Ticagrelor acetyl derivative and preparation method thereof

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a ticagrelor acetyl derivative and a preparation method thereof.The ticagrelor acetyl derivative comprises an impurity A, an impurity B, an impurity C and an impurity D. The preparation method further comprises the three preparation steps that S1, the impurity A is prepared; s2, preparing an impurity B; and S3, preparing an impurity C and an impurity D. According to the method, the structures of the impurity A, the impurity B, the impurity C and the impurity D which are difficult to remove can be successfully speculated, a theoretical basis is provided for subsequent impurity preparation, a new thought is provided for quality control of ticagrelor, and through the preparation steps and the reaction conditions which are clear in logic and easy and convenient to operate, the yield of ticagrelor is improved. According to the present invention, the impurity reference substance with characteristics of low content and difficult separation is successfully prepared, such that the powerful support is provided for the quality control of the ticagrelor, and the impurity content can be accurately monitored and controlled during the ticagrelor preparation process so as to improve the purity and the quality of the final product.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a ticagrelor acetyl derivative and a preparation method thereof. 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: 274693-27-5, and its structural formula is as follows: .

[0003] At present, there have been many reports on the synthesis route and preparation method of Ticagrelor. After analyzing the disclosed synthesis routes and preparation methods, it is found that although the routes are different, the processes are mostly to prepare Ticagrelor through different chemical reactions, different reaction orders and different splicing methods of the following three intermediates A, B and C, among which the structural formulas of intermediate A, intermediate B and intermediate C are as follows: ; In the process of preparing ticagrelor, when the intermediate la is diazotized to generate a triazole compound, glacial acetic acid and alcohol hydroxyl are condensed to obtain the intermediate lb, and the intermediate lb residue is further reacted with TGC hydrochloride to obtain the intermediate lc, and finally the intermediate lc residue is subjected to acid hydrolysis and depropylide protection to obtain the ticagrelor acetylated impurity ld, whose structural formula is as follows: ; Its mass spectrum, H-NMR spectrum and C-NMR spectrum data are as follows: ; The acetylated impurity ld of Ticagrelor is further hydrolyzed or rearranged under acidic conditions to obtain impurities A and B, and can also be oxidized to generate impurities C and D. The synthetic route is as follows: ; These impurities are difficult to remove in the subsequent purification process, thus affecting the purity of the final product of Ticagrelor. Therefore, impurities need to be monitored during the preparation process of Ticagrelor to control the quality of the final product.

[0004] There are studies on monitoring impurities in ticagrelor in the prior art, such as patent applications CN107513066A-a method for preparing a defluorinated ticagrelor derivative, CN107778312A-ticagrelor impurities and preparation methods and uses thereof, CN109553622A-a method for preparing impurities in ticagrelor, etc., which all use chemical methods to synthesize ticagrelor impurities, solving the problem that impurities are difficult to remove in the subsequent purification process and affect the purity of the final product. However, the existing ticagrelor impurity synthesis method prepares an easily accessible impurity reference substance, but it is difficult to apply to the preparation of an impurity reference substance that is difficult to obtain. Since ticagrelor will have low-content and difficult-to-separate impurities during the preparation process, the presence of these impurities will also have an adverse effect on the purity of the final product. For this reason, a new technical solution is needed to solve the above technical problems. Summary of the invention

[0005] The object of the present invention is to provide an acetyl derivative of ticagrelor and a preparation method thereof, so as to solve the problems proposed in the above-mentioned background technology that the current method for synthesizing ticagrelor impurities is difficult to apply to the preparation of impurity reference substances that are difficult to obtain, and that low-content and difficult-to-separate impurities will appear in the preparation process of ticagrelor, so the presence of these impurities will also have an adverse effect on the purity of the final product.

[0006] To achieve the above object, the present invention provides the following technical solution: a ticagrelor acetyl derivative, characterized in that it comprises impurities A, impurities B, impurities C and impurities D, and the structural formulas of the impurities A, impurities B, impurities C and impurities D are as follows: .

