WO2019127294A1 - 一种纯化替格瑞洛的方法 - Google Patents

一种纯化替格瑞洛的方法 Download PDF

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WO2019127294A1
WO2019127294A1 PCT/CN2017/119614 CN2017119614W WO2019127294A1 WO 2019127294 A1 WO2019127294 A1 WO 2019127294A1 CN 2017119614 W CN2017119614 W CN 2017119614W WO 2019127294 A1 WO2019127294 A1 WO 2019127294A1
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ticagrelor
temperature
tertiary amine
isooctane
crude
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PCT/CN2017/119614
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English (en)
French (fr)
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屠勇军
朱国荣
陈云华
周猛
王波
王臻
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浙江天宇药业股份有限公司
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Priority to PCT/CN2017/119614 priority Critical patent/WO2019127294A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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  • the invention relates to the field of medicine and chemical industry, and in particular to a method for purifying ticagrelor.
  • the final step in the synthesis of ticagrelor disclosed in the patents CN1334816A, CN1432017A, WO2011017108 or WO2012138981, etc. is to remove the acetone fork protection under acidic conditions (hydrochloric acid/methanol solution) to obtain ticagrelor. Since the ticagrelor molecule contains six chiral centers and contains a plurality of highly reactive functional groups such as a hydroxyl group, a nitrogen heterocycle, and a thiol group, a side reaction may occur in these positions to generate a corresponding impurity, which is introduced into the georg Ruiluo. The prior art does not address the study and control of impurities in ticagrelor.
  • Patent CN106243108A discloses a preparation method of high-purity ticagrelor, which dissolves ticagrelor in ethyl acetate solvent, adds n-hexane to precipitate a solid, separates the precipitated solid, and dissolves the obtained solid.
  • dimethylformamide the anti-solvent methyl tert-butyl ether is added to precipitate high-purity ticagrelor.
  • the solvent has many kinds of solvents selected, and the residual solvent is difficult to control, especially the residue of high-boiling solvent dimethylformamide. It is not easy to remove, and the process cannot obtain a purity of more than 99.90% ticagrelor.
  • Patent CN106866677A discloses a method for purifying ticagrelor, which dissolves ticagrelor in ethyl acetate and slowly crystallizes at a low temperature in the range of -10 to -25 ° C, although crystallized by a single solvent. Still, it is still impossible to obtain a tigrisin product with a purity greater than 99.90%. The crystallization temperature is too low, and it is difficult to ensure the stability of the process by amplifying the production.
  • the patent CN1817883 discloses four crystals of ticagrelor and the preparation method thereof, and the four crystals are respectively named as crystals of type I, II, III and IV, and have the following diffraction angles in the powder X-ray diffraction diagram ( Special high-intensity peaks of 2 ⁇ ):
  • Type I 5.3 ⁇ 0.1 °, 20.1 ⁇ 0.1 °, 20.7 ⁇ 0.1 °, 21.0 ⁇ 0.1 ° and 21.3 ⁇ 0.1 °;
  • Type II 5.5 ⁇ 0.1 °, 6.8 ⁇ 0.1 °, 10.6 ⁇ 0.1 °, 13.5 ⁇ 0.1 ° and 18.3 ⁇ 0.1 °;
  • Type III 14.0 ⁇ 0.1 °, 17.4 ⁇ 0.1 °, 18.4 ⁇ 0.1 °, 21.4 ⁇ 0.1 ° and 24.1 ⁇ 0.1 °;
  • Type IV 4.9 ⁇ 0.1 °, 9.2 ⁇ 0.1 °, 11.6 ⁇ 0.1 °, 15.6 ⁇ 0.1 ° and 16.4 ⁇ 0.1 °.
  • type II crystals have the best stability, and are also crystalline forms of the listed drugs of the original research company, but the crystallized solvent chloroform of type II crystals is highly toxic, and the solvent residue is not easy to reach the control standard of the drug substance.
  • the invention provides a method for purifying ticagrelor.
  • the crude ticagrelor is dissolved in an acetate solvent, and then an isooctane antisolvent is added thereto for crystallization, separation and drying. After purification, ticagrelor was obtained.
  • the crude ticagrelor, the acetate solvent and the alkyl tertiary amine are mixed under inert gas protection.
