CN102875537A - Novel preparation method of antithrombosis medicine - Google Patents

Novel preparation method of antithrombosis medicine Download PDF

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CN102875537A
CN102875537A CN2012103312665A CN201210331266A CN102875537A CN 102875537 A CN102875537 A CN 102875537A CN 2012103312665 A CN2012103312665 A CN 2012103312665A CN 201210331266 A CN201210331266 A CN 201210331266A CN 102875537 A CN102875537 A CN 102875537A
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formula
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ticagrelor
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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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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The invention provides a novel preparation method which is easily industrially achieved and is simple and convenient to carry out and is established under a new intermediate. The invention relates to a novel preparation method of micromolecule anticoagulant Ticagrelor, and synchronously relates to an intermediate body for synthesizing the Ticagrelor and a preparation method of the intermediate. With the adoption of the synthesis method provided by the invention, 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

一种新的抗血栓药物的制备方法 A method of preparing new antithrombotic drugs

技术领域: FIELD:

[0001] 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。 [0001] The present invention relates to a novel method for preparing ticagrelor In addition, the present invention also relates to novel intermediates used in the process.

背景技术: Background technique:

[0002] 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。 [0002] ticagrelor AstraZeneca developed a novel, small molecule selective anticoagulant, is first bound oral reversible P2Y12 adenosine diphosphate receptor antagonist. 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。 Ticagrelor reversibly purine act on vascular smooth muscle cells (VSMC) 2 the P2Y12 receptor subtypes, significantly inhibited ADP-induced platelet aggregation, and orally rapid onset of action, it is possible to effectively improve acute coronary heart disease symptoms. 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。 Because Kage Lei for antiplatelet effect is reversible, which is particularly suitable for those patients in need of surgery after the early anticoagulation.

[0003] 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。 [0003] The results showed that ticagrelor compared with clopidogrel significantly reduced in patients with myocardial infarction, stroke or cardiovascular death and other primary end point, and no increase in serious bleeding complications. 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。 Phase II trial for the treatment of a coronary artery bypass graft patients, results showed that ticagrelor effective; higher incidence of major bleeding not associated with CABG ticagrelor caused by, including some fatal intracranial hemorrhage. 但在所有出血事件中,替卡格雷组患者的死亡率明显要低。 But in all bleeding events, for Kage Lei mortality was significantly lower.

[0004] [0004]

Figure CN102875537AD00061

[0005]替卡格雷,即式 I 所示的(lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-二氟苯基)环丙基]氨基]-5-(丙基巯基)-3Η-1,2,3-三唑[4,5-d]嘧啶_3基]-5-(2-羟基乙氧基)-I, [0005] ticagrelor, i.e., Formula I (lS, 2S, 3R, 5S) -3- [7 - -2- (3,4- difluorophenyl) [[(lR, 2S) cyclopropylmethyl yl] amino] -5- (propyl-mercapto) -3Η-1,2,3- triazolo [4,5-d] pyrimidin-_3-yl] -5- (2-hydroxyethoxy) -I,

2-环戊二醇。 2-cyclopentyl-diol. 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: Patent WO 00/34283 discloses an alternative synthetic method reported Kage Lei, the specific scheme is as follows:

[0006] [0006]

Figure CN102875537AD00071

[0007] 专利WO 00/34283米用化合物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。 [0007] Patent WO 00/34283 meters compound Formula-2 Formula-3 and the condensation, a condensation product was reduced and then with isoamyl nitrite to form triazole ring structure to continue amination of intermediate Formula-7 intermediate Formula-7 in the presence of butyllithium to give intermediates Formula-8-trifluoromethanesulfonyloxy-acetic acid methyl ester and, by isoamyl nitrite and bromoform reaction of the bromo group converted to an amino group, and then Formula-10 fragment condensation, and reduction of the ester group, to obtain the final deacetone ticagrelor fork protectors.

[0008] 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。 [0008] This route is disadvantageous in that, Formula-3 feed structure due to the influence of strong electron-withdrawing nitro group, two highly reactive chloro group on the ortho position, and Formula 2-structures contain both two active hydroxyl and amino groups, the reaction can easily occur a side reaction, reaction by-products produced in the subsequent purification of intermediates to the great difficulty, Formula-8 during the preparation of intermediate of Formula-7 used expensive trifluoromethanesulfonyl reagent acetate, and the reactants simultaneously present in the structure hydroxyl and amino groups, more side reactions in the reaction, purification is difficult, the reaction route of this patent reports a multi-step, side reactions, each of the intermediate steps are It requires the use of column chromatography is not conducive to industrial implementation.

[0009] 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W000/34283报道的合成方法进行改进,合成路线如下: [0009] U.S. Patent No. US2003 / 0148888 reportedly discloses a synthetic route ticagrelor, the synthesis method of synthesizing patent W000 / 34283 is reported to improve the synthetic route as follows:

[0010] [0010]

Figure CN102875537AD00081

[0011] 首先将专利WO 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米用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。 [0011] First, the raw material used in the Patent No. WO 00/34283 by Formula-2 CBZ protected amino, under strong basic conditions with ethyl bromoacetate converting the hydroxyl group, ethyl group, reduction of the ester group Finally, reductive de-protected CBZ four steps were converted to Formula-a starting material, while the first material above patents Formula-3 nitro reduction to give starting material Formula-b, patent US2003 / 0148888 by Formula-a yards and Formula- b condensation as raw materials, triazole structure is further formed with sodium nitrite, and continued condensation of a compound of Formula-10, free water and finally acetone acidic conditions to give cross protection ticagrelor, this route is that the inadequate feed Formula-b except small two reactive chloro groups on structure, and a long reaction time required starting material Formula-a condensation temperature 100 ° C, and a hydroxyl group in addition to an amino group also, a high temperature for a long time on the reaction side reactions will feed structure Formula-a, and because the raw material contains an amino group, unstable at high temperatures, these factors lead to condensation reaction, side reactions, very dark in color, difficult the subsequent purification of intermediates, it is difficult to guarantee the yield.

