A dioxolane compound, a preparation method and application thereof, and a preparation method of a ticagrelor intermediate

Abstract

The application provides a dioxolane compound and a preparation method and application thereof, and a preparation method of a ticagrelor intermediate, relates to the technical field of drug synthesis. The dioxolane compound provided by the application can be used to prepare the ticagrelor intermediate with the structure of formula B by carrying out a hydrolysis reaction under alkaline conditions and then adding a reducing agent to carry out a reduction reaction, the process is simple, the palladium-carbon hydrogenation reduction is not needed, the preparation process is mild, atomic economy is strong, production safety is high, the product yield is high, the product purity is high, the production cost is low, post-treatment is simple, three wastes are few, and the application is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a dioxolane compound and a preparation method and application thereof, and a preparation method of a ticagrelor intermediate. BACKGROUND

[0002] Ticagrelor (CAS: 857890-39-2) is a selective new small molecule anticoagulant drug developed by Astrazeneca, which can inhibit platelet aggregation and is mainly used for acute coronary syndrome, such as patients receiving drug therapy and percutaneous coronary intervention (PCI) therapy, to reduce the probability of thrombotic cardiovascular events. The synthetic route reported in the original research patent (WO2013 / 182972) of ticagrelor is as follows:

[0003]

[0004] Among them, the compound represented by the structure of formula B is 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol, which is an important intermediate of ticagrelor. Compared with the compound represented by the structure of formula A, the compound represented by the structure of formula B has only one hydroxyethyl group. To prepare the compound represented by the structure of formula B from the compound represented by the structure of formula A, CBZ protection is first required, followed by substitution reaction with ethyl bromoacetate, then lithium borohydride reduction, and finally palladium-carbon hydrogenation reduction to obtain the compound represented by the structure of formula B. The specific reaction route is as follows:

[0005]

[0006] However, the above preparation method needs to use a benzyl oxycarbonyl protection with a large molecular weight, which is particularly low in atomic economy and generates a lot of waste. In addition, the use of ethyl bromoacetate is expensive, and the last step of palladium-carbon hydrogenation reduction is dangerous. Therefore, it is of important application value to provide a ticagrelor intermediate represented by the structure of formula B with low production cost, less waste and high safety. SUMMARY

[0007] Therefore, the purpose of the present application is to provide a dioxolane compound and a preparation method and application thereof, and a preparation method of a ticagrelor intermediate. The ticagrelor intermediate represented by the structure of formula B can be prepared by hydrolysis and reduction of the dioxolane compound provided by the present application, which has high product yield, low production cost, less waste and high safety.

[0008] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions:

[0009] The present application provides a dioxolane compound, which has the structure represented by formula II:

[0010]

[0011] The application provides a preparation method of the above-mentioned dioxolane compound, and comprises the following steps:

[0012] The compound A, an acylation reagent, a first alkaline reagent and a first organic solvent are mixed to perform an acylation reaction, so as to obtain the compound I; the acylation reagent comprises chloroacetyl chloride, bromoacetyl chloride or bromoacetyl bromide;

[0013] The compound I, a second alkaline reagent and a second organic solvent are mixed to perform an etherification reaction in a protective atmosphere, so as to obtain the dioxolane compound.

[0014]

[0015] X in the compound I is chlorine or bromine.

[0016] Preferably, the molar ratio of the compound A to the acylation reagent is 1:0.5-3.

[0017] Preferably, the molar ratio of the compound A to the first alkaline reagent is 1:0.5-3.

[0018] The first alkaline reagent comprises one or more of an organic amine, an alkali metal carbonate, an alkali metal hydroxide and an alkali metal alcoholate.

[0019] The first organic solvent comprises one or more of dichloromethane, toluene, ethyl acetate, acetone, an alcohol solvent, a furan solvent and dimethyl sulfoxide.

[0020] Preferably, the temperature of the amidation reaction is 20-40℃, and the time is 2-6h.

