替格瑞洛 | 274693-27-5

• 物质功能分类: 原料药 - 血液系统用药 - 抗凝血药及抗血小板药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三唑并嘧啶类
• 中文名称: 替格瑞洛
• 中文别名: 替卡格雷；(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-二氟苯基)环丙基]氨基]-5-丙硫基三唑并[4,5-d]嘧啶-3-基]-5-(2-羟乙氧基)-1,2-环戊二醇
• 英文名称: ticagrelor
• 英文别名: (1S,2S,3R,5S)-3-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol；Brilinta；(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3_,4-difluorophenyl)-cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol；TCG；3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-(1S,2S,3R,5S)-1,2-cyclopentanediol；(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylsulfanyltriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
• CAS: 274693-27-5
• 化学式: C₂₃H₂₈F₂N₆O₄S
• 分子量: 522.576
• InChiKey: OEKWJQXRCDYSHL-FNOIDJSQSA-N

物化性质

• 熔点：
  138-140°C
• 沸点：
  777.6±70.0 °C(Predicted)
• 密度：
  1.67
• 溶解度：
  少许溶于甲醇
• 物理描述：
  Solid
• 颜色/状态：
  Crystalline powder
• 蒸汽压力：
  1.21X10-20 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable under recommended storage conditions.

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  164
• 氢给体数：
  4
• 氢受体数：
  12

ADMET

代谢

替格瑞洛的所有代谢产物的完整结构并未得到很好的定义。替格瑞洛可以在环戊烷环的第5位脱烷基，形成活性物质AR-C124910XX。AR-C124910XX的环戊烷环可以进一步葡萄糖醛酸化，或者连接到硫上的烷基链可以被羟基化。替格瑞洛也可以被葡萄糖醛酸化或羟基化。替格瑞洛还可以N位脱烷基，形成AR-C133913XX，它会被进一步葡萄糖醛酸化或羟基化。

The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated.

来源:DrugBank

代谢

CYP3A4是负责ticagrelor代谢及其主要活性代谢物形成的主要酶。Ticagrelor及其主要活性代谢物是P-糖蛋白的弱底物和抑制剂。活性代谢物的系统暴露量大约是ticagrelor暴露量的30-40%。

CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30-40% of the exposure of ticagrelor.

来源:Hazardous Substances Data Bank (HSDB)

代谢

该药物主要通过细胞色素P-450（CYP）同工酶3A4代谢成一个具有与母药相似的抗血小板活性的活性代谢物。

The drug is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to an active metabolite that has similar antiplatelet activity as the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

替卡格雷是一种可逆性口服P2Y(12)受体拮抗剂，正在开发用于预防急性冠脉综合征患者的血栓事件。本研究调查了6名健康男性受试者在单次口服200毫克(14)C-替卡格雷悬浊液后168小时内替卡格雷的药代动力学、代谢和排泄。... 血浆和粪便中的主要循环成分被鉴定为替卡格雷和AR-C124910XX，而在尿液中，主要成分是代谢物M5 (AR-C133913XX)及其葡萄糖醛酸苷结合物M4。尿液中的未改变替卡格雷和AR-C124910XX的水平<0.05%，表明替卡格雷和AR-C124910XX的肾清除率的重要性较小。个体间变异性在尿液和粪便提取物中都较小，只有小的定量差异。所有10种代谢物都得到了全部或部分的特征，并为替卡格雷提出了一个完整的生物转化途径，其中替卡格雷的羟基乙基侧链的氧化丢失形成AR-C124910XX，第二个氧化途径导致替卡格雷的N-脱烷基化，形成AR-C133913XX。

