WO2014036823A1 - Nouveau procédé de préparation d'un médicament antithrombotique - Google Patents

Nouveau procédé de préparation d'un médicament antithrombotique 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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Prior art keywords
formula
compound
ticagrelor
reaction
organic solvent
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PCT/CN2013/073061
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English (en)
Chinese (zh)
Inventor
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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Publication of WO2014036823A1 publication Critical patent/WO2014036823A1/fr

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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de ticagrelor anticoagulant de type micromolécule, un intermédiaire pour la synthèse du ticagrelor et un procédé de préparation de l'intermédiaire. Au moyen de ce procédé de synthèse, la réaction secondaire dans le procédé de réaction peut être efficacement réduite, la pureté de l'intermédiaire est améliorée et la voie de purification de l'intermédiaire est simplifiée.
PCT/CN2013/073061 2012-09-10 2013-03-22 Nouveau procédé de préparation d'un médicament antithrombotique WO2014036823A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2012103312665A CN102875537A (zh) 2012-09-10 2012-09-10 一种新的抗血栓药物的制备方法
CN201210331266.5 2012-09-10

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Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875537A (zh) * 2012-09-10 2013-01-16 常州制药厂有限公司 一种新的抗血栓药物的制备方法
WO2014155389A2 (fr) * 2013-03-25 2014-10-02 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation de ticagrelor
CN104098570A (zh) * 2013-04-07 2014-10-15 杭州领业医药科技有限公司 替卡格雷晶型及其制备方法和用途
CN107573333B (zh) 2013-04-10 2019-10-18 江苏恒瑞医药股份有限公司 替格瑞洛的中间体及其制备方法和替格瑞洛的制备方法
CN103360396B (zh) * 2013-06-27 2015-07-01 苏州明锐医药科技有限公司 一种替格瑞洛的制备方法
CN103524429B (zh) * 2013-09-28 2015-08-19 银杏树药业(苏州)有限公司 一种替格瑞洛及其新的中间体的制备方法
CN103992323B (zh) * 2014-04-18 2017-03-29 南通常佑药业科技有限公司 一种替格瑞洛的制备方法
US10011605B2 (en) 2014-06-18 2018-07-03 Flamma Spa Process for the preparation of triazolo[4,5-D] pyrimidine cyclopentane compounds
CN104193748A (zh) * 2014-08-14 2014-12-10 严白双 一种替卡格雷的合成方法
CN105732632B (zh) * 2014-12-09 2020-05-15 翰宇药业（武汉）有限公司 一种制备替格瑞洛的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) * 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
CN101235024A (zh) * 2008-02-01 2008-08-06 中国科学院上海有机化学研究所 一类苯并二氢吡喃类化合物、合成方法和用途
WO2011017108A2 (fr) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Modulateurs cyclopropylés du récepteur p2y12
WO2012138981A2 (fr) * 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. Nouveaux intermédiaires et procédés pour la préparation du ticagrelor
CN102875537A (zh) * 2012-09-10 2013-01-16 常州制药厂有限公司 一种新的抗血栓药物的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0013488D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Chemical compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034283A1 (fr) * 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
CN101235024A (zh) * 2008-02-01 2008-08-06 中国科学院上海有机化学研究所 一类苯并二氢吡喃类化合物、合成方法和用途
WO2011017108A2 (fr) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Modulateurs cyclopropylés du récepteur p2y12
WO2012138981A2 (fr) * 2011-04-06 2012-10-11 Teva Pharmaceutical Industries Ltd. Nouveaux intermédiaires et procédés pour la préparation du ticagrelor
CN102875537A (zh) * 2012-09-10 2013-01-16 常州制药厂有限公司 一种新的抗血栓药物的制备方法

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