V through amidation, olefin oxidation, cyclization, Hofmann reaction, deprotection and etherification reaction. The synthesis steps are many and the route is long. Expensive catalysts and reagents such as N, N'-carbonyldiimidazole and Pd / C are used, and the production cost is high. It also needs to be carried out under specific temperature, pressure and catalyst. The reaction conditions are relatively harsh and difficult to control, resulting in relatively low yield and purity; Another example is patent application CN106496180A - a method for preparing a ticagrelor intermediate, which uses ortho-substituted benzaldehyde oxime as a starting material, and obtains the target compound key intermediate V through cycloaddition, oxidation, ketal reaction and reduction. The synthesis steps are also relatively large and complicated, and expensive catalysts and reagents such as potassium permanganate and Pd / C are also used, which increases the production cost. Although a highly stereoselective product can be obtained, it is easily affected by various factors in actual operation, resulting in reduced stereoselectivity.

[0007] In summary, the existing preparation method of the key intermediate V of ticagrelor has problems such as limited raw material selection, many and complex reaction steps, high production cost, relatively low yield and purity, and reduced stereoselectivity, which makes it difficult to apply to industrial production. Therefore, a new technical solution is needed to solve the above technical problems. Summary of the invention

[0008] The purpose of the present invention is to provide a method for preparing a ticagrelor intermediate, so as to solve the problems of the current preparation method of the key intermediate V of ticagrelor proposed in the above background technology, such as limited raw material selection, more and more complicated reaction steps, high production cost, relatively low yield and purity, and reduced stereoselectivity.

[0009] To achieve the above object, the present invention provides the following technical solution: a method for preparing a ticagrelor intermediate, comprising the following specific steps: S1. Preparation of intermediate II: intermediate I is used as the starting material, dissolved in a reaction solvent, and subjected to a reduction elimination reaction with zinc powder at 40-60°C to obtain intermediate II. Intermediate II is filtered to obtain intermediate II filtrate, which is directly applied to S2, wherein the molar ratio of intermediate I to zinc powder is 1:1.5-2.5, and the reaction solvent is one or a combination of methanol, ethanol, isopropanol, tetrahydrofuran, tert-butanol, and n-butanol, and the reaction equation is as follows: , X1 is I, Br; S2. Preparation of intermediate III: The filtrate of intermediate II obtained in S1 is subjected to a free radical addition reaction with a halogenating agent to obtain intermediate III, wherein the molar ratio of intermediate II to the halogenating agent is 1:1.1-2.5, and the halogenating agent is one of N-bromosuccinimide and N-chlorosuccinimide, and the reaction equation is as follows: , X2 is Cl, Br; S3, preparation of intermediate IV: intermediate III obtained in S1 undergoes ester exchange reaction with a base and a substrate in a reaction solvent to obtain intermediate IV, wherein the molar ratio of intermediate III to the base and the substrate is 1:1.2-1.8:1.0-2.0, the base is one of sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium hydroxide, and sodium hydroxide, the substrate is one of ethylene carbonate, vinyl sulfate, and vinyl phosphate, and the reaction solvent is one of tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, toluene, and N, N-dimethylformamide or a combination thereof, and the reaction equation is as follows: , X2 is Cl, Br; R1 is C, S, P; S4, preparation of intermediate V: intermediate IV obtained in S3 is subjected to an amination reaction with an amine in the presence of a reaction solvent, a base, a catalyst and its ligand to obtain intermediate V, wherein the molar ratio of intermediate IV to the catalyst, the ligand and the base is 1:0.25-1%:1-4%:1.2-2.5, the catalyst is one of tris(dibenzylideneacetone)dipalladium, palladium acetate, bis(acetonitrile)palladium chloride and di(cyanobenzene)palladium dichloride, and the ligand is 2-dicyclohexylphosphine-2',4',6'- One of triisopropylbiphenyl, tricyclohexylphosphine, and 2-(dicyclohexylphosphino)biphenyl; the base is one of cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide; the amine is one of aniline, dimethyl-pyrrole, alkylamine, benzophenone imine, benzylamine, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, bis(bistrimethylsilyl)amine zinc, and ammonia water; the reaction solvent is one of 2-methyltetrahydrofuran, toluene, and 1,4-dioxane; and the reaction equation is as follows: ; S5. Preparation of intermediate VI: Intermediate V obtained in S4 is reacted with L-tartaric acid to obtain intermediate VI by salt formation, and the reaction equation is as follows: ; According to the above specific preparation steps, the overall synthesis route of ticagrelor intermediates is as follows: , Among them, X1 is I, Br; X2 is Cl, Br; R1 is C, S, P.