Ticagrelor is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. The pharmacokinetics, metabolism, and excretion of ticagrelor were investigated over 168 hr in six healthy male subjects receiving a single oral suspension dose of 200 mg of (14)C-ticagrelor. ... Major circulating components in the plasma and feces were identified as ticagrelor and AR-C124910XX, whereas in urine the major components were metabolite M5 (AR-C133913XX) and its glucuronide conjugate M4. Levels of unchanged ticagrelor and AR-C124910XX were <0.05% in the urine, indicating that renal clearance of ticagrelor and AR-C124910XX is of minor importance. Interindividual variability was small in both urine and fecal extracts with only small quantitative differences. All 10 of the metabolites were fully or partially characterized and a full biotransformation pathway was proposed for ticagrelor, in which oxidative loss of the hydroxyethyl side chain from ticagrelor forms AR-C124910XX and a second oxidative pathway leads to N-dealkylation of ticagrelor, forming AR-C133913XX.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：替格瑞洛是一种结晶性粉末。作为药物Brilinta，用于降低急性冠状动脉综合征（ACS）或有心肌梗死（MI）病史的患者的心血管死亡、心肌梗死和中风的发生率。Brilinta还降低了接受ACS治疗支架的患者支架内血栓形成的风险。人类暴露和毒性：过量症状可能包括出血、胃肠道影响（恶心、呕吐和腹泻）和心室停顿。出血是主要风险。动物研究：该药物的急性毒性被认为是低的。小鼠和大鼠单次给药研究结果显示，替格瑞洛通过灌胃给药在剂量大约是推荐人类日剂量的550倍（按mg/kg计算）时能很好地被耐受。在 mice, rats and marmosets 进行了重复给药研究。观察到各物种有亚临床出血迹象。在高剂量下，啮齿类动物的肝脏重量增加。在大鼠中，替格瑞洛在剂量高达60 mg/kg/day（4.6倍于人类治疗暴露量）时对分娩或产后发育没有影响，但在180 mg/kg剂量时会导致幼崽的母体和发育毒性。在器官形成期间给予替格瑞洛对大鼠的胎儿发育没有影响，口服剂量高达100 mg/kg/day（5.1倍于人类治疗暴露量）和兔子的42 mg/kg/day（相当于人类治疗暴露量）。替格瑞洛及其活性代谢物AR-C124910XX在细菌体外试验、体外小鼠淋巴瘤L5178Y TK+/- 3.7.2C细胞和体内大鼠骨髓微核分析中未表现出任何遗传毒性潜力。

IDENTIFICATION AND USE: Ticagrelor is a crystalline powder. As the drug Brilinta, it is indicated to reduce the rate of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction (MI). Brilinta also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose may include bleeding, gastrointestinal effects (nausea, vomiting and diarrhea) and ventricular pauses. Blood loss is the predominant risk. ANIMAL STUDIES: The acute toxicity of the drug is considered low. The results of single dose studies in mice and rats showed that ticagrelor was well tolerated when given orally by gavage at doses approximately 550 times the recommended human daily dose on a mg/kg basis. Repeat-dose studies were conducted in mice, rats and marmosets. Indications of subclinical bleeding were observed across species. Increased liver weight at high doses occurred in rodents. Ticagrelor had no effects on parturition or postnatal development in rats at doses up to 60 mg/kg/day (4.6 times the human therapeutic exposure), but did cause maternal and developmental toxicity in pups at 180 mg/kg. Ticagrelor given during the period of organogenesis had no effect on fetal development at oral doses up to 100 mg/kg/day in rats (5.1 times the human therapeutic exposure) and up to 42 mg/kg/day in rabbits (equivalent to the human therapeutic exposure). Ticagrelor and the active metabolite AR-C124910XX did not demonstrate any genotoxic potential in bacterial in vitro test, in vitro mouse lymphoma L5178Y TK+/- 3.7.2C cell, and in vivo rat bone marrow micronucleus assays.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在几项大型临床试验中，替格瑞洛治疗期间并未与血清酶水平升高有关联，并且没有报告出现临床上明显的肝损伤。尽管有零星报告称在替格瑞洛治疗期间出现了短暂的、轻度的血清酶水平升高，但这些情况都是短暂的并且无症状的。此外，自从上市以来，没有报告与替格瑞洛治疗相关的孤立性临床上明显的肝损伤或黄疸，产品标签中也没有提到肝毒性。另一方面，有几份报告称与横纹肌溶解和血栓性血小板减少性紫癜相关的黄疸和肝损伤，这些是这些严重不良事件的次要效应。因此，替格瑞洛导致的重大肝损伤虽然发生，但主要是与其他威胁生命的并发症相关联。

In several large clinical trials, ticagrelor was not associated with serum enzyme elevations during therapy and no instances of clinically apparent liver injury were reported. While there have been isolated reports of transient and mild serum enzyme elevations during ticagrelor therapy, these have been short lived and asymptomatic. In addition, since marketing and release, there have been no reports of isolated clinically apparent liver injury or jaundice associated with ticagrelor therapy and hepatotoxicity is not mentioned in the product label. On the other hand, there have been several reports of jaundice and liver injury associated with rhabdomyolysis and with thrombotic thrombocytopenic purpura that represented secondary effects of these severe adverse events. Thus, significant liver injury due to ticagrelor occurs but has occurred largely in association with other life-threatening complications.

