CN108892670B - Preparation method of high-purity ticagrelor - Google Patents
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Abstract
The invention discloses a preparation method of high-purity ticagrelor, which comprises the steps of preparing intermediates TG-1, TG-2, TG-3 and TG-4, refining ticagrelor and the like, wherein the preparation method comprises the steps of adjusting the proportion of reactants, optimizing reaction time, temperature and post-treatment mode, selecting specific catalyst and crystallization solvent, improving the reaction efficiency of the intermediates, shortening the reaction time, improving the purity of the intermediates, obtaining the ticagrelor crude product, and then adopting different crystallization solvents and stage crystallization processes to obtain the ticagrelor with high purity, reducing the production cost, and having the advantages of high efficiency and clean production and strong operability, wherein the purity of the obtained ticagrelor product is not less than 99.8%, and any single impurity is not more than 0.06%.
Description
Technical Field
The invention relates to a preparation method of high-purity ticagrelor, and belongs to the field of drug synthesis.
Background
Ticagrelor (Ticagrelor, also known as Ticagrelor) is a novel selective small-molecule anticoagulant developed by the company asikang, is also the first oral P2Y12 adenosine diphosphate receptor antagonist capable of being combined, has obvious inhibition effect on platelet aggregation caused by ADP, and can further obviously reduce the cardiovascular death rate or myocardial infarction rate of patients with Acute Coronary Syndrome (ACS) and simultaneously obviously reduce the cardiovascular death rate compared with clopidogrel.
The drug was marketed in the european union and the united states in 2010 and 2011 by approval from the european union drug administration (EMEA) and the U.S. Food and Drug Administration (FDA), respectively. At present, the imported preparation ticagrelor tablets are already on the market in China, and the trade name is Beilinda.
There are many reports of synthetic routes and preparation methods of ticagrelor, and looking at the disclosed synthetic routes and preparation methods, the disclosed synthetic routes and preparation methods have a common characteristic that different functional groups of the following three intermediates A, B and C are protected, and groups are deprotected through different chemical reactions, different reaction sequences and different linking modes to prepare ticagrelor.
The scheme for preparing ticagrelor by taking compound A as an intermediate is more, and the ticagrelor is obtained by performing trifluoroacetic anhydride protection on amino and performing deprotection after tricyclic chain connection in national patents of WO97/03084, WO99/05142, WO2000/34283 and WO 2012/138981. Patents CN103130726, CN102250097, WO2010/03224, WO2007/093368, US2011/071290 and the like have studied the preparation method of the pyrimidine ring (intermediate a).
The scheme of taking the compound B as the intermediate is mainly developed around the protection of amino on a three-membered ring, and the patents WO2013/037942, WO2012/085665 and EP2570405 increase the selectivity of condensation reaction through the protection of amino on cyclopropylamine. The preparation of the three-membered ring (intermediate B) was studied in patents WO2012/001531, WO2011/132083, CN1431992, CN1334816, CN101495444 and the like.
The scheme of taking the compound C as an intermediate mainly surrounds the protection of amino and hydroxyl on a five-membered ring, and in the patent WO2012/172426, methyl acetate functional groups are firstly reserved on the five-membered ring, and after the linkage of three intermediates is completed, the ester groups are reduced into alcohol. CN103992323 is that trimethylsilane or tert-butyldimethylsilane protection is carried out on hydroxyl on a long chain, and after the connection of three intermediates is completed, deprotection is carried out to obtain ticagrelor. Patents WO2010/030224, US2010/069408 and CN102659815 investigated the synthesis and preparation methods of five-membered rings (intermediate C).
The above background analysis is more detailed in the granted Chinese patent CN105153167 by Shenzhen Xin Li Tai company, and the application CN107337675 by Hunan Tian Ji Cao Tang pharmaceutical Co Ltd is mentioned, and the above two patents use ethylene glycol as a reaction solvent in the preparation of the ticagrelor intermediate TG-1, and the influence is that the organic solvent is directly diluted by water during the post-treatment, the consumption is large, the environmental protection is not facilitated, the polarity of the reaction solvent is large, and the reaction temperature is high, and the impurity is also greatly influenced.