[0007] The preparation steps of the above-mentioned ticagrelor acetyl derivative are as follows: S1. Preparation of impurity A: First, the alcoholic hydroxyl group of compound I is reacted with an acetylating agent to obtain compound II. When compound II is obtained by the reaction, the molar ratio of compound I to the acetylating agent is 1:1.2-1.8, wherein the acetylating agent is one of acetyl chloride, acetic anhydride, and glacial acetic acid, and the reaction solvent used is one of toluene and tetrahydrofuran, and the reaction temperature is -10-5°C; Secondly, the halogen in compound II is converted into an amine group through an amination reaction to obtain compound III. A reaction solvent and an amination reagent are used in the reaction to obtain compound III, wherein the molar ratio of compound II to the amination reagent is 1:1.05-2.8, the amination reagent is one of bistrimethylsilyl lithium amide, bistrimethylsilyl sodium amide, and ammonia water, the reaction solvent is one of toluene and tetrahydrofuran, and the reaction temperature is 50-80°C; Then, the compound III is hydrolyzed under acidic conditions to obtain impurity A. When the impurity A is obtained by the reaction, the molar ratio of the compound III to the acid is 1:10-50, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40°C; The synthetic route for preparing impurity A is as follows: ; S2. Preparation of impurity B: First, compound IV is subjected to a diazotization reaction to obtain compound V. When the compound V is obtained by the reaction, a reaction solvent, a diazotization reagent, a base and an acid are used, wherein the addition ratio of compound IV to the diazotization reagent is 1:1.1-2.0, the diazotization reagent is one of nitrous acid, sodium nitrite and potassium nitrite, the reaction solvent is one of toluene, tetrahydrofuran and acetonitrile, the base is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and sodium bicarbonate, the acid is glacial acetic acid, and the reaction temperature is 0-40°C; Secondly, compound V is first spliced ​​with TGA, and then its alcohol hydroxyl group is reacted with an acetylating agent to obtain compound VI. When the compound VI is obtained by the reaction, a reaction solvent and an alkaline reagent are used, wherein the ratio of compound V to the alkaline reagent is 1:1.1-2.5, the alkaline reagent is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, and triethylamine, the reaction solvent is one of dimethyl sulfoxide, tetrahydrofuran, and acetonitrile, and the reaction temperature is 60-90°C; Then, the compound VI is hydrolyzed under acidic conditions to obtain impurity B, wherein the molar ratio of the compound VI to the acid is 1:10-50 when the impurity B is obtained by the reaction, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40° C.; The synthetic route for preparing impurity B is as follows: ; S3. Preparation of impurity C and impurity D: First, compound II and TGC hydrochloride are substituted with a base to synthesize compound VII. When compound VII is obtained by reaction, the ratio of compound II to the base is 1:1.1-2.5, wherein the base is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, and potassium tert-butoxide, and the reaction solvent used is one of toluene, tetrahydrofuran, and acetonitrile, and the reaction temperature is 20-50°C; Secondly, compound VII is oxidized to obtain compound VIII. When the compound VIII is obtained by the reaction, a reaction solvent and an oxidant are used, wherein the molar ratio of compound VII to the oxidant is 1:1-2, the oxidant is one or more of sodium hypochlorite, hydrogen peroxide, potassium permanganate, and chloric acid, the reaction solvent is one of dimethyl sulfoxide, methanol, and ethanol, and the reaction temperature is -10 to 10°C; Secondly, further oxidize to obtain compound IX. When the reaction obtains compound IX, a reaction solvent and an oxidant are used. The molar ratio of compound VII to the oxidant is 1:2.5-5. The oxidant is one or more of sodium hypochlorite, hydrogen peroxide, potassium permanganate, and chloric acid. The reaction solvent is one of dimethyl sulfoxide, methanol, and ethanol. The reaction temperature is 10-30°C. Finally, compound VIII and compound IX are hydrolyzed under acidic conditions to obtain impurity C and impurity D, respectively. When the impurity C is obtained by reaction, the molar ratio of compound VIII to the acid is 1:10-50, and when the impurity D is obtained by reaction, the molar ratio of compound IX to the acid is 1:10-50, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40°C; The synthetic routes for preparing impurities C and D are as follows: .