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

使用期间对哺乳的影响：目前没有关于哺乳期间使用替卡格雷的已发表信息。由于替卡格雷及其活性代谢物99%以上与血浆蛋白结合，乳汁中的量可能较低。然而，尤其是在哺乳新生儿或早产儿时，可能更倾向于使用替代药物。如果哺乳母亲使用，监测婴儿是否有瘀伤和出血。 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发表信息。 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发表信息。

◉ Summary of Use during Lactation:No published information is available on the use of ticagrelor during breastfeeding. Because ticagrelor and its active metabolite are more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

ticagrelor 和地高辛联合应用对地高辛的药代动力学没有实质性影响；因此，这些药物可以同时使用，无需调整剂量。然而，由于P-糖蛋白抑制可能导致地高辛浓度增加，在开始使用ticagrelor治疗以及ticagrelor治疗有任何变化后，应监测血清地高辛浓度。

Concomitant administration of ticagrelor and digoxin did not substantially affect pharmacokinetics of digoxin; therefore, these drugs may be used concomitantly without dosage adjustments. However, because of the possibility of increased digoxin concentrations as a result of P-glycoprotein inhibition, serum digoxin concentrations should be monitored during initiation of and following any change in ticagrelor therapy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

当替格瑞洛与每日维持剂量超过100毫克的阿司匹林联合使用时，替格瑞洛的疗效可能会降低。

When ticagrelor is used in conjunction with aspirin maintenance dosages exceeding 100 mg daily, efficacy of ticagrelor may be reduced.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

替格瑞洛的口服生物利用度为36%。单次口服200mg替格瑞洛后，其达到的最大血药浓度为923ng/mL，达峰时间为1.5小时，药时曲线下面积为6675ng·h/mL。替格瑞洛的活性代谢物达到的最大血药浓度为264ng/mL，达峰时间为3.0小时，药时曲线下面积为2538ng·h/mL。

Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a Cmax of 923ng/mL, with a Tmax of 1.5 hours and an AUC of 6675ng\*h/mL. The active metabolite of ticagrelor reaches a Cmax of 264ng/mL, with a Tmax of 3.0 hours and an AUC of 2538ng\*h/mL.

来源:DrugBank

吸收、分配和排泄

• 消除途径

一个放射性标记的替卡格雷剂量中有57.8%在粪便中回收，26.5%在尿液中回收。不到1%的剂量以未代谢的母药形式回收。活性代谢物AC-C124910XX在粪便中占回收的21.7%。代谢物AR-C133913XX在尿液中占回收的9.2%，在粪便中占2.7%。其他次要代谢物主要在尿液中回收。

A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly recovered in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

替卡格雷的稳态分布容积为88升。

The steady state volume of distribution of ticagrelor is 88 L.

来源:DrugBank

吸收、分配和排泄

• 清除

替卡格雷的肾脏清除率为0.00584升/小时。

The renal clearance of ticagrelor is 0.00584L/h.

来源:DrugBank

吸收、分配和排泄

药物主要通过细胞色素P-450（CYP）同工酶3A4代谢为一种具有与母药相似的抗血小板活性的活性代谢物。替格瑞洛及其活性代谢物的血浆浓度以剂量依赖性方式增加，分别在约1.5小时和2.5小时达到峰值。替格瑞洛主要通过粪便排出，较少通过尿液排出；尿液中回收的母药和活性代谢物不到剂量的1%。...替格瑞洛及其活性代谢物广泛（超过99%）与人血浆蛋白结合。与高脂肪餐同服可使替格瑞洛的系统暴露增加21%，使活性代谢物的峰值血浆浓度降低22%，但对替格瑞洛的峰值血浆浓度或活性代谢物的系统暴露无影响。

