CN105801583A - Purification method of ticagrelor - Google Patents

Purification method of ticagrelor Download PDF

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CN105801583A
CN105801583A CN201410844859.0A CN201410844859A CN105801583A CN 105801583 A CN105801583 A CN 105801583A CN 201410844859 A CN201410844859 A CN 201410844859A CN 105801583 A CN105801583 A CN 105801583A
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ticagrelor
solvent
purification
method
weight
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CN201410844859.0A
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乔德水
鹿婷
陈�胜
高雪芹
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徐州万邦金桥制药有限公司
上海复星医药(集团)股份有限公司
江苏万邦生化医药股份有限公司
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Abstract

Belonging to the technical field of pharmaceutical industry, the invention relates to the preparation field of ticagrelor, in particular to a purification method of ticagrelor. Directed at the purification blank of ticagrelor at present, especially the blank of purification technology for the product obtained by a preparation method involved in the invention, the invention discloses a purification method of ticagrelor. The method consists of the steps of: dissolving a ticagrelor crude product in a first solvent, performing hot filtration to remove solid therein, and adding a second solvent into the filtrate while it is hot, conducting cooling till a lot of solid precipitate, carrying out low temperature heat preservation until no solid precipitate, and carrying out filtration and drying, thus obtaining a ticagrelor pure product. The purification method disclosed by the invention can decrease the total impurity content of the product from 4.5% to less than 0.2%, the purified ticagrelor has purity of more than 99.75%, and the biggest individual impurity is below 0.1%.

Description

一种替格瑞洛的纯化方法 Alternatively one kind of purification method ticagrelor

技术领域 FIELD

[0001] 本发明涉及替格瑞洛的制备领域,特别是涉及替格瑞洛的纯化方法,属于医药工业技术领域。 [0001] The present invention relates to the field of preparing ticagrelor, in particular, relates to a method for purifying ticagrelor belongs to the technical field of pharmaceutical industry.

[0002] [0002]

背景技术 Background technique

[0003] 替格瑞洛(Ticagrelor,亦称替卡格雷)属于环戊基三唑并啼啶类化合物, 化学名为(15; 25; 55)-3-[7-[(1《25)-2-(3, 4-二氟苯基)环丙氨基]_5_(硫丙基)-3f [1,2,3]三唑[4,5-J]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1,2-二醇,分子式:C23H2SF2N604S,CAS 号:274693-27-5,结构式如下: [0003] ticagrelor (Ticagrelor, also known as ticagrelor) belonging cyclopentyl-triazolo cry piperidine compound, the chemical name (15; 25; 55) -3- [7 - [(1 "25) 2- (3,4-difluorophenyl) cyclopropylamino] _5_ (sulfopropyl) -3f [1,2,3] triazolo [4,5-J] pyrimidin-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol, molecular formula: C23H2SF2N604S, number CAS: 274693-27-5, the following structural formula:

Figure CN105801583AD00031

替格瑞洛是由美国阿斯利康(AstraZeneca)公司研发的一种新型的、具有选择性的小分子抗凝血药。 Ticagrelor is a novel, selective small molecule by the US AstraZeneca (AstraZeneca) research and development of anticoagulants. 该药能可逆性地作用于血管平滑肌细胞(VSMC)上的嘌呤2受体(purinoc印tor2, P2)亚型P2Y12,对ADP引起的血小板聚集有明显的抑制作用,且口服使用后起效迅速,因此能有效改善急性冠心病患者的症状。 Reversible drug can act on vascular smooth muscle cells (of VSMC) purine 2 receptor (purinoc printing tor2, P2) the P2Y12 subtype, significantly inhibited platelet aggregation induced by ADP, and rapid onset of action for oral use and thus can effectively improve the symptoms of patients with acute coronary artery disease. 而因替格瑞洛的抗血小板作用是可逆的,其对于那些需要在先期进行抗凝治疗后再行手术的病人尤为适用。 The result for the antiplatelet effect of ticagrelor is reversible, it is particularly suitable for those who need anticoagulant therapy in patients early after surgery of. 替格瑞洛相比其竞争者氯吡格雷最引人注意的优势是可以显著降低心血管源性和所有原因引起的死亡。 Ticagrelor compared to clopidogrel its competitors the most notable advantage is significantly reduced mortality from cardiovascular and all causes. 是一种前景广阔的抗凝血药。 It is a promising anti-clotting drugs.