  • the alkyl tertiary amine is selected from the group consisting of triethylamine, diisopropylethylamine, N-methylmorpholine or N-methylpiperidine.
  • the acetate solvent is selected from the group consisting of ethyl acetate, isopropyl acetate or tert-butyl acetate.
  • the mass ratio of the crude ticagrelor, the acetate solvent, the isooctane and the alkyl tertiary amine is 1: (5.0 to 10): (5.0 to 10): (0.001 to 0.01); preferably 1:9. :10:0.005.
  • the temperature of the feed liquid is raised from 60 to 70 ° C to 75 to 80 ° C, and then the temperature is lowered to 0 to 5 ° C for crystallization; preferably, the temperature of the feed liquid is raised to 75-80 ° C and then the temperature is maintained 1 to 2 After a few hours, the temperature is lowered and crystallized.
  • the cooling rate is 5 to 10 ° C / h.
  • the drying is carried out in a vacuum drying oven at a drying temperature of 45 to 55 °C.
  • the ticagrelor obtained after purification is the crystalline form of ticagrelor II.
  • the crude purity of ticagrelor used was between 98.5% and 99.0%.
  • the DSC, XRD pattern of the ticagrelor refined product obtained by the method of the present invention is consistent with the crystal form disclosed in CN1817883.
  • the invention improves the stability of the liquid in the crystallization process by adding a trace amount of the tertiary alkylamine, effectively controls the content of the related impurities, and obtains the ticagrelor product with a purity of 99.90% or more.
  • the present invention can stably obtain ticagrelor type II crystals under the conditions of ensuring high purity of ticagrelor.
  • Figure 1 is a liquid chromatogram of ticagrelor prepared in the reference example.
  • Example 2 is a liquid chromatogram of ticagrelor prepared in Example 1.
  • Example 3 is a liquid chromatogram of ticagrelor prepared in Example 2.
  • Example 4 is a liquid chromatogram of ticagrelor prepared in Example 3.
  • Figure 5 is a liquid chromatogram of ticagrelor prepared in Example 4.
  • Figure 6 is an XRD spectrum of ticagrelor prepared in Example 1.
  • Figure 7 is a DSC chart of ticagrelor prepared in Example 1.
  • Figure 8 is an XRD spectrum of ticagrelor prepared in Example 2.
  • Figure 9 is a DSC spectrum of ticagrelor prepared in Example 2.
  • Figure 10 is an XRD spectrum of ticagrelor prepared in Example 3.
  • Figure 11 is a DSC spectrum of ticagrelor prepared in Example 3.
  • Figure 12 is an XRD spectrum of ticagrelor prepared in Example 4.
  • Figure 13 is a DSC chart of ticagrelor prepared in Example 4.
  • XRD pattern PANalytical "X'pert Powder” powder X-ray diffractometer, copper palladium, incident wavelength: 1.54 angstroms.
  • DSC map METTLER TOLEDO differential scanning calorimeter, sample loading 5.00mg, heating rate 10.00K / min
  • Liquid chromatogram Agilent 1260 high performance liquid chromatography.
  • Reference Example Nitrogen protection, 10 g of ticagrelor crude (prepared from tigrisin crude according to the method disclosed in WO0192263, purity 98.7%), 90 g of ethyl acetate were added to a four-necked flask, and the feed was completed, and the temperature was raised to the feed liquid. The temperature is 60-70 ° C, and the crude product is completely dissolved. The temperature was controlled at 60 to 70 ° C, 100 g of isooctane was slowly added dropwise over 1 to 2 hours, and the temperature of the liquid was raised to 75 to 80 ° C for 2 hours.
  • FIG. 1 is a liquid chromatogram of ticagrelor prepared in the reference example.
  • the HPLC related data is as follows:
  • Example 1 Nitrogen protection, 10 g of ticagrelor crude (prepared from tigrelopin according to the method disclosed in WO 01022263, purity 98.8%), 90 g of ethyl acetate, 10 mg of triethylamine were separately added to a four-necked flask. After the feeding is completed, the temperature is raised to a temperature of 60 to 70 ° C, and the crude product is completely dissolved. The temperature was controlled at 60 to 70 ° C, 100 g of isooctane was slowly added dropwise over 1 to 2 hours, and the temperature of the solution was raised to 75 to 80 ° C for 2 hours.