[0021] Preferably, the molar ratio of the compound I to the second alkaline reagent is 1:1.5-4.

[0022] The second alkaline reagent comprises one or more of an alkali metal hydride, an alkali metal carbonate, an alkali metal hydroxide, an organic amine and an alkali metal alcoholate.

[0023] The second organic solvent comprises one or more of tetrahydrofuran, dichloromethane, ethyl acetate, acetone, an alcohol solvent and dimethyl sulfoxide.

[0024] Preferably, the temperature of the etherification reaction is-10-30℃, and the time is 2-5h.

[0025] The application further provides an application of the dioxolane compound in the preparation of ticagrelor.

[0026] The application further provides a preparation method of the ticagrelor intermediate, comprising the following steps:

[0027] The dioxolane compound, the third alkaline reagent and the third organic solvent are mixed to perform a hydrolysis reaction, and then a reducing agent is added to perform a reduction reaction, so that the ticagrelor intermediate with the structure of formula B is obtained.

[0028]

[0029] Preferably, the molar ratio of the dioxolane compound to the third alkaline reagent is 1:1-4.

[0030] The third alkaline reagent comprises one or more of alkali metal hydroxide, alkali metal carbonate and alkali metal alcoholate.

[0031] The third organic solvent comprises one or more of toluene, ethylene glycol, isopropyl alcohol, dimethyl sulfoxide and dimethyl formamide.

[0032] The temperature of the hydrolysis reaction is 80-150 DEG C, and the time is 12-20 h.

[0033] Preferably, the molar ratio of the dioxolane compound to the reducing agent is 1:1.5-4.

[0034] The reducing agent comprises one or more of lithium aluminum hydride, sodium borohydride, potassium borohydride and borane.

[0035] The temperature of the reduction reaction is 0-50 DEG C, and the time is 8-16 h.

[0036] The dioxolane compound with the structure shown in formula II is subjected to a hydrolysis reaction under alkaline conditions, and then a reducing agent is added to perform a reduction reaction, so that the ticagrelor intermediate with the structure of formula B is prepared, the process is simple, no palladium carbon hydrogenation reduction is needed, the preparation process is mild, atomic economy is strong, production safety is high, the product yield is high, the purity is high, the production cost is low, the post-treatment is simple, the three wastes are less, and the industrial production is suitable.

[0037] The preparation method of the dioxolane compound of the application does not need to perform the steps of protecting and deprotecting the amino group of the compound A, the process is simple, atomic economy is strong, the product yield is high, raw materials are easy to obtain, the post-treatment is simple, and the industrial production is suitable. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 The hydrogen spectrum of the compound with the structure shown in I-1 is shown in the figure;

[0039] Figure 2 The hydrogen spectrum of the compound with the structure shown in formula I-2 is shown in the figure;

[0040] Figure 3 a hydrogen spectrum of a compound having a structure shown in Formula II;

[0041] Figure 4 a hydrogen spectrum of a tegraril intermediate having a structure shown in Formula B. DETAILED DESCRIPTION

[0042] The present application provides a dioxolane compound having a structure shown in Formula II:

[0043]

[0044] The present application provides a preparation method of the dioxolane compound described in the above technical solution, comprising the following steps:

[0045] mixing compound A, an acylation reagent, a first alkaline reagent and a first organic solvent to perform an acylation reaction to obtain compound I; the acylation reagent comprises chloroacetyl chloride, bromoacetyl chloride or bromoacetyl bromide;

[0046] mixing compound I, a second alkaline reagent and a second organic solvent to perform an etherification reaction under a protective atmosphere to obtain the dioxolane compound;

[0047]

[0048] X in compound I is chlorine or bromine.

[0049] Unless otherwise specified, the materials and equipment used in the present application are commercially available in the art.

[0050] The present application mixes compound A, an acylation reagent, a first alkaline reagent and a first organic solvent to perform an acylation reaction to obtain compound I; the acylation reagent comprises chloroacetyl chloride, bromoacetyl chloride or bromoacetyl bromide.