The ticagrelor is prepared by a one-pot method in the following steps, toluene is used as a reaction solvent, the simple organic phase and the water phase are separated after the reaction is finished, and then the next reaction is carried out, but the solvent is used for carrying out a series of reactions, and the reaction temperature is high, so that the reaction selectivity is poor, and more organic impurities are generated.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity ticagrelor, which comprises the steps of adjusting the proportion of reactants, optimizing the reaction time, selecting a specific catalyst and a crystallization solvent, and simultaneously obtaining a crude ticagrelor product by adopting a staged crystallization process, so that the ticagrelor with high purity is obtained, the production cost is reduced, the advantages of high efficiency and clean production are achieved, the operability is strong, the purity of the obtained ticagrelor product is not lower than 99.8%, and any single impurity is not more than 0.06%.
The technical scheme adopted by the invention is as follows:
a preparation method of high-purity ticagrelor comprises the following synthetic route:
a preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 1, 4-dioxane, TG-SM-3 and TG-SM-2 into a reactor, sequentially adding a catalyst and N, N-diisopropylethylamine, introducing nitrogen, heating up for refluxing, keeping the temperature and stirring, concentrating under reduced pressure to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, concentrating the washed organic layer under reduced pressure to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating up for refluxing, dropwise adding N-hexane into the solution, cooling for crystallization after the completion, filtering, and drying in vacuum to obtain an off-white or off-white solid TG-1;
s2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding a sodium nitrite solution, reacting until the raw material disappears, adjusting the pH to 8-9 with a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time with ethyl acetate, washing the organic phase with a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
s3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 with ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react, adding water after the reaction is finished, adjusting the pH to 5-6 with 10% acetic acid solution, separating liquid, sequentially washing an organic phase with water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
s4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system, separating liquid, extracting the water phase for 2 times by using ethyl acetate, washing the organic phase once by using a saturated sodium bicarbonate aqueous solution, decompressing and evaporating an organic layer, adding ethyl acetate, stirring until the ethyl acetate is completely dissolved, heating to reflux, dropwise adding n-hexane, stirring continuously after stirring and cooling, filtering, and drying in vacuum to obtain a white solid or a white-like solid TG-4 which is a crude product;
s5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with an ethyl acetate/n-hexane solvent, and drying under reduced pressure to obtain a white or off-white ticagrelor solid.
Preferably, in the step S1, the molar ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1-2: 1: 8-50: 1-5: 2-10, the solvent is 1, 4-dioxane, the reflux temperature of the reaction is 90-110 ℃, and the stirring time of the reaction is 8-12 h.
Preferably, at least one of the following technical features is also included:
in step S1, the catalyst is sodium iodide and/or sodium p-toluenesulfonate;
in the step S1, the mass ratio of TG-SM-2 to dichloromethane to water is 1:5-8: 8-12;
in the step S1, dropwise adding n-hexane with the mass 4-6 times of that of the crude product, wherein the cooling temperature for crystallization is 15-20 ℃, and the crystallization time is 2-3 h;
in step S1, the n-hexane contains 0.1-1% by mass of squalane.
Preferably, at least one of the following technical features is also included:
in the step S2, the mass ratio of TG-1, ethyl acetate, water, concentrated hydrochloric acid and sodium nitrite solution is 1: 2-20: 2-20: 0.2-1: 0.1-0.5, ethyl acetate and water as solvent, 10-15 ℃ of reaction temperature, 1-3h of reaction time, and 0.1-1mol/L of sodium nitrite solution;
in the step S2, the amount of ethyl acetate extraction was 5 to 8 times the weight of TG-1.
Preferably, at least one of the following technical features is also included:
in the step S3, the mass ratio of TG-2 to TG-SM-1 to ethyl acetate to N, N-diisopropylethylamine is 1: 0.7-1.2: 2-20: 0.3-2, the solvent is ethyl acetate, the reaction temperature is 10-30 ℃, and the reaction time is 2-4 h;
in said step S3, the amount of water added at the end of the reaction is 3 to 6 times the weight of TG-2.
Preferably, at least one of the following technical features is also included:
in the step S4, the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 0.5-5: 2.5-3.5: 1-3: 2-6, the solvent is methanol, the reaction temperature is 0-5 ℃, the reaction time is 1-3h, and the system control temperature is 10-20 ℃;
in the step S4, the amount of ethyl acetate used for extraction is 4-6 times of the weight of TG-3, n-hexane is added dropwise, and stirring is continued for 1-2h after the temperature is reduced to 20-25 ℃.
Preferably, in the step S5, the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 3-6: 4.5-9.
Preferably, in step S5, the crystallization solution includes n-hexane and n-tetradecane, and the crystallization step is: dripping n-hexane, cooling and crystallizing to 15-20 deg.C, crystallizing for 3-4 hr, dripping n-tetradecane, cooling and crystallizing to 8-12 deg.C, and crystallizing for 0.5-1.5 hr.
