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A kind of preparation method of 2',3'-di-o-acetyl-5'-deoxy-5-fluorocytidine

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, high cost of trifluoromethanesulfonic acid, and no practical value. and other problems, to avoid expensive, easy separation, and shorten the reaction time.

Active Publication Date: 2015-08-19
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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  • A kind of preparation method of 2',3'-di-o-acetyl-5'-deoxy-5-fluorocytidine
  • A kind of preparation method of 2',3'-di-o-acetyl-5'-deoxy-5-fluorocytidine
  • A kind of preparation method of 2',3'-di-o-acetyl-5'-deoxy-5-fluorocytidine

Examples

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Effect test

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 anhydrous toluene, add 12mL anhydrous N,N-dimethylformamide, hexamethyldisilazane (240mL, 1.1mol), and heat to Dissolve completely 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), polymer-supported tetrachloride at room temperature Titanium (50g) and 1200mL of anhydrous dichloromethane were reacted for 3h, filtered, the filter cake was washed with dichloromethane (60mL×3), the filtrate and washing liquid were collected and washed with water (100mL×3), and the organic phase was dried with anhydrous sodium sulfate After filtering, 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 white solid. The yield was 89.3%, the optical purity was 99.5%, and the melting point was 189~191°C.

Embodiment example 2

[0036] Implementation case 2 Suspend 5-fluorocytosine (129g, 1mol) in 180mL anhydrous toluene, add 8mL anhydrous N , N -Dimethylformamide, hexamethyldisilazane (240mL, 1.1mol), heated to 118℃ for 1h, all dissolved, cooled to 70℃, evaporated to dryness under reduced pressure, add 1,2,3- at room temperature three- O -Acetyl-5-deoxyribose (312.3g, 1.2mol), macromolecule-supported ferric chloride (20g) and 1200mL of anhydrous dichloromethane react for 5h, filter, filter cake with dichloromethane (60mL×3) Wash, collect the filtrate and washing liquid (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 268.7g of white solid, the yield is 81.6% , The optical purity is 99.2%, the melting point is 189~191℃.

Embodiment example 3

[0037] Implementation case 3 Add 5-fluorocytosine (129g, 1mol) to 180mL anhydrous N , N -To dimethylformamide, add hexamethyldisilazane (240mL, 1.1mol), heat to 119°C for 30 minutes, and then cool to 80°C, evaporate to dryness under reduced pressure, add 1,2, 3-Three- O -Acetyl-5-deoxyribose (234g, 0.9mol), macromolecule supported copper chloride (150g) and 1500mL of anhydrous 1,2-dichloroethane react for 2h, filter, filter cake with 1,2-di 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 invention belongs to the technical field of synthesis of fine chemical intermediates, in particular to a pharmaceutical intermediate 2',3'-di- O - the preparation method of acetyl-5'-deoxy-5-fluorocytidine, this intermediate is used to prepare antitumor drug capecitabine and the like. Background technique [0002] The chemical name of capecitabine is 5'-deoxy-5-fluoro- N -[(pentyloxy)carbonyl]cytidine is an oral nucleoside antineoplastic drug developed by Roche Pharmaceuticals. Clinically, it is mainly used to treat malignant tumors such as metastatic colorectal cancer, breast cancer, colon cancer and gastric cancer. Capecitabine has a broad market prospect due to its broad anti-cancer spectrum and few adverse reactions since it was launched. 2’,3’-two- O -Acetyl-5'-deoxy-5-fluorocytidine is an important intermediate in the synthesis of nucleoside antineoplastic drug capecitabine. [0003] In the existing technology, 2’,3’-two- O The preparat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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