[0051] In the present application, the molar ratio of compound A to the acylation reagent can be 1:0.5-3, and in specific embodiments, can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0052] In the present application, the molar ratio of compound A to the first alkaline reagent can be 1:0.5-3, and in specific embodiments, can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0053] In the present application, the first basic reagent can include one or more of organic amine, alkali metal carbonate, alkali metal hydroxide and alkali metal alcoholate; the organic amine can include triethylamine and / or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the alkali metal carbonate can include one or more of sodium carbonate, potassium carbonate and cesium carbonate; the alkali metal hydroxide can include one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide; and the alkali metal alcoholate can include one or more of sodium methoxide, potassium methoxide, cesium methoxide, potassium tert-butoxide, sodium tert-butoxide and cesium tert-butoxide.

[0054] In the present application, the first organic solvent can include one or more of dichloromethane, toluene, ethyl acetate, acetone, alcohol solvent, furan solvent and dimethyl sulfoxide; the alcohol solvent can include one or more of methanol, ethanol and isopropanol; and the furan solvent can include tetrahydrofuran and / or 2-methyltetrahydrofuran. In the present application, the mass-volume ratio of compound A to the first organic solvent can be 1 g: 3-10 mL, and in specific embodiments, can be 1 g: 5 mL.

[0055] In the present application, the mixing of compound A, acylating reagent, first basic reagent and first organic solvent can include adding compound A, first organic solvent and first basic reagent, and adding acylating reagent dropwise under ice water bath. The present application does not have special limitation on the dropping speed of the acylating reagent, and the acylating reagent can be added dropwise at a uniform speed.

[0056] In the present application, the temperature of the amidation reaction can be 20-40°C, and in specific embodiments, can be 20°C, 25°C, 30°C, 35°C or 40°C; and the time of the amidation reaction can be 2-6 h, and in specific embodiments, can be 2 h, 2.5 h, 3 h, 3.4 h, 4 h, 4.5 h, 5 h, 5.5 h or 6 h.

[0057] After the amidation reaction is completed, the present application can further include post-treatment, which can include adding water to the obtained amidation reaction liquid for washing, and rotary evaporation of the obtained organic layer to dryness under reduced pressure to obtain compound I.

[0058] After obtaining compound I, the present application mixes compound I, second basic reagent and second organic solvent, and performs etherification reaction under a protective atmosphere to obtain dioxolane compound.

[0059] In this invention, the second alkaline reagent may include one or more of alkali metal hydrides, alkali metal carbonates, alkali metal hydroxides, organic amines, and alkali metal alkoxides; the alkali metal hydrides may include one or more of sodium hydride, potassium hydride, and cesium hydride; the alkali metal carbonates may include one or more of sodium carbonate, potassium carbonate, and cesium carbonate; the alkali metal hydroxides may include one or more of sodium hydroxide, potassium hydroxide, and cesium hydroxide; the organic amines may include triethylamine and / or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); the alkali metal alkoxides may include one or more of sodium methoxide, potassium methoxide, cesium methoxide, potassium tert-butoxide, sodium tert-butoxide, and cesium tert-butoxide.

[0060] In this invention, the molar ratio of compound I to the second basic reagent can be 1:1.5 to 4, and in specific embodiments it can be 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0061] In this invention, the second organic solvent may include one or more of tetrahydrofuran, dichloromethane, ethyl acetate, acetone, alcohol solvents, and dimethyl sulfoxide; the alcohol solvent may include one or more of methanol, ethanol, and isopropanol. In this invention, the mass-to-volume ratio of compound I to the second organic solvent may be 1g:3-8mL, and in specific embodiments may be 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, or 1g:8mL.

[0062] In this invention, mixing the compound I, the second basic reagent, and the second organic solvent may include: adding the compound I and the second organic solvent, and adding the second basic reagent in batches at 0-5°C.