[0012] 专利W02011/017108报道了另一条合成路线,合成路线如下: [0012] Patent W02011 / 017108 reported another synthetic route, the following synthetic route:

[0013] [0013]

Figure CN102875537AD00082

[0014] 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。 [0014] except that the use of higher structure chloro group as active ingredients Formula-3 with a compound of Formula-a starting material is condensed and then reduced to give intermediate Formula-c, the subsequent reaction step of the method in Patent US2003 / 0148888 reports consistent, the same starting material of this route Formula-a presence of amino and hydroxyl groups simultaneously, with the Formula-3 problem prone to side reactions during the condensation, the subsequent purification difficult to intermediates.

发明内容 SUMMARY

[0015] 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-[ [ (IR,2S) -2- (3,4- 二氟苯基)环丙基]氨基]-5-(丙基巯基)-3Η-1,2,3-三唑[4,5-d]嘧啶_3基]-5-(2-羟基乙氧基)-I,2-环戍二醇(替卡格雷): [0015] The present invention provides a novel, industrially easily implemented based on a simple and economic method of novel intermediates, which are prepared by the following reaction scheme (is, 2S, 3R, 5S) -3 - [7- [[(IR, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] -5- (propyl-mercapto) -3Η-1,2,3- triazolo [ 4,5-d] pyrimidin-_3-yl] -5- (2-hydroxyethoxy) -I, 2- diol Shu ring (ticagrelor):

[0016] [0016]

Figure CN102875537AD00091

[0017] 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。 An object of the [0017] present invention is to provide a new synthetic ticagrelor intermediates and methods for preparing the intermediate.

[0018] 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。 [0018] Another object of the present invention is to provide a new synthetic route ticagrelor prepared. 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。 This synthesis method can effectively reduce the side reactions in the process, to improve the purity of the intermediates, the way simplify purification of intermediates, can be economical, high quality obtained by this method ticagrelor synthetic products.

[0019] 为实现第一个目的,一种合成替卡格雷的中间体,如式Formula-E : [0019] To achieve the first object, a synthetic ticagrelor intermediates such as Formula Formula-E:

[0020] [0020]

Figure CN102875537AD00101

[0021] 其中R为Cl〜C6低级烷基,优选乙基。 [0021] Cl~C6 wherein R is a lower alkyl, preferably ethyl.

[0022] 一种合成替卡格雷的中间体,如式Formula-F [0022] A synthetic ticagrelor intermediates such as Formula Formula-F

[0023] [0023]

Figure CN102875537AD00102

[0024] 其中R的定义同上。 [0024] wherein R is as defined above.

[0025] 一种合成替卡格雷中间体,如式Formula-G [0025] A synthetic ticagrelor intermediates such as Formula Formula-G

[0026] [0026]

Figure CN102875537AD00103

[0027] 其中R的定义同上。 [0027] wherein R is as defined above.

[0028] 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HCl反应生成式Formula-E化合物。 [0028] The method for synthesizing Intermediate Kage Lei Formula-E Formula-3 compound is a compound of formula with a compound of formula Formula-D part off the condensation reaction of a compound of formula HCl Formula-E in an alkaline environment.

[0029] [0029]

Figure CN102875537AD00104

[0030] 本发明中间体式Fonnula-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Cl〜C4齒代芳烃,C2〜C6的醚,C2〜C6的腈,优选为四氢呋喃。 The reaction [0030] Intermediate compounds of formula Fonnula-E synthesis method of the present invention is a chemical reaction medium is an inert organic solvent, the inert solvent is an aromatic hydrocarbon substituting Cl~C4 teeth, C2~C6 ethers, nitriles C2~C6, preferably tetrahydrofuran.

[0031] 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。 [0031] The present invention is intermediates of Formula chemical reaction Formula-E compound synthesis method employed may be organic bases diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine.

[0032] 上述反应体系中所加入式Formula-D化合物(制备方法见US2003/0148888),式Formula-3化合物以及有机碱的摩尔比为I : I : I〜I : 3 : 6,优选为I : I. 6 : 3。 [0032] The molar ratio of the compound of formula Formula-D (preparation US2003 / 0148888), a compound of formula Formula-3 and an organic base added in the reaction system is I: I: I~I: 3: 6, preferably I : I. 6: 3.

[0033] 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O〜10摄氏度。 [0033] Further according to the present invention, the temperature of the intermediate of formula Formula-E synthesis method is a chemical reaction of -10~50 ° C, preferably O~10 degrees Celsius.

