WO2014036823A1 - Novel preparation method of antithrombosis medicine - Google Patents

Novel preparation method of antithrombosis medicine Download PDF

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Publication number
WO2014036823A1
WO2014036823A1 PCT/CN2013/073061 CN2013073061W WO2014036823A1 WO 2014036823 A1 WO2014036823 A1 WO 2014036823A1 CN 2013073061 W CN2013073061 W CN 2013073061W WO 2014036823 A1 WO2014036823 A1 WO 2014036823A1
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formula
compound
ticagrelor
reaction
organic solvent
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PCT/CN2013/073061
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French (fr)
Chinese (zh)
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王兵
孙光祥
顾斌
王敏峰
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常州制药厂有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to a novel process for the preparation of ticagrelor, and in addition, the invention relates to novel intermediates for use in the process.
  • Ticagrelor is a novel, selective small molecule anticoagulant developed by AstraZeneca. It is the first reversible combined oral P2Y12 adenosine diphosphate receptor antagonist. Ticagrelor reversibly acts on the ⁇ 2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC), which has a significant inhibitory effect on platelet aggregation induced by ADP, and has a rapid onset of action after oral administration, thus effectively improving acute Symptoms of patients with coronary heart disease. Because the antiplatelet effect of ticagrelor is reversible, it is especially useful for patients who need to undergo anticoagulation before surgery.
  • VSMC vascular smooth muscle cells
  • ticagrelor significantly reduced the primary endpoint of myocardial infarction, stroke, or cardiovascular death in patients with clopidogrel, while severe bleeding complications did not increase.
  • the second phase of the trial was aimed at patients with coronary artery bypass grafting and the results showed that ticagrelor was effective; ticagrelor caused a higher incidence of major bleeding events unrelated to coronary artery bypass grafting, including some fatal intracranial hemorrhage. However, in all bleeding events, the mortality of patients in the ticagrelor group was significantly lower.
  • Ticagrelor (IS, 2S, 3R, 5S) -3- [7_ [ [ (1R, 2S) _2_ (3, 4-difluorophenyl)cyclopropyl]amino] -5 - (propyl decyl) -3H-1, 2, 3-triazole [4, 5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol.
  • Patent WO 00/34283 discloses a synthesis method of ticagrelor, and the specific synthetic route is as follows:
  • Patent W0 00/34283 is condensed with the compound Formula-2 and Formula-3, the condensation product is reduced, and then reacted with isoamyl nitrite to form a triazole ring structure, and the amination is continued to obtain the intermediate Formula-7, intermediate.
  • Formula-7 is reacted with methyl trifluoromethanesulfonylacetate in the presence of butyllithium to give the intermediate Formula-8, which is converted to a bromo group by reaction with isoamyl nitrite and bromoform, and then with the fragment Formula- 10 condensation, and reduction of ester groups, and finally deacetone fork protection to obtain ticagrelor.
  • the disadvantage of this route is that the two chlorine groups in the ortho position are highly active due to the influence of the strong electron withdrawing group nitro group in the structure of the raw Formula-3, and the Formula-2 structure contains both the amino group and the hydroxyl group.
  • Two reactive groups are prone to side reactions in the reaction, and the by-products produced in the reaction bring great difficulties to the purification of the subsequent intermediates.
  • the intermediate Formula-7 is used in the preparation of Formula-8. Methyl fluoromethanesulfonylacetate, and hydroxyl and amino groups are present in the reactant structure, and the side reaction in the reaction is more More, the purification is difficult.
  • This patent reports that there are many reaction steps and many side reactions. The purification of column intermediates in each step of intermediates is not conducive to industrialization.
  • Formula-d firstly uses the raw material Formula-2 used in the patent W0 00/34283 to convert the hydroxyl group to the ethyl oxyacetate group and reduce the ester group by reacting with CBZ to protect the amino group under strong alkaline conditions and ethyl bromoacetate. Finally, the final four steps of the de-CBZ protection are converted into the raw material Formula-a, and the raw material Formula-3 in the above patent is first subjected to nitro reduction to obtain the raw material Formula-b, and the patent US2003/0148888 is adopted.
  • Formula-a and Formula-b are condensed as raw materials, and then reacted with sodium nitrite to form a triazole structure, which continues to condense with compound Formula-10. Finally, hydrolysis under acetone conditions removes acetone fork to obtain ticagrelor. This route is insufficient.
  • the two chlorine groups on the structure of the raw material Formula-b have low activity, and require a long-term reaction at a high temperature of 100 ° C when condensed with the raw material Formula-a, and the hydroxyl group of the raw material Formula-a has a hydroxyl group in addition to the amino group. The reaction will cause side reactions. At the same time, since the raw materials contain amino groups and are unstable at high temperatures, these factors cause many side reactions and deep colors in the condensation reaction, which makes it difficult to purify the subsequent intermediates, and the yield is difficult to ensure.
  • Patent W02011/017108 reports another synthetic route, the synthetic route is as follows:
  • the present invention provides a new, industrially easy to implement, simple and economical process for establishing new intermediates which are prepared by the following reaction schemes (IS, 2S, 3R, 5S)-3-[7 -[[(lR, 2S)_2_(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylindolyl) _311-1,2,3-triazole [4,5-(1 Pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol (ticagal):
  • Another object of the present invention is to provide a novel synthetic route for the preparation of ticagrelor.
  • the synthesis method can effectively reduce the side reaction in the reaction process, improve the purity of the intermediate, and simplify the purification method of the intermediate, and the ticagrelor product can be obtained economically and high quality by the synthesis method.
  • R is a C1 ⁇ C6 lower sulfhydryl group, preferably an ethyl group.
  • a synthetic intermediate of ticagrelor such as Formula-G
  • the method for synthesizing the intermediate formulation of the ticagrelor formula-E is that the compound of the formula Formula-D and the compound of the formula Formula-3 are reacted in an alkaline environment to remove a condensed portion of the HC1 to form a Formula-E compound.
  • the reaction medium for the chemical reaction in the synthesis method of the intermediate Formula-E compound of the present invention is an inert organic solvent, and the inert solvent is a C1 ⁇ C4 halogenated aromatic hydrocarbon, a C2 ⁇ C6 ether, a C2 ⁇ C6
  • the nitrile is preferably tetrahydrofuran.
  • the organic base used in the chemical reaction in the synthesis method of the intermediate Formula-E compound of the present invention may be diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine.
  • the compound of the formula Formula-D added in the above reaction system (for the preparation method, see US2003/0148888), the molar ratio of the compound of the formula 0 1 to 1 1-3 and the organic base is 1: 1: wide 1: 3: 6, preferably For 1 : 1. 6 : 3
  • the temperature of the chemical reaction in the intermediate formula Formula-E synthesis method of the present invention is _10 to 50 ° C, preferably 0 to 10 ° C.
  • the synthesis method of the intermediate formula Formula-E compound of the invention has a reaction time of 2 to 3 hours.
  • the synthesis method of the present invention uses a compound of the formula Formula-D to react with a compound of the formula Formula-3, and the ester group is more stable with respect to a hydroxyl group containing an active hydrogen, and it is difficult to cause a side reaction in the reaction of docking with a halogen.
  • the synthetic routes of ticagrelor disclosed in the patents W0 00/34283 US 2003/0148888 and W02011/017108 respectively use compounds containing active hydroxyl and amino groups, Formula-2 and Formula-a, respectively.
  • the present inventors conducted a detailed study on the key condensation reactions reported in the above three patents, and at the same time made many improvements, including temperature control, molar ratio control, selection of organic bases, and changes in reaction order, which are difficult to suppress side reactions.
  • the production can not solve the problem of poor purity and low yield.
  • we were surprised to find that the compound Formula-D containing only one active group amino group in the structure is condensed with Formula-3, and the isoamyl nitrite is triazine.
  • the ester group in the structure is reduced to a hydroxyl group, which can greatly reduce the by-products in the reaction, and effectively simplify the purification process of the intermediate, and the quality of the final product ticagrelor is greatly improved.
  • the method for synthesizing the intermediate-formula compound of the ticagrelor is: using the formula of Formula-E as a raw material, and reducing the nitro group in the structure to an amino group by a reduction reaction to obtain a compound Formul a- F
  • the reaction medium for carrying out the chemical reaction in the synthesis method of the intermediate Formula-F compound of the present invention is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether and a mixed solvent thereof, preferably methanol. , ethanol.
  • the catalyst used in the chemical reaction in the synthesis method of the intermediate formula Formula-F compound of the present invention is a palladium carbon catalyst, preferably palladium carbon containing 10% palladium.
  • the mass ratio of the formula-E compound to be added to the above reaction system, palladium-containing 10% palladium carbon is
  • the temperature of the chemical reaction in the intermediate formula Formula-F synthesis method of the present invention is 0 to 50 ° C, preferably 2 CT 30 ° C.