  • Example 1 disclosed in CN1817883 5.48° 5.5 ⁇ 0.1° 6.70° 6.8 ⁇ 0.1° 10.56° 10.6 ⁇ 0.1° 13.41° 13.5 ⁇ 0.1° 14.76° 14.9 ⁇ 0.1° 18.26° 18.3 ⁇ 0.1° 19.06° 19.2 ⁇ 0.1°
  • Example 2 Nitrogen protection, 10 g of ticagrelor crude (prepared from tigrisin crude according to the method disclosed in WO0192263, purity 98.9%), 90 g of ethyl acetate, 50 mg of diisopropyl B, respectively, were placed in a four-necked flask. amine. After the feeding is completed, the temperature is raised to a temperature of 60 to 70 ° C, and the crude product is completely dissolved. The temperature was controlled at 60 to 70 ° C, 100 g of isooctane was slowly added dropwise over 1 to 2 hours, and the temperature of the liquid was raised to 75 to 80 ° C for 2 hours.
  • Example 3 Nitrogen protection, 10 g of ticagrelor crude (prepared from tigrelopin according to the method disclosed in WO0192263, purity 98.6%), 90 g of isopropyl acetate, 50 mg of N-methyl, respectively, in a four-necked flask. Porphyrin. After the feeding is completed, the temperature is raised to a temperature of 60 to 70 ° C, and the crude product is completely dissolved. The temperature was controlled at 60 to 70 ° C, 100 g of isooctane was slowly added dropwise over 1 to 2 hours, and the temperature of the liquid was raised to 75 to 80 ° C for 2 hours.
  • Example 3 disclosed in CN1817883 5.38° 5.5 ⁇ 0.1°
  • Example 4 Nitrogen protection, 10 g of ticagrelor crude product (the crude product of ticagrelor was prepared according to the method disclosed in WO0192263, purity 98.6%), 90 g of t-butyl acetate, 50 mg of N-methyl, respectively, in a four-necked flask. Piperidine. After the feeding is completed, the temperature is raised to a temperature of 60 to 70 ° C, and the crude product is completely dissolved. The temperature was controlled at 60 to 70 ° C, 100 g of isooctane was slowly added dropwise over 1 to 2 hours, and the temperature of the liquid was raised to 75 to 80 ° C for 2 hours.
  • FIG. 5 is a liquid chromatogram of ticagrelor prepared in Example 4.