[0008] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention, through in-depth research on the synthesis route of ticagrelor and the generation mechanism of impurities, successfully inferred the structures of impurities A, impurity B, impurity C and impurity D that are difficult to remove, which not only provides a theoretical basis for the subsequent preparation of impurities, but also provides a new idea for the quality control of ticagrelor. Through logically clear and easy-to-operate preparation steps and reaction conditions, a low-content and difficult-to-separate impurity reference substance is successfully prepared, which provides strong support for the quality control of ticagrelor, so that the content of impurities can be more accurately monitored and controlled during the preparation process of ticagrelor, thereby improving the purity and quality of the final product; 2. The present invention ensures the high efficiency of the reaction and the purity of the product by adjusting the molar ratio of the reactants, selecting the appropriate reaction solvent and temperature and other conditions, and improves the preparation efficiency of the impurity reference substance. Not only can the impurity reference substance be used for quantitative and qualitative detection in the synthesis process of ticagrelor, which helps to timely discover and remove impurities, thereby improving the purity of the final product, but also can reduce production costs, making the preparation of the impurity reference substance more economical and feasible, and can also provide a useful reference for the synthesis of other similar impurities; 3. The impurity reference substance prepared by the present invention can not only be used for quality control and purity detection of ticagrelor, but also can be used as an important reference substance for the discovery and development of new drugs in the fields of new drug research and development, drug metabolism research, etc., and can help promote technological innovation and development in the field of drug synthesis; 4. The present invention innovatively proposes a method for preparing impurities of ticagrelor acetyl derivatives, which not only successfully solves the problem of difficult preparation and acquisition of ticagrelor impurity reference substances in the prior art, but also significantly improves the purity and quality of ticagrelor products, promotes the development of ticagrelor synthesis technology, and provides new ideas and methods for the synthesis of ticagrelor and its derivatives through in-depth research on the preparation method and reaction mechanism of impurities, which helps to improve the preparation level of ticagrelor. It also provides useful reference and reference for the synthesis of other similar drugs, and provides patients with safer and more effective drug options. DETAILED DESCRIPTION

[0009] The following examples are used to further illustrate the content of the present invention, but do not limit the application of the present invention.

[0010] Example 1: Preparation of impurity A First, compound I (42.9 g, 0.1 mol) was dissolved in 200 mL of toluene, stirred evenly, and then acetyl chloride (0.9 g, 0.12 mol) was slowly added dropwise in an ice bath. The reaction was allowed to proceed for half an hour. The reaction of compound I was completed by TLC. Water (200 mL) was added to quench the reaction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After recrystallization from ethanol, 41.5 g of white solid compound II was obtained with a yield of 88%. Secondly, compound II (47.1 g, 0.1 mol) was added to the reaction bottle, tris(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), N2 (nitrogen) was replaced three times, and then a tetrahydrofuran (THF) solution of lithium bis(trimethylsilylamide) (105 mL, 0.105 mol) was added to the reaction bottle, and the temperature was raised to 50 °C. ~55℃, stirred for 3~8h, the reaction progress was monitored by TLC, after the reaction was completed, the temperature was lowered to 20~30℃, 5% sodium sulfate (Na2SO4) aqueous solution was added to the reaction solution and stirred for 30min, extraction and separation were performed, methanol was added to the organic phase, the temperature was raised to 50~60℃, and stirred for 6~12h. After the reaction was completed, the mixture was concentrated and evaporated to dryness under reduced pressure, acetonitrile (140mL) was added to the crude product, the temperature was raised to reflux to dissolve, and the mixture was filtered while hot. The filtrate was cooled to 0~5℃ for crystallization overnight, filtered, and the filter cake was dried in a vacuum oven at 50℃ to obtain 35.3g of white solid compound III with a yield of 78%; Then, compound III (45.2 g, 0.1 mol) was added to a reaction flask, 200 mL of toluene was added to dissolve it, the temperature was lowered to 0°C, and then hydrochloric acid / methanol (3 mL / 6 mL) solution was added dropwise to the reaction flask, and the reaction was kept warm for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 200 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 45 mL of ethyl acetate was added to the crude product and the temperature was raised to dissolve, and then 135 mL of petroleum ether was added dropwise to the reaction flask, the temperature was slowly lowered to 0-5°C, the mixture was stirred for crystallization for 2 h, and the filter cake was dried in a vacuum drying oven at 50°C to obtain 32.6 g of white solid impurity A with a yield of 79%.

