Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine

A technology of acetyl and flucytidine, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problem of environmental and operator damage, trifluoromethanesulfonic acid is expensive and has no practical value and other problems, to avoid expensive, easy to separate, and shorten the reaction time

Active Publication Date: 2013-03-27
ZHEJIANG XIANFENG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tin tetrachloride is strongly hydrolyzed in the air and is extremely corrosive. It is a dangerous chemical that is harmful to the environment and operators. It is difficult to operate in industrial production, and the product yield is low and the quality is poor. Direct recrystallization to obtain the desired target product
[0016] Because trifluoromethanesulfonic acid is expensive and highly toxic, resulting in higher production costs and greater damage to the environment, this method has no practical value in industrial production

Method used

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  • Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine
  • Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine
  • Preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine

Examples

Experimental program
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Embodiment example 1

[0034] Example 1 Preparation of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine

[0035] Suspend 5-fluorocytosine (129g, 1mol) in 180mL of anhydrous toluene, add 12mL of anhydrous N,N-dimethylformamide, hexamethyldisilazane (240mL, 1.1mol), and heat for 45min to Completely dissolve at 117°C, cool to 70°C, evaporate to dryness under reduced pressure, add 1,2,3-tri-O-acetyl-5-deoxyribose (234g, 0.9mol) at room temperature, polymer loaded tetrachloride Titanium (50g) was reacted with 1200mL of anhydrous dichloromethane for 3h, filtered, the filter cake was washed with dichloromethane (60mL×3), the filtrate was collected and washed with water (100mL×3), and the organic phase was dried with anhydrous sodium sulfate , filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized with 800 mL of ethanol to obtain 264.7 g of a white solid, with a yield of 89.3%, an optical purity of 99.5%, and a melting point of 189-191°C.

Embodiment example 2

[0036] Example 2 Suspend 5-fluorocytosine (129g, 1mol) in 180mL of anhydrous toluene, add 8mL of anhydrous N , N -Dimethylformamide, hexamethyldisilazane (240mL, 1.1mol), heated to 118°C for 1h to completely dissolve, cooled to 70°C, evaporated to dryness under reduced pressure, added 1,2,3- three- O-Acetyl-5-deoxyribose (312.3g, 1.2mol), polymer loaded ferric chloride (20g) and 1200mL of anhydrous dichloromethane were reacted for 5h, filtered, and the filter cake was dichloromethane (60mL×3) Wash, collect the filtrate and wash with water (100mL×3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize the residue with 800mL of ethanol to obtain 268.7g of white solid with a yield of 81.6% , optical purity 99.2%, melting point 189~191°C.

Embodiment example 3

[0037] Example 3 Add 5-fluorocytosine (129g, 1mol) to 180mL anhydrous N , N -In dimethylformamide, add hexamethyldisilazane (240mL, 1.1mol), heat to 119°C for 30min to dissolve completely, cool to 80°C, evaporate to dryness under reduced pressure, add 1,2, 3-three- O -Acetyl-5-deoxyribose (234g, 0.9mol), polymer-loaded copper chloride (150g) and 1500mL of anhydrous 1,2-dichloroethane were reacted for 2h, filtered, and the filter cake was washed with 1,2-bis Wash with ethyl chloride (80mL×3), collect the filtrate and wash with water (100mL×3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize the residue with 800mL ethanol to obtain a white solid 258.1g, yield 87.1%, optical purity 98.9%, melting point 188~189℃.

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Abstract

The invention discloses a preparation method of 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine. The preparation method comprises the following steps of: carrying out glycosylation reaction on 1,2,3-tri-O-acetyl-5-deoxyribose and bi-silanized 5-fluorocytosine under the catalysis of polymer-supported lewis acid which can be separated and reused for multiple times to obtain reaction liquid, and separating and purifying the reaction liquid to obtain a high-purity important capecitabine intermediate, namely the 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine. According to the preparation method, the catalyst is stable and efficient, can be easily separated from a reaction system and is free of pollution and single in stereoselectivity; the content of an Alpha isomer in the reaction liquid is smaller than 1.4 percent and can be removed by recrystallization; and the 2',3'-bi-O-acetyl-5'-deoxy-5-fulurocytidine has the optical purity up to 99.6 percent and is suitable for industrial production.

Description

Technical field [0001] The present invention belongs to the field of fine chemical intermediate synthesis technology, which involves a kind of medicine intermediate 2 ’, 3’-two- O -This-5'-deoxyladoside is used for preparation methods. This intermediate is used to prepare anti-tumor drug perbinbinbaria and so on. Background technique [0002] Capecitabine chemical name is 5’-deoxy-5-fluorine-fluorine- N -[(Tanxan) cytoside is an oral nucleoside anti -tumor drug developed by Roche Pharmaceutical Company.Clinically, it is mainly used to treat malignant tumors such as metastatic colon and rectal cancer, breast cancer, colon cancer, and gastric cancer.Since Koriebin has a wide range of anti -cancer spectrals and less adverse reactions since its launch, it has a broad market prospect.2 ’, 3’- 2- O -Acetyl-5'-deoxy-5-fluorine is an important intermediate of synthetic nucleoside anti-tumor drug perbine. [0003] Among the existing technologies, 2 ’, 3’-2- O -Themid-5'-deoxygenidoside pr...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
Inventor 姚福友卢娓陈小平熊云茂高飞飞
Owner ZHEJIANG XIANFENG TECH
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