[0010] Compared with the prior art, the present invention has the following beneficial effects: The present invention prepares the key intermediate V of ticagrelor through a four-step synthesis process of reduction elimination reaction-free radical addition reaction-ester exchange reaction-amination reaction, which greatly shortens the route of the key intermediate V of ticagrelor, simplifies the synthesis process of the intermediate V, and significantly improves the production efficiency and yield, reduces the production cycle, reduces the consumption of raw materials and the generation of by-products compared to the multi-step and complex synthesis process in the prior art, and meets the needs of industrial production. The intermediate V is then converted into the intermediate VI in its salt form by a salt-forming method, which not only improves the stability and solubility of the intermediate V, but also facilitates the separation and purification of the intermediate V, and also protects the active group of the drug, meets the requirements of drug research and development and production, and promotes the optimization and progress of the preparation technology of the intermediate V of ticagrelor; 2. The present invention optimizes the reaction conditions and selects efficient and more economical catalysts, ligands and reaction solvents, so that each step of the synthesis process strives to maximize the utilization of raw materials, improves the stereoselectivity and resource utilization of the reaction, helps to obtain high-purity target products, reduces the difficulty and cost of subsequent separation and purification, and also enables each step of the synthesis process to be carried out under relatively mild conditions, so that the reaction steps are relatively simpler and easier to operate and control, which helps to reduce production costs and the difficulty of operation in the production process, improves the market competitiveness of products, and also reduces the generation of harmful substances, helps to reduce pollution to the environment, and conforms to the development trend of green chemistry; 3. The present invention directly cyclizes the intermediate II with a halogenating agent through a free radical addition reaction to obtain the intermediate III, effectively avoiding the problem of waste of raw materials caused by cumbersome steps such as the use of benzylhydroxylamine and palladium carbon debenzylation, effectively saving the use of raw materials, shortening the reaction route, reducing the production cost of the intermediate V, and improving the overall economic benefits; 4. The present invention uses one of ethylene carbonate, ethylene sulfate, and ethylene phosphate as a substrate to directly carry out an ester exchange reaction with the intermediate III to obtain a side chain of an alcohol hydroxyl group, thereby avoiding the use of reducing agents such as sodium borohydride, effectively reducing the generation of by-products, and improving the purity and yield of the intermediate V, which is beneficial to subsequent industrial production and ensures that the quality of the final product meets the standards; 5. In the amination reaction, the present invention uses halogen to directly obtain a compound with a primary amine group after amination. Compared with the prior art, the cumbersome operations such as amino group protection and deprotection are omitted, the synthesis process is further simplified, the production cost is reduced, the production efficiency is improved, and the stereoselectivity of the intermediate is maintained, thereby ensuring the effectiveness and safety of the final product. 6. The present invention effectively reduces the generation of waste and pollution to the environment by avoiding the use of highly toxic and highly polluting reagents and catalysts (such as potassium permanganate, palladium carbon, etc.) and optimizing the reaction conditions. It conforms to the current concepts of green chemistry and sustainable development, helps to promote the industrial production process of ticagrelor, and has broad application prospects and market value. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is a high-resolution mass spectrum of the intermediate VI of the present invention; Figure 2 is the H NMR spectrum of the intermediate VI of the present invention (solvent: DMSO-d6); Figure 3 The carbon NMR spectrum (solvent: DMSO-d6) of the intermediate VI of the present invention. DETAILED DESCRIPTION

[0012] The following examples are used to further illustrate the content of the present invention, but do not limit the application of the present invention. Embodiment 1:

[0013] This embodiment provides a method for preparing a ticagrelor intermediate, and the specific preparation steps are as follows: First, prepare intermediate II: put zinc powder (9.75 g, 0.15 mol) into a reaction bottle, add a small amount of methanol to dissolve it, dissolve intermediate I (31.4 g, 0.1 mol) in methanol (150 mL) and add it to the dropping funnel, replace with N2 three times, heat to 40°C, add the methanol solution of intermediate I dropwise, keep warm for 2 h, monitor the reaction progress by TLC, filter after the reaction is completed, and the filtrate of intermediate II is directly put into the preparation of intermediate III; Secondly, prepare intermediate III: add N-bromosuccinimide (NBS) (17.8 g, 0.11 mol) to the filtrate of intermediate II, stir evenly, heat to reflux for 2 h, cool to room temperature and stir overnight, filter to obtain a crude product, reflux and slurry the crude product with isopropanol for 1 h, cool to 0-10°C for crystallization, filter, and dry the filter cake in a vacuum oven at 50°C to obtain a white solid intermediate III (20.1 g, yield 84.8%); Then, prepare intermediate IV: add intermediate III (23.7 g, 0.1 mol) to a reaction bottle, add tetrahydrofuran (118 mL) to dissolve it, then add potassium carbonate (16.5 g, 0.12 mol) and ethylene carbonate (8.8 g, 0.1 mol) in sequence, stir the reaction for 6 to 12 h, monitor the reaction progress by TLC, after the reaction is completed, concentrate and evaporate to dryness under reduced pressure to obtain a crude product, add ethyl acetate and water to the crude product, wash twice, wash once with a saturated sodium chloride aqueous solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is recrystallized from ethyl acetate-petroleum ether to obtain intermediate IV (16.8 g, yield 59.8%).

[0014] Then prepare intermediate V: add intermediate IV (28.1 g, 0.1 mol) to the reaction bottle, add tri(dibenzylideneacetone)dipalladium (0.23 g, 0.025% mol) and its ligand 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.47 g, 0.1% mol), toluene (140 mL), potassium carbonate (16.6 g, 0.12 mol), replace with N2 three times, then add THF solution of lithium bis(trimethylsilylamide) (120 mL, 0.12 mol) to the reaction bottle, heat to the internal temperature of 70-80°C, stir for 3-8 h, monitor the reaction progress by TLC, after the reaction is completed, cool to 20-30°C, add 5% Na2SO4 aqueous solution to the reaction solution and stir for 30 minutes, extract and separate, add methanol to the organic phase, heat to 50-60°C, stir for 6-12 h. After the reaction is completed, the mixture is concentrated and evaporated to dryness under reduced pressure. Acetonitrile (140 mL) is added to the crude product, and the mixture is heated to reflux to dissolve. The mixture is filtered while hot, and the filtrate is cooled to 0-5°C for crystallization overnight. The filter cake is dried in a vacuum oven at 50°C to obtain a white solid intermediate V (15.2 g, yield 70%). Embodiment 2:

[0015] This embodiment provides a method for preparing a ticagrelor intermediate, and the specific preparation steps are as follows: First, prepare intermediate II: put zinc powder (13.7 g, 0.2 mol) into a reaction bottle, add a small amount of methanol to dissolve it, dissolve intermediate I (31.4 g, 0.1 mol) in methanol (150 mL) and add it to the dropping funnel, replace with N2 three times, heat to 50°C, add the methanol solution of intermediate I dropwise, keep warm for 2 h, monitor the reaction progress by TLC, filter after the reaction is completed, and the filtrate of intermediate II is directly put into the preparation of intermediate III; Secondly, prepare intermediate III: add NBS (17.8 g, 0.18 mol) to the filtrate of intermediate II, stir evenly, heat to reflux for 2 h, cool to room temperature and stir overnight, filter to obtain a crude product, reflux and slurry the crude product with isopropanol for 1 h, cool to 0-10°C for crystallization, filter, and dry the filter cake in a vacuum oven at 50°C to obtain a white solid intermediate III (0.6 g, yield 86.7%); Then prepare intermediate IV: add intermediate III (23.7 g, 0.1 mol) to a reaction bottle, add tetrahydrofuran (118 mL) to dissolve it, then add potassium tert-butoxide (16.8 g, 0.15 mol) and vinyl sulfate (18.6 g, 0.15 mol) in sequence, stir the reaction for 6 to 12 h, monitor the reaction progress by TLC, after the reaction is completed, concentrate and evaporate to dryness under reduced pressure to obtain a crude product, add ethyl acetate and water to the crude product, wash twice, wash once with a saturated sodium chloride aqueous solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is recrystallized from ethyl acetate-petroleum ether to obtain intermediate IV (19 g, yield 68%).