Wherein the mass ratio of the n-hexane to the n-tetradecane is 10: 3.5-4.5.
In the present invention, TG-SM-1 (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine (R) -mandelate; TG-SM-2: 2- (3aR.4S.6R,6aS) -6-aminotetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxan-4-yl ] -ethanol (2R,3R) -2, 3-dihydroxysuccinate; TG-SM-3: 4, 6-dichloro-2- (propylsulfanyl) -5-aminopyrimidine, are commercially available.
In the invention, the mass ratio of the reactions S2, S3 and S4 is the theoretical yield of TG-2 and TG-3 calculated by taking the intermediate TG-1 as a starting material, and the next reaction is directly carried out.
The invention has the beneficial effects that:
1. firstly, in the process of producing the intermediate TG-1, 4-dioxane is used as a solvent, and a catalyst sodium iodide and/or sodium p-toluenesulfonate is added, so that the reaction efficiency and the product purity are improved, the original reaction time is shortened from 16-20h to 8-12h, and the solvent 1, 4-dioxane is recycled, so that the process is energy-saving and environment-friendly, and the purity of the intermediate TG-1 is more than 99.0%.
2. And (3) dripping normal hexane containing squalane to separate out crystals of the intermediate TG-1, wherein the squalane can increase the activity of the normal hexane and improve the purity of the intermediate TG-1, and the quality of the Ticagrelor finished product is easier to control by refining the intermediate TG-1.
3. In the step of refining ticagrelor, a staged crystallization process is adopted, n-hexane is used for crystallization, and then n-tetradecane is used for crystallization at a lower temperature, so that crystals are completely separated out, more impurities are removed, and finally the ticagrelor product with the purity not lower than 99.8% and any single impurity not higher than 0.06% is obtained.
In conclusion, the invention adjusts the proportion of reactants, optimizes the reaction time, the temperature and the post-treatment mode, selects the specific catalyst and the crystallization solvent, improves the reaction efficiency of the intermediate, shortens the reaction time, improves the purity of the intermediate, obtains ticagrelor with high purity by adopting different crystallization solvents and stage crystallization processes after obtaining the crude ticagrelor, reduces the production cost, has the advantages of high efficiency and clean production, and has strong operability, the purity of the obtained ticagrelor product is not lower than 99.8%, and any single impurity is not more than 0.06%.
Drawings
Fig. 1 is a molecular structural formula of ticagrelor.
Detailed Description
Embodiments of the present invention are further described below with reference to the accompanying drawings.
Example 1
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 8mol of 1, 4-dioxane, 1mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 1mol of catalyst and 2mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 90 ℃ for refluxing, keeping the temperature and stirring for 8h, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 4 times of the crude product into the solution, cooling to 15 ℃ after the solution is finished, crystallizing for 2h, filtering, and vacuum drying to obtain a white-like solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1:8: 1: 2, and the catalyst is sodium p-toluenesulfonate.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:5: 8.
Wherein the normal hexane contains 0.1% of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.1mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value of 8 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 5 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1, ethyl acetate, water, concentrated hydrochloric acid and sodium nitrite solution is 1: 2: 0.2: 0.1.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 10 ℃ for 2 hours, adding water with the mass of 3 times of that of TG-2 after the reaction is finished, adjusting the pH value to 5 by using 10% acetic acid solution, separating, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 0.7: 2: 0.3.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 0 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 1h under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to 10 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight of 4-6 times of that of TG-3, washing an organic phase once by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer to dryness, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring for 1h after stirring and cooling to 20 ℃, filtering, and performing vacuum drying to obtain a white-like solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 0.5: 2.5: 1: 2.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with an ethyl acetate solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 3: 4.5.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:3.5, and the crystallization steps are as follows: firstly, dripping n-hexane, cooling and crystallizing to 15 ℃, wherein the crystallization time is 3 hours, then dripping n-tetradecane, cooling and crystallizing to 8 ℃, and the crystallization time is 0.5 hours.
Example 2
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 25mol of 1, 4-dioxane, 1.5mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 3mol of catalyst and 6mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 100 ℃ for refluxing, keeping the temperature and stirring for 10 hours, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 5 times of the crude product into the solution, cooling to 18 ℃ for crystallization for 2.5 hours after the solution is finished, filtering, and vacuum drying to obtain a white-like solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1.5: 1: 25: 3: 6, and the catalyst is 2mol of sodium iodide and 1mol of sodium p-toluenesulfonate.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:6: 10.