  • Figure 12 is an XRD spectrum of ticagrelor prepared in Example 4.
  • Figure 13 is a DSC chart of ticagrelor prepared in Example 4, wherein the initial melting temperature was 137.89 ° C and the peak temperature was 142.14 ° C.
  • the HPLC related data is as follows:
  • Example 4 disclosed in CN1817883 5.41° 5.5 ⁇ 0.1° 6.71° 6.8 ⁇ 0.1° 10.56° 10.6 ⁇ 0.1° 13.42° 13.5 ⁇ 0.1° 14.79° 14.9 ⁇ 0.1° 18.24° 18.3 ⁇ 0.1° 19.10° 19.2 ⁇ 0.1° 22.60° 22.7 ⁇ 0.1 ° 24.21° 24.3 ⁇ 0.1° 26.97° 27.1 ⁇ 0.1°

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Abstract

本发明提供了一种纯化替格瑞洛的方法，在烷基叔胺存在下，将替格瑞洛粗品溶于乙酸酯类溶剂，随后在其中加入异辛烷反溶剂进行结晶，分离、干燥后得到纯化后的替格瑞洛。本发明通过添加微量烷基叔胺在替格瑞洛的结晶料液中，提高了该料液在结晶过程中的稳定性，有效控制了有关杂质的含量，可以获得纯度99.90％以上的替格瑞洛成品；并在保证替格瑞洛高纯度的条件下可以稳定地获得替格瑞洛II型结晶。

Description

一种纯化替格瑞洛的方法 技术领域
本发明涉及医药化工领域，具体涉及一种纯化替格瑞洛的方法。
背景技术
替格瑞洛(Ticagrelor)，化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙氨基]-5-(硫丙基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1,2-二醇，结构式如式1所示：
Figure PCTCN2017119614-appb-000001
替格瑞洛(Ticagrelor)是由阿斯利康公司开发的一种新型的、具有选择性的小分子抗凝血药。该药能可逆性地作用于血管平滑肌细胞上的嘌呤2受体亚型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。
专利CN1334816A、CN1432017A、WO2011017108或WO2012138981等公开的替格瑞洛的合成工艺中最后一步反应均为酸性条件下(盐酸/甲醇溶液)脱除丙酮叉保护得到替格瑞洛。由于替格瑞洛分子中含有6个手性中心，且含有多个羟基、氮杂环、巯基等高反应活性的官能团，因此这些位置可能会发生副反应而产生相应杂质，进而引入到替格瑞洛中。现有技术未涉及替格瑞洛中的杂质研究及控制。
专利CN106243108A公开了一种高纯度的替格瑞洛的制备方法，该方法将替格瑞洛溶于乙酸乙酯溶剂中，加入正己烷析出固体，分离析出的固体，再将所得的固体溶于二甲基甲酰胺中，加入反溶剂甲基叔丁基醚析出高纯度替格瑞洛，该专利所选溶剂种类较多，残留溶剂不易控制，尤其是高沸点溶剂二甲基甲酰胺的残留不易去除，且该工艺无法获得纯度大于99.90％替格瑞洛精制品。
专利CN106866677A公开了一种替格瑞洛的纯化方法，该方法将替格瑞洛溶于乙酸乙酯中，冷却至-10到-25℃的温度范围内低温下缓慢结晶，尽管采用单 一溶剂结晶，仍无法获得纯度大于99.90％替格瑞洛精制品。结晶温度过低，放大生产不易保证工艺的稳定性。
此外，专利CN1817883公开了替格瑞洛的四种结晶及其制备方法，四种结晶分别命名为Ⅰ、Ⅱ、Ⅲ、Ⅳ型结晶，在粉末X-射线衍射图中，分别具有以下衍射角度(2θ)的特殊高强度峰：
Ⅰ型：5.3±0.1°、20.1±0.1°、20.7±0.1°、21.0±0.1°和21.3±0.1°；
Ⅱ型：5.5±0.1°、6.8±0.1°、10.6±0.1°、13.5±0.1°和18.3±0.1°；
Ⅲ型：14.0±0.1°、17.4±0.1°、18.4±0.1°、21.4±0.1°和24.1±0.1°；
Ⅳ型：4.9±0.1°、9.2±0.1°、11.6±0.1°、15.6±0.1°和16.4±0.1°。
在上述晶型中，Ⅱ型结晶稳定性最佳，同时也为原研公司上市药品所具有晶型，但Ⅱ型结晶的结晶溶剂氯仿毒性较大，溶剂残留不易达到原料药的控制标准。