[0011] Example 2: Preparation of impurity A First, compound I (42.9 g, 0.1 mol) was dissolved in 200 mL of tetrahydrofuran, stirred evenly, and then acetic anhydride (1.8 g, 0.18 mol) was slowly added dropwise in an ice bath. The reaction was allowed to proceed for half an hour. The reaction of compound I was completed by TLC. Water (200 mL) was added to quench the reaction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After recrystallization from ethanol, 32.09 g of white solid compound II was obtained with a yield of 68%. Secondly, compound II (47.1 g, 0.1 mol) was added to the reaction bottle, tri(dibenzylideneacetone)dipalladium (0.92 g, 0.1% mol) and its ligand 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.88 g, 0.2% mol), toluene (140 mL), sodium carbonate (19.1 g, 0.18 mol) were added, and N2 was replaced three times. Then, a THF solution of sodium bis(trimethylsilylamine) (280 mL, 0.28 mol) was added to the reaction bottle, and the temperature was raised to 75-80°C, stirred for 3-8 h, and the reaction progress was monitored by TLC. After the reaction was completed, the temperature was lowered to 20-30°C, and 5% The Na2SO4 aqueous solution was stirred for 30 min, extracted and separated, methanol was added to the organic phase, the temperature was raised to 50-60°C, and stirred for 6-12 h. After the reaction was completed, it was concentrated under reduced pressure and evaporated to dryness. Acetonitrile (140 mL) was added to the crude product, the temperature was raised to reflux to dissolve, and it was filtered while hot. The filtrate was cooled to 0-5°C for crystallization overnight, filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 21.7 g of white solid compound III, with a yield of 48%; Then, compound III (45.2 g, 0.1 mol) was added to a reaction flask, 200 mL of toluene was added to dissolve it, the temperature was raised to 30-40°C, and then hydrochloric acid / methanol (15 mL / 30 mL) solution was added dropwise to the reaction flask, and the reaction was kept warm for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 200 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 45 mL of ethyl acetate was added to the crude product and the temperature was raised to dissolve, and then 135 mL of petroleum ether was added dropwise to the reaction flask, the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 h, and filtered, and the filter cake was dried in a vacuum drying oven at 50°C to obtain 16.07 g of white solid impurity A, with a yield of 39%.

[0012] The structural formula of impurity A prepared in Example 1 and Example 2 is as follows: ; Its mass spectrum, H-NMR spectrum and C-NMR spectrum data are as follows: .

