WO2015067110A1 - Procédé de préparation d'intermédiaire de ticagrelor - Google Patents

Procédé de préparation d'intermédiaire de ticagrelor Download PDF

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Publication number
WO2015067110A1
WO2015067110A1 PCT/CN2014/088176 CN2014088176W WO2015067110A1 WO 2015067110 A1 WO2015067110 A1 WO 2015067110A1 CN 2014088176 W CN2014088176 W CN 2014088176W WO 2015067110 A1 WO2015067110 A1 WO 2015067110A1
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WO
WIPO (PCT)
Prior art keywords
rel
dimethyl
ethanol
oxy
acid
Prior art date
Application number
PCT/CN2014/088176
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English (en)
Chinese (zh)
Inventor
许学农
Original Assignee
苏州明锐医药科技有限公司
哲人药业南京有限公司
许学农
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Application filed by 苏州明锐医药科技有限公司, 哲人药业南京有限公司, 许学农 filed Critical 苏州明锐医药科技有限公司
Publication of WO2015067110A1 publication Critical patent/WO2015067110A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems

Definitions

  • the invention belongs to the technical field of organic synthesis route design and preparation technology of raw materials and intermediates, in particular to a intermediate of ticagrelor 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2 - A process for the preparation of dimethyl-4H-cyclopenta-1,3-dioxa-4-yl]oxy]ethanol.
  • Ticagrelor is a new type of selective small molecule anticoagulant developed by AstraZeneca. It is also the first reversible combined oral P2Y12 adenosine II. Phosphate receptor antagonists have a significant inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease.
  • the drug was marketed in the European Union and the United States in 2010 and 2011 through the approval of the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA).
  • EMEA European Medicines Agency
  • FDA US Food and Drug Administration
  • the imported formulation of ticagrelor tablets has been approved by the CFDA for listing in China.
  • the chemical name of the intermediate C studied in the present invention is: 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene-1,3 -Dioxa-4-yl]oxy]ethanol, the main synthetic routes are as follows:
  • Patent WO2011017108, WO9905142, CN102659815, etc. reported that cyclopentadiene is used as a raw material, which is formed into a ring by Diels-Alder reaction, and then subjected to oxidation, ketalization, reduction, amino protection, esterification and reduction, deprotection and the like to obtain a target intermediate. Body C.
  • Another more commonly used method is to control the optical purity of the preparation process by using D-ribose as a starting material through its inherent natural chiral center.
  • Patent WO2011017108, WO2013092900 and Bioorganic & Medicinal Chemistry Letters 2012, 22, pp. 3598-3602 report D-ribose by fork acetone, 1-position methylation, 5-iodo, zinc/acetic acid ring opening, hydroxyl amination, A method for preparing intermediate C by a step of cyclization, amino protection, esterification and reduction, deprotection, and the like.
  • the object of the present invention is to overcome the defects of the prior art and provide a new intermediate of ticagrelor 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetrahydro-2 according to the synthesis concept of green chemistry. , a method for preparing 2-dimethyl-4H-cyclopenteno-1,3-dioxa-4-yl]oxy]ethanol, which is simple, economical and environmentally friendly, and is advantageous for industrial production of the drug And can promote the economic and technological development of ticagrelor bulk drugs.
  • the method comprises the steps of: (1R, 2R, 3R, 4R)-rel-1, 2; 3,4-diepoxycyclopentane (I) simultaneously occurring in a mixed solvent of acetone and water with sodium azide Ring-opening reaction and ketalization reaction give compound (3aR, 4S, 6R, 6aS)-rel-6-azido tetrahydrogen -2,2-dimethyl-4H-cyclopenteno-1,3-dioxo-4-ol (II); compound (3aR, 4S, 6R, 6aS)-rel-6-azido four Hydrogen-2,2-dimethyl-4H-cyclopenteno-1,3-dioxo-4-ol (II) is formed by etherification with 2-haloethanol to form compound 2-[[(3aR) , 4S, 6R, 6aS)-rel-6-azidotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-di
  • the molar ratio of (1R, 2R, 3R, 4R)-rel-1, 2; 3,4-diepoxycyclopentane (I) and sodium azide in the ring-opening reaction is 1:1 Preferably, it is 1:1.1-1.3.
  • the molar ratio of the alcohol (II) to the 2-haloethanol is from 1:1 to 3, preferably from 1:1.5 to 2.0.
  • the halogen in the 2-haloethanol is chlorine, bromine or iodine, preferably chlorine or bromine.
  • the acid binding agent of the etherification reaction is potassium carbonate, potassium hydroxide, potassium t-butoxide, sodium methoxide, sodium hydride, triethylamine, pyridine or sodium hydroxide, preferably potassium t-butoxide or sodium hydride.
  • the reduction reaction may be carried out by reduction of metallic iron, zinc, tin, aluminum, indium or bismuth, or may be reduced by hydrazine hydrate/iron trichloride, sodium borohydride, zinc borohydride or lithium aluminum hydride, and palladium may also be used.
  • Hans ester 1,4-dihydropyridine (HEH) under carbon catalysis Reduction preferably Hans ester 1,4-dihydropyridine (HEH) reduction under the catalysis of palladium on carbon.
  • the resolving agent for the resolution reaction is L-tartaric acid, D-tartaric acid, L-mandelic acid, D-mandelic acid, diacetyl-L-tartaric acid, dibenzoyl-L-tartaric acid, D-camphorsulfonic acid L-camphorsulfonic acid, L-phenylglycine, D-phenylglycine, L-malic acid, D-malic acid, L-aspartic acid or L-glutamic acid, preferably L-tartaric acid or D-mandelic acid.
  • the ticagrelor intermediate 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene) of the present invention is compared to the prior art.
  • the preparation method of p-1,3-dioxa-4-yl]oxy]ethanol has the advantages that the synthesis steps are simple, the reaction conditions are mild and easy to control, the raw materials are cheap and easy to obtain, the product yield and the product purity are high, suitable For large-scale industrial production.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de l'intermédiaire du ticagrelor 2-[[(3aR,4S,6R,6aS)-6-aminotétrahydro-2,2-diméthyl-4H-cyclopenta-1,3-dioxan-4-yl]oxy]éthanol (intermédiaire C). Le procédé de préparation utilise le (1R,2R,3R,4R)-rel-1,2:3,4-diépoxycyclopentane (I) comme matière première, et le produit cible est obtenu au moyen des étapes successives d'ouverture du cycle azide, de formation de cétal, d'éthérification, de réduction et de résolution. La matière première du procédé de préparation est aisément accessible, le procédé est simple, le coût de production peut être contrôlé efficacement, et la qualité du produit est améliorée, facilitant une mise au point technique économique de principes actifs ticagrelor en vrac.
PCT/CN2014/088176 2013-11-07 2014-10-09 Procédé de préparation d'intermédiaire de ticagrelor WO2015067110A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310547549.8A CN103588750B (zh) 2013-11-07 2013-11-07 替卡格雷中间体的制备方法
CN201310547549.8 2013-11-07