  • the synthesis method of the intermediate formula Formula-F compound of the invention has a reaction time of 15 to 20 hours.
  • the above reaction may be carried out by reducing iron powder or zinc powder, but the iron powder and zinc powder reduction and acid addition process are more vigorous and easy to rush, and the post-treatment three wastes are more, and the yield is not satisfactory.
  • the synthetic method for synthesizing ticagrelor intermediate Formula-G according to the present invention is as follows: a compound of Formula-F is formed into a triazole ring in a reaction structure with an isoamyl nitrite in an inert organic solvent to obtain a compound of Formula-G,
  • the reaction medium for carrying out the chemical reaction in the synthesis method of the intermediate Formula-G compound of the present invention is an inert organic solvent, preferably acetonitrile.
  • the temperature of the chemical reaction in the intermediate formula Formula-G synthesis method of the present invention is 30 to 80 ° C, preferably 65 to 75 ° C.
  • the synthesis time of the intermediate formula Formula-G compound of the present invention is 0.5 to 8 hours, preferably 2 hours.
  • Formula-10 compound (see WO 0 00/34283 for preparation) to remove one molecule of hydrogen chloride under alkaline conditions to obtain Formula-H compound
  • the reaction medium for carrying out the chemical reaction in the step of the present invention is an inert organic solvent, and the inert solvent is preferably methylene chloride.
  • the organic base used in the chemical reaction in the step of the present invention may be diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine.
  • the molar ratio of the formula Formula-G compound, the formula Formula-10 compound and the organic base to be added to the above reaction system is 1:1: 1:3:6, preferably 1:2:3.
  • the temperature of the chemical reaction in the step of the present invention is -1 CT50 ° C, preferably 2 CT 30 ° C.
  • the reaction time of the step of the invention is 15 ⁇ 20 hours
  • a synthetic formula of a formula-e compound Formula-H compound is subjected to a reduction reaction in an inert organic solvent to give a compound of the formula Formula-e.
  • the reaction medium for carrying out the chemical reaction in the step of the present invention is an inert organic solvent, preferably tetrahydrofuran.
  • the reducing agent used in the chemical reaction in the step of the present invention is preferably sodium borohydride.
  • the reduction catalyst used in the chemical reaction in the step of the present invention is preferably lithium bromide.
  • the molar ratio of the Formmula-H compound, sodium borohydride and lithium bromide added in the above reaction system is 1:1: 1:5:5, preferably 1:2.5:2.5.
  • the temperature of the chemical reaction in the step of the present invention is 0 to 80 ° C, preferably 4 CT 50 ° C.
  • the reaction time of the step of the present invention is 5 hours, preferably 2 hours.
  • Patent WO 00/34283 reports that the conversion of ester groups to hydroxyl groups by DIBAL-H reduction, due to the high risk of DIBAL-H use, and the complicated post-treatment process, the reduction of ester groups by lithium bromide catalyzed by sodium borohydride. The obtained Formula-e compound effectively solves these problems.
  • a synthetic formula of the compound of formula 1 (ticagrelor) Formula-e compound is obtained by acid-catalyzed hydrolysis and de-acetone protection in an inert organic solvent to obtain a compound L
  • the crude product of ticagrelor in the step of the present invention is selected from the group consisting of isopropanol, isopropanol-water, diethyl ether, methyl t-butyl, ethyl acetate, acetone, acetone-diethyl ether, acetone-methyl tert-butyl ether, acetone.
  • the present invention employs a synthetic process that is economical, efficient, has low environmental pollution, is simple to produce, and is suitable for industrial production.
  • the reaction system was kept stirring at 0 to 5 ° C for two hours, and no residue of the raw material was detected by TLC. After adding 250 mL of ethyl acetate, the solution was diluted with water, and washed with water (300 mL), and brine (300 mL), dried over anhydrous sodium sulfate and evaporated to give 150 g of pale yellow oil.
  • reaction was carried out at 40 ° C for one hour, and no residual material was detected by TLC.
  • the reaction is carried out by adding 500 ml of ethyl acetate, and the organic phase is washed once with 300 mL of water and 300 mL of brine. Step reaction.
  • the organic phase was combined, and the organic phase was washed with 100 ml of water and 100 ml of brine, and the organic phase was dried over anhydrous sodium sulfate, deactivated with activated carbon, filtered, and concentrated to give 19 . lg oil. Adding 152.6 ml of acetonitrile to the above oil, heating and dissolving, stirring slowly, cooling to 3CT40 °C, adding O.

Abstract

A preparation method of micromolecule anticoagulant ticagrelor, an intermediate for synthesizing ticagrelor and a preparation method of the intermediate. With the synthesis method, the side reaction in the reaction process can be effectively reduced, the purity of the intermediate is improved, and the purifying way of the intermediate is simplified.

Description

种新的抗血栓药物的制备方法  Method for preparing new antithrombotic drugs
技术领域:  Technical field:
本发明涉及一种替卡格雷新的制备方法， 此外， 本发明还涉及该方法中使用的 新的中间体。  The present invention relates to a novel process for the preparation of ticagrelor, and in addition, the invention relates to novel intermediates for use in the process.
背景技术:  Background technique:
替卡格雷是阿斯利康公司研发的一种新型的、 具有选择性的小分子抗凝血药， 是第一个可逆的结合型口服 P2Y12腺苷二磷酸受体拮抗剂。 替卡格雷能可逆性地作 用于血管平滑肌细胞 (VSMC)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。 因为替卡格雷的抗血小板作用是可逆的， 其对于那些需在先期进行抗凝治疗后 再进行手术的病人尤为适用。  Ticagrelor is a novel, selective small molecule anticoagulant developed by AstraZeneca. It is the first reversible combined oral P2Y12 adenosine diphosphate receptor antagonist. Ticagrelor reversibly acts on the 嘌呤2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC), which has a significant inhibitory effect on platelet aggregation induced by ADP, and has a rapid onset of action after oral administration, thus effectively improving acute Symptoms of patients with coronary heart disease. Because the antiplatelet effect of ticagrelor is reversible, it is especially useful for patients who need to undergo anticoagulation before surgery.
研究结果显示， 替卡格雷与氯吡格雷相比， 能明显降低患者心梗、 卒中或心血 管死亡等首要终点事件， 而严重出血并发症没有增加。 第二阶段试验针对的是冠状 动脉搭桥患者的用药， 结果表明替卡格雷有效； 替卡格雷所造成的与冠状动脉搭桥 术无关的主要出血事件发生率较高， 包括了一些致命的颅内出血。 但在所有出血事 件中， 替卡格雷组患者的死亡率明显要低。  The results of the study showed that ticagrelor significantly reduced the primary endpoint of myocardial infarction, stroke, or cardiovascular death in patients with clopidogrel, while severe bleeding complications did not increase. The second phase of the trial was aimed at patients with coronary artery bypass grafting and the results showed that ticagrelor was effective; ticagrelor caused a higher incidence of major bleeding events unrelated to coronary artery bypass grafting, including some fatal intracranial hemorrhage. However, in all bleeding events, the mortality of patients in the ticagrelor group was significantly lower.
Figure imgf000002_0001
Figure imgf000002_0001
替卡格雷， 即式 1所示的 (IS, 2S, 3R, 5S) -3- [7_ [ [ (1R， 2S) _2_ (3， 4-二氟苯基） 环丙基]氨基] -5- (丙基巯基) -3H-1, 2, 3-*** [4, 5-d]嘧啶 -3基] -5- ( 2-羟基乙氧 基） -1, 2-环戊二醇。 专利 WO 00/34283公开报道了一种替卡格雷的合成方法， 具体合成路线如下: Ticagrelor, (IS, 2S, 3R, 5S) -3- [7_ [ [ (1R, 2S) _2_ (3, 4-difluorophenyl)cyclopropyl]amino] -5 - (propyl decyl) -3H-1, 2, 3-triazole [4, 5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol. Patent WO 00/34283 discloses a synthesis method of ticagrelor, and the specific synthetic route is as follows:
Figure imgf000003_0001
Figure imgf000003_0001
1 专利 W0 00/34283采用化合物 Formula-2和 Formula-3进行缩合， 缩合产物经 过还原， 再与亚硝酸异戊酯反应形成三氮唑环结构， 继续胺化得到中间体 Formula- 7， 中间体 Formula-7在丁基锂存在下与三氟甲磺酰基乙酸甲酯反应得到中间体 Formula-8, 通过与亚硝酸异戊酯和溴仿反应将氨基转化为溴基团， 再与片段 Formula-10缩合， 并还原酯基团， 最后脱丙酮叉保护得到替卡格雷。  1 Patent W0 00/34283 is condensed with the compound Formula-2 and Formula-3, the condensation product is reduced, and then reacted with isoamyl nitrite to form a triazole ring structure, and the amination is continued to obtain the intermediate Formula-7, intermediate. Formula-7 is reacted with methyl trifluoromethanesulfonylacetate in the presence of butyllithium to give the intermediate Formula-8, which is converted to a bromo group by reaction with isoamyl nitrite and bromoform, and then with the fragment Formula- 10 condensation, and reduction of ester groups, and finally deacetone fork protection to obtain ticagrelor.