为了克服现有技术的不足，需进一步研究替格瑞洛的纯化工艺，有效控制其中的杂质以获得纯度大于99.90％的替格瑞洛，同时研发一种在保证高纯度的条件下稳定地获得II晶型替格瑞洛的方法。
发明内容
本发明的目的在于针对现有技术中存在的上述不足，提供一种纯化替格瑞洛的方法，提供纯度大于99.90％的II晶型替格瑞洛。
本发明提供的一种纯化替格瑞洛的方法，在烷基叔胺存在下，将替格瑞洛粗品溶于乙酸酯类溶剂，随后在其中加入异辛烷反溶剂进行结晶，分离、干燥后得到纯化后的替格瑞洛。
替格瑞洛粗品、乙酸酯类溶剂和烷基叔胺在惰性气体保护下混合。
所述的烷基叔胺选自三乙胺、二异丙基乙胺、N-甲基吗啉或N-甲基哌啶。
所述的乙酸酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯。
所述的替格瑞洛粗品、乙酸酯类溶剂、异辛烷和烷基叔胺的质量比为1:(5.0～10):(5.0～10):(0.001～0.01)；优选1:9:10:0.005。
将替格瑞洛粗品、乙酸酯类溶剂及烷基叔胺混合，并升温至60～70℃使所述替格瑞洛粗品溶清；优选地，在粗品完全溶清之后，保持在温度60～70℃下滴加入异辛烷；更优选地，在1-2小时内滴加完毕异辛烷。
加入异辛烷之后将料液温度从60～70℃升高至75～80℃，然后降温至0～5℃析晶；优选地，料液温度升高至75-80℃后保温1～2小时后再降温析晶。
所述降温的速度为5～10℃/h。
所述干燥在真空干燥箱内进行，干燥温度为45～55℃。
纯化后得到的替格瑞洛为替格瑞洛的II晶型。
所采用的替格瑞洛的粗品纯度在98.5％～99.0％。
本发明的方法获得的替格瑞洛精制品的DSC，XRD图谱与CN1817883公开的II晶型相一致。
本发明提供的纯化方法的有益效果在于：
(1)本发明通过添加微量烷基叔胺，提高了料液在结晶过程中的稳定性，有效控制了有关杂质的含量，可以获得纯度99.90％以上的替格瑞洛成品。
(2)本发明在保证替格瑞洛高纯度的条件下可以稳定地获得替格瑞洛II型结晶。
附图说明
图1为参考例所制备的替格瑞洛的液相色谱图。
图2为实施例1所制备的替格瑞洛的液相色谱图。
图3为实施例2所制备的替格瑞洛的液相色谱图。
图4为实施例3所制备的替格瑞洛的液相色谱图。
图5为实施例4所制备的替格瑞洛的液相色谱图。
图6为实施例1所制备的替格瑞洛的XRD谱图。
图7为实施例1所制备的替格瑞洛的DSC谱图。
图8为实施例2所制备的替格瑞洛的XRD谱图。
图9为实施例2所制备的替格瑞洛的DSC谱图.
图10为实施例3所制备的替格瑞洛的XRD谱图。
图11为实施例3所制备的替格瑞洛的DSC谱图
图12为实施例4所制备的替格瑞洛的XRD谱图。
图13为实施例4所制备的替格瑞洛的DSC谱图。
具体实施方式
为使本领域内的技术人员更好地理解本发明的技术方案，下面结合具体实施例及附图对本发明作进一步说明。
以下为本发明的操作实例
XRD图谱：帕纳科“X'pert Powder”粉末X射线衍射仪，铜钯，入射波长：1.54埃。
DSC图谱：梅特勒-托利多差示扫描量热仪，样品装载量5.00mg，升温速率10.00K/min
液相色谱图：Agilent 1260高效液相色谱仪。
参考例：氮气保护，在四口烧瓶内分别加入10g替格瑞洛粗品(替格瑞洛粗品按照专利WO0192263公开的方法制备，纯度98.7％)、90g乙酸乙酯，投料完毕，升温至料液温度60～70℃，粗品完全溶清。控制温度60～70℃，1～2小时内缓慢滴加100g异辛烷，滴毕，将料液温度升至75～80℃，保温2小时。保温完毕，以5～10℃/h的速度缓慢降温至0～5℃析晶，将所得晶体过滤后，放入真空干燥箱内，升温至45～55℃，减压干燥18小时。得替格瑞洛精制品9.5g,收率95％。图1为参考例所制备的替格瑞洛的液相色谱图。HPLC相关数据如下：
Figure PCTCN2017119614-appb-000002
实施例1：氮气保护，在四口烧瓶内分别加入10g替格瑞洛粗品(替格瑞洛粗品按照专利WO0192263公开的方法制备，纯度98.8％)、90g乙酸乙酯、10mg三乙胺。投料完毕，升温至料液温度60～70℃，粗品完全溶清。控制温度60～70℃，1～2小时内缓慢滴加100g异辛烷，滴毕，将料液温度升至75～80℃，保 温2小时。保温完毕，以5～10℃/h的速度缓慢降温至0～5℃析晶，将所得晶体过滤后，放入真空干燥箱内，升温至45～55℃，减压干燥18小时。得替格瑞洛精制品9.3g，收率93％。图2为实施例1所制备的替格瑞洛的液相色谱图。图6为实施例1所制备的替格瑞洛的XRD谱图。图7为实施例1所制备的替格瑞洛的DSC谱图，其中起始熔融温度为137.94℃，峰值温度为142.06℃。HPLC相关数据如下：
Figure PCTCN2017119614-appb-000003