[0013] Example 3: Preparation of impurity B First, compound IV (37.08 g, 0.1 mol) was added to a reaction flask, 180 mL of toluene and 28 mL of glacial acetic acid were added, stirred to dissolve, and cooled to 0°C. Then, sodium nitrite aqueous solution (7.5 g / 150 mL) was slowly added to the reaction flask, and the reaction was kept warm for 1 h. Then, sodium carbonate aqueous solution was added to the reaction flask, and the solution pH was adjusted to 7-9, and the solution was allowed to stand for stratification. The aqueous layer was extracted with 150 mL of toluene, and the organic phases were combined and washed once with 150 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness to obtain a crude product. The crude product was slurried with ethyl acetate petroleum ether (20 mL-200 mL), filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 32.46 g of white solid compound V, with a yield of 85%; Secondly, compound V (38.1 g, 0.1 mol) was added to a reaction flask, and 58 mL of dimethyl sulfoxide, TGA (0.22 g, 1 mmol), and triethylamine (11.1 g, 1.1) were added, and the mixture was stirred to dissolve. The reaction temperature was then raised to 60 °C and kept for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, acetyl chloride (9.42 g, 0.12) was added to the reaction flask, and the reaction was stirred for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, 150 mL of water and 50 mL of ethyl acetate were added, stirred and separated, and the aqueous layer was extracted twice with 150 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain a crude product. 30 mL of ethyl acetate and 150 mL of petroleum ether were added to the crude product to obtain 55.6 g of white solid compound VI, with a yield of 92%. Then, compound VI (60.46 g, 0.1 mol) was added to the reaction flask, 200 mL of toluene was added to dissolve it, the temperature was lowered to 0°C, and then hydrochloric acid / methanol (3 mL / 6 mL) solution was added dropwise to the reaction flask, and the reaction was kept warm for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of ethyl acetate was added to the crude product and the temperature was raised to dissolve, and then 180 mL of petroleum ether was added dropwise to the reaction flask, the temperature was slowly lowered to 0-5°C, the crystallization was stirred for 2 h, and the filter cake was dried in a vacuum oven at 50°C to obtain 50.8 g of white solid impurity B with a yield of 90%.

[0014] Example 4: Preparation of Impurity B First, compound IV (37.08 g, 0.1 mol) was added to a reaction flask, and 180 mL of tetrahydrofuran and 28 mL of glacial acetic acid were added. The mixture was stirred to dissolve and the temperature was raised to 40°C. Then, an aqueous sodium nitrite solution (13.6 g / 272 mL) was slowly added to the reaction flask. After the addition was completed, the mixture was kept warm for 1 h. Then, an aqueous sodium carbonate solution was added to the reaction flask. When the pH of the solution was adjusted to 7-9, the mixture was allowed to stand for 4 hours to separate the layers. The aqueous layer was extracted with 150 mL of toluene, the organic phases were combined, and the mixture was washed once with 150 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness to obtain a crude product. The crude product was slurried with ethyl acetate-petroleum ether (20 mL-200 mL), filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 21.00 g of white solid compound V with a yield of 55%. Secondly, compound V (38.1g, 0.1mol) was added to the reaction bottle, 58mL acetonitrile, TGA (0.22g, 1mmol), triethylamine (25.3g, 2.5), stirred to dissolve, then the reaction temperature was raised to 90°C for 6h, the reaction progress was monitored by TLC, after the reaction, acetyl chloride (14.13g, 0.18) was added to the reaction bottle, the reaction was stirred for 2h, and the reaction progress was monitored by TLC, after the reaction was completed, 150mL water and 50mL ethyl acetate were added and stirred to separate, the water layer was extracted twice with 150mL ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, concentrated and evaporated to dryness to obtain a crude product. 30mLz ethyl acetate and 150mL petroleum ether were added to the crude product to obtain 49.6g of white solid compound VI, with a yield of 82%; Then, compound VI (60.46 g, 0.1 mol) was added to a reaction flask, 200 mL of toluene was added to dissolve it, the temperature was raised to 40°C, and then hydrochloric acid / methanol (15 mL / 30 mL) solution was added dropwise to the reaction flask, and the reaction was kept warm for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of ethyl acetate was added to the crude product and the temperature was raised to dissolve, and then 180 mL of petroleum ether was added dropwise to the reaction flask, the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 h, and filtered, and the filter cake was dried in a vacuum drying oven at 50°C to obtain 37.8 g of white solid impurity B with a yield of 67%.

[0015] The structural formula of impurity B prepared in Example 3 and Example 4 is as follows: ; Its mass spectrum, H-NMR spectrum and C-NMR spectrum data are as follows: .