[0016] Then prepare intermediate V: add intermediate IV (28.1 g, 0.1 mol) to the reaction bottle, add tri(dibenzylideneacetone)dipalladium (0.46 g, 0.05% mol) and its ligand 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.94 g, 0.2% mol), toluene (140 mL), sodium carbonate (19.1 g, 0.18 mol), replace with N2 three times, then add THF solution of lithium bis(trimethylsilylamide) (180 mL, 0.18 mol) to the reaction bottle, heat to the internal temperature of 80-90°C, stir for 3-8 h, monitor the reaction progress by TLC, after the reaction is completed, cool to 20-30°C, add 5% Na2SO4 aqueous solution to the reaction solution and stir for 30 minutes, extract and separate, add methanol to the organic phase, heat to 50-60°C, stir for 6-12 h. After the reaction is completed, the mixture is concentrated and evaporated to dryness under reduced pressure. Acetonitrile (140 mL) is added to the crude product, and the mixture is heated to reflux to dissolve. The mixture is filtered while hot, and the filtrate is cooled to 0-5°C for crystallization overnight. The filter cake is dried in a vacuum oven at 50°C to obtain a white solid intermediate V (16.7 g, yield 77%). Embodiment 3:

[0017] This embodiment provides a method for preparing a ticagrelor intermediate, and the specific preparation steps are as follows: First, prepare intermediate II: put zinc powder (16.2 g, 0.25 mol) into a reaction bottle, add a small amount of methanol to dissolve it, dissolve intermediate I (31.4 g, 0.1 mol) in methanol (150 mL) and add it to the dropping funnel, replace with N2 three times, heat to 60°C, add the methanol solution of intermediate I dropwise, keep warm for 2 h, monitor the reaction progress by TLC, filter after the reaction is completed, and the filtrate of intermediate II is directly put into the preparation of intermediate III; Secondly, prepare intermediate III: add N-chlorosuccinimide (NCS) (33.4 g, 0.25 mol) to the filtrate of intermediate II, stir evenly, heat to reflux for 2 h, cool to room temperature and stir overnight, filter to obtain a crude product, reflux and slurry the crude product with isopropanol for 1 h, cool to 0-10°C for crystallization, filter, and dry the filter cake in a vacuum oven at 50°C to obtain a white solid intermediate III (16.2 g, yield 68%); Then prepare intermediate IV: add intermediate III (23.7 g, 0.1 mol) to a reaction bottle, add dichloromethane (118 mL) to dissolve it, then add sodium hydroxide (7.2 g, 0.18 mol) and vinyl phosphate (21.4 g, 0.2 mol) in sequence, stir the reaction for 6 to 12 h, monitor the reaction progress by TLC, after the reaction is completed, concentrate and evaporate to dryness under reduced pressure to obtain a crude product, add ethyl acetate and water to the crude product, wash twice, wash once with a saturated sodium chloride aqueous solution, separate the liquids, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product is recrystallized from ethyl acetate-petroleum ether to obtain intermediate IV (16 g, yield 58%).

[0018] Then prepare intermediate V: add intermediate IV (28.1 g, 0.1 mol) to the reaction bottle, add tri(dibenzylideneacetone)dipalladium (28.1 g, 0.1 mol) and its ligand 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.92 g, 0.4% mol), 2-methyltetrahydrofuran (140 mL), sodium tert-butoxide (24.0 g, 0.25 mol), replace with N2 three times, then add THF solution of lithium bis(trimethylsilylamide) (180 mL, 0.18 mol) to the reaction bottle, heat to the internal temperature of 90-100°C, stir for 3-8 h, monitor the reaction progress by TLC, after the reaction is completed, cool to 20-30°C, add 5% Na2SO4 aqueous solution to the reaction solution and stir for 30 minutes, extract and separate, add methanol to the organic phase, heat to 50-60°C, stir for 6-12 h. After the reaction is completed, the mixture is concentrated and evaporated to dryness under reduced pressure. Acetonitrile (140 mL) is added to the crude product, and the mixture is heated to reflux to dissolve. The mixture is filtered while hot, and the filtrate is cooled to 0-5°C for crystallization overnight. The filter cake is dried in a vacuum oven at 50°C to obtain a white solid intermediate V (17.6 g, yield 81%).

