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A kind of preparation method of 5-fluorocytosine

A technology of flucytosine and fluoroacetonitrile, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of increased production cost and low reaction yield, and achieve the effects of prolonging service life, high purity, and improving atom utilization

Active Publication Date: 2020-06-23
浙江伟锋药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Although the synthetic route provided by this invention application is relatively short, the final total yield is only about 50%, which needs to be further improved. In addition, the lower reaction yield will also lead to the increase of production cost

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  • A kind of preparation method of 5-fluorocytosine
  • A kind of preparation method of 5-fluorocytosine
  • A kind of preparation method of 5-fluorocytosine

Examples

Experimental program
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Embodiment 1

[0039] This embodiment provides a preparation method of 5-fluorocytosine, specifically, comprising the following steps:

[0040] Step 1: firstly add an organic solvent, fluoroacetonitrile, ethyl formate and an organic base into the autoclave, heat up the reaction in a carbon monoxide environment, then release the pressure and lower the temperature to obtain the first reaction solution containing the intermediate 1.

[0041] Among them, after passing the pressure of carbon monoxide, the pressure in the autoclave rises to 1.0-1.5MPa. When the temperature is raised in the carbon monoxide environment, the reaction temperature is 90-105°C, the reaction time is 8h-16h, and the pressure in the autoclave is maintained at 3.0MPa- 3.5MPa, when the pressure is released and the temperature is lowered to -5°C ~ -10°C, the mass ratio of fluoroacetonitrile to ethyl formate is 2.5:1 ~ 3.5:1. In this example, the mass ratio of fluoroacetonitrile to ethyl formate It is 2.5:1.

[0042] In this ...

Embodiment 2

[0083] This embodiment provides a method for preparing 5-fluorocytosine, the reaction steps and reaction mechanism are the same as those in Example 1, and the specific operations are as follows:

[0084] Step 1, add 170kg of toluene to the 1000L autoclave, then add 17.5kg of fluoroacetonitrile, 5.0kg of ethyl formate and 15kg of sodium methoxide, replace the air in the autoclave with nitrogen, and then replace the nitrogen in the autoclave with carbon monoxide, Continuously feed carbon monoxide to raise the pressure in the autoclave to 1.5Mpa, raise the temperature to 105°C for reaction under agitation, and keep the pressure in the autoclave at 3.5MPa. After 16 hours of reaction, cool down to below 50°C, release the pressure, and then transfer the reaction solution Cool down to a 1000L autoclave to -10°C to obtain a reaction solution containing Intermediate 1.

[0085] In this embodiment, the mass ratio of fluoroacetonitrile to ethyl formate is 3.5:1.

[0086] Step 2: Add met...

Embodiment 3

[0100] This embodiment provides a method for preparing 5-fluorocytosine, the reaction steps and reaction mechanism are the same as those in Example 1, and the specific operations are as follows:

[0101] Step 1, add 170kg of toluene to the 1000L autoclave, then add 15.3kg of fluoroacetonitrile, 5.0kg of ethyl formate and 15kg of sodium methoxide, replace the air in the autoclave with nitrogen, and then replace the nitrogen in the autoclave with carbon monoxide, Continuously feed carbon monoxide to increase the pressure in the autoclave to 1.3Mpa, raise the temperature to 100°C for reaction under stirring conditions, and keep the pressure in the autoclave at 3.2MPa, after 12 hours of reaction, cool down to below 50°C, release the pressure, and then transfer the reaction solution Cool down to a 1000L autoclave to -8°C to obtain a reaction solution containing Intermediate 1. Same as in Example 1, ethyl formate and fluoroacetonitrile react under the action of sodium methoxide to p...

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Abstract

The invention provides a preparation method of 5-fluorocytosine. The method is characterized by including the following steps that 1, an organic solvent, fluoroacetonitrile, ethyl formate and organicbase are added into an autoclave for a heating reaction in a predetermined gaseous environment, then decompressing and cooling are conducted, and first reaction liquid containing an intermediate 1 isobtained; 2, an alcohol solution of hydrogen chloride is added into a reaction still, the first reaction liquid is added for reaction after cooling, a second reaction liquid is obtained after reaction, water is added into the second reaction liquid, the pH value is adjusted to be 6-8, a first organic layer is obtained after standing, and the first organic layer is distilled to obtain an intermediate 2; 3, the intermediate 2 and urea are subjected to an aldimine condensation reaction, and then a crude product of 5-fluorocytosine is obtained. According to the method, the synthesis process is simple, there are a few required reaction steps, the total yield is relatively high, the safety of reaction is high, the production efficiency is improved, and the production cost is reduced.

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. Background technique [0002] 5-Fluorocytosine, also known as flucytosine, 5-fluorocytidine, Ancozhi, and Anla spray, is a white or off-white crystalline powder, which is mainly used to treat fungal infections caused by cryptococcus and candida , such as fungal sepsis, endocarditis, meningitis, mucocutaneous candidiasis, candidal endocarditis, candidal arthritis, cryptococcal meningitis, and chromomycosis. This product is the drug of choice for the treatment of severe systemic albicans and cryptococcal infections in foreign countries, and it is used for the treatment of fungal meningitis, fungal respiratory tract infection and black mycosis. [0003] In addition to being an antibacterial drug itself, 5-fluorocytosine is also the main intermediate for the preparation of capecitabine. Capecitabine can...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 卢娓高飞飞高军龙陈小平张文灿
Owner 浙江伟锋药业有限公司
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