[0016] Example 5: Preparation of Impurity C and Impurity D First, compound II (47.19 g, 0.1 mol) was added to a reaction flask, and 200 mL of toluene was added to dissolve it. The solution was stirred until clear. Then, a potassium carbonate / water solution (15.1 g / 30 mL) solution was added dropwise to the reaction flask. The solution was kept warm for 1 h, and the temperature was lowered to 20 ° C. Then, TGC hydrochloride ((1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine hydrochloride) was added to the reaction flask. The solution was kept warm for 1 h, and the reaction was monitored by TLC. Process, the aqueous phase was extracted twice with 250mL×2 toluene, the organic phases were combined, the organic phases were washed with 200mL saturated NaCl (sodium chloride) aqueous solution, the organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 50mL ethyl acetate was added to the crude product and heated to dissolve, then 150mL petroleum ether was added dropwise to the reaction bottle, the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2h, filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 52.60g of compound VII, with a yield of 87%; Secondly, compound VII (60.4 g, 0.1 mol) was added to a reaction flask, 200 mL of dimethyl sulfoxide was added to dissolve it, the solution was stirred and cooled to -10 °C, and then sodium hypochlorite / water solution (7.4 g / 15 mL) was added dropwise to the reaction flask. After the addition, the solution was kept warm for 1 h. The reaction progress was monitored by TLC. After the reaction was completed, 150 mL × 2 water was added to wash twice, the organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 50 mL of acetonitrile was added to the crude product, the temperature was raised and dissolved, and then the temperature was slowly lowered to 0-5 °C, stirred for crystallization for 2 h, and filtered. The filter cake was dried in a vacuum oven at 50 °C to obtain 46.55 g of compound VIII, with a yield of 75%; Next, compound VII (60.4 g, 0.1 mol) was added to a reaction flask, 200 mL of dimethyl sulfoxide was added to dissolve it, the solution was stirred and dissolved, the temperature was lowered to 10°C, and then a sodium hypochlorite / water solution (18.6 g / 37 mL) solution was added dropwise to the reaction flask, and the mixture was kept warm for 1 h. The reaction progress was monitored by TLC. After the reaction was completed, 150 mL×2 of water was added to wash twice, the organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 50 mL of acetonitrile was added to the crude product, the temperature was raised and dissolved, and then the temperature was slowly lowered to 0-5°C, stirred and crystallized for 2 h, and filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 35.01 g of compound IX, with a yield of 55%; Then, compound VIII (62.07 g, 0.1 mol) was added to the reaction flask, 200 mL of toluene was added to dissolve it, the temperature was lowered to 0°C, and then hydrochloric acid / methanol (3 mL / 6 mL) solution was added dropwise to the reaction flask, and the reaction was kept warm for 12 hours. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of tetrahydrofuran was added to the crude product, the temperature was raised to dissolve, and then the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 hours, and filtered, and the filter cake was dried in a vacuum oven at 50°C to obtain 49.88 g of white solid impurity C, with a yield of 86%; Finally, compound IX (63.67 g, 0.1 mol) was added to the reaction flask, 200 mL of toluene was added to dissolve it, the temperature was lowered to 0°C, and then hydrochloric acid / methanol (3 mL / 6 mL) solution was added dropwise to the reaction flask. The reaction was kept warm for 12 h after the addition was completed. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of tetrahydrofuran was added to the crude product, the temperature was raised to dissolve, and then the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 h, and filtered. The filter cake was dried in a vacuum oven at 50°C to obtain 47.73 g of white solid impurity D with a yield of 80%.