[0004] 作为一种替代地替格瑞洛的制备方法,本发明的发明人给出了一种全新的替格瑞洛的制备方法,并已经递交了相关的专利申请,受理号CN201310527897. 9,该方法合成路线如下: [0004] As an alternative method for the preparation of ticagrelor, the present invention presents a new method for the preparation of ticagrelor, and has filed a related patent application, acceptance No. CN201310527897. 9 the method of scheme is as follows:

Figure CN105801583AD00041

通过该方法制备得到的产品中总杂含量在4. 5%。 The total content of the product obtained heteroaryl prepared by this method 4.5%. 由于目前现有技术中与本发明中所涉及到的制备方法不同,因此所产生的带入产品中的杂质成分不同。 Different prior art due to the current production method of the present invention is directed to, and therefore into different impurities in the resulting product. 因此,基于这一制备方法,配套形成一种适合的精制纯化工艺,对于工业化生产来说具有重要的意义,但是遗憾地是包括国内外的现有技术与中对于这一部分均没有相关的研究和报道。 Thus, based on this preparation method, supporting the formation of a suitable refining purification process, is of great significance for industrial production, it includes but Unfortunately the prior art and in this portion are domestic and for research and No reported.

[0005] [0005]

发明内容 SUMMARY

[0006] 针对目前替格瑞洛的纯化空白,特别是本发明涉及制备方法所获得产品纯化技术的空白,本发明公开了一种替格瑞洛的纯化方法,包括以下步骤:取替格瑞洛粗品热溶解于第一溶剂中,热过滤去除其中固体,并趁热向滤液中加入第二种溶剂,降温至有大量固体析出时低温保温,至不再有固体析出,过滤、干燥,得到替格瑞洛纯品;所述第一溶剂为二氯甲烷、乙腈、丙酮、甲醇、乙醇、正丁醇或乙酸乙酯中的一种或几种;所述第二溶剂为正己烷、环己烷、戊烷、异辛烷或环戊烷中的一种或几种。 [0006] For the current blank blank ticagrelor for the purification, in particular the present invention relates to a method for the preparation of products obtained by purification techniques, the present invention discloses a method for purifying ticagrelor, comprising the steps of: replace Gray the crude product was dissolved in hot Luo first solvent, wherein the solid removed by hot filtration and hot second solvent was added to the filtrate, the precipitated solid was lowered to a large number of heat at low temperature, until no solid was precipitated, filtered and dried to give ticagrelor pure; the first solvent is dichloromethane, acetonitrile, acetone, methanol, ethanol, n-butanol, or one or more of ethyl acetate; the second solvent is n-hexane, ring one or more of hexane, pentane, isooctane, cyclopentane or in.

[0007] 优选地,所述第一溶剂为乙酸乙酯;所述第二溶剂为正己烷。 [0007] Preferably, the first solvent is ethyl acetate; the second solvent is n-hexane.

[0008] 作为一种优选,本发明还进一步公开了所述第一溶剂重量为替格瑞洛粗品重量的5~10倍,优选为5倍。 [0008] As a preference, the present invention further discloses that the first solvent is 5 to 10 times the weight of crude ticagrelor by weight, preferably 5 times.

[0009] 同时,本发明还优选公开所述第二溶剂重量为第一溶剂重量的1~5倍,更为优选地为2倍。 [0009] Meanwhile, the present invention is disclosed further preferred second solvent is 1 to 5 times by weight of the first solvent by weight, more preferably 2-fold.

[0010] 同时,本发明还公开了所述低温为25°c以下,优选地这一温度为10°C~15°C。 [0010] Meanwhile, the present invention also discloses a low temperature of 25 ° c or less, preferably this temperature is 10 ° C ~ 15 ° C. 低温保温时间优选为0. 5~2小时,特别优选地保温时间为1小时。 Low temperature holding time is preferably 0.5 to 2 hours, particularly preferably the incubation time is 1 hour.

[0011] 进一步地,我们还优选所述干燥指40~50°C真空干燥,其中优选为40°C真空干燥, 干燥时间优选为8小时。 [0011] Furthermore, we also preferred that the drying means 40 ~ 50 ° C was dried in vacuo, 40 ° C for preferably wherein vacuum drying, drying time is preferably 8 hours.

[0012] 作为另一技术方案,我们还优选在干燥后还包括有淋洗步骤,所述洗涤液为第一溶剂和第二溶剂的混合溶液,混合质量比为1:1~5,优选地这一混合质量比为1: 2。 [0012] As another aspect, we also preferably further comprises, after the drying step of rinsing, the washing solution is a mixed solution of a first solvent and a second solvent, mixing mass ratio of 1: 1 to 5, preferably the mixing mass ratio of 1: 2.