此路线的不利之处在于， 原料 Formula-3结构中由于受到强吸电子基团硝基的 影响， 邻位上的两个氯基团活性很高， 并且 Formula-2结构中同时含有氨基和羟基 两个活性基团， 反应中极易发生副反应， 反应中产生的副产物给后续中间体的纯化 带来很大困难， 中间体 Formula-7制备 Formula-8过程中采用了价格昂贵的试剂三 氟甲磺酰基乙酸甲酯， 并且反应物结构中同时存在羟基和氨基， 反应中副反应较 多， 纯化困难， 此专利报道的路线反应步骤多， 副反应多， 各步中间体都需采用柱 层析纯化不利于产业化的实施。 The disadvantage of this route is that the two chlorine groups in the ortho position are highly active due to the influence of the strong electron withdrawing group nitro group in the structure of the raw Formula-3, and the Formula-2 structure contains both the amino group and the hydroxyl group. Two reactive groups are prone to side reactions in the reaction, and the by-products produced in the reaction bring great difficulties to the purification of the subsequent intermediates. The intermediate Formula-7 is used in the preparation of Formula-8. Methyl fluoromethanesulfonylacetate, and hydroxyl and amino groups are present in the reactant structure, and the side reaction in the reaction is more More, the purification is difficult. This patent reports that there are many reaction steps and many side reactions. The purification of column intermediates in each step of intermediates is not conducive to industrialization.
美国专利 US2003/0148888公开报道了一种替卡格雷的合成路线， 该合成方法 对专利 W0 00/34283报道的合成方法进行改进， 合成路线如下：  U.S. Patent No. 2003/0148888 discloses a synthetic route to ticagrelor which is improved by the synthetic method reported in the patent W0 00/34283, which is synthesized as follows:
Figure imgf000004_0001
Figure imgf000004_0001
Formula-a Formula- b  Formula-a Formula- b
NaN02 NaN0 2
Vf 、N
Figure imgf000004_0002
Vf, N
Figure imgf000004_0002
Formula-e  Formula-e
Formula-d 首先将专利 W0 00/34283中使用的原料 Formula-2通过上 CBZ保护氨基、 强碱 性条件下与溴乙酸乙酯反应将羟基转化为氧基乙酸乙酯基团、 还原酯基团， 最后还 原脱 CBZ保护共四步反应转化为原料 Formula-a, 同时先将上述专利中的原料 Formula-3进行硝基还原得到原料 Formula-b， 专利 US2003/0148888 采用  Formula-d firstly uses the raw material Formula-2 used in the patent W0 00/34283 to convert the hydroxyl group to the ethyl oxyacetate group and reduce the ester group by reacting with CBZ to protect the amino group under strong alkaline conditions and ethyl bromoacetate. Finally, the final four steps of the de-CBZ protection are converted into the raw material Formula-a, and the raw material Formula-3 in the above patent is first subjected to nitro reduction to obtain the raw material Formula-b, and the patent US2003/0148888 is adopted.
Formula-a和 Formula-b为原料进行缩合， 再与亚硝酸钠反应形成三氮唑结构， 继 续与化合物 Formula-10缩合， 最后酸性条件下水解脱除丙酮叉保护得到替卡格 雷， 此路线不足之处在于原料 Formula-b结构上的两个氯基团活性小， 与原料 Formula-a缩合时需要 100°C高温长时间反应， 并且原料 Formula-a结构上除氨基 外还有羟基， 高温长时间反应会发生副反应， 同时由于原料中都含有氨基， 高温下 不稳定， 这些因素导致缩合反应中副反应多， 颜色很深， 为后续中间体的纯化带来 困难， 收率难以保证。 Formula-a and Formula-b are condensed as raw materials, and then reacted with sodium nitrite to form a triazole structure, which continues to condense with compound Formula-10. Finally, hydrolysis under acetone conditions removes acetone fork to obtain ticagrelor. This route is insufficient. The two chlorine groups on the structure of the raw material Formula-b have low activity, and require a long-term reaction at a high temperature of 100 ° C when condensed with the raw material Formula-a, and the hydroxyl group of the raw material Formula-a has a hydroxyl group in addition to the amino group. The reaction will cause side reactions. At the same time, since the raw materials contain amino groups and are unstable at high temperatures, these factors cause many side reactions and deep colors in the condensation reaction, which makes it difficult to purify the subsequent intermediates, and the yield is difficult to ensure.
专利 W02011/017108报道了另一条合成路线， 合成路线如下：
Figure imgf000005_0001
Patent W02011/017108 reports another synthetic route, the synthetic route is as follows:
Figure imgf000005_0001
1 不同之处在于采用结构中氯基团活性更高的原料 Formula-3为原料与化合物 Formula-a缩合， 再还原得到中间体 Formula-c, 后面反应步骤与专利  1 The difference is that the formula III, which is a more active chlorine group in the structure, is condensed with the compound Formula-a, and then reduced to obtain the intermediate Formula-c, the subsequent reaction steps and patents.
US2003/0148888报道的方法一致， 此路线同样存在原料 Formula-a同时存在氨基和 羟基， 与 Formula-3缩合时容易发生副反应的问题， 给后续中间体的纯化带来困 难。 The method reported in US 2003/0148888 is consistent. This route also has the problem that the starting material Formula-a has both an amino group and a hydroxyl group, and the side reaction is prone to occur when it is condensed with Formula-3, which makes the subsequent intermediate purification difficult.
发明内容  Summary of the invention
本发明提供一种新的， 工业上容易实现的、 简便的并建立在新的中间体上的经 济方法， 该方法通过以下反应方案来制备（IS, 2S, 3R, 5S)-3-[7-[[(lR, 2S)_2_(3, 4- 二氟苯基)环丙基]氨基] -5- (丙基巯基） _311-1,2,3-***[4,5-(1]嘧啶-3基]-5- (2-羟基乙氧基） -1,2-环戊二醇 （替卡格雷） ： The present invention provides a new, industrially easy to implement, simple and economical process for establishing new intermediates which are prepared by the following reaction schemes (IS, 2S, 3R, 5S)-3-[7 -[[(lR, 2S)_2_(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylindolyl) _311-1,2,3-triazole [4,5-(1 Pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol (ticagal):
Figure imgf000006_0001
Figure imgf000006_0001
本发明的一个目的是提供用于合成替卡格雷的新中间体以及该中间体的制备方 法。 It is an object of the present invention to provide novel intermediates for the synthesis of ticagrelor and methods for preparing the intermediates.
本发明的另一个目的是提供一种制备替卡格雷的新合成路线。 该合成方法可以 有效减少反应过程中的副反应， 提高中间体的纯度， 简化中间体的纯化方式， 通过 该合成方法可以经济的、 高质量的得到的替卡格雷产品。  Another object of the present invention is to provide a novel synthetic route for the preparation of ticagrelor. The synthesis method can effectively reduce the side reaction in the reaction process, improve the purity of the intermediate, and simplify the purification method of the intermediate, and the ticagrelor product can be obtained economically and high quality by the synthesis method.
为实现第一个目的， 一种合成替卡格雷的中间体， 如式 Formula-E: For the first purpose, an intermediate for the synthesis of ticagrelor, such as Formula-E:
Figure imgf000006_0002
Figure imgf000006_0002
Formula- 其中 R为 C1~C6低级垸基， 优选乙基。  Formula- wherein R is a C1~C6 lower sulfhydryl group, preferably an ethyl group.
一种合成替卡格雷的中间体， 如式 Formula-F
Figure imgf000007_0001
An intermediate for the synthesis of ticagrelor, such as Formula-F
Figure imgf000007_0001
Formula- 其中 R的定义同上。  Formula- where R is as defined above.
一种合成替卡格雷中间体， 如式 Formula-G  A synthetic intermediate of ticagrelor, such as Formula-G
Figure imgf000007_0002
Figure imgf000007_0002
Formula-G 其中 R的定义同上。 Formula-G where R is as defined above.
所述合成替卡格雷中间体 Formula-E化合物的方法为式 Formula-D化合物与式 Formula-3化合物在碱性环境下脱掉缩合一份子 HC1反应生成式 Formula-E化合 物。  The method for synthesizing the intermediate formulation of the ticagrelor formula-E is that the compound of the formula Formula-D and the compound of the formula Formula-3 are reacted in an alkaline environment to remove a condensed portion of the HC1 to form a Formula-E compound.