Wherein the normal hexane contains 0.5 percent of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.5mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value to 8 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 6 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1:10: 10: 0.6: 0.3.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 20 ℃ for 3 hours, adding water with the mass 5 times that of TG-2 after the reaction is finished, adjusting the pH value to 6 by using 10% acetic acid solution, separating liquid, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 1.0: 10: 1.0.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 2 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 2 hours under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to 15 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight 5 times that of TG-3, washing an organic phase for one time by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer to dryness, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring and cooling to 22 ℃, continuously stirring for 1.5 hours, filtering, and vacuum-drying to obtain a white solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 2.5: 3: 2: 4.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with a normal hexane solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1:5: 6.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:4, and the crystallization step comprises the following steps: firstly, dripping n-hexane, cooling and crystallizing to 18 ℃, wherein the crystallization time is 3.5h, then dripping n-tetradecane, cooling and crystallizing to 10 ℃, and the crystallization time is 1 h.
Example 3
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 50mol of 1, 4-dioxane, 2mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 5mol of catalyst and 10mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 110 ℃ for refluxing, keeping the temperature and stirring for 12h, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 6 times of the crude product into the solution, cooling to 20 ℃ after the solution is finished, crystallizing for 3h, filtering, and drying in vacuum to obtain an off-white solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 2: 1: 50: 5:10, and the catalyst is sodium iodide.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:8: 12.
Wherein the normal hexane contains 1% of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 1mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value 9 with saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time with ethyl acetate with the weight of 8 times of that of TG-1, washing the organic phase with saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1: 20: 20: 1: 0.5.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 30 ℃ for 4 hours, adding water with the mass of 6 times of that of TG-2 after the reaction is finished, adjusting the pH value to 6 by using 10% acetic acid solution, separating liquid, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 1.2: 20: 2.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 5 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 1-3h under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to 20 ℃, separating liquid, extracting the water phase for 2 times by using ethyl acetate with the weight of 6 times of that of TG-3, washing the organic phase once by using a saturated sodium bicarbonate water solution, decompressing and evaporating the organic layer to dryness, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring for 2h after stirring and cooling to 25 ℃, filtering, and vacuum-drying to obtain a white solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1:5: 3.5: 3: 6.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with a normal hexane solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1:6: 9.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:4.5, and the crystallization steps are as follows: firstly, dripping n-hexane, cooling and crystallizing to 20 ℃, wherein the crystallization time is 4 hours, then dripping n-tetradecane, cooling and crystallizing to 12 ℃, and the crystallization time is 1.5 hours.
Example 4
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 1, 4-dioxane, 1.6mol TG-SM-3 and 1mol TG-SM-2 into a reactor, sequentially adding 4mol of catalyst and 8mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 90 ℃ for refluxing, keeping the temperature and stirring for 9 hours, decompressing and concentrating to remove 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating and refluxing, dropwise adding N-hexane with the mass of 5 times of the crude product into the solution, cooling to 16 ℃ for crystallization for 2.5 hours after the solution is finished, filtering, and vacuum drying to obtain a white-like solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1.6: 1: 20: 4: 8, and the catalyst is sodium iodide.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:6: 11.
Wherein the normal hexane contains 0.8 percent of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.2mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value of 9 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 7 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1: 15: 5: 0.5: 0.2.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the temperature of 15 ℃ for 4 hours, adding water with the mass of 4 times of that of TG-2 after the reaction is finished, adjusting the pH value to 5 by using 10% acetic acid solution, separating liquid, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 0.8: 15: 1.5.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 1 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 3 hours under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to be 12 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight being 4 times that of TG-3, washing an organic phase for one time by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring and cooling to 24 ℃, continuously stirring for 1 hour, filtering, and vacuum drying to obtain a white-like solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 3: 2.8: 1.5: 5.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with an ethyl acetate solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 4: 8.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:3.5, and the crystallization steps are as follows: firstly, dripping n-hexane, cooling and crystallizing to 16 ℃, wherein the crystallization time is 4 hours, then dripping n-tetradecane, cooling and crystallizing to 11 ℃, and the crystallization time is 1.2 hours.