[0034] 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 [0034] Intermediate compounds of formula Formula-E synthesis method of the present invention the reaction time is 2 to 3 hours

[0035] 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。 Synthesis Method [0035] The present invention employs a compound of formula Formula-3 with a compound of formula Formula-D reaction, the ester group with a more stable and less likely to occur a side reaction in the reaction for the halogen docked active hydrogen-containing hydroxyl group. 专利WO00/34283,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轻基和氨基的化合物Formula-2和Formula-a分别与式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。 Patent WO00 / 34283, US2003 / 0148888 and W02011 / 017108, respectively, for Scheme Kage Lei publicly reported using light reactive compound containing an amino group and Formula-2 Formula-a, respectively, and the formula Formula-3 and a compound of Formula-b , under basic conditions is difficult to avoid side reactions and the condensation of hydroxy group of chlorine, intermediate purification difficulties, difficult to control the purity of the product.

[0036] 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,亚硝酸异戍酯成三氮唑结构后,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。 [0036] The present invention is a condensation of the key above three patents reported reaction is carried out a detailed study, while a number of improvements, including temperature control, the feed molar ratio control, choice of the organic base, the reaction feeding sequence changes are difficult suppressing side reactions and poor purity can not solve the problem of low yield, the experiments we surprisingly found that the use of the structure contains only one active amino group with a compound of formula formula-D formula-3 condensates, isoamyl nitrite ester into the triazole structure, then the structure of the ester group is reduced to a hydroxyl group, can greatly reduce the reaction by-products, and simplify purification of intermediates, final products ticagrelor quality greatly improved.

[0037] 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。 [0037] The method for synthesis of Intermediate Kage Lei compound of Formula-F: A compound of formula Formula-E as a raw material, reaction by reduction of a nitro group reduced to an amino structure to give a compound of Formula-F.

[0038] [0038]

Figure CN102875537AD00111

[0039] 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。 The reaction [0039] chemical reaction intermediate synthesis compounds of Formula-F medium of the present invention is selected from methanol, ethanol, isopropanol, tetrahydrofuran, methyl tertiary butyl ether and mixed solvents thereof, preferably methanol, ethanol.

[0040] 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。 [0040] The intermediate of formula Formula-F of the present invention process for catalyst synthesis of compounds of the chemical reaction the catalyst employed is palladium on carbon, preferably palladium on carbon containing 10% palladium.

[0041] 上述反应体系中所加入式Formula-E化合物,含钮10 %的钮碳的质量比为1::0.01〜1: 1,优选为I : O. I 〜I : 0.15。 A compound of formula Formula-E [0041] added in the reaction system, 10% of the mass containing the button knob carbon is 0.01~1 :: 1: 1, preferably I: O. I ~I: 0.15.

[0042] 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O〜50摄氏度,优选为20〜30摄氏度。 [0042] Further according to the present invention, the temperature of the intermediate of formula Formula-F chemical synthesis reaction is O~50 ° C, preferably 20 to 30 degrees Celsius.

[0043] 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[0044] 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。 Process is more easily induced with vigorous [0043] The present invention is intermediates of Formula Formula-F compound synthesis reaction time is 15 ~ 20 hours [0044] The reaction may be iron or zinc reduction method, the reduction of iron and zinc with acid red material, multiple post-processing waste, the yield is not satisfactory.

[0045] 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, [0045] The synthesis of the present invention a method for the synthesis of Intermediate Kage Lei Formula-G is the formula: Formula-F compound of formula in an inert organic solvent with isoamyl nitrite ester formed triazole ring structure of formula Formula- G compound,

[0046] [0046]

Figure CN102875537AD00121

[0047] 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。 The reaction [0047] The chemical reaction of the present invention the intermediate of Formula Formula-G Synthesis of Compound process medium is an inert organic solvent, preferably acetonitrile.

[0048] 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I : I〜I : 5,优选为I : 2。 Molar ratio of [0048] the reaction system was added as a compound of formula Formula-F and isoamyl nitrite is I: I~I: 5, preferably from I: 2.

[0049] 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。 [0049] Further according to the present invention, the temperature of the intermediate of formula Formula-G chemical synthesis reaction is 30~80 ° C, preferably 65~75 ° C.

[0050] 本发明中间体式Formula-G化合物合成方法反应时间为O. 5〜8小时,优选I〜2小时。 [0050] The present invention is an intermediate compound of formula Formula-G synthesis reaction time is O. 5~8 hours, preferably I~2 hours.

[0051] 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: [0051] To accomplish another object of the present invention, using the above intermediate in the synthesis ticagrelor, comprising the steps of:

[0052] I.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Formula-IO化合物(制备方法见专利WO 00/34283)在碱性条件脱去一分子氯化氢得到式Formula-H化合物 [0052] Formula-G Formula-H compound of Formula I. The synthesis of compounds of the formula in an inert organic solvent with a compound of formula Formula-IO (preparation described in Patent No. WO 00/34283) removal of one molecule of hydrogen chloride under basic conditions to give the formula Formula -H compound

[0053] [0053]

Figure CN102875537AD00122

[0054] 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烷。 [0054] The reaction is carried out a chemical reaction step of the present invention are inert organic solvent medium, the inert solvent is preferably dichloromethane.

[0055] 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。 [0055] The chemical reaction of the organic bases employed in the present invention may be a step of diisopropylethylamine, triethylamine or pyridine, preferably diisopropylethylamine.

[0056] 上述反应体系中所加入式Formula-G化合物,式Formula-IO化合物以及有机碱的摩尔比为I : I : I〜I : 3 : 6,优选为1:2:3。 The molar ratio of the added compound of formula Formula-G,-IO Formula and an organic base compound of formula [0056] in the reaction system is I: I: I~I: 3: 6, preferably from 1: 2: 3.