Figure imgf000007_0003
Figure imgf000007_0003
Formula-D Formula-: 本发明中间体式 Formula-E化合物合成方法中进行化学反应的反应介质为惰性 有机溶剂， 所述惰性溶剂为 C1~C4卤代芳烃， C2~C6的醚， C2~C6的腈， 优选为四 氢呋喃。  Formula-D Formula-: The reaction medium for the chemical reaction in the synthesis method of the intermediate Formula-E compound of the present invention is an inert organic solvent, and the inert solvent is a C1~C4 halogenated aromatic hydrocarbon, a C2~C6 ether, a C2~C6 The nitrile is preferably tetrahydrofuran.
本发明中间体式 Formula-E化合物合成方法中进行化学反应所采用的有机碱可 以为二异丙基乙胺， 三乙胺或吡啶， 优选为二异丙基乙胺。 上述反应体系中所加入式 Formula-D化合物（制备方法见 US2003/0148888)， 式 ?01~ 1£1-3化合物以及有机碱的摩尔比为1 : 1 :广1 : 3 : 6， 优选为 1 : 1. 6 : 3 The organic base used in the chemical reaction in the synthesis method of the intermediate Formula-E compound of the present invention may be diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine. The compound of the formula Formula-D added in the above reaction system (for the preparation method, see US2003/0148888), the molar ratio of the compound of the formula 0 1 to 1 1-3 and the organic base is 1: 1: wide 1: 3: 6, preferably For 1 : 1. 6 : 3
另外本发明中间体式 Formula-E合成方法中的化学反应的温度为 _10~50摄氏 度， 优选为 0~10摄氏度。  Further, the temperature of the chemical reaction in the intermediate formula Formula-E synthesis method of the present invention is _10 to 50 ° C, preferably 0 to 10 ° C.
本发明中间体式 Formula-E化合物合成方法反应时间为 2~3小时  The synthesis method of the intermediate formula Formula-E compound of the invention has a reaction time of 2 to 3 hours.
本发明的合成方法采用通式为 Formula-D的化合物与式 Formula-3化合物反 应， 酯基相对于含有活泼氢的羟基更稳定难以在和卤素对接的反应中产生副反应。 专利 W0 00/34283 US2003/0148888和 W02011/017108公开报道的替卡格雷的合成 路线分别采用含活泼羟基和氨基的化合物 Formula-2和 Formula-a分别与式  The synthesis method of the present invention uses a compound of the formula Formula-D to react with a compound of the formula Formula-3, and the ester group is more stable with respect to a hydroxyl group containing an active hydrogen, and it is difficult to cause a side reaction in the reaction of docking with a halogen. The synthetic routes of ticagrelor disclosed in the patents W0 00/34283 US 2003/0148888 and W02011/017108 respectively use compounds containing active hydroxyl and amino groups, Formula-2 and Formula-a, respectively.
Formula-3和 Formula-b化合物反应， 碱性条件下难以避免产生羟基和氯基团的缩 合副反应， 中间体提纯困难， 很难控制产品的纯度。 The reaction of Formula-3 with Formula-b compounds makes it difficult to avoid the condensation reaction of hydroxyl groups and chlorine groups under alkaline conditions. The purification of intermediates is difficult, and it is difficult to control the purity of the product.
本发明人对上述三项专利中报道的关键缩合反应进行了细致研究， 同时进行了 很多改进， 包括温度控制， 投料摩尔比控制， 有机碱的选择， 反应投料顺序的改变 都很难抑制副反应的产生， 不能解决纯度差、 收率低的问题， 实验中我们惊异的发 现采用结构中只含有一个活泼基团氨基的化合物 Formula-D与式 Formula-3缩合， 亚硝酸异戊酯成三氮唑结构后， 再将结构中酯基还原成羟基， 可以大大减少反应中 的副产物， 有效简化中间体的纯化过程， 最终产品替卡格雷质量大大提高。  The present inventors conducted a detailed study on the key condensation reactions reported in the above three patents, and at the same time made many improvements, including temperature control, molar ratio control, selection of organic bases, and changes in reaction order, which are difficult to suppress side reactions. The production can not solve the problem of poor purity and low yield. In the experiment, we were surprised to find that the compound Formula-D containing only one active group amino group in the structure is condensed with Formula-3, and the isoamyl nitrite is triazine. After the azole structure, the ester group in the structure is reduced to a hydroxyl group, which can greatly reduce the by-products in the reaction, and effectively simplify the purification process of the intermediate, and the quality of the final product ticagrelor is greatly improved.
所述合成替卡格雷中间体 Formula-F化合物的方法为： 采用式 Formula-E化合 物为原料， 通过还原反应将结构中硝基还原为氨基得到化合物 Formula-F The method for synthesizing the intermediate-formula compound of the ticagrelor is: using the formula of Formula-E as a raw material, and reducing the nitro group in the structure to an amino group by a reduction reaction to obtain a compound Formul a- F
Figure imgf000008_0001
Figure imgf000008_0001
Formula-I Formula-F 本发明中间体 Formula-F化合物合成方法中进行化学反应的反应介质为选自甲 醇、 乙醇、 异丙醇、 四氢呋喃、 甲基叔丁基醚及其混合溶剂， 优选为甲醇， 乙醇。  Formula-I Formula-F The reaction medium for carrying out the chemical reaction in the synthesis method of the intermediate Formula-F compound of the present invention is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether and a mixed solvent thereof, preferably methanol. , ethanol.
本发明中间式体 Formula-F化合物合成方法中进行化学反应所采用的催化剂为 钯碳催化剂， 优选为含钯 10%的钯碳。 上述反应体系中所加入式 Formula-E化合物， 含钯 10%的钯碳的质量比为 The catalyst used in the chemical reaction in the synthesis method of the intermediate formula Formula-F compound of the present invention is a palladium carbon catalyst, preferably palladium carbon containing 10% palladium. The mass ratio of the formula-E compound to be added to the above reaction system, palladium-containing 10% palladium carbon is
1 : : 0. 0Γΐ : 1, 优选为 1 : 0.广1 : 0. 15。 1 : : 0. 0Γΐ : 1, preferably 1: 0. Wide 1: 0. 15.
另外本发明中间体式 Formula-F合成方法中的化学反应的温度为 0~50摄氏 度， 优选为 2CT30摄氏度。  Further, the temperature of the chemical reaction in the intermediate formula Formula-F synthesis method of the present invention is 0 to 50 ° C, preferably 2 CT 30 ° C.
本发明中间体式 Formula-F化合物合成方法反应时间为 15~20小时  The synthesis method of the intermediate formula Formula-F compound of the invention has a reaction time of 15 to 20 hours.
上述反应可采用铁粉或锌粉还原的方法， 但铁粉和锌粉还原加酸引发过程较为 剧烈容易冲料， 后处理三废多， 收率不理想。  The above reaction may be carried out by reducing iron powder or zinc powder, but the iron powder and zinc powder reduction and acid addition process are more vigorous and easy to rush, and the post-treatment three wastes are more, and the yield is not satisfactory.
本发明所述的合成替卡格雷中间体式 Formula-G的合成方法为： 式 Formula-F 化合物在惰性有机溶剂中与亚硝酸异戊酯反应结构中形成三氮唑环得到式 Formula- G化合物，  The synthetic method for synthesizing ticagrelor intermediate Formula-G according to the present invention is as follows: a compound of Formula-F is formed into a triazole ring in a reaction structure with an isoamyl nitrite in an inert organic solvent to obtain a compound of Formula-G,
Figure imgf000009_0001
Figure imgf000009_0001
Formula-I Formula-G 本发明中间式 Formula-G化合物合成方法中进行化学反应的反应介质为惰性有 机溶剂， 优选为乙腈。  Formula-I Formula-G The reaction medium for carrying out the chemical reaction in the synthesis method of the intermediate Formula-G compound of the present invention is an inert organic solvent, preferably acetonitrile.
上述反应体系中所加入式 Formula-F化合物和亚硝酸异戊酯的摩尔比为  The molar ratio of the formula Formula F compound and isoamyl nitrite added in the above reaction system is
1 :广 1 : 5, 优选为 1 : 2。 1 : Wide 1: 5, preferably 1: 2.
另外本发明中间体式 Formula-G合成方法中的化学反应的温度为 30~80摄氏 度， 优选为 65~75摄氏度。  Further, the temperature of the chemical reaction in the intermediate formula Formula-G synthesis method of the present invention is 30 to 80 ° C, preferably 65 to 75 ° C.
本发明中间体式 Formula-G化合物合成方法反应时间为 0. 5~8小时， 优选广 2 小时。  The synthesis time of the intermediate formula Formula-G compound of the present invention is 0.5 to 8 hours, preferably 2 hours.
