5-fluorocytosine preparation method

A technology of fluorocytosine and methyl fluoroacetate, which is applied in the field of preparation of 5-fluorocytosine, can solve problems such as high cost, complex equipment, and large pollution, and achieve reduced production cycle and cost, easy recycling, and reduced waste liquid The effect of emissions

Active Publication Date: 2013-12-11
ASTATECH CHENGDU BIOPHARM CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is the use of highly toxic chemicals, complex equipment, cumbersome post-treatment, large pollution and high cost in the traditional synthesis method

Method used

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preparation example Construction

[0032] The specific operation steps of the preparation method of 5-fluorocytosine include:

[0033] a. Add sodium methoxide to toluene in batches. After the addition, first add ethyl formate dropwise, then add methyl fluoroacetate dropwise. After the dropwise stirring is completed for 1.0-2.0 hours, heat up to 36-38°C for 5-8 hours; Then add methanol and sodium methoxide, stir and lower the temperature to 15-25°C, then add urea to react for 4-6 hours. Adjust the pH to 3-4 with hydrochloric acid, control the temperature below 20°C and stir for 1-2 hours; filter to obtain a solid, wash with water to obtain compound 5-FU;

[0034] b. 5-FU, thionyl chloride and DMF are heated up to reflux reaction until the content of 5-FU is ≤0.2%. After the reaction is over, atmospheric distillation recovers thionyl chloride, and then distillation under reduced pressure yields compound 5- FU-1; Wherein, DMF is as the catalyst of chlorination reaction;

[0035] c. Heat ammonia water and 5-FU-1 ...

Embodiment 1

[0056] a. In a 1L three-necked flask, nitrogen gas was introduced, and toluene (500 g) was added. Sodium methoxide (52.9 g, 0.98 mol) was added in batches, and the temperature was controlled below 30°C. After the addition, the temperature was lowered to 10°C, and ethyl formate (72.5 g, 0.98 mol) was added dropwise. During the dropwise addition, the temperature of the reaction system was controlled at 10-20°C.

[0057] After the ethyl formate was added dropwise, methyl fluoroacetate (60 g, 0.65 mol) was added dropwise, and the temperature was controlled at 15-20°C during the dropwise addition. After dripping and stirring for 1.0 h, the temperature was raised to 36-38° C., and the reaction was stirred for 5 h. Add methanol (65g) and sodium methoxide (30g, 0.56mol), stir and cool down to 20°C.

[0058] Urea (67.2 g, 1.12 mol) was added, and the reaction was stirred at room temperature (28° C.) for 5 hours. Recover methanol by desolvation under reduced pressure, and then add wa...

Embodiment 2

[0063] a. In a 1L three-necked flask, nitrogen gas was introduced, and toluene (500 g) was added. Sodium methoxide (52.9 g, 0.98 mol) was added in batches, and the temperature was controlled below 30°C. After the addition, the temperature was lowered to 10°C, and ethyl formate (72.5 g, 0.98 mol) was added dropwise. During the dropwise addition, the temperature of the reaction system was controlled at 10-20°C.

[0064] After the ethyl formate was added dropwise, methyl fluoroacetate (60 g, 0.65 mol) was added dropwise, and the temperature was controlled at 15-20°C during the dropwise addition. After dripping and stirring for 1.0 h, the temperature was raised to 36-38° C., and the reaction was stirred for 5 h. Add methanol (65g) and sodium methoxide (30g, 0.56mol), stir and cool down to 20°C.

[0065] Urea (67.2 g, 1.12 mol) was added, and the reaction was stirred at room temperature (28° C.) for 5 hours. Recover methanol by desolvation under reduced pressure, and then add wa...

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Abstract

The invention belongs to the field of organic chemical synthesis, particularly relates to a 5-fluorocytosine preparation method, and aims to solve the technical problems about use of highly toxic chemicals, complex equipment, tedious post-processing, large pollution and high cost in a traditional synthesis method. The technical scheme to solve the technical problems by the invention is to provide the 5-fluorocytosine preparation method which comprises the following steps: enabling methyl fluoroacetate to conduct a condensation reaction with ethyl formate and then conduct a reaction with urea, a chlorination reaction with thionyl chloride, then an ammonolysis reaction with ammonium hydroxide and finally a hydrolysis reaction with sulfuric acid to obtain 5-fluorocytosine. The invention provides the novel method with high yield, low pollution and low cost for the industrial production of 5-fluorocytosine.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and in particular relates to a preparation method of 5-fluorocytosine. Background technique [0002] 5-Fluorocytosine, also known as flucytosine, 5-fluorocytidine, Anquezhi, and Anlapa, is a white or off-white crystalline powder, and its structure is shown in Formula 1: [0003] [0004] The inhibitory effect of 5-fluorocytosine on fungi is due to the fact that it enters the cells of sensitive fungi, and under the action of cytosine deaminase, it removes the amino group to form an anti-metabolite - 5-fluorouracil. The latter is transformed into 5-fluorouridine deoxynucleoside to inhibit thymidine synthetase, blocking the transformation of uridine deoxynucleoside into thymidine and affecting the synthesis of DNA. It has a good inhibitory effect on Candida, Cryptococcus and Geothrix, and it also has effects on some Aspergillus, as well as Cladosporium and bottle fungi that cause skin m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/47
Inventor 郭鹏邓建陈兴闫革新庄明晨查文伟贾淼
Owner ASTATECH CHENGDU BIOPHARM CORP
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