[0057] 另外本发明步骤中的化学反应的温度为-10〜50摄氏度,优选为20〜30摄氏度。 [0057] Further according to the present invention, the temperature in step chemical reaction of -10~50 ° C, preferably 20 to 30 degrees Celsius. [0058] 本发明步骤反应时间为15〜20小时 [0058] The reaction time of Step 15 ~ 20 according to the present invention is h

[0059] 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。 [0059] Formula-H compounds of Formula 2. Formula-e Synthesis of the formula in an inert organic solvent to give a compound of formula by reduction Formula-e.

[0060] [0060]

Figure CN102875537AD00131

[0061] 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。 [0061] The reaction is carried out a chemical reaction step of the present invention is an inert organic solvent medium, preferably tetrahydrofuran.

[0062] 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。 Step [0062] The present invention is a chemical reaction in the reducing agent used is preferably sodium borohydride.

[0063] 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。 [0063] Step reduction catalyst of the present invention, the chemical reaction employed is preferably lithium bromide.

[0064] 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I : I : I 〜I : 5 : 5,优选为I : 2.5 : 2.5。 Formmula-H compound, sodium borohydride and the molar ratio of lithium bromide [0064] added in the reaction system is I: I: I ~I: 5: 5, preferably I: 2.5: 2.5.

[0065] 另外本发明步骤中的化学反应的温度为O〜80摄氏度,优选为40〜50摄氏度。 [0065] Further steps of the present invention the temperature of the chemical reaction is O~80 ° C, preferably 40~50 ° C.

[0066] 本发明步骤反应时间为I〜5小时,优选I〜2小时。 Step [0066] The reaction time of the present invention I~5 hours, preferably I~2 hours.

[0067] 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。 [0067] Patent WO 00/34283 reported by DIBAL-H reduction of the ester group into a hydroxyl group, since DIBAL-H high risk during use, while the waste treatment process is complicated more, and catalytic lithium bromide using sodium borohydride reduction of the ester group to give a compound of formula formula-e effective solution to these problems.

[0068] 3.式I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 Synthesis of the compound of formula Formula-e an inert organic solvent [0068] 3. A compound of formula I (ticagrelor) was freed of acetone by acid-catalyzed cross protected L of water to give compound

[0069] [0069]

Figure CN102875537AD00132

[0070] 本发明步骤中对替卡格雷粗品在选自异丙醇、异丙醇-水、乙醚、甲基叔丁基、乙酸乙酯、丙酮、丙酮-乙醚、丙酮-甲基叔丁基醚、丙酮-正己烷、丙酮-石油醚、乙酸乙酯-乙醚、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I (替卡格雷)。 [0070] Step ticagrelor of the present invention is selected from the crude isopropanol, isopropanol - water, diethyl ether, methyl t-butyl, ethyl acetate, acetone, acetone - ether, acetone - 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 crystallized crystallization solvent mixtures to give crystalline formula I (ticagrelor).

[0071]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。 [0071] In summary, the present invention uses economical, efficient, less environmental pollution, simple production operations, the synthesis process for industrial production.

[0072] 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。 [0072] The following examples further illustrate embodiments in conjunction with the present invention, but the present invention is not limited to the embodiments described conditions. 具体实施方式: Detailed ways:

[0073] 实施例I [0073] Example I

[0074] 式Formula-E化合物的合成(结构式中R为乙基): Synthesis of Compound of Formula-E [0074] formula (in the formula R is ethyl):

[0075] 将60g(0. 23mol, I. Oeq)式Formula-D化合物(结构式中R为乙基,制备方法见US2003/0148888),140mL(O. 74mol,3. Oeq)DIPEA,加入900mL THF 中,室温搅拌O. 5 小时待用。 [0075] A 60g (0. 23mol, I. Oeq) Formula-D compound of formula (see formula in which R US2003 / 0148888 is ethyl, prepared), 140mL (O. 74mol, 3. Oeq) DIPEA, 900mL THF was added stirred at room temperature O. 5 hours stand. 将99. 2g(0. 37mol, I. 6eq)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。 The 99. 2g (0. 37mol, I. 6eq) Formula-3 180mLTHF compound of formula is added, cooled to 0_5 ° C, nitrogen was added dropwise a solution of the above-described stand, about an hour, controlling the temperature at 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。 After the dropwise addition, the reaction system was maintained at 0-5 ° C was stirred for two hours, TLC detected no starting material remaining. 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 二氯甲烷搅拌溶解后加入300g硅胶,搅拌,减压浓缩除尽二氯甲烷,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,滤饼娃胶混合物用IOOOml乙酸乙酯搅拌打衆30分钟,抽滤,母液减压浓缩至干得85. 7g 油状物Formula-E,收率76. I %。 Was added 250mL ethyl acetate solution was diluted with water (300 mL) the organic phase with saturated brine (300 mL) wash, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil 150g, 500ml of methylene chloride was added to the oil and stirred to dissolve after adding 300g of silica gel, stirring, dichloromethane divisible concentrated under reduced pressure, 500ml of n-hexane was added, stirred for beating 30 minutes, filtered off with suction, the mother liquor was concentrated under reduced pressure to recover unreacted starting material Formula-3 and a small amount of product Formula-E, the filter cake The mixture was stirred baby play all the gum for 30 minutes IOOOml ethyl acetate, filtered off with suction, the mother liquor was concentrated to dryness under reduced pressure 85. 7g oil Formula-E, yield 76. I%.