Example 5
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 8mol of 1, 4-dioxane, 1mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 3mol of catalyst and 10mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 90 ℃ for refluxing, keeping the temperature and stirring for 10 hours, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating liquid, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 6 times of the crude product into the solution, cooling to 15 ℃ after the solution is finished, crystallizing for 2.5 hours, filtering, and vacuum drying to obtain an off-white solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1:8: 3: 10, and the catalyst is sodium iodide.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:5: 10.
Wherein the normal hexane contains 1% of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.6mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value 8 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 6 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1: 20: 2: 0.6: 0.5.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 10 ℃ for 3 hours, adding water with the mass of 6 times of that of TG-2 after the reaction is finished, adjusting the pH value to 5 by using 10% acetic acid solution, separating, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 1.0: 20: 0.3.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 2 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 3 hours under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to 10 ℃, separating liquid, extracting the water phase for 2 times by using ethyl acetate with the weight 5 times that of TG-3, washing the organic phase once by using a saturated sodium bicarbonate water solution, decompressing and evaporating the organic layer to dryness, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring for 1 hour after stirring and cooling to 25 ℃, filtering, and vacuum-drying to obtain white solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 2.5: 5: 2.5: 2: 6.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with a normal hexane solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 3: 6.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:4.5, and the crystallization steps are as follows: firstly, dripping n-hexane, cooling and crystallizing to 15 ℃, wherein the crystallization time is 3.5h, then dripping n-tetradecane, cooling and crystallizing to 12 ℃, and the crystallization time is 0.5 h.
Example 6
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 25mol of 1, 4-dioxane, 1mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 5mol of catalyst and 2mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 100 ℃ for refluxing, keeping the temperature and stirring for 12h, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 4 times of the crude product into the solution, cooling to 18 ℃ after the solution is finished, crystallizing for 3h, filtering, and vacuum drying to obtain a white-like solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1: 25: 5:2, and the catalyst is 4mol of sodium iodide and 1mol of sodium p-toluenesulfonate.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:6: 12.
Wherein the normal hexane contains 0.1% of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.8mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value 8 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 8 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1: 2: 10: 1: 0.1.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 20 ℃ for 4 hours, adding water with the mass of 3 times of that of TG-2 after the reaction is finished, adjusting the pH value to 5 by using 10% acetic acid solution, separating, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2 to TG-SM-1 to ethyl acetate to N, N-diisopropylethylamine is 1: 1.2: 2: 1.5.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 5 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 1h under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to 15 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight 6 times that of TG-3, washing an organic phase for one time by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer to dryness, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring and cooling to 20 ℃, continuously stirring for 1.5h, filtering, and vacuum-drying to obtain a white-like solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1:5: 0.5: 3: 2.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with a normal hexane solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1:5: 9.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:3.5, and the crystallization steps are as follows: firstly, dripping n-hexane, cooling and crystallizing to 18 ℃, wherein the crystallization time is 4 hours, then dripping n-tetradecane, cooling and crystallizing to 8 ℃, and the crystallization time is 1 hour.
Example 7
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 50mol of 1, 4-dioxane, 1.5mol of TG-SM-3 and 1mol of TG-SM-2 into a reactor, sequentially adding 1mol of catalyst and 6mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 110 ℃ for refluxing, keeping the temperature and stirring for 8h, decompressing and concentrating to remove 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 5 times of the crude product into the solution, cooling to 20 ℃ for crystallization for 2h after the solution is finished, filtering, and vacuum drying to obtain a white-like solid TG-1;
wherein the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1.5: 1: 50: 1:6, and the catalyst is sodium p-toluenesulfonate.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:8: 8.
Wherein the normal hexane contains 0.5 percent of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.5mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value 9 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 5 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1:10: 20: 0.2: 0.3.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 30 ℃ for 2 hours, adding water with the mass 5 times that of TG-2 after the reaction is finished, adjusting the pH value to 6 by using 10% acetic acid solution, separating liquid, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2, TG-SM-1, ethyl acetate and N, N-diisopropylethylamine is 1: 0.7: 10: 2.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 0 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 2 hours under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to be 20 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight being 4 times that of TG-3, washing an organic phase for one time by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring and cooling to 22 ℃, continuously stirring for 2 hours, filtering, and vacuum drying to obtain a white solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1: 0.5: 2.5: 3.5: 1: 4.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with a normal hexane solvent, and drying under reduced pressure to obtain a white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1:6: 4.5.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:4, and the crystallization step comprises the following steps: firstly, dripping n-hexane, cooling and crystallizing to 20 ℃, wherein the crystallization time is 3 hours, then dripping n-tetradecane, cooling and crystallizing to 10 ℃, and the crystallization time is 1.5 hours.