Publications (1)

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WO2015067110A1 true WO2015067110A1 (fr) 2015-05-14

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WO (1) WO2015067110A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588750B (zh) * 2013-11-07 2014-11-26 苏州明锐医药科技有限公司 替卡格雷中间体的制备方法
CN106496179A (zh) * 2016-10-19 2017-03-15 青岛云天生物技术有限公司 一种替格瑞洛中间体的合成工艺
CN106496180A (zh) * 2016-10-19 2017-03-15 青岛云天生物技术有限公司 一种替格瑞洛中间体的制备方法
CN107382953A (zh) * 2017-07-25 2017-11-24 安徽诺全药业有限公司 一种制备多取代环戊烷衍生物的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013092900A1 (fr) * 2011-12-23 2013-06-27 Lek Pharmaceuticals D.D. Synthèse de composés de triazolopyrimidine
CN103304437A (zh) * 2013-05-16 2013-09-18 广州同隽医药科技有限公司 一种无叠氮合成磷酸奥司他韦的方法
CN103408746A (zh) * 2013-07-23 2013-11-27 西北工业大学 一种端基含双叠氮基的聚乙二醇单甲醚的制备方法
CN103588750A (zh) * 2013-11-07 2014-02-19 苏州明锐医药科技有限公司 替卡格雷中间体的制备方法

Family Cites Families (3)

* 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
CA2768043A1 (fr) * 2009-07-27 2011-02-10 Auspex Pharmaceuticals, Inc. Modulateurs cyclopropyles du recepteur p2y12
CN102659815B (zh) * 2012-05-04 2013-07-17 开原亨泰制药股份有限公司 一种制备选择性抗凝血药替卡格雷及其中间体的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013092900A1 (fr) * 2011-12-23 2013-06-27 Lek Pharmaceuticals D.D. Synthèse de composés de triazolopyrimidine
CN103304437A (zh) * 2013-05-16 2013-09-18 广州同隽医药科技有限公司 一种无叠氮合成磷酸奥司他韦的方法
CN103408746A (zh) * 2013-07-23 2013-11-27 西北工业大学 一种端基含双叠氮基的聚乙二醇单甲醚的制备方法
CN103588750A (zh) * 2013-11-07 2014-02-19 苏州明锐医药科技有限公司 替卡格雷中间体的制备方法

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CN103588750A (zh) 2014-02-19

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