[0017] Example 6: Preparation of Impurity C and Impurity D First, compound II (47.19 g, 0.1 mol) was added to a reaction flask, 200 mL of toluene was added to dissolve it, and the solution was stirred until clear. Then, potassium carbonate / water solution (15.1 g / 30 mL) was added dropwise to the reaction flask, and the temperature was kept for reaction for 1 h. Then, TGC hydrochloride was added to the reaction flask, and the temperature was raised to 50°C for reaction for half an hour. The reaction progress was monitored by TLC. The aqueous phase was extracted twice with 250 mL×2 toluene, and the organic phases were combined. The organic phases were washed with 200 mL of saturated NaCl aqueous solution, dried with anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure. 50 mL of ethyl acetate was added to the crude product and the temperature was raised to dissolve. Then, 150 mL of petroleum ether was added dropwise to the reaction flask, the temperature was slowly lowered to 0-5°C, and the mixture was stirred for crystallization for 2 h. The filter cake was dried in a vacuum oven at 50°C to obtain 51.39 g of compound VII with a yield of 85%. Secondly, compound VII (60.4 g, 0.1 mol) was added to a reaction flask, 200 mL of dimethyl sulfoxide was added to dissolve it, the solution was stirred and dissolved, and the temperature was lowered to 10°C. Then, a sodium hypochlorite / water solution (15 g / 30 mL) solution was added dropwise to the reaction flask, and the temperature was kept for 1 hour after the addition was completed. The reaction progress was monitored by TLC. After the reaction was completed, 150 mL×2 of water was added to wash twice, the organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 50 mL of acetonitrile was added to the crude product, the temperature was raised and dissolved, and then the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 hours, and filtered. The filter cake was dried in a vacuum drying oven at 50°C to obtain 27.93 g of compound VIII, with a yield of 45%; Next, compound VII (60.4 g, 0.1 mol) was added to a reaction flask, 200 mL of dimethyl sulfoxide was added to dissolve it, the mixture was stirred and dissolved, the temperature was raised to 30°C, and then a sodium hypochlorite / water solution (37.2 g / 75 mL) solution was added dropwise to the reaction flask. The mixture was kept warm for 1 h after the addition was completed. The reaction progress was monitored by TLC. After the reaction was completed, 150 mL×2 of water was added to wash twice, the organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 50 mL of acetonitrile was added to the crude product, the mixture was heated and dissolved, and then the temperature was slowly lowered to 0-5°C, stirred and crystallized for 2 h, and filtered. The filter cake was dried in a vacuum oven at 50°C to obtain 31.8 g of compound IX, with a yield of 50%. Then, compound VIII (62.07 g, 0.1 mol) was added to the reaction flask, 200 mL of toluene was added to dissolve it, the temperature was raised to 40°C, and then hydrochloric acid / methanol (15 mL / 30 mL) solution was added dropwise to the reaction flask, and the temperature was kept for 2 hours after the addition. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of tetrahydrofuran was added to the crude product, the temperature was raised to dissolve, and then the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 hours, and filtered, and the filter cake was dried in a vacuum drying oven at 50°C to obtain 38.32 g of white solid impurity C, with a yield of 66%; Finally, compound IX (63.67 g, 0.1 mol) was added to the reaction flask, 200 mL of toluene was added to dissolve it, the temperature was raised to 40°C, and then hydrochloric acid / methanol (3 mL / 6 mL) solution was added dropwise to the reaction flask. The reaction was kept warm for 2 h after the addition was completed. The reaction progress was monitored by TLC. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added for washing, the aqueous phase was extracted with 250 mL of toluene, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, 60 mL of tetrahydrofuran was added to the crude product, the temperature was raised to dissolve, and then the temperature was slowly lowered to 0-5°C, stirred for crystallization for 2 h, and filtered. The filter cake was dried in a vacuum oven at 50°C to obtain 38.78 g of white solid impurity D with a yield of 65%.

[0018] The structural formula of impurity C prepared in Example 5 and Example 6 is as follows: ; Its mass spectrum, H-NMR spectrum and C-NMR spectrum data are as follows: .

[0019] The structural formula of impurity D prepared in Example 5 and Example 6 is as follows: ; Its mass spectrum, H-NMR spectrum and C-NMR spectrum data are as follows: .