[0019] In the preparation methods of the ticagrelor intermediates provided in Examples 1, 2 and 3, intermediate VI was finally prepared: L-tartaric acid (15.8 g, 0.1 mol) was added to a reaction flask, and ethanol (100 mL) was added to the reaction flask, the temperature was raised to an internal temperature of 20 to 50 ° C, stirred to dissolve, and then an ethanol solution of intermediate V (21.7 g, 0.1 mol) was added dropwise, and the mixture was stirred for 1 h after the dropwise addition, and then the temperature was slowly lowered to an internal temperature of 0 to 5 ° C, stirred and crystallized for 2 h, filtered, and the filter cake was dried in a vacuum drying oven at 50 ° C to obtain a white solid intermediate VI, whose high-resolution mass spectrum, nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum are shown as follows: Figure 1 , Figure 2 and Figure 3 As shown, and its mass spectrum and nuclear magnetic hydrogen spectrum data are as follows: .

Claims

1. A method for preparing a ticagrelor intermediate, characterized in that: The specific steps are as follows: S1. Preparation of intermediate II: intermediate I is used as a starting material, dissolved in a reaction solvent, and undergoes a reduction elimination reaction with zinc powder to obtain intermediate II; S2, preparation of intermediate III: intermediate II obtained in S1 undergoes free radical addition reaction with a halogenating agent to obtain intermediate III; S3, preparation of intermediate IV: the intermediate III obtained in S1 undergoes an ester exchange reaction with a base and a substrate in a reaction solvent to obtain intermediate IV; S4, preparation of intermediate V: intermediate IV obtained in S3 is subjected to an amination reaction with an amine in the presence of a reaction solvent, a base, a catalyst and its ligand to obtain intermediate V; S5, preparation of intermediate VI: intermediate V obtained in S4 is reacted with L-tartaric acid to obtain intermediate VI by salt formation; Its synthetic route is as follows: ， Among them, X1 is I, Br; X2 is Cl, Br; R1 is C, S, P.

2. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S1, the molar ratio of intermediate I to zinc powder is 1:1.5-2.

5.

3. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S1, the reaction solvent is one or a combination of methanol, ethanol, isopropanol, tetrahydrofuran, tert-butanol, and n-butanol; and the temperature of the reduction elimination reaction is 40 to 60°C.

4. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S1, the intermediate II is filtered to obtain the intermediate II filtrate which is directly applied to S2.

5. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S2, the molar ratio of intermediate II to the halogenating agent is 1:1.1-2.5, wherein the halogenating agent is one of N-bromosuccinimide and N-chlorosuccinimide.

6. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S3, the molar ratio of intermediate III to base and substrate is 1:1.2~1.8:1.0~2.0, wherein the base is one of sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, potassium hydroxide, and sodium hydroxide, and the substrate is one of ethylene carbonate, vinyl sulfate, and vinyl phosphate.

7. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S3, the reaction solvent is one or a combination of tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, toluene, and N, N-dimethylformamide.

8. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S4, the molar ratio of intermediate IV to catalyst, ligand and base is 1:0.25~1%:1~4%:1.2~2.5, wherein the catalyst is one of tri(dibenzylideneacetone)dipalladium, palladium acetate, bis(acetonitrile)palladium chloride, and di(cyanobenzene)palladium dichloride; the ligand is one of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tricyclohexylphosphine, and 2-(dicyclohexylphosphino)biphenyl; and the base is one of cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butoxide, and potassium tert-butoxide.

9. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S4, the amine is one of aniline, dimethyl-pyrrole, alkylamine, benzophenone imine, benzylamine, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, zinc bis(bistrimethylsilyl)amine, and ammonia water.

10. The method for preparing a ticagrelor intermediate according to claim 1, characterized in that: In S4, the reaction solvent is one of 2-methyltetrahydrofuran, toluene and 1,4-dioxane.

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