[0076] NMR δ H(CDCl3) 8. 56 (1Η, d, J = 7. 6Ηζ),4· 70 (1Η, t, J = 6. 8Ηζ),4· 66 (1H, dd, J=5. 6Hz, J = I. 6Hz) ,4. 55(lH,dd,J = 5. 6Hz, J = I. 2Hz) ,4. 25 〜4. 20(4H,m) ,4. 06 (1H,d, J = 4. 0Hz) ,3. 19 〜3. 03(2H,m),2· 36 〜2. 30(lH,m),2· 03(lH,d,J = 14. 8Hz),I. 81 〜I. 74 (2H, m),I. 42 (3H, s),I. 29 (3H, t, J = 7. 2Hz),I. 26 (3H, s),I. 04 (3H, t, J = 7. 2Hz) · [0076] NMR δ H (CDCl3) 8. 56 (1Η, d, J = 7. 6Ηζ), 4 · 70 (1Η, t, J = 6. 8Ηζ), 4 · 66 (1H, dd, J = 5 . 6Hz, J = I. 6Hz), 4. 55 (lH, dd, J = 5. 6Hz, J = I. 2Hz), 4. 25 ~4. 20 (4H, m), 4. 06 (1H, d, J = 4. 0Hz), 3. 19 ~3. 03 (2H, m), 2 · 36 ~2. 30 (lH, m), 2 · 03 (lH, d, J = 14. 8Hz), I. 81 ~I. 74 (2H, m), I. 42 (3H, s), I. 29 (3H, t, J = 7. 2Hz), I. 26 (3H, s), I. 04 ( 3H, t, J = 7. 2Hz) ·

[0077] 实施例2 [0077] Example 2

[0078] 式Formula-F化合物的合成(结构式中R为乙基): Synthesis of compound of Formula-F [0078] formula (in the formula R is ethyl):

[0079] 将65g(132mmol)式F化合物溶于70mL甲醇中,氮气保护下加入6. 5g含量为10%的钯碳,置换氢气。 [0079] The F Compound 65g (132mmol) was dissolved in 70mL of methanol formula, 6. 5g was added palladium on carbon content of 10% under nitrogen atmosphere, hydrogen was replaced. 室温下常压反应20小时,TLC检测无原料剩余。 Atmospheric pressure at room temperature for 20 hours, TLC detected no starting material remaining. 过滤钯碳,滤饼用50mL甲醇洗涤,浓缩滤液得到57g油状物,无需纯化直接用于下步反应,收率93. 4%。 Palladium-carbon was filtered, the filter cake was washed with 50mL of methanol, and the filtrate was concentrated to give 57g oil without purification was used directly in the next step, yield 93.4%.

[0080] NMR δ H(CDCl3) 6. 32 (1Η, d, J = 7. 6Hz),4. 64 (1H, t,J = 7. 2Hz),4· 57 〜4· 54 (2Η,m),4· 33 〜4. 20 (3Η, m),4· 12 〜4. 07 (1Η, m),3. 98 (1Η, d, J = 4. OHz),3. 76 (2Η, br s), [0080] NMR δ H (CDCl3) 6. 32 (1Η, d, J = 7. 6Hz), 4. 64 (1H, t, J = 7. 2Hz), 4 · 57 ~4 · 54 (2Η, m ), 4 · 33 ~4. 20 (3Η, m), 4 · 12 ~4. 07 (1Η, m), 3. 98 (1Η, d, J = 4. OHz), 3. 76 (2Η, br s),

3. 16 〜3. 09 (1Η, m),3· 03 〜2. 96 (1Η, m),2· 32 〜2. 25 (1Η, m),I. 88 (1Η, d, J = 14. 8Ηζ), 3. 16 ~3. 09 (1Η, m), 3 · 03 ~2. 96 (1Η, m), 2 · 32 ~2. 25 (1Η, m), I. 88 (1Η, d, J = 14 . 8Ηζ),

1. 77 〜I. 71 (2Η, m),I. 41 (3Η, s),I. 29 (3Η, t, J = 7. 2Ηζ),I. 24 (3Η, s),I. 01 (3Η, t, J =7. 2Ηζ). 1. 77 ~I. 71 (2Η, m), I. 41 (3Η, s), I. 29 (3Η, t, J = 7. 2Ηζ), I. 24 (3Η, s), I. 01 ( 3Η, t, J = 7. 2Ηζ).

[0081] 实施例3 [0081] Example 3

[0082] 式Formula-G化合物的合成(结构式中R为乙基): Synthesis of the compounds of Formula-G [0082] formula (in the formula R is ethyl):

[0083]将 52g(113mmol, I. Oeq)式G 化合物溶于150mL 乙臆中。 [0083] The Compound G 52g (113mmol, I. Oeq) was dissolved in 150mL of formula B in the chest. 力口入30. 4mL(226mmol, Force mouth 30. 4mL (226mmol,

2. Oeq)亚硝酸异戊酯,加热到70°C反应I小时,TLC检测无原料剩余。 2. Oeq) isoamyl nitrite, the reaction was heated to 70 ° C I h, TLC detected no starting material remaining. 将反应冷却到室温后浓缩得到51. Ig棕色油状物,收率96.0%,无需进一步纯化,直接用于下步反应。 After the reaction was cooled and concentrated to give room to a brown oil 51. Ig, 96.0% yield, used without further purification, it was used directly in the next step.

