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Preparation method of Ticagrelor intermediate

A technology for ticagrelor and intermediates, which is applied in the field of preparation of ticagrelor intermediates, can solve the problems of unsuitability for large-scale industrial production, column purification of products, and many side reactions, and achieve high product yields and excellent reaction conditions. Gentle and easy to control, easy to operate effect

Active Publication Date: 2012-11-28
JINAN RUIFENG PHARMA +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0027] It is not difficult to find out that although there are many synthetic routes of announced trans-(1R, 2S)-2-(3,4-difluorophenyl)-cyclopropylamine, there are still many weak points: the steps are longer, As a result, the yield is not high, or there are too many side reactions, and the product needs column purification; expensive and hard-to-buy reagents are used; flammable and explosive dangerous reagents and reagents that pollute the environment are used. These unfavorable factors make these The synthetic route is not suitable for large-scale industrial production of the product

Method used

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  • Preparation method of Ticagrelor intermediate
  • Preparation method of Ticagrelor intermediate
  • Preparation method of Ticagrelor intermediate

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Embodiment Construction

[0051] The present invention is further illustrated by the following examples, which are only for illustration and not for limiting the present invention.

[0052] The preparation method of this ticagrelor intermediate adopts the following steps:

[0053] (1) Preparation of ethyl 3,4-difluorocinnamate:

[0054] a) Preparation of phosphorus ylide feed liquid:

[0055] Add 16.6g of triethyl phosphite, 80ml of tetrahydrofuran, and 12.2ml of ethyl α-bromoacetate to the first reaction flask in sequence, stir, heat, and reflux for 2 hours, stop heating, cool down to room temperature naturally, and then control the temperature in an ice-water bath Add 12.5 g of sodium tert-butoxide in batches to the first reaction flask at around 0°C, stir for 1 hour, and use it directly for the reaction of preparing ethyl 3,4-difluorocinnamate;

[0056] b) Preparation of ethyl 3,4-difluorocinnamate:

[0057] Add 12.8g of 3,4-difluorobenzaldehyde (I) and 60ml of tetrahydrofuran to the second react...

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Abstract

The invention relates to the medicine chemical synthesis field, and especially discloses a preparation method of a Ticagrelor intermediate. The preparation method comprises the following steps: 1) taking 3,4-difluorobenzaldehyde (I) as an initial raw material, reacting with a phosphorus ylide material liquid to obtain (E)-3-(3,4-difluorophenyl)-2-acrylic acid ester (II); 2) performing a Simons-Smith asymmetric cyproteronethe reaction on the (E)-3-(3,4-difluorophenyl)-2-acrylic acid ester (II) to obtain trans-(1R,2R)-2-(3,4-difluorophenyl) cyclopropanecarboxylic acid ester (III); 3) performing aminolysis on the trans-(1R,2R)-2-(3,4-difluorophenyl) cyclopropanecarboxylic acid ester to obtain trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxamide (IV); and 4) performing a Huffman rearrangement reaction on the trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxamide (IV) to obatain the Ticagrelor intermediate (V). The method of the invention has the advantages of simple process, convenient operation, mild reaction condition and easy control, low cost and easy acquisition of raw material, high product yield and product purity, and is adapted to large scale industrial production.

Description

(1) Technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of a ticagrelor intermediate. (2) Background technology [0002] Ticagrelor, English name ticagrelor, chemical name (1S, 2S, 3R, 5s)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino]- 5-(thiopropyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2 -diol is a novel, selective small molecule anticoagulant drug developed by AstraZeneca. The drug has obvious inhibitory effect on platelet aggregation caused by ADP, and the effect is rapid after oral administration, so it can effectively improve the symptoms of patients with acute coronary heart disease. [0003] Trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine is an important intermediate for the synthesis of ticagrelor, and its structural formula is [0004] [0005] The preparation method of currently announced trans-(1R, 2S)-2-(3,4-difluorophenyl)-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/40C07C209/58
Inventor 刘效祥张强高云兵姚冬娜
Owner JINAN RUIFENG PHARMA
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