[0063] In this invention, the temperature of the etherification reaction can be -10 to 30°C, and in specific embodiments, it can be -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, or 30°C; the time of the etherification reaction can be 2 to 5 hours, and in specific embodiments, it can be 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours. In this invention, the protective atmosphere can include nitrogen, argon, or helium.

[0064] After the etherification reaction is completed, the present invention may further include post-treatment, which may include: quenching the etherification reaction solution with water, extracting with an organic extractant, and rotary evaporating the resulting organic layer under reduced pressure to dryness to obtain the dioxane compound. In the present invention, the organic extractant may include one or more of ethyl acetate, dichloromethane, diethyl ether, and toluene.

[0065] The application further provides a preparation method of the intermediate of ticagrelor, comprising the following steps: mixing the dioxolane compound, a third alkaline reagent and a third organic solvent, performing a hydrolysis reaction, and then adding a reducing agent to perform a reduction reaction to obtain the intermediate of ticagrelor with the structure of formula B.

[0066]

[0067] In the application, the third alkaline reagent can include one or more of alkali metal hydroxides, alkali metal carbonates and alkali metal alcoholates; the alkali metal carbonates can include one or more of sodium carbonate, potassium carbonate and cesium carbonate; the alkali metal hydroxides can include one or more of sodium hydroxide, potassium hydroxide and cesium hydroxide; and the alkali metal alcoholates can include one or more of sodium methoxide, potassium methoxide, cesium methoxide, potassium tert-butoxide, sodium tert-butoxide and cesium tert-butoxide.

[0068] In the application, the molar ratio of the dioxolane compound to the third alkaline reagent can be 1:1-4, and in specific embodiments, can be 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0069] In the application, the third organic solvent can include one or more of toluene, ethylene glycol, isopropyl alcohol, dimethyl sulfoxide and dimethyl formamide. In the application, the mass-volume ratio of the dioxolane compound to the third organic solvent can be 1g:3-12mL, and in specific embodiments, can be 1g:3mL, 1g:4mL, 1g:5mL, 1g:6mL, 1g:7mL, 1g:8mL, 1g:9mL or 1g:10mL.

[0070] In the application, the temperature of the hydrolysis reaction can be 80-150℃, and in specific embodiments, can be 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃, 125℃, 130℃, 135℃, 140℃, 145℃ or 150℃; and the time of the hydrolysis reaction can be 12-20h, and in specific embodiments, can be 12h, 13h, 14h, 15h, 16h, 17h, 8h, 19h or 20h. In the application, the hydrolysis reaction obtains a reaction solution containing a compound with the structure of formula III.

[0071]

[0072] After the hydrolysis reaction is completed, the reaction solution containing the compound with the structure of formula III obtained is cooled to 0-5℃, a reducing agent is added to perform a reduction reaction, and the intermediate of ticagrelor with the structure of formula B is obtained.

[0073] In the present application, the reducing agent can include one or more of lithium aluminum hydride, sodium borohydride, potassium borohydride, and borane.

[0074] In the present application, the molar ratio of the dioxolane compound to the reducing agent can be 1:1.5-4, and in specific embodiments, can be 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, or 1:4.

[0075] In the present application, the reducing agent can be mixed first after being added, and then the reduction reaction can be performed. In the present application, the temperature of the mixing can be 0-5°C, and in specific embodiments, can be 0°C, 1°C, 2°C, 3°C, 4°C, or 5°C; the time of the mixing can be 0.5-2h, and in specific embodiments, can be 0.5h, 1h, 1.5h, or 2h.

[0076] In the present application, the temperature of the reduction reaction can be 0-50°C, and in specific embodiments, can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C; the time of the reduction reaction can be 8-16h, and in specific embodiments, can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, or 16h.