Comparative example 1
A preparation method of high-purity ticagrelor comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 1, 4-dioxane, 3mol TG-SM-3 and 1mol TG-SM-2 into a reactor, sequentially adding 6mol of catalyst and 1mol of N, N-diisopropylethylamine, introducing nitrogen, heating to 120 ℃ for refluxing, keeping the temperature and stirring for 14h, decompressing and concentrating to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, decompressing and concentrating a washed organic layer to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating for refluxing, dropwise adding N-hexane with the mass of 3 times of the crude product into the solution, cooling to 10 ℃ after the solution is finished, crystallizing for 4h, filtering, and drying in vacuum to obtain an off-white solid TG-1;
wherein the catalyst is sodium iodide.
Wherein the mass ratio of TG-SM-2 to dichloromethane to water is 1:10: 5.
Wherein the normal hexane contains 1.5 percent of squalane by weight.
S2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding 0.1mol/L sodium nitrite solution until the raw material disappears, adjusting the pH value 8 by using a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time by using ethyl acetate with the weight 4 times that of TG-1, washing the organic phase by using a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
wherein the mass ratio of TG-1 to ethyl acetate to water to concentrated hydrochloric acid to sodium nitrite solution is 1: 25: 0.1: 0.8.
S3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 by using ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react at the reaction temperature of 8 ℃ for 5 hours, adding water with the mass of 2 times of that of TG-2 after the reaction is finished, adjusting the pH value to 6 by using 10% acetic acid solution, separating, sequentially washing an organic phase by using water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
wherein the mass ratio of TG-2 to TG-SM-1 to ethyl acetate to N, N-diisopropylethylamine is 1: 1.5: 1: 1.5.
S4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling to 6 ℃, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting for 4 hours under controlled temperature, adding water and ethyl acetate, controlling the temperature of the system to be 8 ℃, separating liquid, extracting a water phase for 2 times by using ethyl acetate with the weight being 7 times that of TG-3, washing an organic phase for one time by using a saturated sodium bicarbonate water solution, decompressing and evaporating an organic layer, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring, cooling to 15 ℃, continuing to stir for 3 hours, filtering, and vacuum-drying to obtain a white-like solid TG-4 which is a crude product;
wherein the mass ratio of TG-3, methanol, hydrochloric acid methanol solution, water, ethyl acetate and n-hexane is 1:6: 0.4: 2: 4: 1.
S5: refining of ticagrelor:
and (4) adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with an ethyl acetate solvent, and drying under reduced pressure to obtain the off-white ticagrelor solid.
Wherein the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 2: 10.
The crystallization solution comprises n-hexane and n-tetradecane, the mass ratio of the n-hexane to the n-tetradecane is 10:3, and the crystallization step comprises the following steps: firstly, dripping n-hexane, cooling and crystallizing to 12 ℃, wherein the crystallization time is 2 hours, then dripping n-tetradecane, cooling and crystallizing to 5 ℃, and the crystallization time is 2 hours.
Comparative example 2
The difference from example 1 is that:
s1: no catalyst was added in the preparation of intermediate TG-1.
Comparative example 3
The difference from example 2 is that:
s1: in the preparation of the intermediate TG-1, the catalyst is sodium sulfide.
Comparative example 4
The difference from example 3 is that:
s1: in the preparation of intermediate TG-1, squalane was not present in the n-hexane.
Comparative example 5
The difference from example 4 is that:
s5: refining of ticagrelor:
the crystallization solution is n-hexane, and the crystallization steps are as follows: firstly, dripping normal hexane, cooling and crystallizing to 16 ℃, wherein the crystallization time is 5 h.
Comparative example 6
The difference from example 5 is that:
s5: refining of ticagrelor:
the crystallization solution is n-hexane, and the crystallization steps are as follows: dropping n-hexane, cooling and crystallizing to 15 ℃, wherein the crystallization time is 3.5h, then dropping n-hexane, cooling and crystallizing to 12 ℃, wherein the crystallization time is 0.5, and the mass ratio of the n-hexane in the two times is 10: 4.5.
The present invention is not limited to the above-described embodiments, and various changes may be made by those skilled in the art, and any changes equivalent or similar to the present invention are intended to be included within the scope of the claims.