[0013] 并且,我们还给出一种优选方案,即所述替格瑞洛在30°C ~60°C溶解于第一溶剂中,优选地这一温度为50 °C。 [0013] Further, we give a further preferred embodiment, i.e. the ticagrelor at 30 ° C ~ 60 ° C is dissolved in the first solvent, the temperature is preferably 50 ° C.

[0014] 本发明的发明人经过大量的研究,利用杂质与成品在混合溶剂中的溶解性差异, 对杂质和产品予以分离。 [0014] The inventors of the present invention after extensive research, using the difference in solubility of impurities in the finished mixed solvent, impurities and products to be separated.

[0015] 采用本发明所公开的纯化方法可以将产品中总杂含量由4. 5%降低至0. 2%以下, 经纯化的替格瑞洛纯度在99. 75%以上,最大单杂在0. 1%以下。 [0015] The purification method disclosed in the present invention may be the product of the total heteroatoms content is reduced from 4.5 to 0.2% or less, ticagrelor purified purity above 99.75%, the largest single hetero 0.1% or less.

[0016] 本发明纯化后产品纯度高、纯化工艺中产品流失少,产率高。 [0016] After purification of the present invention is of high purity, less product loss in the purification process, high yields. 纯化方法简单、易于控制操作,纯化成本低,适合于工业化应用推广。 Purification method is simple, easy control, low cost purification, is suitable for industrial application and promotion.

[0017] [0017]

具体实施方式 Detailed ways

[0018] 为进一步理解本发明,下面结合实施对本发明所公开的技术方案进行详细说明, 本发明的保护范围不受以下实施例的限制。 [0018] For a further understanding of the present invention, the following embodiments in conjunction with the technical scheme disclosed in the present invention in detail, the scope of the present invention is not limited to the following embodiments.

[0019] 以下实施例中所述实验方法,如无特殊说明,均为常规方法,所涉及试剂和材料, 如无特殊说明,均为商业途径的市售产品。 [0019] In the following examples the experimental procedure, if no special instructions, are conventional methods, reagents and materials involved, if no special instructions, are commercially marketed products.

[0020] 下述实施例中所用粗品是通过以下方法获得: 根据本发明人此前专利,受理号CN201310527897. 9中介绍的方法制备得到,所得粗品用于该纯化。 The crude was used in Example Embodiment [0020] The following are obtained by the following method: Preparation method of the present invention obtained previously Patent No. CN201310527897 9 receives the presentation according to the obtained crude product was used for the purification.

[0021] 实施例1 将自制的100 g替格瑞洛粗品(HPLC纯度95. 5 %,异构体1. 3 %)与500 g乙酸乙酯,升温至50 °C搅拌溶清。 [0021] Example 1 100 g of ticagrelor homemade crude product (HPLC purity 95.5%, isomer 1.3%) and 500 g of ethyl acetate, warmed to 50 ° C a clear solution and stirred. 热滤,收集滤液,向滤液中加入1000 g正己烷。 Filtered hot, the filtrate was collected, 1000 g of n-hexane was added to the filtrate. 加毕,降温搅拌析晶,直至析出大量白色固体,10 °C~15 °C保温搅拌1 h。 After addition, the cooling crystallization was stirred until a white solid precipitated large, 10 ° C ~ 15 ° C incubation stirred for 1 h. 过滤,滤饼用150 g乙酸乙酯和300 g正己烷混合液淋洗。 Filtered cake was washed with 150 g of ethyl acetate and rinsed with a mixture of 300 g of n-hexane. 40 °C真空干燥8小时,得87 g类白色固体,HPLC纯度达99.89 %,异构体0.003 %;最大单一杂质量0.005 %,总杂质量0.011 %。 40 ° C and dried in vacuo for 8 hours to give 87 g white solid, HPLC purity of 99.89%, 0.003% isomer; largest single impurity of 0.005%, 0.011% total impurities.

