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2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof

A technology of flucytidine salt and acetyl group, which is applied in the field of medicinal chemistry, can solve problems such as poor product quality, harsh reaction conditions, and cumbersome operation processes, and achieve the effects of controlling process costs, reducing reaction steps, and reducing environmental pollution

Active Publication Date: 2012-04-25
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In this method, the nucleophilic reaction is carried out after the substitution of trimethylchlorosilane and sodium iodide, which has problems such as low reaction yield, cumbersome operation process, and poor product quality.
[0016] In the above synthetic methods, 2′, 3′-di-O-acetyl-5′-deoxy-5-fluorocytidine is used as the key intermediate for preparing capecitabine, but there are harsh reaction conditions and the The disadvantages of special reagents, low yield, low product purity, and poor stability have brought many problems to the subsequent synthesis of capecitabine.

Method used

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  • 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof
  • 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof
  • 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine hydrochloride

[0043]

[0044] (1), the protection reaction of 5-fluorocytosine

[0045] In a dry 3L glass reaction bottle, connect the tail gas (ammonia) absorption device and the reflux tube for standby, add 300ml of dichloromethane, 100g (0.775mol) of 5-fluorocytosine, 140ml of hexamethyldisilazane, 0.5 ml iodotrimethylsilane, heat up to 70-80°C, reflux for 10-15 hours, and the liquid dissolves.

[0046] (2) Synthesis of iodide

[0047] In another reaction flask, put 500ml of dichloromethane, 201g of 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose, lower the temperature to 0°C, and add 145ml of iodotrimethylsilane , keep warm at 0°C for 5 hours.

[0048] (3) Add the protected 5-fluorocytosine reaction solution into the iodide reaction solution, and react at room temperature for 3-5 hours. Then, 60 ml of isopropanol was added to the feed liquid, and a yellow-white solid was precipitated. Then, 380 ml of 10%...

Embodiment 2

[0052] Synthesis of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine hydrobromide

[0053]

[0054] (1) In a 2L glass reaction bottle, add 200ml of dichloromethane, add 52g of 5-fluorocytosine and 100ml of N,O-bis(trimethylsilyl)acetamide under stirring, heat up to 30-40°C, React for 3 to 5 hours, and the feed liquid is completely dissolved.

[0055] (2) In another reaction flask, put 300ml of dichloromethane, 104g of 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose, cool down to 0°C, add trimethyl 85ml of iodosilane, heat at 0-5°C and react for 3-5 hours.

[0056] (3) Add the protected 5-fluorocytosine reaction solution into the iodide reaction solution, and react at room temperature for 3-6 hours. Then 50 ml of methanol was added to the feed liquid, and a yellow-white solid was precipitated. Add 300ml of 20% hydrobromic acid to the feed solution, and stir until the solid is completely dissolved. Separate layers, discard the dichloromethane layer, add 10 g of activated carbon to...

Embodiment 3

[0060] Synthesis of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine hydroiodide

[0061]

[0062] (1) In a 2L glass reaction bottle, connect the tail gas (ammonia) absorption device for standby, replace with nitrogen for 5 minutes, add 200ml of dichloromethane, add 65g of 5-fluorocytosine and 92ml of hexamethyldisilazide under stirring alkane, 0.2ml iodotrimethylsilane, the temperature of the system was raised to 60-70°C, and the reaction was carried out for 10-15 hours until the feed solution was completely dissolved.

[0063] (2) In another reaction flask, put 300ml of dichloromethane, 130g of 5-deoxy-1,2,3-tri-O-acetyl-β-D-ribofuranose, cool down to 0°C, add trimethyl 110ml of iodosilane, keep warm at 0°C for 3-5 hours.

[0064] (3) Add the protected 5-fluorocytosine reaction solution into the iodide reaction solution, and react at room temperature for 3-5 hours. Then, 50 ml of isopropanol was added to the feed liquid, and a yellow-white solid was precipitated. Then add 3...

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Abstract

The invention relates to a 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound of formula (I) or a solvate thereof. The compound is prepared by using 5-deoxy-1,2,3-tri-O-acetyl-beta-D-ribofuranose as a raw material, carrying out condensation reaction on 5-deoxy-1,2,3-tri-O-acetyl-beta-D-ribofuranose and protected 5-flucytosine under the activation of iodotrimethylsilane to obtain a reaction product, and carrying out deprotection, acidification and crystallization. According to the invention, a novel intermediate for synthesizing Capecitabine is developed, one pot process is adopted for reacting to obtain the 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound, and high-purity Capecitabine can be further synthesized by using the 2',3'- di-O-acetyl-5'-deoxy-5-fulurocytidineonium compound as a key intermediate. The compound has the characteristics of clear structure, high purity and stable quality. The use of the compound to synthesize Capecitabine can reduce reaction steps, control process cost, and reduce environmental pollution.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, specifically, the invention relates to 2', 3'-di-O-acetyl-5'-deoxy-5-fluorocytidine salt compounds and preparation methods thereof, such compounds It is a key intermediate for the preparation of anti-tumor drug capecitabine. Background technique [0002] Among anti-tumor and anti-viral drugs, a large number of nucleoside compounds are used clinically. Based on the principle of metabolic antagonism, they produce anti-disease effects by interfering with or inhibiting the nucleic acid replication of viruses and tumor cells. Usually biologically active nucleosides require the presence of a 5-hydroxyl group and function by being phosphorylated in vivo. Removing the 5-hydroxyl group will produce a series of compounds that are meaningful for biochemical and physiological research, because they cannot be incorporated into nucleic acids by phosphorylation, thereby achieving the purpose of red...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
Inventor 王树鹏吴柯李保勇董廷华张兆珍于志海吴兆申曹见敏王晓龙
Owner 山东安信制药有限公司
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