The drug is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 to an active metabolite that has similar antiplatelet activity as the parent drug.Plasma concentrations of ticagrelor and its active metabolite increase in a dose-dependent manner with peak concentrations achieved within approximately 1.5 and 2.5 hours, respectively. Ticagrelor is primarily eliminated in the feces and to a lesser extent in urine; less than 1% of a dose is recovered in urine as the parent drug and active metabolite. ... Both ticagrelor and its active metabolite are extensively (more than 99%) bound to human plasma proteins. Administration with a high-fat meal increases systemic exposure of ticagrelor by 21% and decreases peak plasma concentrations of the active metabolite by 22%, but has no effect on peak plasma concentrations of ticagrelor or on systemic exposure to the active metabolite.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• 海关编码：
  2933990090
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H315,H319,H335
• 储存条件：
  室温

制备方法与用途

抗血小板凝集药：替格瑞洛

简介

替格瑞洛是一种新型的抗血小板凝集药物，由美国阿斯利康公司研发。它是一种可逆结合型口服P2Y12腺苷二磷酸受体拮抗剂，能有效抑制ADP引起的血小板聚集。该药起效迅速，对于急性冠心病患者有显著疗效。与噻吩并吡啶类药物不同，替格瑞洛对P2Y12受体是可逆抑制剂，因此特别适用于需要先期进行抗凝治疗再行手术的病人。

阿斯利康公司自1999年开始研制替格瑞洛，于2010年12月获得欧盟批准，用于预防急性冠状动脉综合征患者的动脉粥样硬化血栓形成事件。尽管美国FDA在2010年底暂时推迟了其上市申请，但随后于2011年7月正式批准该药物，并将其商品名为Brilique。

临床评价

替格瑞洛获得FDA批准是基于PLATO临床研究结果，结果显示与氯吡格雷相比，替格瑞洛能降低心脏病发作、中风或死亡的危险性约16%。这种药物不仅改善了患者的存活率，还被广泛推荐作为急性冠状动脉综合征的治疗策略。

尽管替格瑞洛显示出优越性，但其每天需服用两次，并且可能会引起呼吸困难等不良反应。此外，该药半衰期较短（仅有12小时），需要频繁给药，这对依从性不佳的患者来说是一个挑战。

市场分析

近年来，随着社会经济的发展和人民生活水平提高，血栓类疾病的发病率逐年上升，推动了抗血栓药物市场的扩大。心肌梗塞和脑梗塞的发生与血栓形成密切相关，因此抗血栓药物市场增长迅速，已成为全球药物开发的重要领域之一。

根据IMSHealth的统计数据显示，2008年全球抗血栓药物市场规模约为180亿美元，其中中国的市场增速尤为显著，从2009年的52亿元上升到23亿元，年均增速达32%。阿斯利康的替格瑞洛有望与氯吡格雷等药物形成竞争格局。

替格瑞洛作为第一个口服、作用可逆的ADP受体拮抗剂，在临床应用中显示出优于氯吡格雷的效果，其迅速逆转的特点使其特别适用于手术患者。预计到2014年，替格瑞洛销售额将达到19.5亿美元。

用途

• 抗血凝药
• 减少急性冠脉综合征（ACS）患者的心血管死亡和心脏病发作

此药物主要用于预防急性冠状动脉综合征患者的动脉粥样硬化血栓形成事件。

反应信息

• 作为反应物：
  描述：

  替格瑞洛 在 盐酸 、 sodium nitrite 作用下， 以 水 、 乙腈 为溶剂， 反应 40.0h， 以94.8%的产率得到
  参考文献：
  名称：

  一种替格瑞洛及中间体的亚硝基衍生物的制备方法

  摘要：

  本发明提供如式III所示替格瑞洛的N‑亚硝基衍生物(N‑((1R,2S)‑2‑(3,4‑二氟苯基)环丙基)‑N‑(3‑((1R,2S,3S,4S)‑2,3‑二羟基‑4‑(2‑羟乙氧基)环戊基)‑5‑(丙硫基)‑3H‑[1,2,3]三唑并[4,5‑d]嘧啶‑7‑基)亚硝酰胺)及其中间体如式II所示N‑亚硝基衍生物(N‑((1R,2S)‑2‑(3,4‑二氟苯基)环丙基)‑N‑(3‑((3aS,4R,6S,6aR)‑6‑(2‑羟乙氧基)‑2,2‑二甲基‑四氢‑4H‑环戊基[d][1,3]二氧基‑4‑基)‑5‑(丙硫基)‑3H‑[1,2,3]三唑并[4,5‑d]嘧啶‑7‑基)亚硝酰胺)的制备方法，及上述两个化合物在替格瑞洛质量研究中的应用。

