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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  • 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 product formed by the ring-closing reaction of ethyl cyanoacetate and thiourea under alkaline conditions is reacted with trifluoropropane under alkaline conditions, and then undergoes nitration reaction, After reduction reaction, carry out ring-closure reaction with formic acid again; After the product of generation carries out chlorination reaction, product carries out condensation reaction with 2-(thiomethyl) ethylamine under alkaline condition; Under the action of TMSOTF, it reacts with 1,2,3,5-tetraacetyl-β-D-ribofuranose, and the product is hydrolyzed under alkaline conditions to obtain the cangrelor intermediate. The method of the present invention does not need to use silica gel column chromatography, which greatly saves the process cost; and does not involve carbon disulfide, fuming nitric acid or concentrated sulfuric acid in the preparation process, and does not have any danger; in addition, no precious metal hydrogenation reducing agent is used, which not only reduces The cost is low and the operation risk is reduced; the method of the invention is easy to operate, safe and reliable, and 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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