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A kind of preparation method of 5-flucytosine suitable for industrialized production

A technology for flucytosine and fluoropyrimidine, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of large hidden dangers in production safety, high rate of three wastes and high cost of raw materials, and achieves the effects of less pollution of three wastes, convenient post-processing and stable product quality.

Active Publication Date: 2017-11-07
ZHEJIANG XIANFENG TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Aiming at the above technical problems, the present invention provides a method for preparing 5-fluorocytosine suitable for industrial production, which does not use highly toxic chemical raw material phosphorus oxychloride, and solves the problem of high raw material cost and production safety in the existing process. Big hidden dangers and high rate of three wastes

Method used

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  • A kind of preparation method of 5-flucytosine suitable for industrialized production

Examples

Experimental program
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Effect test

example 1

[0023] Example 1 Preparation of 2-methoxy-4-chloro-5-fluoropyrimidine (I)

[0024] 2-Methoxy-5-fluorouracil (144g, 1mol), toluene 500g, N,N-dimethylaniline (110g, 0.92mol), temperature controlled at 35-40°C, phosphorus pentachloride (412g , 2mol), each batch is about 20g, one batch every 3 minutes, and the addition is completed in about 1 hour. After the addition, the temperature was raised to 85°C, and stirring was continued for 3 hours. After cooling to room temperature, the reaction solution was poured into 1500 g of ice water, stirred for 30 minutes, separated, and the organic phase was spin-dried to obtain 2-methoxy-4-chloro- The crude product of 5-fluoropyrimidine (I) was 167 g, no further purification was needed; the aqueous phase was spun under reduced pressure until no water was evaporated to obtain an acidic aqueous phase concentrate for later use.

example 2

[0025] Example 2 Preparation of 2-methoxy-4-amino-5-fluoropyrimidine (Ⅱ)

[0026] Put 167g of the crude product of 2-methoxy-4-chloro-5-fluoropyrimidine (I) obtained in Example 1 into a 1L autoclave, add 350g of ammonia water, after sealing, heat up to 100°C, pressure 0.7Mpa, stir 2 hours. Cool the reaction solution to 0-5°C, precipitate solids, filter, and dry the filter cake to obtain 128 g of white solids (the total yield of two steps is 89.5%), and the ammonia filtrate is used for later use.

example 3

[0027] Preparation of Example 3 5-fluorocytosine

[0028] The acidic aqueous phase concentrate obtained in Example 1, 2-methoxy-4-chloro-5-fluoropyrimidine (I) (128g, 0.895mol) and sodium iodide (6.7g, 0.045mol) were stirred at 130°C After 5 hours, after cooling to room temperature, the ammonia water filtrate in Example 2 was added dropwise to the reaction solution until pH=8.3, a large amount of solids were precipitated, filtered, the filter cake was recrystallized with water, and white 5-fluorocytosine was obtained after drying 98g of solid (84.9% yield, 77.7% molar yield of the total route).

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Abstract

The invention relates to a 5-fluctyosine preparation method suitable for industrial production, belonging to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: by using 2-methoxy-5-fluorouracil as a raw material, chlorinating with phosphorous pentachloride to obtain 2-methoxy-4-chloro-5-fluoropyrimidine, and concentrating the acidic water phase obtained by after-treatment for later use; carrying out amination reaction on the 2-methoxy-4-chloro-5-fluoropyrimidine and an aminating agent to obtain 2-methoxy-4-amido-5-fluoropyrimidine; and carrying out acidic hydrolysis on the 2-methoxy-4-amido-5-fluoropyrimidine by using the concentrated acidic water phase recycled from chlorination to obtain the 5-fluctyosine. The 5-fluctyosine preparation method provided by the invention has the advantages of high yield, convenient after-treatment and fewer three-waste pollutants, solves the problems of high virulent product consumption, difficulty in acidic waste gas treatment, high pollution, high cost and the like in the traditional technique, and is suitable for industrial production application. The total mole yield is up to 70% or above.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of 5-fluorocytosine suitable for industrial production. Background technique [0002] In the prior art, US447369 and EP0063352 use fluorine gas / hydrogen fluoride to carry out fluorination reaction on cytosine, but the use of highly corrosive and highly toxic fluorine gas has extremely high requirements for production operations and production equipment, and the production risk is extremely high , It is more difficult in industrialization; CN103435557A condenses methyl fluoroacetate and ethyl formate, then reacts with urea to generate 5-fluorouracil, and 5-fluorouracil is chlorinated with thionyl chloride to obtain 2.4-dichloro-5-fluoropyrimidine, After ammoniation and hydrolysis with sulfuric acid, 5-fluorocytosine can be obtained. In this method, the yield of urea cyclization to 5-fluorouracil is low, and sulfur dioxide...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 朱敏亮王玉群王国才黄火杨刚张丽娜
Owner ZHEJIANG XIANFENG TECH
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