  公开号：

  CN111320631A
• 作为产物：
  描述：

  tert-butyl ((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)(3-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)carbamate 在 磷酸 作用下， 以 乙醇 、 水 为溶剂， 反应 24.0h， 以87%的产率得到替格瑞洛
  参考文献：
  名称：

  [EN] SYNTHESIS OF TRIAZOLOPYRIMIDINE COMPOUNDS
  [FR] SYNTHÈSE DE COMPOSÉS DE TRIAZOLOPYRIMIDINE

  摘要：

  本发明涉及有机合成领域，描述了特定三唑吡咯啉化合物及其中间体的合成，以及相关衍生物，适用于制备泰加格罗（TCG）。

  公开号：

  WO2013037942A1

文献信息

• Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds
  作者：Aijie Cai、Wenhao Yan、Chao Wang、Wei Liu

  DOI：10.1002/anie.202111993

  日期：2021.12.20

  An aryl radical activation strategy has been developed that can engage unactivated alkyl iodides in copper-catalyzed Negishi-type cross-coupling reactions. The strategy is based on the largely overlooked yet highly efficient reactivity of aryl radicals to abstract iodine atoms from alkyl iodides.

  已经开发出一种芳基自由基活化策略，可以在铜催化的 Negishi 型交叉偶联反应中使用未活化的烷基碘。该策略基于芳基自由基从烷基碘化物中提取碘原子的很大程度上被忽视但高效的反应性。
• NOVEL PROCESSES FOR THE PREPARATION OF PHENYLCYCLOPROPYLAMINE DERIVATIVES AND USE THEREOF FOR PREPARING TICAGRELOR
  申请人：Khile Anil Shahaji

  公开号：US20130165696A1

  公开（公告）日：2013-06-27

  Provided herein are novel processes for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. Provided further herein are novel acid addition salts of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, and process for their preparation. The intermediate and its acid addition salts are useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.

  本文提供了一种制备苯基环丙胺衍生物的新型工艺，这些衍生物在三唑并[4,5-d]嘧啶化合物的制备中是有用的中间体。特别提供了一种新颖、商业可行且在工业上具有优势的工艺，用于制备一种基本纯的替卡格雷中间体，即trans-(1R,2S)-2-(3,4-二氟苯基)-环丙胺。此外，本文还提供了trans-(1R,2S)-2-(3,4-二氟苯基)-环丙胺的新型酸加盐，以及其制备工艺。该中间体及其酸加盐对于高产率和纯度制备替卡格雷或其药用可接受盐是有用的。
• Synthesis of Triazolopyrimidine Compounds
  申请人：LEK Pharmaceuticals d.d.

  公开号：EP2570405A1

  公开（公告）日：2013-03-20

  The present invention relates to the filed of organic synthesis and describes the synthesis of specific triazolopyrimidine compounds and intermediates thereof as well as related derivatives, suitable for the preparation of ticagrelor (TGC)

  本发明涉及有机合成领域，描述了特定三唑吡咯啉化合物及其中间体的合成，以及相关衍生物，适用于替卡格雷洛（TGC）的制备。
• Novel triazolo pyrimidine compounds
  申请人：——

  公开号：US20030148888A1

  公开（公告）日：2003-08-07

  The present invention relates to a pyrimidine compound (I) useful as a pharmaceutical intermediate, to a process for preparing said pyrimidine compound, to intermediates used in said process, and to the use of said pyrimidine compound in the preparation of pharmaceuticals.

  本发明涉及一种嘧啶化合物（I），其作为药物中间体有用，涉及制备所述嘧啶化合物的方法，用于所述方法中使用的中间体，以及用于制备药物中使用所述嘧啶化合物。
• Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts
  申请人：LEK Pharmaceuticals d.d.

  公开号：EP2644590A1

  公开（公告）日：2013-10-02

  The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.

  这项发明涉及有机合成领域，描述了合成特定中间体的方法，适用于制备三唑吡咯啉类化合物，如替卡格雷。