为了实现本发明另一个目的， 利用上述中间体合成替卡格雷， 包括如下步骤： 1.式 Formula-H化合物的合成式 Formula-G化合物在惰性有机溶剂中与式  In order to achieve another object of the present invention, the use of the above intermediate to synthesize ticagrelor comprises the following steps: 1. A synthetic formula of the formula Formula-H compound Formula-G compound in an inert organic solvent
Formula-10化合物（制备方法见专利 W0 00/34283)在碱性条件脱去一分子氯化氢得 到式 Formula-H化合物
Figure imgf000010_0001
Formula-10 compound (see WO 0 00/34283 for preparation) to remove one molecule of hydrogen chloride under alkaline conditions to obtain Formula-H compound
Figure imgf000010_0001
Formula-G Formula-H 本发明步骤中进行化学反应的反应介质为惰性有机溶剂， 所述惰性溶剂优选为 二氯甲垸。  Formula-G Formula-H The reaction medium for carrying out the chemical reaction in the step of the present invention is an inert organic solvent, and the inert solvent is preferably methylene chloride.
本发明步骤中进行化学反应所采用的有机碱可以为二异丙基乙胺， 三乙胺或吡 啶， 优选为二异丙基乙胺。  The organic base used in the chemical reaction in the step of the present invention may be diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine.
上述反应体系中所加入式 Formula-G化合物， 式 Formula-10化合物以及有机 碱的摩尔比为 1:1:广1:3:6， 优选为 1:2:3  The molar ratio of the formula Formula-G compound, the formula Formula-10 compound and the organic base to be added to the above reaction system is 1:1: 1:3:6, preferably 1:2:3.
另外本发明步骤中的化学反应的温度为 -1CT50摄氏度， 优选为 2CT30摄氏度。 本发明步骤反应时间为 15~20小时  Further, the temperature of the chemical reaction in the step of the present invention is -1 CT50 ° C, preferably 2 CT 30 ° C. The reaction time of the step of the invention is 15~20 hours
2.式 Formula-e化合物的合成式 Formula-H化合物在惰性有机溶剂中通过还原 反应得到式 Formula-e化合物。  2. A synthetic formula of a formula-e compound Formula-H compound is subjected to a reduction reaction in an inert organic solvent to give a compound of the formula Formula-e.
Figure imgf000010_0002
Figure imgf000010_0002
Formula-H Formula-e 本发明步骤中进行化学反应的反应介质为惰性有机溶剂， 优选为四氢呋喃。 本发明步骤中进行化学反应所采用的还原剂优选为硼氢化钠。  Formula-H Formula-e The reaction medium for carrying out the chemical reaction in the step of the present invention is an inert organic solvent, preferably tetrahydrofuran. The reducing agent used in the chemical reaction in the step of the present invention is preferably sodium borohydride.
本发明步骤中进行化学反应所采用的还原催化剂优选为溴化锂。  The reduction catalyst used in the chemical reaction in the step of the present invention is preferably lithium bromide.
上述反应体系中所加入式 Formmula-H化合物， 硼氢化钠以及溴化锂的摩尔比 为 1:1:广 1:5 :5， 优选为 1:2.5:2.5  The molar ratio of the Formmula-H compound, sodium borohydride and lithium bromide added in the above reaction system is 1:1: 1:5:5, preferably 1:2.5:2.5.
另外本发明步骤中的化学反应的温度为 0~80摄氏度， 优选为 4CT50摄氏度。 本发明步骤反应时间为广 5小时， 优选广 2小时。 专利 WO 00/34283中报道了通过 DIBAL-H还原将酯基转化为羟基， 由于 DIBAL- H使用过程中危险性高， 同时后处理过程复杂三废多， 而采用溴化锂催化硼氢化钠 来还原酯基得到式 Formula-e化合物有效解决了这些问题。 Further, the temperature of the chemical reaction in the step of the present invention is 0 to 80 ° C, preferably 4 CT 50 ° C. The reaction time of the step of the present invention is 5 hours, preferably 2 hours. Patent WO 00/34283 reports that the conversion of ester groups to hydroxyl groups by DIBAL-H reduction, due to the high risk of DIBAL-H use, and the complicated post-treatment process, the reduction of ester groups by lithium bromide catalyzed by sodium borohydride. The obtained Formula-e compound effectively solves these problems.
3.式 1化合物 （替卡格雷） 的合成式 Formula-e化合物惰性有机溶剂中通过酸 催化水解脱丙酮叉保护得到化合物 L  3. A synthetic formula of the compound of formula 1 (ticagrelor) Formula-e compound is obtained by acid-catalyzed hydrolysis and de-acetone protection in an inert organic solvent to obtain a compound L
Figure imgf000011_0001
Figure imgf000011_0001
Formula-e 1  Formula-e 1
本发明步骤中对替卡格雷粗品在选自异丙醇、 异丙醇 -水、 ***、 甲基叔丁 基、 乙酸乙酯、 丙酮、 丙酮-***、 丙酮-甲基叔丁基醚、 丙酮-正己垸、 丙酮 -石油 醚、 乙酸乙酯-***、 乙酸乙酯-正己垸、 乙酸乙酯-正庚垸、 乙酸乙酯 -石油醚及其 混合物的结晶溶剂中结晶得到结晶态的式 1 (替卡格雷） 。  The crude product of ticagrelor in the step of the present invention is selected from the group consisting of isopropanol, isopropanol-water, diethyl ether, methyl t-butyl, ethyl acetate, acetone, acetone-diethyl ether, acetone-methyl tert-butyl ether, acetone. Form 1 in a crystalline solvent of n-hexane, acetone-petroleum ether, ethyl acetate-diethyl ether, ethyl acetate-n-hexane, ethyl acetate-n-heptane, ethyl acetate-petroleum ether and mixtures thereof (Ticagre).
总之， 本发明采用的是经济的、 高效的、 环境污染小的、 生产操作简单、 适合 工业生产的合成工艺。  In summary, the present invention employs a synthetic process that is economical, efficient, has low environmental pollution, is simple to produce, and is suitable for industrial production.
下面结合实施例进一步阐明本发明的内容， 但本发明的内容不局限于实施例的 条件描述。  The content of the present invention will be further clarified below with reference to the embodiments, but the content of the present invention is not limited to the description of the conditions of the embodiments.
具体实施方式： detailed description:
实施例 1 Example 1
式 Formula-E化合物的合成 （结构式中 R为乙基） ： Synthesis of a Formula-E compound (where R is an ethyl group):
将 60g (0. 23 mol, 1. 0 eq) 式 Formula-D化合物（结构式中 R为乙基， 制备方 法见 US2003/0148888) , 140mL (0. 74mol, 3. 0 eq) DIPEA, 加入 900mL THF中， 室 温搅拌 0. 5小时待用。 将 99. 2g (0. 37 mol, 1. 6 eq)式 Formula- 3化合物加入 180mLTHF中， 冷至 0_5°C， 氮气保护滴加上述的待用溶液， 约一小时， 控制温度在 0-5°C。 滴加完后， 保持反应体系在 0_5°C搅拌两小时， TLC检测无原料剩余。 加入 250mL乙酸乙酯稀释溶液， 用水洗 （300mL) 有机相， 饱和食盐水 （300mL) 洗一 次， 无水硫酸钠干燥， 浓缩得到 150g淡黄色油状物，向油状物中加入 500ml二氯甲 垸搅拌溶解后加入 300g硅胶， 搅拌， 减压浓缩除尽二氯甲垸， 加入 500ml正己 烷， 搅拌打浆 30分钟， 抽滤， 母液减压浓缩回收未反应的原料 Formula-3和少量 产品 Formula-E, 滤饼硅胶混合物用 1000ml乙酸乙酯搅拌打浆 30分钟， 抽滤， 母 液减压浓缩至干得 85.7g油状物 Formula-E， 收率 76. 1% 。 60 g (0.23 mol, 1.0 eq) of the formula Formula-D compound (where R is ethyl, for the preparation method see US2003/0148888), 140 mL (0.74 mol, 3. 0 eq) DIPEA, added to 900 mL of THF 5小时待待用。 At room temperature, stirring 0. 5 hours for use. 99. 2g (0. 37 mol, 1. 6 eq) of Formula Formula 3 compound was added to 180 mL of THF, cooled to 0-5 ° C, and the above-mentioned solution was added dropwise with nitrogen gas protection for about one hour, and the temperature was controlled at 0-5. °C. After the completion of the dropwise addition, the reaction system was kept stirring at 0 to 5 ° C for two hours, and no residue of the raw material was detected by TLC. After adding 250 mL of ethyl acetate, the solution was diluted with water, and washed with water (300 mL), and brine (300 mL), dried over anhydrous sodium sulfate and evaporated to give 150 g of pale yellow oil. After dissolving, add 300 g of silica gel, stir, concentrate under reduced pressure to remove dichloromethane, and add 500 ml of positive The alkane was stirred and beaten for 30 minutes, filtered with suction, and the mother liquor was concentrated under reduced pressure to recover the unreacted raw material Formula-3 and a small amount of Formula-E. The filter cake silica gel mixture was beaten with 1000 ml of ethyl acetate for 30 minutes, suction filtered, and the mother liquor was concentrated under reduced pressure. 1%。 The yield of 85.7g oil Forma-E, yield 76. 1%.