表1实施例1所得晶型XRD图谱中主要2θ衍射角对比表
实施例1 CN1817883公开的II晶型
5.48° 5.5±0.1°
6.70° 6.8±0.1°
10.56° 10.6±0.1°
13.41° 13.5±0.1°
14.76° 14.9±0.1°
18.26° 18.3±0.1°
19.06° 19.2±0.1°
22.57° 22.7±0.1°
24.15° 24.3±0.1°
26.95° 27.1±0.1°
实施例2：氮气保护，在四口烧瓶内分别加入10g替格瑞洛粗品(替格瑞洛粗品按照专利WO0192263公开的方法制备，纯度98.9％)、90g乙酸乙酯、50mg二异丙基乙胺。投料完毕，升温至料液温度60～70℃，粗品完全溶清。控制温度60～70℃，1～2小时内缓慢滴加100g异辛烷，滴毕，将料液温度升至75～80℃，保温2小时。保温完毕，以5～10℃/h的速度缓慢降温至0～5℃析晶，将所得晶体过滤后，放入真空干燥箱内，升温至45～55℃，减压干燥18小时。得替格瑞洛精制品9.2g，收率92％。图3为实施例2所制备的替格瑞洛的液相色谱图。图8为实施例2所制备的替格瑞洛的XRD谱图。图9为实施例2所制备的替格瑞洛的DSC谱图，其中起始熔融温度为139.00℃，峰值温度为142.47℃。HPLC相关数据如下：
Figure PCTCN2017119614-appb-000004
表2实施例2所得晶型XRD图谱中主要2θ衍射角对比表
实施例2 CN1817883公开的II晶型
5.44° 5.5±0.1°
6.70° 6.8±0.1°
10.54° 10.6±0.1°
13.40° 13.5±0.1°
14.78° 14.9±0.1°
18.23° 18.3±0.1°
19.06° 19.2±0.1°
22.55° 22.7±0.1°
24.18° 24.3±0.1°
26.93° 27.1±0.1°
实施例3：氮气保护，在四口烧瓶内分别加入10g替格瑞洛粗品(替格瑞洛粗品按照专利WO0192263公开的方法制备，纯度98.6％)、90g乙酸异丙酯、50mgN-甲基吗啉。投料完毕，升温至料液温度60～70℃，粗品完全溶清。控制温度60～70℃，1～2小时内缓慢滴加100g异辛烷，滴毕，将料液温度升至75～80℃，保温2小时。保温完毕，以5～10℃/h的速度缓慢降温至0～5℃析晶，将所得晶体过滤后，放入真空干燥箱内，升温至45～55℃，减压干燥18小时。得替格瑞洛精制品9.1g，收率91％。图4为实施例3所制备的替格瑞洛的液相色谱图。图10为实施例3所制备的替格瑞洛的XRD谱图。图11为实施例3所制备的替格瑞洛的DSC谱图，其中起始熔融温度为137.73℃，峰值温度为142.42℃。HPLC相关数据如下：
Figure PCTCN2017119614-appb-000005
表3实施例3所得晶型XRD图谱中主要2θ衍射角对比表
实施例3 CN1817883公开的II晶型
5.38° 5.5±0.1°
6.70° 6.8±0.1°
10.55° 10.6±0.1°
13.41° 13.5±0.1°
14.76° 14.9±0.1°
18.26° 18.3±0.1°
19.06° 19.2±0.1°
22.57° 22.7±0.1°
24.15° 24.3±0.1°
26.95° 27.1±0.1°
实施例4：氮气保护，在四口烧瓶内分别加入10g替格瑞洛粗品(替格瑞洛粗品按照专利WO0192263公开的方法制备，纯度98.6％)、90g乙酸叔丁酯、50mg N-甲基哌啶。投料完毕，升温至料液温度60～70℃，粗品完全溶清。控制温度60～70℃，1～2小时内缓慢滴加100g异辛烷，滴毕，将料液温度升至75～80℃，保温2小时。保温完毕，以5～10℃/h的速度缓慢降温至0～5℃析晶，将所得晶体过滤后，放入真空干燥箱内，升温至45～55℃，减压干燥18小时。得替格瑞洛精制品9.0g，收率90％。图5为实施例4所制备的替格瑞洛的液相色谱图。图12为实施例4所制备的替格瑞洛的XRD谱图。图13为实施例4所制备的替格瑞洛的DSC谱图，其中起始熔融温度为137.89℃，峰值温度为142.14℃。HPLC相关数据如下：
Figure PCTCN2017119614-appb-000006
表4实施例4所得晶型XRD图谱中主要2θ衍射角对比表
实施例4 CN1817883公开的II晶型
5.41° 5.5±0.1°
6.71° 6.8±0.1°
10.56° 10.6±0.1°
13.42° 13.5±0.1°
14.79° 14.9±0.1°
18.24° 18.3±0.1°
19.10° 19.2±0.1°
22.60° 22.7±0.1°
24.21° 24.3±0.1°