TABLE 1 Effect of ticagrelor products prepared in each example and comparative example
As can be seen from the data in the above table, the ticagrelor products prepared in examples 1 to 7 within the process range of the present invention have higher purity of intermediate TG-1 and ticagrelor product, better yield of ticagrelor product, low content of any single impurity, and better effect than that of comparative example 1: the process parameters are different; comparative example 2: no catalyst is added in step S1; comparative example 3: step S1 selecting sodium sulfide as catalyst; comparative example 4: no squalane is added to the n-hexane dripped in the step S1; comparative example 5: directly crystallizing by one step by using normal hexane; comparative example 6: the solvent used for the stage crystallization is n-hexane, and the effect of the embodiment 2 is particularly optimal. According to the preparation method of the high-purity ticagrelor, provided by the invention, in the process of preparing the intermediate of TG-1, sodium iodide and/or sodium p-toluenesulfonate are/is used as a catalyst, a normal hexane crystallization solvent containing squalane is used, the reaction time is shortened, the purity of the intermediate TG-1 is also improved, after a crude ticagrelor product is obtained, different crystallization solvents and stage crystallization processes are adopted, the purity of the obtained ticagrelor product is not lower than 99.8%, and any single impurity is not more than 0.06%. Reduces the production cost and has the advantages of high efficiency and clean production.
Claims (7)
1. A preparation method of high-purity ticagrelor is characterized by comprising the following steps: the method comprises the following steps:
s1: preparation of intermediate TG-1:
sequentially adding 1, 4-dioxane, TG-SM-3 and TG-SM-2 into a reactor, sequentially adding a catalyst and N, N-diisopropylethylamine, introducing nitrogen, heating up for refluxing, keeping the temperature and stirring, concentrating under reduced pressure to remove the 1, 4-dioxane, cooling to room temperature, adding dichloromethane and water, separating, sequentially washing an organic layer with water and a saturated sodium chloride solution, concentrating the washed organic layer under reduced pressure to obtain a crude product, adding ethyl acetate, stirring to completely dissolve, heating up for refluxing, dropwise adding N-hexane into the solution, cooling for crystallization after the completion, filtering, and drying in vacuum to obtain an off-white or off-white solid TG-1;
s2: preparation of intermediate TG-2:
adding ethyl acetate, the intermediate TG-1 obtained in the step S1, water into a reactor in sequence, cooling, introducing nitrogen, dropwise adding concentrated hydrochloric acid, dropwise adding a sodium nitrite solution, reacting until the raw material disappears, adjusting the pH to 8-9 with a saturated sodium carbonate solution, separating liquid, extracting the aqueous phase for 1 time with ethyl acetate, washing the organic phase with a saturated sodium chloride solution, and evaporating under reduced pressure to obtain TG-2;
s3: preparation of intermediate TG-3:
adding the intermediate TG-2 obtained in the step S2 into a reactor, dissolving the intermediate TG-2 with ethyl acetate, adding TG-SM-1, stirring, adding N, N-diisopropylethylamine, introducing nitrogen to react, adding water after the reaction is finished, adjusting the pH to 5-6 with 10% acetic acid solution, separating liquid, sequentially washing an organic phase with water and saturated sodium bicarbonate aqueous solution, and concentrating an organic layer under reduced pressure until the organic layer is dried to obtain TG-3;
s4: preparation of intermediate TG-4:
adding the intermediate TG-3 obtained in the step S3 into a reactor, adding methanol for dissolving, cooling, introducing nitrogen, dropwise adding a hydrochloric acid methanol solution for reacting under the condition of temperature control, adding water and ethyl acetate, controlling the temperature of a system, separating liquid, extracting a water phase for 2 times by using ethyl acetate, washing an organic phase for one time by using a saturated sodium bicarbonate aqueous solution, decompressing and evaporating an organic layer, adding ethyl acetate, stirring to be completely dissolved, heating to reflux, dropwise adding n-hexane, stirring continuously after stirring and cooling, filtering, and drying in vacuum to obtain a white solid or a white-like solid TG-4 which is a crude product;
s5: refining of ticagrelor:
adding ethyl acetate and the crude product obtained in the step S4 into a reactor, introducing nitrogen, heating the system to reflux, stirring and dissolving, then dropwise adding a crystallization solution, crystallizing, filtering, washing with an ethyl acetate/n-hexane solvent, and drying under reduced pressure to obtain a white or off-white ticagrelor solid;
in step S1, the catalyst is sodium p-toluenesulfonate;
in the step S1, the mass ratio of TG-SM-2 to dichloromethane to water is 1:5-8: 8-12;
in the step S1, dropwise adding n-hexane with the mass 4-6 times of that of the crude product, wherein the cooling temperature for crystallization is 15-20 ℃, and the crystallization time is 2-3 h;
in the step S1, the normal hexane contains 0.1 to 1 mass percent of squalane;
in step S5, the crystallization solution includes n-hexane and n-tetradecane, and the crystallization step is: dripping n-hexane, cooling and crystallizing to 15-20 deg.C, crystallizing for 3-4 hr, dripping n-tetradecane, cooling and crystallizing to 8-12 deg.C, and crystallizing for 0.5-1.5 hr;
said TG-SM-3 is
Said TG-SM-2 is
Said TG-1 is
Said TG-2 is
Said TG-SM-1 is
Said TG-3 is
Said TG-4 is
2. A process for preparing ticagrelor in high purity according to claim 1, wherein:
in the step S1, the mol ratio of TG-SM-3, TG-SM-2, 1, 4-dioxane, catalyst and N, N-diisopropylethylamine is 1-2: 1: 8-50: 1-5: 2-10, the solvent is 1, 4-dioxane, the reflux temperature of the reaction is 90-110 ℃, and the stirring time of the reaction is 8-12 h.