NMR 6 H(CDC13) 8.56 (1H, d, J=7.6Hz) , 4.70(1H, t, J=6.8Hz) , 4.66 (1H, dd, J=5.6Hz, J=l.6Hz), 4.55 (1H, dd, J= 5.6Hz, J=l.2Hz) , 4.25^4.20 (4H, m) , 4.06 (1H, d, J=4.0Hz), 3. 19^3.03 (2H, m), 2.36^2.30 (1H, m) , NMR 6 H(CDC1 3 ) 8.56 (1H, d, J = 7.6 Hz), 4.70 (1H, t, J = 6.8 Hz), 4.66 (1H, dd, J = 5.6 Hz, J = 1.6 Hz), 4.55 (1H, dd, J= 5.6Hz, J=l.2Hz), 4.25^4.20 (4H, m) , 4.06 (1H, d, J=4.0Hz), 3. 19^3.03 (2H, m), 2.36 ^2.30 (1H, m) ,
2.03 (1H, d, J=14.8Hz), 1.8Γΐ.74 (2H, m) , 1.42 (3H, s) , 1.29 (3H, t, J=7.2Hz) , 1.26 (3H, s), 1.04(3H, t, J=7.2Hz) .  2.03 (1H, d, J=14.8Hz), 1.8Γΐ.74 (2H, m) , 1.42 (3H, s) , 1.29 (3H, t, J=7.2Hz) , 1.26 (3H, s), 1.04 ( 3H, t, J=7.2Hz).
实施例 2 Example 2
式 Formula-F化合物的合成 （结构式中 R为乙基） ： Synthesis of a Formula-F compound (where R is an ethyl group):
将 65g(132 mmol)式 F化合物溶于 70 mL甲醇中， 氮气保护下加入 6.5g 含量 为 10%的钯碳， 置换氢气。 室温下常压反应 20小时， TLC检测无原料剩余。 过滤钯 碳， 滤饼用 50mL甲醇洗涤， 浓缩滤液得到 57 g油状物， 无需纯化直接用于下步反 应， 收率 93.4%。  65 g (132 mmol) of the compound of the formula F was dissolved in 70 mL of methanol, and 6.5 g of palladium carbon having a content of 10% was added under a nitrogen atmosphere to replace the hydrogen. The reaction was carried out at room temperature for 20 hours under normal pressure, and no residual material remained in the TLC. The palladium carbon was filtered, and the filter cake was washed with 50 mL of methanol. The filtrate was concentrated to give 57 g of oil, which was used in the next step without purification, yield 93.4%.
NMR δ H(CDC13) 6.32 (1H, d, J=7.6Hz) , 4.64 (1H, t, J=7.2Hz) , NMR δ H (CDC1 3 ) 6.32 (1H, d, J = 7.6 Hz), 4.64 (1H, t, J = 7.2 Hz),
4.57~4.54(2H，m)， 4.33^4.20 (3H, m) , 4. 12^4.07 (1H, m) , 3.98 (1H, d, J=4.0Hz) ,4.57~4.54(2H,m), 4.33^4.20 (3H, m) , 4. 12^4.07 (1H, m) , 3.98 (1H, d, J=4.0Hz),
3.76 (2H, br s)， 3. 16^3.09 (1H, m), 3.03^2.96 (1H, m) , 2.32^2.25 (1H, m) , 1.88(1H, d, J=14.8Hz), 1· 77~L 71 ( 2H, m) , 1.41 (3H, s) , 1.29 (3H, t, J=7.2Hz) , 1.24 (3H, s), 1.0K3H, t, J=7.2Hz) . 3.76 (2H, br s), 3. 16^3.09 (1H, m), 3.03^2.96 (1H, m) , 2.32^2.25 (1H, m) , 1.88(1H, d, J=14.8Hz), 1 · 77~L 71 ( 2H, m) , 1.41 (3H, s) , 1.29 (3H, t, J=7.2Hz), 1.24 (3H, s), 1.0K3H, t, J=7.2Hz).
实施例 3 Example 3
式 Formula-G化合物的合成 （结构式中 R为乙基） ： Synthesis of a Formula-G compound (where R is an ethyl group):
将 52g(113 mmol, 1.0 eq)式 G化合物溶于 150mL乙腈中。 加入 30.4mL(226 mmol, 2.0 eq)亚硝酸异戊酯， 加热到 70°C反应 1小时， TLC检测无原料剩余。 将 反应冷却到室温后浓缩得到 51. lg棕色油状物， 收率 96.0%， 无需进一步纯化， 直 接用于下步反应。  52 g (113 mmol, 1.0 eq) of the compound of formula G was dissolved in 150 mL of acetonitrile. 30.4 mL (226 mmol, 2.0 eq) of isoamyl nitrite was added, and the mixture was heated to 70 ° C for 1 hour, and no residual material was detected by TLC. The reaction was cooled to rt then EtOAc (EtOAc m.
NMR 6 H(CDC13) 5.52 (1H, q, J=3.5Hz) , 5. 18 (1H, dt, J=10.0Hz, J=3.5Hz) ,NMR 6 H(CDC1 3 ) 5.52 (1H, q, J = 3.5 Hz), 5. 18 (1H, dt, J = 10.0 Hz, J = 3.5 Hz),
4.85 (1H, dd, J=6.5Hz, J=2.0Hz) , 4.20^4. 11 (3H, m) , 4.08 (2H, d, J=4.0Hz) , 3.2 3.18 (2H, m), 2.79^2.73 (2H, m) , 1.87~1.80 (2H， m)， 1.55 (3H, s) , 4.85 (1H, dd, J=6.5Hz, J=2.0Hz), 4.20^4. 11 (3H, m) , 4.08 (2H, d, J=4.0Hz) , 3.2 3.18 (2H, m), 2.79^ 2.73 (2H, m) , 1.87~1.80 (2H, m), 1.55 (3H, s) ,
1.36 (3H, s), 1.26(3H, t, J=7.5Hz) , 1.09 (3H, J=7.5Hz) . 实施例 4 1.36 (3H, s), 1.26 (3H, t, J=7.5Hz), 1.09 (3H, J=7.5Hz). Example 4
式 Formula-H化合物的合成 （结构式中 R为乙基） ： Synthesis of a Formula-H compound (where R is an ethyl group):
将 36g (76. 3 mmol, 1. 0 eq)式 Formula-G化合物溶于 360mL DCM中， 加入 12. 9g (76. 3 mmol, 1. 0 eq)式 Formula- 10化合物（制备方法见专利 W0 00/34283) 和 40. OmL (228. 9 mmol, 30 eq) DIPEA。 室温搅拌过夜， TLC检测无原料剩余。 反 应液用 300mL水和 300mL饱和食盐水各洗一次， 分取有机相， 无水硫酸钠干燥， 过 滤， 减压浓缩至干得 45. lg油状物， 收率 97. 8%， 直接用于下步反应。  36 g (76. 3 mmol, 1. 0 eq) of Formula-G compound was dissolved in 360 mL of DCM, and 12.9 g (76. 3 mmol, 1. 0 eq) of Formula- 10 compound was added (for the preparation method, see Patent W0). 00/34283) and 40. OmL (228. 9 mmol, 30 eq) DIPEA. Stir at room temperature overnight and no residual material was detected by TLC. The aliquot of the reaction solution was washed with 300 mL of water and 300 mL of brine, and the organic phase was separated, dried over anhydrous sodium sulfate. Step reaction.
ESI-MS: 605 (M+H+)  ESI-MS: 605 (M+H+)
实施例 5 Example 5
式 Formula-e化合物的合成： Synthesis of Formula-e compounds:
在氮气保护下将 0. 26g (6. 87 mmol, 2. 5 eq) 硼氢化钠， 0. 6g (6. 9 mmol, 2. 5 eq)溴化锂加入 5mL THF中。 上述反应液控制温度在 50°C， 搅拌 45分钟。 滴加 30g (49. 6mmol, 1. 0 eq)式 Formula-H化合物溶解在 100mL THF的溶液， 控制温度 在 50°C， 滴加 30分钟， 滴加结束后再滴 2mL甲醇。 滴加 180mL水， 大量气体生 成， 控制滴加速度， 防止冲料， 滴加完后 40°C反应一小时， TLC检测无原料剩余。 反应加入 500mL乙酸乙酯萃取产品， 有机相用 300mL水和 300mL饱和食盐水各洗一 次， 无水硫酸钠干燥， 浓缩有机相得到 24. 4g油状物， 收率 87. 4%， 直接用于下步 反应。  0. 26g (6. 87 mmol, 2. 5 eq) of sodium borohydride, 0.6 g (6.9 mmol, 2. 5 eq) of lithium bromide were added to 5 mL of THF under nitrogen. The above reaction liquid was controlled at a temperature of 50 ° C and stirred for 45 minutes. A solution of 30 g (49. 6 mmol, 1.0 eq) of the formula-H compound dissolved in 100 mL of THF was added dropwise, and the temperature was controlled at 50 ° C for 30 minutes, and 2 mL of methanol was added dropwise after the completion of the dropwise addition. 180 mL of water was added dropwise, and a large amount of gas was generated to control the dropping rate to prevent the punching. After the dropwise addition, the reaction was carried out at 40 ° C for one hour, and no residual material was detected by TLC. The reaction is carried out by adding 500 ml of ethyl acetate, and the organic phase is washed once with 300 mL of water and 300 mL of brine. Step reaction.
