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Preparation method of ticagrelor intermediate

A technology for ticagrelor and intermediates, which is applied in the field of preparation of new anticoagulant drug ticagrelor intermediates, can solve the problems of long preparation route and failure to meet the requirements of green chemical atom economy, and achieve product yield And the effect of high product purity, fast and convenient preparation process

Active Publication Date: 2014-05-14
安徽超宸信息科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since the preparation process of intermediates A, B and C itself cannot be omitted, and the amino group of intermediate B must be PG-protected when intermediates A and B are condensed, the entire preparation route is relatively long and requires protection and deprotection. Does not meet the atom economy requirements of green chemistry

Method used

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  • Preparation method of ticagrelor intermediate
  • Preparation method of ticagrelor intermediate
  • Preparation method of ticagrelor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment one (condensation reaction):

[0031] Add 6-amino-2,3-dihydro-2-thioxo-4(1H)-pyrimidinone (II) (14.3g, 0.1mol), (1R,2S)-2-(3, 4-Difluorophenyl)cyclopropylamine (Intermediate B) (25.4 g, 0.15 mol) and acetic acid 25 mL. The temperature was raised to 170° C., and the reaction was carried out for 6 hours, and the raw materials basically disappeared as detected by TLC. Cool down to 50°C, add 500 mL of water, and stir at 0-5°C for 24 hours. Filter, recrystallize the filter cake with 50% ethanol, and dry it under vacuum at 50-55°C to obtain off-white solid 6-[[N-(1R.2S)-2-(3,4-difluorophenylcyclopropane)-1 -yl]amine]-2,3-dihydro-2-thio-4(1H)-pyrimidinone (III) 22.3 g, yield 75.3%.

Embodiment 2

[0032] Embodiment two (alkylation reaction / scheme one):

[0033] Add 6-[[N-(1R.2S)-2-(3,4-difluorophenylcyclopropane)-1-yl]amine]-2,3-dihydro-2-thio -4(1H)-Pyrimidinone (III) (2.96g, 10mmol), potassium hydroxide solution (0.1M, 50mL) and methanol 25mL, add bromopropane (1.53g, 12.5mmol) methanol solution 25mL dropwise at room temperature . The reaction was stirred at room temperature for 15 hours. The solvent was recovered under reduced pressure, the residue was extracted 3 times with dichloromethane, the organic phases were combined, dried, and distilled under reduced pressure to obtain the oil 6-hydroxyl-4-[[N-(1R.2S)-2-(3,4- Difluorophenylcyclopropane)-1-yl]amine]-2-(propylmercapto)pyrimidine (IV) 2.9 g, yield 86.1%.

Embodiment 3

[0034] Embodiment three (nitration reaction / scheme one):

[0035] Add 6-hydroxy-4-[[N-(1R.2S)-2-(3,4-difluorophenylcyclopropane)-1-yl]amine]-2-(propylmercapto)pyrimidine to the reaction flask (IV) (1.7g, 5mmol) and 20ml of acetic acid, add 5ml of 65% nitric acid dropwise under stirring at room temperature, heat up to 30-35°C, stir slowly until the reaction solution is yellow-green, and solids are precipitated, then cool down to 5-10°C, Add 20ml of water, stir for 2 hours, filter, wash the filter cake with 5mL of ice water, and dry in vacuum for 2 hours to obtain a light yellow solid 6-hydroxy-4-[[N-(1R.2S)-2-(3,4-di Fluorophenylcyclopropane)-1-yl]amine]-5-nitro-2-(propylmercapto)pyrimidine (V) 1.60 g, yield 83.8%.

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Abstract

The invention discloses a preparation method of a ticagrelor intermediate, namely, 6-chloro-4-[[N-(1R,2S)-2-(3,4-difluorophenylcyclopropane)-1-yl]amine]-5-nitro-2-(mercaptopropyl)pyridine (I). The method comprises the following step: performing a unit reaction consisting of condensation, alkylation, nitration and chlorination on 6-amino-2,3-dihydro-2-sulfo-4(1H)-pyrimidone (II) serving as a raw material to obtain the ticagrelor intermediate, namely, 6-chloro-4-[[N-(1R,2S)-2-(3,4-difluorophenylcyclopropane)-1-yl]amine]-5-nitro-2-(mercaptopropyl)pyridine (I). The preparation method is simple in process, economical, environment-friendly and high in chemical and chiral purity, and the economical and technical development of ticagrelor serving as a bulk pharmaceutical can be promoted.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a novel anticoagulant drug ticagrelor intermediate. Background technique [0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine di The phosphate receptor antagonist has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011, respectively, and was launched in the EU and the US under the trade name Brilinta. Its imported preparation, ticagrelor tablets, has been approved by the China Food and Drug Administration...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 许学农
Owner 安徽超宸信息科技有限公司
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