Preparation method of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine

A technology of acetyl and flucytidine, which is applied to the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the cumbersome and complicated preparation methods of 5-deoxy-5-fluorocytidine, high production costs, and unnecessary Suitable for production conditions and other issues

Inactive Publication Date: 2011-11-23
NANJING VARSAL MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The above three methods are commonly used at present. The preparation method of the raw material 5-deoxy-5-fluorocytidine in method 1 is

Method used

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  • Preparation method of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine
  • Preparation method of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine

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Experimental program
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Embodiment 1

[0019] Dissolve 5-fluorocytosine (1.29g) in 30ml anhydrous toluene, cool to about 0°C, add trimethylsilyl trifluoromethanesulfonate (1.11g) and sodium iodide (3.0g) with stirring, The reaction was stirred for 30 minutes. Then, 5-deoxytriacetylribose (2.6g) was added, and the reaction was stirred at 0°C for 3 hours. After filtration, the filtrate was concentrated to dryness under reduced pressure, and dichloromethane and saturated sodium bicarbonate solution were added to the residue to extract. The aqueous layer was extracted with dichloromethane / methanol (10 / 1). The organic layers were combined and dried over anhydrous sodium sulfate . Filtered, concentrated to dryness under reduced pressure, and added 5 times the amount of isopropanol crystals to obtain 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine (2.67g, 81.1%), HPLC: 99.1%, mp 191.0-192.5°C.

Embodiment 2

[0021] Dissolve 5-fluorocytosine (1.29g) in 30ml anhydrous acetonitrile, cool to about 0°C, add trimethylsilyl trifluoromethanesulfonate (1.11g) and sodium iodide (3.0g) with stirring, The reaction was stirred for 30 minutes. Then, 5-deoxytriacetylribose (2.6g) was added, and the reaction was stirred at 0°C for 3 hours. After filtration, the filtrate was concentrated to dryness under reduced pressure, and dichloromethane and saturated sodium bicarbonate solution were added to the residue to extract. The aqueous layer was extracted with dichloromethane / methanol (10 / 1). The organic layers were combined and dried over anhydrous sodium sulfate . Filter, concentrate to dryness under reduced pressure, add 5 times the amount of isopropanol crystals to obtain 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine (2.60g, 79.0%), HPLC: 98.7%, mp 190.4-192.5°C.

Embodiment 3

[0023] Dissolve 5-fluorocytosine (1.29g) in 30ml of dry dichloromethane, cool to about 0℃, add trimethylsilyl trifluoromethanesulfonate (1.11g) and sodium iodide (3.0g) while stirring ), the reaction is stirred for 30 minutes. Then, 5-deoxytriacetylribose (2.6g) was added, and the reaction was stirred at 0°C for 3 hours. After filtration, the filtrate was concentrated to dryness under reduced pressure, and dichloromethane and saturated sodium bicarbonate solution were added to the residue to extract. The aqueous layer was extracted with dichloromethane / methanol (10 / 1). The organic layers were combined and dried over anhydrous sodium sulfate . Filter, concentrate to dryness under reduced pressure, add 5 times the amount of isopropanol crystals to obtain 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine (2.7g, 82.0%), HPLC: 99.2%, mp 191.5-192.5°C.

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Abstract

The invention provides a preparation method of capecitabine intermediate 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, which is suitable for actual industrial big production and has the advantages of high yield and quality and fine stability. The preparation method of capecitabine intermediate comprises the step of innovatively using a trifluoromethanesulfonic acid trimethylsilyl ester catalyst as the silanization agent of 5-fluorocytosine. The method has the advantages of high yield and good quality, and the process is simple and easy to operate.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry. Specifically, it relates to a preparation method of capecitabine intermediate 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine. Background technique [0002] The chemical name of capecitabine is 5’-deoxy-5-fluoro-N 4 -Pentoxycarbonyl cytidine, ie 5’-deoxy-5-fluoro-N 4 -(pentyloxycarbony)cytidine. [0003] 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine is an important intermediate raw material for the preparation of the antitumor drug capecitabine. Its structural formula is as follows: [0004] [0005] Currently, there are three main synthetic routes for capecitabine intermediate 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine reported in the literature and patents, which are listed as follows: [0006] [0007] References: Drugs of the Future 1996, 21(4): 358-360 [0008] [0009] Reference: Bioorganic & Medicinal Chemistry 8(2000): 1697-1706 [0010] [0011] Reference: EP0602454 [0012] The above three ...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
Inventor 叶祥曾裕建孙珏胡林周惠陈应春
Owner NANJING VARSAL MEDICINE TECH DEV
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