ESI-MS: 563 (M+H+)  ESI-MS: 563 (M+H+)
实施例 6 Example 6
式 1化合物 （替卡格雷） 的合成： Synthesis of the compound of formula 1 (ticagrelor):
将 24g (42. 7 mmol)式 Formula-e化合物溶于 120mL甲苯中， 5_10°C下滴加 50mL/50mL浓盐酸 /甲醇， 滴加完后保持温度在 5°C左右反应 30分钟。 加入 50mL 水， 静置分层， 分取含有产品盐酸盐的水和甲醇相， 水 /甲醇体系用饱和碳酸氢钠 溶液调节水相 ί¾到 6-7， 加入 200mL乙酸乙酯提取产品， 分取有机相， 水层用 200ml乙酸乙酯再提取一次， 合并有机相， 有机相分别用 100ml水和 100ml饱和食 盐水洗， 取有机相， 用无水硫酸钠干燥， 活性炭脱色， 过滤， 浓缩得到 19. lg油状 物。 将上述油状物中加入 152. 8ml乙腈， 加热溶解， 搅拌下， 缓慢冷却至 3CT40 °C， 加入 O. lg替卡格雷晶种进行诱导， 慢慢有大量固体析出， 搅拌冷却至 0~5°C， 搅拌析晶 3小时， 抽滤， 滤饼干燥， 得类白色固体 14. ½， 将得到的粗品用 144ml 乙酸乙酯加热完全溶解， 缓慢滴加 115. 2ml正己垸， 慢慢有大量白色固体析出， 搅 拌冷却至 0~5°C， 搅拌析晶 3小时， 抽滤， 滤饼用 20ml乙酸乙酯 /正己垸 =10/8的 混合溶剂洗涤， 抽干， 滤饼 40°C下真空干燥， 得白色固体 12. 9g， HPLC纯度〉 99%， 收率： 57. 8% 。 24 g (42. 7 mmol) of the Formula-e compound was dissolved in 120 mL of toluene, and 50 mL / 50 mL of concentrated hydrochloric acid / methanol was added dropwise at 5-10 ° C, and the reaction was kept at about 5 ° C for 30 minutes after the dropwise addition. Add 50mL of water, let stand for layering, separate the water and methanol phase containing the product hydrochloride, adjust the water phase ί3⁄4 to 6-7 with saturated sodium bicarbonate solution in water/methanol system, add 200mL ethyl acetate to extract the product, and divide The organic phase was taken, and the aqueous layer was extracted with ethyl acetate (200 ml). The organic phase was combined, and the organic phase was washed with 100 ml of water and 100 ml of brine, and the organic phase was dried over anhydrous sodium sulfate, deactivated with activated carbon, filtered, and concentrated to give 19 . lg oil. Adding 152.6 ml of acetonitrile to the above oil, heating and dissolving, stirring slowly, cooling to 3CT40 °C, adding O. lg ticagrelor seed crystals for induction, slowly depositing a large amount of solids, stirring and cooling to 0~5° C, stirring and crystallization for 3 hours, suction filtration, the filter cake was dried to give a white solid 14.1⁄2, and the obtained crude product was dissolved in 144 ml of ethyl acetate, and slowly added dropwise, 115. 2 ml of hexane, slowly a large amount of white The solid precipitated, stirred and cooled to 0~5 ° C, stirred and crystallized for 3 hours, suction filtered, and the filter cake was washed with 20 ml of ethyl acetate / n-hexane = 10 / 8 mixed solvent, drained, and the filter cake was vacuumed at 40 ° C. 8%。 The white solid 12.9g, HPLC purity > 99%, yield: 57. 8%.
ESI-MS: 523 (M+H+)  ESI-MS: 523 (M+H+)
NMR δ H (DMS0) 9. 35 (1H, d, J=4. OHz) , 7. 35^7. 28 (2H, m) , 7. 08 (1H, m) , 5. 10 (lH，d， J=6. 4Hz) , 5. 03 (1H, d, J=4. OHz) , 4. 96 (1H, q, J=9. 2Hz) , 4. 60^4. 50 (2H, m) 3. 95 (1H, br s) , 3. 76 (1H, m) , 3. 52^3. 47 (4H, m) , 3. 16^3. 09 (1H, m) ,  NMR δ H (DMS0) 9. 35 (1H, d, J=4. OHz) , 7. 35^7. 28 (2H, m) , 7. 08 (1H, m) , 5. 10 (lH,d , J=6. 4Hz) , 5. 03 (1H, d, J=4. OHz) , 4. 96 (1H, q, J=9. 2Hz) , 4. 60^4. 50 (2H, m) 3. 95 (1H, br s) , 3. 76 (1H, m) , 3. 52^3. 47 (4H, m) , 3. 16^3. 09 (1H, m) ,
2. 97^2. 92 (1H, m) , 2. 88^2. 83 (1H, m) 2. 97^2. 92 (1H, m) , 2. 88^2. 83 (1H, m)
2. 63 (1H, dt, J=13. 6Hz, J=8. 4Hz) , 2. 30^2. 22 and 2. 16^2. 08 (1H, m) ,  2. 63 (1H, dt, J=13. 6Hz, J=8. 4Hz) , 2. 30^2. 22 and 2. 16^2. 08 (1H, m) ,
2. 07~2· 00 (1H, m) , 1. 7(Tl. 35 (4H, m) , 0. 99 and 0. 82 (3H, t, J=7. 2) . 2. 07~2· 00 (1H, m), 1. 7 (Tl. 35 (4H, m), 0. 99 and 0. 82 (3H, t, J=7.2).

Claims

权 利 要 求 书 一种合成替卡格雷的中间体， 为式 Formula-E化合物: Claims An intermediate for the synthesis of ticagrelor, a compound of the formula Formula-E:
Figure imgf000015_0001
Figure imgf000015_0001
Formula-E  Formula-E
其中上述结构式中 R为 C1~C6低级烷基。  Wherein R in the above formula is a C1~C6 lower alkyl group.
2. 制备权利要求 1 所述化合物的方法， 该方法为： 式 Formula-D 化合物与式 Formula-3化合物在做碱性环境下脱掉缩合一份子 HC1反应生成式 Formula-E化 合物。 2. A process for the preparation of a compound according to claim 1, which is: a compound of the formula Formula-D and a compound of the formula Formula-3 are reacted in an alkaline environment to remove a condensed portion of HC1 to form a Formula-E compound.
Figure imgf000015_0002
Formula-D Formula-3
Figure imgf000015_0002
Formula-D Formula-3
3. 根据权利要求 2 所述方法， 其特征在于， 所选惰性有机溶剂为 C1~C4 卤代芳 烃， C2〜C6的醚， C2~C6的腈。  The method according to claim 2, wherein the inert organic solvent selected is a C1~C4 halogenated aromatic hydrocarbon, a C2~C6 ether, and a C2~C6 nitrile.
4. 根据权利要求 3所述方法其特征在于所述惰性有机溶剂为四氢呋喃。  4. Process according to claim 3, characterized in that the inert organic solvent is tetrahydrofuran.
5. 根据权利要求 2 所述方法， 其特征在于， 所述有机碱为二异丙基乙胺 5. The method according to claim 2, wherein the organic base is diisopropylethylamine
(DIPEA) , 三乙胺或吡啶。 (DIPEA), triethylamine or pyridine.
6. 根据权利要求 5所述方法， 其特征在于， 所述有机碱为二异丙基乙胺。  6. Process according to claim 5, characterized in that the organic base is diisopropylethylamine.
7. 根据权利要求 2所述方法， 其特征在于， 式 Formula-D化合物， 式 Formula-3化 合物以及有机碱的摩尔比为 1 :1 :1〜1 :3:6。  The method according to claim 2, wherein the molar ratio of the compound of the formula Formula-D, the formula Formula-3 compound and the organic base is 1:1:1 to 1:3:6.
8. 根据权利要求 2所述方法， 其特征在于， 所述反应温度为 -10~50摄氏度。  8. The method according to claim 2, wherein the reaction temperature is -10 to 50 degrees Celsius.