26.97° 27.1±0.1°
表5不同结晶工艺下替格瑞洛主要杂质含量及晶型统计表
序号 晶型 纯度 RRT:0.408 RRT:0.641 RRT:0.705 RRT:0.864 RRT:0.947 RRT:1.362 RRT:1.07
参考例 --- 99.469％ 0.229％ 0.089％ 0.006％ 0.006％ 0.005％ 0.010％ 0.016％
实施例1 II型 99.913％ 0.002％ 未检出 0.002％ 0.001％ 0.002％ 0.007％ 0.013％
实施例2 II型 99.935％ 0.005％ 0.022％ 未检出 未检出 0.006％ 0.003％ 0.010％
实施例3 II型 99.943％ 0.005％ 0.009％ 未检出 未检出 0.007％ 0.006％ 0.010％
实施例4 II型 99.904％ 0.011％ 0.009％ 未检出 未检出 0.009％ 0.009％ 0.027％
注：其中RRT表示相对保留时间。

Claims (11)

  1. 一种纯化替格瑞洛的方法，其特征在于，在烷基叔胺存在下，将替格瑞洛粗品溶于乙酸酯类溶剂，随后在其中加入异辛烷反溶剂进行结晶，分离、干燥后得到纯化后的替格瑞洛。
  2. 根据权利要求1所述的方法，其特征在于，替格瑞洛粗品、乙酸酯类溶剂和烷基叔胺在惰性气体保护下混合。
  3. 根据权利要求1或2所述的方法，其特征在于，所述的烷基叔胺选自三乙胺、二异丙基乙胺、N-甲基吗啉或N-甲基哌啶。
  4. 根据权利要求1或2所述的方法，其特征在于，所述的乙酸酯类溶剂选自乙酸乙酯、乙酸异丙酯或乙酸叔丁酯。
  5. 根据权利要求1至4任一项所述的方法，其特征在于，所述的替格瑞洛粗品、乙酸酯类溶剂、异辛烷和烷基叔胺的质量比为1:(5.0～10):(5.0～10):(0.001～0.01)；优选1:9:10:0.005。
  6. 根据权利要求1至5任一项所述的方法，其特征在于，将替格瑞洛粗品、乙酸酯类溶剂及烷基叔胺混合，并升温至60～70℃使所述替格瑞洛粗品溶清；优选地，在粗品完全溶清之后，保持在温度60～70℃下滴加入异辛烷；更优选地，在1-2小时内滴加完毕异辛烷。
  7. 根据权利要求6所述的方法，其特征在于，加入异辛烷之后将料液温度从60～70℃升高至75～80℃，然后降温至0～5℃析晶；优选地，料液温度升高至75-80℃后保温1～2小时后再降温析晶。
  8. 根据权利要求7所述的方法，其特征在于，所述降温的速度为5～10℃/h。
  9. 根据权利要求1至8任一项所述的方法，其特征在于，所述干燥在真空干燥箱内进行，干燥温度为45～55℃。
  10. 根据权利要求1至9任一项所述的方法，其特征在于，纯化后得到的替 格瑞洛为替格瑞洛的II晶型。
  11. 根据权利要求1至10任一项所述的方法，其特征在于，所采用的替格瑞洛的粗品纯度在98.5％～99.0％。
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WO2015162537A1 (en) * 2014-04-23 2015-10-29 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
CN106243108A (zh) * 2015-06-03 2016-12-21 四川海思科制药有限公司 一种高纯度的替格瑞洛及其制备方法
CN106866677A (zh) * 2017-02-17 2017-06-20 陕西必康制药集团控股有限公司 替卡格雷的纯化以及制备方法

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WO2015162537A1 (en) * 2014-04-23 2015-10-29 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Process for preparation of ticagrelor
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CN106866677A (zh) * 2017-02-17 2017-06-20 陕西必康制药集团控股有限公司 替卡格雷的纯化以及制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110642862A (zh) * 2019-10-29 2020-01-03 株洲千金药业股份有限公司 一种替格瑞洛乙酯化杂质的制备方法

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