Claims

1. A ticagrelor acetyl derivative, characterized in that: Including impurity A, impurity B, impurity C and impurity D, the structural formulas of impurity A, impurity B, impurity C and impurity D are as follows: 。 2. The method for preparing a ticagrelor acetyl derivative according to claim 1, characterized in that: The specific preparation steps are as follows: S1. Preparation of impurity A: First, the alcoholic hydroxyl group of compound I is reacted with an acetylating agent to obtain compound II, and then the halogen in compound II is converted into an amine group through an amination reaction to obtain compound III, and then compound III is hydrolyzed under acidic conditions to obtain impurity A. The synthetic route is as follows: ； S2. Preparation of impurity B: Compound IV is subjected to diazotization reaction to obtain compound V, and then compound V is first spliced ​​with TGA, and then its alcohol hydroxyl group is reacted with an acetylation agent to obtain compound VI, and finally compound VI is hydrolyzed under acidic conditions to obtain impurity B. The synthetic route is as follows: ； S3. Preparation of impurities C and D: First, compound II and TGC hydrochloride are substituted under the action of a base to synthesize compound VII, and then compound VII is oxidized to obtain compound VIII, which is then further oxidized to obtain compound IX. Finally, compound VIII and compound IX are hydrolyzed under acidic conditions to obtain impurities C and impurity D, respectively. The synthetic route is as follows: 。 3. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S1, when the reaction obtains compound II, the molar ratio of compound I to the acetylating agent is 1:1.2-1.8, wherein the acetylating agent is one of acetyl chloride, acetic anhydride, and glacial acetic acid, and the reaction solvent used is one of toluene and tetrahydrofuran, and the reaction temperature is -10-5°C.

4. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S1, a reaction solvent and an amination reagent are used when the compound III is obtained by reaction, wherein the molar ratio of compound II to the amination reagent is 1:1.05-2.8, the amination reagent is one of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and ammonia water, the reaction solvent is one of toluene and tetrahydrofuran, and the reaction temperature is 50-80°C.

5. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S1, when impurity A is obtained by reaction, the molar ratio of compound III to acid is 1:10-50, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40°C.

6. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S2, a reaction solvent, a diazotizing agent, a base and an acid are used in the reaction to obtain compound V, wherein the addition ratio of compound IV to the diazotizing agent is 1:1.1-2.0, the diazotizing agent is one of nitrous acid, sodium nitrite and potassium nitrite, the reaction solvent is one of toluene, tetrahydrofuran and acetonitrile, the base is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and sodium bicarbonate, the acid is glacial acetic acid, and the reaction temperature is 0-40°C.

7. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S2, a reaction solvent and an alkaline reagent are used when the reaction obtains compound VI, wherein the addition ratio of compound V to the alkaline reagent is 1:1.1-2.5, the alkaline reagent is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, and triethylamine, the reaction solvent is one of dimethyl sulfoxide, tetrahydrofuran, and acetonitrile, and the reaction temperature is 60-90°C.

8. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S2, when the impurity B is obtained by reaction, the molar ratio of compound VI to the acid is 1:10-50, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40°C.

9. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S3, when the reaction obtains compound VII, the ratio of compound II to the base is 1:1.1-2.5, wherein the base is one of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, and potassium tert-butoxide, and the reaction solvent used is one of toluene, tetrahydrofuran, and acetonitrile, and the reaction temperature is 20-50°C.

10. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S3, a reaction solvent and an oxidant are used when the reaction obtains compound VIII, wherein the molar ratio of compound VII to the oxidant is 1:1-2, the oxidant is one or more of sodium hypochlorite, hydrogen peroxide, potassium permanganate, and chloric acid, the reaction solvent is one of dimethyl sulfoxide, methanol, and ethanol, and the reaction temperature is -10 to 10°C.

11. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S3, a reaction solvent and an oxidant are used when the reaction obtains compound IX, wherein the molar ratio of compound VII to the oxidant is 1:2.5-5, the oxidant is one or more of sodium hypochlorite, hydrogen peroxide, potassium permanganate, and chloric acid, the reaction solvent is one of dimethyl sulfoxide, methanol, and ethanol, and the reaction temperature is 10-30°C.

12. The method for preparing a ticagrelor acetyl derivative according to claim 2, characterized in that: In S3, when the impurity C is obtained by reaction, the molar ratio of compound VIII to the acid is 1:10-50, and when the impurity D is obtained by reaction, the molar ratio of compound IX to the acid is 1:10-50, wherein the acid is one or more of trifluoroacetic acid, glacial acetic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent used is one or more of toluene, dichloromethane, and ethyl acetate, and the reaction temperature is 0-40°C.

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