[0022] 实施例2 将自制的100 g替格瑞洛粗品(HPLC纯度95. 5 %,异构体1. 3 %)与600 g丙酮,升温至35 °C搅拌溶清。 [0022] Example 2 100 g of ticagrelor homemade crude product (HPLC purity 95.5%, isomer 1.3%) and 600 g of acetone, warmed to 35 ° C a clear solution and stirred. 热滤,收集滤液,向滤液中加入1800 g异辛烷。 Filtered hot, the filtrate was collected, 1800 g of isooctane was added to the filtrate. 加毕,降温搅拌析晶, 直至析出大量白色固体,5 °C~10 °C保温搅拌2 h。 After addition, the cooling crystallization was stirred until a white solid precipitated lot, 5 ° C ~ 10 ° C incubation was stirred 2 h. 过滤,滤饼用200 g丙酮和600 g异辛烷混合液淋洗。 Filtered cake was washed with 200 g of acetone and rinsed with a mixture of 600 g isooctane. 45 °C真空干燥10小时,得83 g类白色固体,HPLC纯度达99. 80 %,异构体0.006 %;最大单一杂质量0.008 %,总杂质量0.020 %。 45 ° C and dried under vacuum for 10 hours to obtain 83 g white solid, HPLC purity of 99.80%, 0.006% isomer; 0.008% largest single impurity, 0.020% total impurities.

[0023] 实施例3 将自制的100 g替格瑞洛粗品(HPLC纯度95. 5 %,异构体1.3 %)与700 g正丁醇,升温至55 °C搅拌溶清。 [0023] 100 g Example 3 The crude homemade ticagrelor (HPLC purity 95.5%, isomer 1.3%) and 700 g of n-butanol, heated to 55 ° C a clear solution and stirred. 热滤,收集滤液,向滤液中加入2800 g正己烷。 Filtered hot, the filtrate was collected, 2800 g of n-hexane was added to the filtrate. 加毕,降温搅拌析晶, 直至析出大量白色固体,15 °C~20 °C保温搅拌2 h。 After addition, the cooling crystallization was stirred until a white solid precipitated large, 15 ° C ~ 20 ° C incubation was stirred 2 h. 过滤,滤饼用230 g正丁醇和920 g 正己烷混合液淋洗。 Filtered cake was washed with 230 g of n-butanol and 920 g of n-hexane mixture is rinsed. 50 °C真空干燥12小时,得83 g类白色固体,HPLC纯度达99. 76 %, 异构体0.008 %;最大单一杂质量0.009 %,总杂质量0.024 %。 50 ° C and dried under vacuum for 12 hours to give 83 g white solid, HPLC purity of 99.76%, 0.008% isomer; 0.009% largest single impurity, 0.024% total impurities.

[0024] 实施例4 将自制的100 g替格瑞洛粗品(HPLC纯度95. 5 %,异构体1.3 %)与800 g二氯甲烷, 升温至40 °C搅拌溶清。 [0024] 100 g Example 4 The crude homemade ticagrelor (HPLC purity 95.5%, isomer 1.3%) and 800 g of methylene chloride, warmed to 40 ° C a clear solution and stirred. 热滤,收集滤液,向滤液中加入800 g环己烷。 Filtered hot, the filtrate was collected, 800 g of cyclohexane was added to the filtrate. 加毕,降温搅拌析晶,直至析出大量白色固体,25 °C保温搅拌1 h。 After addition, the cooling crystallization was stirred until a white solid precipitated large, 25 ° C incubation was stirred for 1 h. 过滤,滤饼用260 g二氯甲烷和260 g环己烷混合液淋洗。 Filtered cake was washed with 260 g of methylene chloride and rinsed with a mixture of 260 g of cyclohexane. 40 °C真空干燥8小时,得84 g类白色固体,HPLC纯度达99. 82 %,异构体0.008 %;最大单一杂质量0.009 %,总杂质量0.018 %。 40 ° C and dried in vacuo for 8 hours to give 84 g white solid, HPLC purity of 99.82%, 0.008% isomer; 0.009% largest single impurity, 0.018% total impurities.

[0025] 实施例5 将自制的100 g替格瑞洛粗品(HPLC纯度95. 5 %,异构体1. 3 %)与1000 g乙腈与甲醇的混合液(质量比1:1),升温至60 °C搅拌溶清。 [0025] 100 g Example 5 made ticagrelor crude (HPLC purity 95.5%, isomer 1.3%) with a mixture of 1000 g (mass ratio 1: 1) acetonitrile and methanol, warmed 60 ° C to a clear solution and stirred. 热滤,收集滤液,向滤液中加入1000 g环己烷。 Filtered hot, the filtrate was collected, 1000 g of cyclohexane was added to the filtrate. 加毕,降温搅拌析晶,直至析出大量白色固体,25 °C保温搅拌2 h。 After addition, the cooling crystallization was stirred until a white solid precipitated large, 25 ° C incubation stirred for 2 h. 过滤,滤饼用150 g乙腈、150 g甲醇和300 g环己烷混合液淋洗。 Filtered cake was washed with 150 g of acetonitrile, 150 g of methanol and 300 g of cyclohexane mixture rinsed. 45 °C真空干燥10小时,得85 g类白色固体,HPLC纯度达99. 83 %,异构体0.009 %;最大单一杂质量0.009 %,总杂质量0.017 %〇 45 ° C and dried under vacuum for 10 hours to obtain 85 g white solid, HPLC purity of 99.83%, 0.009% isomer; 0.009% largest single impurity, 0.017% total impurities billion