[0077] In the present application, when the third organic solvent is a water-immiscible organic solvent, after the reduction reaction is completed, the present application further includes a first post-treatment, which can include: adding water to the obtained reduction reaction liquid to quench, separating the layers, and rotary-evaporating the obtained organic layer to dryness under reduced pressure to obtain a ticagrelor intermediate having the structure of Formula B.

[0078] In the present application, when the third organic solvent is a water-miscible organic solvent, after the reduction reaction is completed, the present application further includes a second post-treatment, which can include: evaporating the organic solvent from the obtained reduction reaction liquid under reduced pressure, adding water and an organic solvent to extract, and rotary-evaporating the obtained organic layer to dryness under reduced pressure to obtain a ticagrelor intermediate having the structure of Formula B. In the present application, the organic solvent can include one or more of ethyl acetate, dichloromethane, diethyl ether, and toluene.

[0079] In order to further illustrate the present application, the dioxolane compound, the preparation method and application thereof, and the preparation method of the ticagrelor intermediate provided by the present application are described in detail below in conjunction with the examples, but they should not be understood as limiting the scope of protection of the present application.

[0080] Example 1

[0081] Preparation of compound I-1 (Formula I-1)

[0082]

[0083] Compound A (200 g), dichloromethane (1 L) and triethylamine (116.8 g, 1.0 eq.) were added to the reaction kettle, and chloroacetyl chloride (130.5 g, 1.0 eq.) was added dropwise under ice water bath, and the temperature was raised to reflux and stirred for 5 h. After the reaction was completed, 500 mL of water was added for washing, and the organic layer was rotary evaporated to dryness under reduced pressure to obtain compound I-1 (281.4 g, yellow gum, yield 97.6%, purity 98.2%).

[0084] Figure 1 The hydrogen spectrum of compound I-1 is as follows, 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, 1H), 4.51 (d, 1H), 4.43-4.36 (m, 1H), 4.34-4.28 (m, 1H), 3.99 (s, 2H), 3.10 (s, 1H), 2.30-2.20 (m, 1H), 1.75-1.67 (m, 1H), 1.39 (s, 3H), 1.25 (s, 3H). It can be seen that the compound having the structure shown in formula I-1 is successfully prepared.

[0085] Example 2

[0086] Preparation of compound I-1 (formula I-1)

[0087]

[0088] Compound A (200 g), dichloromethane (1 L) and triethylamine (116.8 g, 1.0 eq.) were added to the reaction kettle, and chloroacetyl chloride (130.5 g, 1.0 eq.) was added dropwise under ice water bath, and the temperature was raised to reflux and stirred for 5 h. After the reaction was completed, 500 mL of water was added for washing, and the organic layer was rotary evaporated to dryness under reduced pressure to obtain compound I-1 (281.4 g, yellow gum, yield 97.6%, purity 98.2%).

[0089] Example 3

[0090] Preparation of compound I-2 (formula I-2)

[0091]

[0092] Compound A (200 g), dichloromethane (1 L) and triethylamine (116.8 g, 1.0 eq.) were added to the reaction kettle, and chloroacetyl chloride (130.5 g, 1.0 eq.) was added dropwise under ice water bath, and the temperature was raised to reflux and stirred for 5 h. After the reaction was completed, 500 mL of water was added for washing, and the organic layer was rotary evaporated to dryness under reduced pressure to obtain compound I-1 (281.4 g, yellow gum, yield 97.6%, purity 98.2%).

[0093] Figure 2 The hydrogen spectrum of the compound I-2 is as follows: 1 H NMR (400MHz, CDCl3) δ 7.56 (d, 1H), 4.53 (t, 1H), 4.47-4.39 (m, 1H), 4.37-4.29 (m, 1H), 4.01 (s, 2H), 2.58 (s, 1H), 2.33-2.20 (m, 1H), 1.78-1.68 (m, 1H), 1.41 (s, 3H), 1.26 (s, 3H).