[0084] NMR δ H(CDCl3) 5. 52 (1Η, q, J = 3. 5Hz),5· 18 (1Η, dt, J = 10. OHz, J = 3. 5Ηζ), [0084] NMR δ H (CDCl3) 5. 52 (1Η, q, J = 3. 5Hz), 5 · 18 (1Η, dt, J = 10. OHz, J = 3. 5Ηζ),

4. 85(lH,dd, J = 6. 5Hz, J = 2. OHz) ,4. 20 〜4· ll(3H,m),4. 08(2H,d, J = 4. OHz),3· 24 〜 4. 85 (lH, dd, J = 6. 5Hz, J = 2. OHz), 4. 20 ~4 · ll (3H, m), 4. 08 (2H, d, J = 4. OHz), 3 · twenty four ~

3. 18 (2Η, m),2· 79 〜2· 73 (2Η, m),I. 87 〜I. 80 (2Η, m),I. 55 (3Η, s),I. 36 (3Η, s),I. 26 (3Η,t, J = 7. 5Ηζ),I. 09 (3Η, J = 7. 5Ηζ) · 3. 18 (2Η, m), 2 · 79 ~2 · 73 (2Η, m), I. 87 ~I. 80 (2Η, m), I. 55 (3Η, s), I. 36 (3Η, s), I. 26 (3Η, t, J = 7. 5Ηζ), I. 09 (3Η, J = 7. 5Ηζ) ·

[0085] 实施例4 [0085] Example 4

[0086] 式Formula-H化合物的合成(结构式中R为乙基): Synthesis of the compounds of Formula-H [0086] formula (in the formula R is ethyl):

[0087]将 36g(76. 3mmol, I. Oeq)式Formula-G 化合物溶于360mL DCM 中,力卩入12. 9g(76. 3mmol, I. Oeq)式Formu I a-10 化合物(制备方法见专利WO 00/34283)和40. 0mL(228. 9mmol,30eq)DIPEA。 [0087] A 36g (76. 3mmol, I. Oeq) a compound of formula Formula-G was dissolved in 360mL DCM, the force Jie 12. 9g (76. 3mmol, I. Oeq) of formula Formu I a-10 The compound (prepared see patent WO 00/34283) and 40. 0mL (228. 9mmol, 30eq) DIPEA. 室温搅拌过夜,TLC检测无原料剩余。 Was stirred at room temperature overnight, TLC detected no starting material remaining. 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. Ig油状物,收率97.8%,直接用于下步反应。 Each reaction mixture was washed with 300mL of water and 300mL saturated NaCl solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness oil 45. Ig, 97.8% yield, was used directly in the next step .

[0088] ESI-MS :605(M+H+) [0088] ESI-MS: 605 (M + H +)

[0089] 实施例5 [0089] Example 5

[0090] 式Formula-e化合物的合成: Compound of Formula-e [0090] Synthesis of the formula:

[0091]在氮气保护下将 O. 26g(6. 87mmol,2. 5eq)硼氢化钠,O. 6g(6. 9mmol,2. 5eq)溴化锂加入5mL THF中。 [0091] Under a blanket of nitrogen O. 26g (6. 87mmol, 2. 5eq) of sodium borohydride, O. 6g (6. 9mmol, 2. 5eq) in 5mL THF was added lithium bromide. 上述反应液控制温度在50°C,搅拌45分钟。 The reaction solution temperature was controlled at 50 ° C, stirred for 45 minutes. 滴加30g(49. 6mmol, I. Oeq)式Formula-H化合物溶解在IOOmL 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。 Was added dropwise 30g (49. 6mmol, I. Oeq) Formula-H compound of the formula dissolved in IOOmL THF solution, controlling the temperature at 50 ° C, was added dropwise for 30 minutes after the end of dropwise 2mL of methanol was added dropwise. 滴加180mL7jC,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。 Dropwise 180mL7jC, generating a large amount of gas, dropping control to prevent red material, 40 ° C after the dropwise addition reaction-hours, TLC detected no starting material remaining. 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。 The reaction product was extracted with ethyl acetate 500mL was added, the organic phase washed once each with 300mL water and 300mL saturated brine, dried over anhydrous sodium sulfate, organic phase was concentrated to give 24. 4g oil, 87.4% yield, was used directly in the next step reaction.

[0092] ESI-MS :563 (M+H+) [0092] ESI-MS: 563 (M + H +)

[0093] 实施例6 [0093] Example 6

[0094] 式I化合物(替卡格雷)的合成: [0094] The compounds of formula I (ticagrelor) Synthesis of:

[0095]将 24g (42. 7mmo1)式Formula-e 化合物溶于12OmL 甲苯中,5-10 °C 下滴力口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。 [0095] A 24g (42. 7mmo1) a compound of formula Formula-e was dissolved in 12OmL of toluene, at 5-10 ° C opening force drops 50mL / 50mL of concentrated hydrochloric acid / methanol was added dropwise maintaining the temperature after the reaction at about 5 ° C 30 minutes. 加入50mL /K,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PH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IOOml水和IOOml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. Ig油状物。 Was added 50mL / K, standing stratified dispensing comprising water and methanol hydrochloride product phase, water / methanol system with a saturated sodium bicarbonate solution The aqueous phase was adjusted to PH 6-7, 200mL of ethyl acetate was added to extract the product, The organic phase was separated, the aqueous layer was re-extracted once with 200ml of ethyl acetate, the combined organic phases, the organic phase respectively IOOml IOOml water and saturated brine, the organic phase was dried over anhydrous sodium sulfate, decolorized with charcoal, filtered, and concentrated to give 19. Ig oil.