9. 一种合成替卡格雷的中间体， 为式 Formula-F化合物：  9. An intermediate for the synthesis of ticagrelor, a compound of the formula Formula-F:
14 替换页 （细则第 26条) R14 Replacement page (Article 26) R
Figure imgf000016_0001
Figure imgf000016_0001
Formula-F  Formula-F
其中上述结构式中 R为 C1~C6低级烷基。  Wherein R in the above formula is a C1~C6 lower alkyl group.
制备权利要求 9 所述化合物的方法， 该方法为： 式 Formula-E化合物在有机溶 剂中通过催化剂催化氢化的方式将硝基还原为氨基。 A process for the preparation of a compound according to claim 9 which is characterized in that the compound of the formula Formula-E is reduced to an amino group by catalytic hydrogenation of the catalyst in an organic solvent.
Figure imgf000016_0002
Figure imgf000016_0002
Formula-E Formula-F  Formula-E Formula-F
根据权利要求 10所述方法， 其特征在于， 所有机溶剂为选自甲醇、 乙醇、 异丙 醇、 四氢呋喃、 甲基叔丁基醚及其混合溶剂。 The method according to claim 10, wherein the all-agent solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, and a mixed solvent thereof.
根据权利要求 10所述方法， 其特征在于， 所述催化剂为钯碳催化剂。 The method according to claim 10, wherein the catalyst is a palladium carbon catalyst.
根据权利要求 10所述方法， 其特征在于， 所述加入式 Fomiula-E化合物与含钯 10%的钯碳的质量比为 1::0.01~1:1。 The method according to claim 10, wherein the mass ratio of said compound of Fomiula-E to palladium-containing 10% palladium carbon is 1: 1: 0.01 to 1:1.
根据权利要求 10 所述方法， 其特征在于， 所述化学反应的温度为 0~50摄氏 度。 The method according to claim 10, wherein the temperature of the chemical reaction is 0 to 50 degrees Celsius.
一种合成替卡格雷的中间体， 为式 Formula-G化合物 An intermediate for the synthesis of ticagrelor, a compound of the formula Formula-G
Figure imgf000016_0003
Figure imgf000016_0003
Formula-G  Formula-G
其中上述结构式中 R为 C1~C6低级烷基。  Wherein R in the above formula is a C1~C6 lower alkyl group.
制备权利要求 15所述化合物的方法， 该方法为： 式 Formula-F化合物在有机溶 A process for the preparation of a compound according to claim 15 which is: Formula Formula F compound in organic solution
15 替换页 （细则第 26条) 剂中与亚硝酸异戊酯反应形成三氮唑环结构的式 Foramla-G化合物。 15 Replacement page (Article 26) A Foramla-G compound of the formula which is reacted with isoamyl nitrite to form a triazole ring structure.
r O^ ^ ^人 N r O^ ^ ^人N
Figure imgf000017_0001
Figure imgf000017_0001
Formula-F Formula-G Formula-F Formula-G
17.根据权利要求 16所述方法， 其特征在于， 所述有机溶剂为乙腈。 The method according to claim 16, wherein the organic solvent is acetonitrile.
18.根据权利要求 16所述方法， 其特征在于， 所述所加入式 Fonnula-F化合物和亚 硝酸异戊酯的摩尔比为 1 :1〜1 :5。  The method according to claim 16, wherein the molar ratio of the added Fonnula-F compound to isoamyl nitrite is 1:1 to 1:5.
19.根据权利要求 16 所述方法， 其特征在于， 所述化学反应的温度为 0~80 摄氏 度。  The method according to claim 16, wherein the temperature of the chemical reaction is 0 to 80 degrees Celsius.
20.—种合成替卡格雷的方法， 包括如下步骤- 20. A method of synthesizing ticagrelor comprising the following steps -
(a)式 Formula-G化合物在惰性有机溶剂中与式 Formula-10化合物在碱性条件脱去 一分子氯化氢缩合得到式 Formula-H化合物 Formula (A) Formula-G compound is condensed with a formula Formula-10 compound in an inert organic solvent under basic conditions to obtain a compound of formula Formula-H.
Figure imgf000017_0002
Figure imgf000017_0002
Formula-G Formula-H  Formula-G Formula-H
其中上述结构式中 R为 C1 C6低级垸基 Wherein R in the above structural formula is a C1 C6 lower sulfhydryl group
(b) 式 Formula-H化合物在惰性有机溶剂中通过还原反应， 还原结构中酯基得到式 Formula-e化合物。  (b) Formulation of a Formula-H compound by reduction in an inert organic solvent to reduce the ester group in the structure.
Figure imgf000017_0003
Figure imgf000017_0003
Formula-H Formula-e  Formula-H Formula-e
(c)式 Formula-e化合物在有机溶剂中通过酸催化水解脱丙酮叉保护得到式 1化合物 (替卡格雷） 粗品， 粗品经过溶剂精制得到高质量的替卡格雷产品。  Formula (e) Formula-e compound is deprotected by acid-catalyzed hydrolysis in an organic solvent to obtain a crude compound of the compound of formula 1 (ticagrelor), and the crude product is solvent-refined to obtain a high-quality ticagrelor product.
16 替换页 （细则第 26条)
Figure imgf000018_0001
16 Replacement page (Article 26)
Figure imgf000018_0001
Formula-e 1 根据权利要求 20 所述方法， 其特征在于， 所述步骤 a所选反应介质为二氯甲 院。  Formula-e 1 The method according to claim 20, wherein the reaction medium selected in the step a is a dichlorohydrazine.
根据权利要求 20所述方法， 其特征在于， 所述步骤 a所釆用的有机碱可以为二 异丙基乙胺， 三乙胺或吡啶。 The method according to claim 20, wherein the organic base used in the step a may be diisopropylethylamine, triethylamine or pyridine.
根据权利要求 22所述方法， 其特征在于， 所述有机碱为二异丙基乙胺。 The method according to claim 22, wherein the organic base is diisopropylethylamine.
根据权利要求 20所述方法， 其特征在于， 所述步骤 a中加入式 Formula-G化合 物， 式 Formula-10化合物以及有机碱的摩尔比为 1 :1 :1〜1:3:6。 The method according to claim 20, wherein a molar ratio of the formula Formula-G compound to the formula-10 compound and the organic base is 1:1:1 to 1:3:6.
根据权利要求 20所述方法， 其特征在于， 所述步骤 a反应的温度为 -10~50摄氏 度。 The method according to claim 20, wherein the temperature of the step a reaction is -10 to 50 degrees Celsius.
根据权利要求 20所述方法， 其特征在于， 所述歩骤 b所述惰性有机溶剂为四氨 呋喃。 The method according to claim 20, wherein the inert organic solvent of the step b is tetraammine.
根据权利要求 20所述方法， 其特征在于， 所述步骤 b采用的还原剂优选为硼氢 化钠。 The method according to claim 20, characterized in that the reducing agent used in the step b is preferably sodium borohydride.
根据权利要求 20所述方法， 其特征在于， 所述步骤 b采用的还原催化剂为溴化 锂。 The method according to claim 20, wherein the reduction catalyst used in the step b is lithium bromide.
根据权利要求 20所述方法， 其特征在于， 所述步骤 b加入式 Forauila-H化合 物， 硼氢化钠以及溴化锂的摩尔比为 1 :1 :1 1 :5:5。 The method according to claim 20, wherein said step b is added to the compound of Forauila-H, and the molar ratio of sodium borohydride and lithium bromide is 1:1:1:5:5.
根据权利要求 20所述方法， 其特征在于， 所述歩骤 b反应的温度为 0~80摄氏 度。 The method according to claim 20, wherein the temperature of the reaction of the step b is 0 to 80 degrees Celsius.
根据权利要求 20所述方法， 其特征在于， 所述步骤 c中精制溶剂选自异丙醇、 异丙醇 -水、 ***、 甲基叔丁基、 乙酸乙酯、 丙酮、 丙酮-***、 丙酮-甲基叔丁 基醚、 丙酮-正己垸、 丙酮-石油醚、 乙酸乙酯-***、 乙酸乙酯-正己烷、 乙酸乙 酯-正庚烷、 乙酸乙酯 -石油醚及其混合物的结晶溶剂中结晶得到结晶态的式 1The method according to claim 20, wherein the solvent in the step c is selected from the group consisting of isopropanol, isopropanol-water, diethyl ether, methyl t-butyl, ethyl acetate, acetone, acetone-diethyl ether, acetone. Crystallization of methyl tert-butyl ether, acetone-n-hexane, acetone-petroleum ether, ethyl acetate-diethyl ether, ethyl acetate-n-hexane, ethyl acetate-n-heptane, ethyl acetate-petroleum ether and mixtures thereof Crystallization in a solvent gives a crystalline form 1
(替卡格雷） 。 (Ticagre).
17 替换页 （细则第 26条) 17 Replacement page (Article 26)
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