Claims (10)

1. 一种替格瑞洛的纯化方法,其特征是,包括以下步骤:取替格瑞洛粗品热溶解于第一溶剂中,热过滤去除其中固体,并趁热向滤液中加入第二种溶剂,降温至有大量固体析出时低温保温,至不再有固体析出,过滤、干燥,得到替格瑞洛纯品;所述第一溶剂为二氯甲烷、乙腈、丙酮、甲醇、乙醇、正丁醇或乙酸乙酯中的一种或几种;所述第二溶剂为正己烷、环己烷、戊烷、异辛烷或环戊烷中的一种或几种。 CLAIMS 1. A method for the purification of ticagrelor, characterized by comprising the steps of: hot replace ticagrelor crude was dissolved in the first solvent, wherein the solid filtered off hot, and the hot filtrate was added to a second the solvent was cooled to a low temperature when the precipitated solid was incubated, until no solid was precipitated, filtered and dried to give pure ticagrelor; said first solvent is dichloromethane, acetonitrile, acetone, methanol, ethanol, n one or more alcohol or ethyl acetate; the second solvent is n-hexane, cyclohexane, pentane, isooctane, or in one or more cyclopentane.
2. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,所述第一溶剂为乙酸乙酯。 2. The method according to claim ticagrelor for purification of claim 1 wherein said first solvent is ethyl acetate.
3. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,所述第二溶剂为正己烷。 3. The method as claimed in claim ticagrelor for purification of claim 1 wherein the second solvent is n-hexane.
4. 根据权利要求1或2所述的替格瑞洛的纯化方法,其特征是,所述第一溶剂重量为替格瑞洛粗品重量的5~10倍。 4. A method according to claim ticagrelor for purification which is characterized in claim 1 or 2, the weight of the first solvent for 5 to 10 times by weight of crude ticagrelor.
5. 根据权利要求1或3所述的替格瑞洛的纯化方法,其特征是,所述第二溶剂重量为第一溶剂重量的1~5倍。 5. The method as claimed in claim ticagrelor for the purification, characterized in that said or 13, said second solvent is 1 to 5 times the weight of the first weight of the solvent.
6. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,所述低温为25°C以下。 The method for purification according to claim 1 ticagrelor, wherein said low is below 25 ° C.
7. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,所述干燥指40~50°C真空干燥。 7. The method as claimed in claim ticagrelor for purification, characterized in that said drying means according to 1 40 ~ 50 ° C and dried in vacuo.
8. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,干燥后还包括有淋洗步骤,所述洗涤液为第一溶剂和第二溶剂的混合溶液,混合质量比为1:1~5。 8. The method of claim 1 for the purification of ticagrelor, characterized in that, after drying further comprising the step of rinsing, the washing solution is a mixed solution of a first solvent and a second solvent, mixing mass ratio as claimed in claim 1: 1-5.
9. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,所述替格瑞洛在30 °C ~60 °C溶解于第一溶剂中。 9. The method for purification according to claim 1 ticagrelor, characterized in that said ticagrelor at 30 ° C ~ 60 ° C is dissolved in the first solvent.
10. 根据权利要求1所述的替格瑞洛的纯化方法,其特征是,还任选其中的一种或几种优选条件: (1) 所述第一溶剂重量为替格瑞洛粗品重量的5倍; (2) 所述第二溶剂重量为第一溶剂重量的2倍; (3) 所述低温为10°C~15°C ; (4) 所述干燥指40°C真空干燥' (5) 所述洗涤液为第一溶剂和第二溶剂的混合溶液,混合质量比为1:2 ; (6) 所述替格瑞洛在50°C溶解于第一溶剂中。 10. The method for purification according to claim 1 ticagrelor, wherein, further optionally one or more of the preferred conditions wherein: (1) the first solvent is weight by weight crude ticagrelor 5 times; (2) the second solvent is 2 times the weight of the first solvent by weight; (3) the low temperature is 10 ° C ~ 15 ° C; (4) the drying means 40 ° C and dried in vacuo ' (5) the washing liquid is a mixed solution of a first solvent and a second solvent, mixing mass ratio of 1: 2; (6) the ticagrelor 50 ° C and dissolved in a first solvent.
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