[0096] 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30〜40°C,加入O. Ig替卡格雷晶种进行诱导,慢慢有大量固体析出,搅拌冷却至O〜5°C,搅拌析晶3小时,抽滤,滤饼干燥,得类白色固体14. 4g,将得到的粗品用144ml乙酸乙酯加热完全溶解,缓慢滴加115. 2ml正己烷,慢慢有大量白色固体析出,搅拌冷却至O〜5°C,搅拌析晶3小时,抽滤,滤饼用20ml乙酸乙酯/正己烷=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%0 [0096] The above oil 152. 8ml acetonitrile were added, dissolved by heating with stirring, slowly cooled to 30~40 ° C, was added O. Ig induced ticagrelor seed, there are large amount of solid precipitated and slowly cooled with stirring to O~5 ° C, crystallization was stirred for 3 hours and filtered off with suction, the filter cake was dried to give an off-white solid 14. 4g, heating the resulting crude product was completely dissolved with 144ml ethyl acetate and n-hexane was slowly added dropwise 115. 2ml, slowly large amount of white solid was precipitated, stirring was cooled to O~5 ° C, crystallization was stirred for 3 hours and filtered off with suction, the filter cake was washed with n-hexane ethyl acetate 20ml / = 10/8 mixed solvent, drained and the cake dried 40 ° C under vacuum to give a white solid 12. 9g, HPLC purity> 99%, yield: 578% 0

[0097] ESI-MS :523 (M+H.) [0097] ESI-MS: 523 (M + H.)

[0098]匪R δ H (DMSO) 9. 35 (1Η, d, J = 4. OHz),7. 35 〜7. 28 (2H,m),7. 08 (1H,m),5. 10 (1H, d, J = 6. 4Hz),5. 03 (1H, d, J = 4. OHz),4. 96 (1H, q, J = 9. 2Hz),4· 60 〜4. 50 (2Η,m),3· 95(lH,br s),3· 76(lH,m),3· 52 〜3· 47(4H,m),3· 16 〜3· 09(lH,m),2· 97 〜2· 92 (1Η,m),2· 88 〜2· 83 (1Η, m) 2. 63 (1Η, dt, J = 13. 6Hz, J = 8. 4Ηζ),2· 30 〜2· 22and 2. 16 〜2. 08 (1Η, m),2· 07 〜2. 00 (1Η, m),I. 70 〜I. 35 (4Η, m),O. 99and 0. 82 (3H, t, J = 7. 2). [0098] bandit R δ H (DMSO) 9. 35 (1Η, d, J = 4. OHz), 7. 35 ~7. 28 (2H, m), 7. 08 (1H, m), 5. 10 (1H, d, J = 6. 4Hz), 5. 03 (1H, d, J = 4. OHz), 4. 96 (1H, q, J = 9. 2Hz), 4 · 60 ~4. 50 ( 2Η, m), 3 · 95 (lH, br s), 3 · 76 (lH, m), 3 · 52 ~3 · 47 (4H, m), 3 · 16 ~3 · 09 (lH, m), 2 · 97 ~2 · 92 (1Η, m), 2 · 88 ~2 · 83 (1Η, m) 2. 63 (1Η, dt, J = 13. 6Hz, J = 8. 4Ηζ), 2 · 30 ~ 2 · 22and 2. 16 ~2. 08 (1Η, m), 2 · 07 ~2. 00 (1Η, m), I. 70 ~I. 35 (4Η, m), O. 99and 0. 82 (3H , t, J = 7. 2).

Claims (31)

