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Preparation method of Cangrelor intermediate

A technology for intermediates and compounds, applied in the field of preparation of cangrelor intermediate 6-N-ethyl-2-thio)adenosine, capable of solving problems such as low yield, unfavorable environment, production operation, and high price

Inactive Publication Date: 2016-10-12
北京广博德赛医药技术开发有限责任公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, the market supply of raw material 2-mercaptoadenosine is low and the price is high, and the preparation of the raw material requires the use of highly toxic carbon disulfide, and the by-product is highly toxic hydrogen sulfide, which is not conducive to the environment and production operations, and the yield is low and each step is expensive. Silica gel column chromatography is required, which is not conducive to the realization of industrial production

Method used

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  • Preparation method of Cangrelor intermediate
  • Preparation method of Cangrelor intermediate
  • Preparation method of Cangrelor intermediate

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Embodiment 1

[0066] A preparation method of 6-N-(2-(methylthio)ethyl-2-((3,3,3-trifluoropropyl)thio)adenosine (I), comprising the following steps:

[0067] (1) Preparation of compound 16

[0068] At room temperature, weigh 101.5g ((1.88mol) of sodium methoxide and add it to a 3L reaction bottle of 670g ethanol, stir to dissolve it completely, add 67.3g (0.88mol) of thiourea. Heat to 55°C, weigh ethyl cyanoacetate Add 100g (0.884mol) of the ester into the reaction flask and heat to reflux. After 4.5h of reflux, the TLC reaction is complete, lower to 15°C, filter, wash the filter cake once with 170g of ethanol, take out the filter cake, add it to a 3L reaction flask, and add Stir 1.3kg of water to dissolve it, add acetic acid below 20°C, adjust the pH to 4, and a large amount of solids precipitate out. Suction filtration. The filter cake is dried at 45°C overnight to obtain 115.4g of the product, with a yield of 91.7%.

[0069] (2) Preparation of compound 17

[0070] At room temperature, w...

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Abstract

The invention discloses a preparation method of a Cangrelor intermediate. The preparation method comprises the following steps of enabling ethyl cyanoacetate and thiourea to perform closed-loop reaction to generate a product under the alkaline condition, reacting the product and trifluoropropane under the alkaline condition, performing nitration reaction and reduction reaction, and performing closed-loop reaction with formic acid; chlorinating the generated product, and performing condensation reaction on the product and 2-(thiomethyl)ethylamine under the alkaline condition; reacting the obtained product and 1,2,3,5-tetraacetyl-beta-D-ribofuranose under the actions of alkylating agent and TMSOTF (trimethylsilyl trifluoromethanesulfonate), and hydrolyzing the product under the alkaline condition, so as to obtain the Cangrelor intermediate. The preparation method has the advantages that the silica-gel column chromatography is not needed, so that the technology cost is greatly reduced; the carbon disulfide, fuming nitric acid or concentrated sulfuric acid is not used in the preparation process, so that any danger is avoided; the noble metal hydrogenating reducing agent is not needed, so that the cost is reduced, and the operation danger is decreased; the operation is easy, safe and reliable, and the preparation method is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a method for preparing cangrelor intermediate 6-N-(2-(methylthio)ethyl-2-((3,3,3-trifluoropropyl)thio)adenosine (I) The preparation method belongs to the technical field of drug synthesis. [0002] Background technique [0003] 6-N-(2-(methylthio)ethyl-2-((3,3,3-trifluoropropyl)thio)adenosine (I) is an N-alkyl-2-substituted ATP analog , is the core structure of the intravenous P2Y12 receptor antagonist Cangrelor (1). Cangrelor (1) (cangrelor / Kengreal) is an intravenous P2Y12 receptor antagonist for the treatment of patients with coronary artery disease (CAD) undergoing PCI. Antithrombotic therapy. On June 22, 2015, the FDA approved cangrelor to reduce the risk of serious complications associated with PCI, such as myocardial infarction and stent thrombosis. [0004] [0005] At present, there are mainly two methods for synthesizing the compound (I). One is to use 2-mercaptoadenosine (2) as a raw material to attac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H1/00
CPCC07H19/167C07H1/00
Inventor 吴渊田华
Owner 北京广博德赛医药技术开发有限责任公司
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