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Preparation method of Cangrelor intermediate

A technology for intermediates and compounds is applied in the field of preparation of cangrelor intermediate 6-N-ethyl-2-thio)adenosine, and can solve the problems of low yield, high price, unfavorable industrial production and the like

Inactive Publication Date: 2016-10-12
北京信益泰医药科技开发有限公司
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  • Summary
  • 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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] A preparation method of 6-N-(2-(methylthio)ethyl-2-((3,3,3-trifluoropropyl)thio)adenosine (I), comprising the following steps:

[0082] (1) Preparation of compound 16

[0083] At room temperature, take by weighing sodium ethoxide 127.8g ((1.88mol) and join the 3L reaction flask of 670g ethanol, stir to dissolve all, add thiourea 67.3g (0.884mol). Heat to 45°C, weigh ethyl cyanoacetate 100 g (0.884 mol) of ester was added to the reaction flask and heated to reflux. After 2 h of reflux, TLC reaction was completed, and the temperature was lowered to 15 ° C. Filtered, the filter cake was washed once with 200 g of absolute ethanol, the filter cake was taken out, and added to a 3L reaction flask, Add water 1kg and stir to make it dissolve, add acetic acid below 20 ° C, adjust pH=4, a large amount of solid is separated out. Suction filtration. Filter cake is dried overnight at 46 ° C to obtain product 116.4g, yield 92%.

[0084] (2) Preparation of compound 17

[0085] At roo...

Embodiment 2

[0104] (1) At room temperature, weigh 103.2 g (0.92 mol) of potassium tert-butoxide into a 1 L reaction flask of 450 g of methanol, stir to dissolve it completely, and add 30.4 g (0.4 mol) of thiourea. Heated to 45°C, weighed 47.43 g (0.42 mol) of ethyl cyanoacetate into the reaction flask and heated to reflux. After refluxing for 2.7 hours, the TLC reaction was completed, lowered to 15°C, filtered, and the filter cake was washed once with 116 g of methanol, Take out the filter cake, add it into a 1L reaction flask, add 570 g of water and stir to dissolve it, add 15% hydrochloric acid below 20°C, adjust pH=4, and a large amount of solids are precipitated. Suction filtration. The filter cake was dried at 45°C overnight to obtain 49.97 g of product with a yield of 87.5%.

[0105] (2) Preparation of compound 17

[0106] At room temperature, weigh 190 g (1.4 mol) of DBU and add it to a 2L three-necked flask, add 301 g of DMSO and stir, add 43 g (0.3 mol) of compound 16, start st...

Embodiment 3

[0122](1) At room temperature, weigh 159.2 g (1.42 mol) of triethylamine and add it to a 2L reaction flask of 750 g of methanol, stir to dissolve it completely, and add 45 g (0.59 mol) of thiourea. Heated to 45°C, weighed 68.2g (0.6mol) of ethyl cyanoacetate into the reaction flask and heated to reflux. After refluxing for 2.5h, the TLC reaction was completed, lowered to 15°C, filtered, and the filter cake was washed with 190g of isopropanol. Once, take out the filter cake, add it into a 2L reaction flask, add 810g of water and stir to dissolve it, add 40% formic acid below 20°C, adjust pH=4, and a large amount of solid is precipitated. Suction filtration. The filter cake was dried at 45°C overnight to obtain 76 g of product with a yield of 89.9%.

[0123] (2) Preparation of compound 17

[0124] At room temperature, weigh 32.83g (1.37mol) of lithium hydroxide and add it to a 2L there-necked flask, add 588g of DMF and stir, add 70g (0.49mol) of compound, start stirring, and a...

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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 pharmaceutical 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 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] There are two main methods for synthesizing this compound (I) at present. One is to use 2-mercaptoadenosine (2) as a raw material, attack the chloro...

Claims

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Application Information

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IPC IPC(8): C07H19/167C07H1/00
CPCC07H19/167C07H1/00
Inventor 郭亮亮刘力杰冯文化
Owner 北京信益泰医药科技开发有限公司
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