3. A process for preparing ticagrelor in high purity according to claim 1, wherein: also comprises at least one technical characteristic as follows:
in the step S2, the mass ratio of TG-1, ethyl acetate, water, concentrated hydrochloric acid and sodium nitrite solution is 1: 2-20: 2-20: 0.2-1: 0.1-0.5, ethyl acetate and water as solvent, 10-15 ℃ of reaction temperature, 1-3h of reaction time, and 0.1-1mol/L of sodium nitrite solution;
in the step S2, the amount of ethyl acetate extraction was 5 to 8 times the weight of TG-1.
4. A process for preparing ticagrelor in high purity according to claim 1, wherein: also comprises at least one technical characteristic as follows:
in the step S3, the mass ratio of TG-2 to TG-SM-1 to ethyl acetate to N, N-diisopropylethylamine is 1: 0.7-1.2: 2-20: 0.3-2, the solvent is ethyl acetate, the reaction temperature is 10-30 ℃, and the reaction time is 2-4 h;
in said step S3, the amount of water added at the end of the reaction is 3 to 6 times the weight of TG-2.
5. A process for preparing ticagrelor in high purity according to claim 1, wherein: also comprises at least one technical characteristic as follows:
in the step S4, the solvent is methanol, the reaction temperature is 0-5 ℃, the reaction time is 1-3h, and the system temperature is controlled to be 10-20 ℃;
in the step S4, the amount of ethyl acetate used for extraction is 4-6 times of the weight of TG-3, n-hexane is added dropwise, and stirring is continued for 1-2h after the temperature is reduced to 20-25 ℃.
6. A process for preparing ticagrelor in high purity according to claim 1, wherein:
in the step S5, the mass ratio of the crude product, the ethyl acetate and the crystallization solution is 1: 3-6: 4.5-9.
7. A process for preparing ticagrelor in high purity according to claim 1, wherein: the mass ratio of n-hexane to n-tetradecane is 10: 3.5-4.5.
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| CN111978326A (en) * | 2019-05-24 | 2020-11-24 | 南京一心和医药科技有限公司 | Production process of ticagrelor competitive product |
| CN110467619A (en) * | 2019-08-08 | 2019-11-19 | 山西德元堂药业有限公司 | A kind of preparation method of ticagrelor |
| CN111848632A (en) * | 2020-09-07 | 2020-10-30 | 河南师范大学 | Preparation method of platelet aggregation inhibitor ticagrelor |
| CN115181101A (en) * | 2022-06-01 | 2022-10-14 | 浙江东亚药业股份有限公司 | Preparation method of ticagrelor synthesis intermediate |
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| CN104140425A (en) * | 2013-05-06 | 2014-11-12 | 上海科胜药物研发有限公司 | Method of preparing antiplatelet aggregation medicine ticagrelor |
| CN104250251B (en) * | 2013-06-25 | 2017-05-17 | 上海京新生物医药有限公司 | Preparation method for ticagrelor |
| WO2016030704A1 (en) * | 2014-08-30 | 2016-03-03 | Cipla Limited | Solid form of intermediate of ticagrelor |
| WO2016128996A2 (en) * | 2015-02-14 | 2016-08-18 | Strides Shasun Limited | An improved process for preparation of ticagrelor and intermediates thereof |
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