[0094] Example 4

[0095] Preparation of dioxolane compound (formula II)

[0096]

[0097] Under nitrogen protection, a dry reaction kettle was added with a compound of structural formula I-1 (200 g) and tetrahydrofuran (1 L), and the temperature was controlled at 0-5 DEG C under ice water bath. Sodium hydride (67.3 g, containing 40 wt% paraffin oil, 2.1 eq.) was added in batches, and the reaction was stirred for 3 h. After the reaction was completed, 500 mL of water was added for quenching, 500 mL of ethyl acetate was added for extraction, and the organic phase was rotary evaporated to dryness under reduced pressure to obtain a dioxolane compound (white solid, 158.3 g, yield 92.7%, purity 99.5%) shown in formula II.

[0098] Figure 3 The hydrogen spectrum of the dioxolane compound shown in formula II is as follows, 1 H NMR (400MHz, CDCl3) δ 6.88 (d, 2H), 4.58-4.50 (m, 4H), 4.45-4.36 (m, 2H), 4.13-3.96 (m, 4H), 3.95-3.93 (m, 2H), 2.35-2.25 (m, 1H), 1.85-1.76 (m, 1H), 1.41 (s, 3H), 1.21 (s, 3H); LC-MS (ESI) m / z: 427.2 (M+H) + It can be seen that the compound shown in formula II is successfully prepared.

[0099] Example 5

[0100] Preparation of dioxolane compound (formula II)

[0101]

[0102] Into a dry reaction flask, compound I-1 (200 g) and dichloromethane (1200 mL) were added under nitrogen protection, temperature was controlled at 0-5°C with ice water bath, sodium hydroxide (80.1 g, 2.5 eq.) was added in batches, and the reaction was stirred for 3 h. After the reaction was completed, 600 mL of water was added for quenching, and the organic phase was separated by rotary evaporation under reduced pressure to obtain a dioxolane compound (white solid, 163.3 g, yield 95.6%, purity 99.3%) with the structure shown in formula II. The dioxolane compound was the same as that in Example 4.

[0103] Example 6

[0104] Preparation of a dioxolane compound (formula II)

[0105]

[0106] Into a dry reaction flask, compound I-2 (200 g) and acetone (800 mL) were added under nitrogen protection, temperature was controlled at 0-5°C with ice water bath, sodium methoxide (80.8 g, 2.2 eq.) was added in batches, and the reaction was stirred for 5 h. After the reaction was completed, the acetone was evaporated, 400 mL of water and 400 mL of ethyl acetate were added, and the organic phase was separated by rotary evaporation under reduced pressure to obtain a dioxolane compound (white solid, 135.4 g, yield 93.4%, purity 98.6%) with the structure shown in formula II.

[0107] Example 7

[0108] Preparation of a ticagrelor intermediate (formula B)

[0109]

[0110] Into a dry reaction flask, a dioxolane compound (200 g) with the structure shown in formula II, toluene (1200 mL), and sodium hydroxide (39.4 g, 2.1 eq.) were added, and the reaction was stirred at 110°C for 16 h. After the reaction was completed, the temperature was slowly lowered to 0-5°C, lithium aluminum hydride (78.5 g, 2.1 eq.) was added in batches while controlling the temperature at 0-5°C, and the reaction was stirred for 1 h after being warmed to 40°C. After the reaction was completed, 1500 mL of water was added for quenching, and the organic phase was separated by rotary evaporation under reduced pressure to obtain a ticagrelor intermediate (colorless transparent liquid, 188.7 g, yield 92.6%, purity 99.5%) with the structure shown in formula B.

[0111] Figure 4 The hydrogen spectrum of the ticagrelor intermediate with the structure shown in formula B is as follows: 1H NMR (400 MHz, CDCI3) δ 4.68-4.58 (m, 1H), 4.52-4.42 (m, 1H), 3.85 (d, 1H), 3.72-3.42 (m, 8H), 3.38-3.30 (m, 1H), 2.18-2.04 (m, 1H), 1.92-1.76 (m, 1H), 1.36 (s, 3H), 1.24 (s, 3H). It can be known that the intermediate of ticagrelor with the structure shown in formula B is successfully prepared.