1. 一种合成替卡格雷的中间体,为式Formula-E化合物: 1. A synthetic intermediate ticagrelor, Formula-E is a compound of the formula:
Figure CN102875537AC00021
其中上述结构式中R为Cl〜C6低级烷基。 Wherein the above formula R is a lower alkyl group Cl~C6.
2.制备权利要求I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HCl反应生成式Formula-E化合物。 I 2. A method as claimed in claim preparing the compound, which is: Formula-3 a compound of formula with a compound of formula Formula-D part off the condensation reaction of a compound of formula HCl Formula-E do alkaline environment.
Figure CN102875537AC00022
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Cl〜C4卤代芳烃,C2〜C6的醚,C2〜C6的腈。 3. The method according to claim 2, wherein the inert organic solvent is selected Cl~C4 halogenated aromatic hydrocarbons, C2~C6 ether, 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. The method according to claim 3 wherein said 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(DIPEA),三乙胺或吡啶。 5. The method according to claim 2, wherein the organic base is diisopropylethylamine (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。 6.5 The method according to claim, wherein 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I : I : I〜I : 3 : 6。 7. The method according to claim 2, wherein the compound of formula Formula-D compound of formula Formula-3 and the molar ratio of the organic base is I: I: I~I: 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 -10~50 ° C.
9. 一种合成替卡格雷的中间体,为式Formula-F化合物: A synthetic intermediate ticagrelor, Formula-F is a compound of the formula:
Figure CN102875537AC00023
其中上述结构式中R为Cl〜C6低级烷基。 Wherein the above formula R is a lower alkyl group Cl~C6.
10.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。 10. The method for preparing a compound as claimed in claim 9, the method is: Formula-E compound of formula by catalytic hydrogenation catalyst reduction of the nitro-amino manner in an organic solvent.
Figure CN102875537AC00031
11.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。 11. The method according to claim 10, characterized in that all the solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, methyl tertiary butyl ether and mixed solvents thereof.
12.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。 12. The method according to claim 10, wherein the catalyst is a palladium on carbon catalyst.
13.根据权利要求10所述方法,其特征在于,所述加入式Formula-E化合物与含钮10%的钯碳的质量比为I : : O. 01〜I : I。 13. The method according to claim 10, characterized in that the added mass of the compound of formula Formula-E containing 10% palladium on carbon button ratio of I:: O. 01~I: I.
14.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O〜50摄氏度。 14. The method of claim 10, wherein said chemical reaction temperatures O~50 degrees Celsius.
15. —种合成替卡格雷的中间体,为式Formula-G化合物 15. - ticagrelor synthetic intermediate, Formula-G is a compound of formula
Figure CN102875537AC00032
其中上述结构式中R为Cl〜C6低级烷基。 Wherein the above formula R is a lower alkyl group Cl~C6.
16.制备权利要求15所述化合物的方法,该方法为:式Formula-F化合物在有机溶剂中与亚硝酸异戍酯反应形成三氮唑环结构的式Formula-G化合物。 16. The method for preparing a compound as claimed in claim 15, which is:-F Formula compound of formula in an organic solvent is reacted with isoamyl nitrite to form a compound of formula Formula-G triazole ring structure.
Figure CN102875537AC00033
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。 17. 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Formula-F化合物和亚硝酸异戊酯的摩尔比为I : I〜I : 5。 18. The method according to claim 16, wherein the molar ratio of the added compound of formula Formula-F and isoamyl nitrite is I: I~I: 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O〜80摄氏度。 19. The method according to claim 16, wherein said chemical reaction temperatures O~80 degrees Celsius.
20. 一种合成替卡格雷的方法,包括如下步骤: (a)式Formula-G化合物在惰性有机溶剂中与式Formula-IO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 20. A method for the synthesis of ticagrelor, comprising the steps of: Formula-G compound (a) with a compound of Formula Formula Formula-IO off part of the hydrogen chloride resulting from the condensation of formula Formula-H compound under basic conditions in an inert organic solvent
Figure CN102875537AC00041
其中上述结构式中R为Cl〜C6低级烷基(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Formu I ae 化合物。 Wherein the above formula R is a lower alkyl group Cl~C6 Formula-H compound formula (b) by a reduction reaction, reduction of the ester group to give the structure of formula in an inert organic solvent Formu I ae compound.
Figure CN102875537AC00042
(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I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 compound of formula (C) free acetone to give protected compound of formula fork I (ticagrelor) of the crude product by acid-catalyzed water in an organic solvent, the crude product was purified via solvent ticagrelor high quality products.
Figure CN102875537AC00043
21.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烷。 21. The method according to claim 20, wherein said step of a chosen reaction medium is methylene chloride.
22.根据权利要求20所述方法,其特征在于,所述步骤a所采用的有机碱可以为二异丙基乙胺,三乙胺或吡啶。 22. The method according to claim 20, wherein said step employed a base may be an organic diisopropylethylamine, triethylamine or pyridine.
23.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。 23. The method according to claim 22, wherein the organic base is diisopropylethylamine.
24.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-IO化合物以及有机碱的摩尔比为I : I : I〜I : 3 : 6。 24. The method according to claim 20, wherein the molar ratio of the added step a compound of formula Formula-G, Formula-IO compounds of formula and an organic base is I: I: I~I: 3: 6.
25.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。 25. The method according to claim 20, wherein the temperature of the reaction is a step of -10~50 ° C.
26.根据权利要求20所述方法,其特征在于,所述步骤b所述惰性有机溶剂为四氢呋喃。 26. The method according to claim 20, wherein said step b said inert organic solvent is tetrahydrofuran.
27.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。 27. The method according to claim 20, wherein said reducing agent is preferably employed in step b is sodium borohydride.
28.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。 28. The method according to claim 20, characterized in that, the reduction catalyst employed in step b is lithium bromide.
29.根据权利要求20所述方法,其特征在于,所述步骤b加入式Formula-H化合物,硼氢化钠以及溴化锂的摩尔比为I : I : I〜I : 5 : 5。 29. The method according to claim 20, wherein said step b is added a compound of formula Formula-H, the molar ratio of sodium boron hydride and lithium bromide as I: I: I~I: 5: 5.
30.根据权利要求20所述方法,其特征在于,所述步骤b反应的温度为O〜80摄氏度。 30. The method according to claim 20, wherein the reaction temperature of step b is O~80 degrees Celsius.
31.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、乙醚、甲基叔丁基、乙酸乙酯、丙酮、丙酮-乙醚、丙酮-甲基叔丁基醚、丙酮-正己烷、丙酮-石油醚、乙酸乙酯-乙醚、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I (替卡格雷)。 31. The method according to claim 20, wherein said step (c) is selected from solvent refined isopropanol, isopropanol - water, diethyl ether, methyl t-butyl, ethyl acetate, acetone, acetone - diethyl ether acetone - 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 crystalline solvent crystallized to obtain a crystalline state of formula I (ticagrelor).
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