[0112] Example 8

[0113] Preparation of the intermediate of ticagrelor (formula B)

[0114]

[0115] The dioxolane compound with the structure shown in formula II (200 g), ethylene glycol (2000 mL), potassium hydroxide (65.8 g, 2.5 eq.) were added into a dry reaction kettle, and the reaction was stirred at 150°C for 12 h. After the reaction was completed, the temperature was slowly reduced to 0-5°C, and sodium borohydride (44.4 g, 2.5 eq.) was added in batches at 0-5°C, and the reaction was stirred for 1 h after temperature was kept, and then the temperature was increased to 50°C and stirred for 12 h. After the reaction was completed, the ethylene glycol was evaporated under reduced pressure, 500 mL of water and 1000 mL of ethyl acetate were added, and the organic phase was separated and evaporated under reduced pressure to obtain the intermediate of ticagrelor with the structure shown in formula B (colorless transparent liquid, 186.3 g, yield 91.4%, purity 99.6%).

[0116] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the principles of the present application, several improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing a ticagrelor intermediate, characterized in that, Includes the following steps: A dioxane compound, a third basic reagent, and a third organic solvent are mixed and hydrolyzed. Then, a reducing agent is added to carry out a reduction reaction to obtain a ticagrelor intermediate with the structure of formula B. The dioxacyclopentane compounds have the structure shown in Formula II: Formula II; ； The third alkaline reagent includes one or more of alkali metal hydroxides, alkali metal carbonates, and alkali metal alkoxides; The third organic solvent includes one or more of toluene, ethylene glycol, isopropanol, dimethyl sulfoxide, and dimethylformamide; The reducing agent includes one or more of lithium aluminum hydride, sodium borohydride, potassium borohydride, and borane.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the dioxane compound to the third basic reagent is 1:1~4; The hydrolysis reaction is carried out at a temperature of 80~150℃ for 12~20h.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the dioxane compound to the reducing agent is 1:1.5~4; The reduction reaction is carried out at a temperature of 0~50℃ for 8~16 hours.

4. The preparation method according to any one of claims 1 to 3, characterized in that, The preparation method of the dioxane compounds includes the following steps: Compound A, an acylation reagent, a first basic reagent, and a first organic solvent are mixed and subjected to an amidation reaction to obtain compound I; the acylation reagent includes chloroacetyl chloride, bromoacetyl chloride, or bromoacetyl bromide; the first basic reagent includes one or more of organic amines, alkali metal carbonates, alkali metal hydroxides, and alkali metal alkoxides; the first organic solvent includes one or more of dichloromethane, toluene, ethyl acetate, acetone, alcohol solvents, furan solvents, and dimethyl sulfoxide. The compound I, the second basic reagent, and the second organic solvent are mixed and etherified under a protective atmosphere to obtain the dioxacyclopentane compound; the second basic reagent includes one or more of alkali metal hydrides, alkali metal carbonates, alkali metal hydroxides, organic amines, and alkali metal alkoxides; the second organic solvent includes one or more of tetrahydrofuran, dichloromethane, ethyl acetate, acetone, alcohol solvents, and dimethyl sulfoxide. ； In compound I, X is chlorine or bromine.

5. The preparation method according to claim 4, characterized in that, The molar ratio of compound A to the acylation reagent is 1:0.5~3; The molar ratio of compound A to the first basic reagent is 1:0.5~3.

6. The preparation method according to claim 4, characterized in that, The amidation reaction is carried out at a temperature of 20-40°C for 2-6 hours.

7. The preparation method according to claim 4, characterized in that, The molar ratio of compound I to the second basic reagent is 1:1.5~4.

8. The preparation method according to claim 4, characterized in that, The etherification reaction is carried out at a temperature of -10 to 30°C for 2 to 5 hours.

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