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Preparation method of 5-flucytosine

A technology of fluorocytosine and intermediates, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of high price of methyl fluoroacetate and increase the production cost of 5-fluorocytosine, achieve significant industrial value, reduce production costs, and increase total output rate effect

Active Publication Date: 2018-05-15
ZHEJIANG XIANFENG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, one of the raw materials used in the synthetic route provided by the application for this invention is methyl fluoroacetate, which is a highly toxic drug, and its production has been restricted, and the price of methyl fluoroacetate is relatively high, which increases the production of 5-fluorocytosine cost

Method used

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  • Preparation method of 5-flucytosine
  • Preparation method of 5-flucytosine
  • Preparation method of 5-flucytosine

Examples

Experimental program
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Effect test

Embodiment 1

[0030] This embodiment provides a preparation method of 5-fluorocytosine, specifically, comprising the following steps:

[0031] Step 1: add 600kg toluene in reactor, cool, add 188kg solid sodium methylate under agitation condition, utilize nitrogen to replace the air in reactor, add 282kg ethyl formate in reactor, control temperature during adding to be 10 -20°C, then add 188kg of methyl chloroacetate, control the temperature at 10-25°C during the addition process, raise the temperature to 65-75°C after the addition, and react for 12 hours to obtain intermediate 1, cool to below 20°C, and transfer to the intermediate Add 333.7kg of liquid sodium methoxide and 507.6kg of oxymethylisourea to 1, heat up to 35-45°C after the addition, react for 7 hours, remove the solvent from the reaction solution, then dissolve it in 1000kg of water, let it stand for stratification, and adjust the water phase pH value to 3-4, cooled, filtered, washed, dried to obtain 212.9kg of intermediate 2, ...

Embodiment 2

[0038] This embodiment provides a preparation method of 5-fluorocytosine, specifically, comprising the following steps:

[0039] Step 1: add 600kg toluene in reactor, cooling, add 225.6kg solid sodium methylate under stirring condition, utilize nitrogen to replace the air in reactor, add 376kg ethyl formate in reactor, control temperature during adding 10-20°C, then add 188kg of methyl chloroacetate, control the temperature at 10-25°C during the addition process, raise the temperature to 65-75°C after the addition, and react for 8 hours to obtain intermediate 1, cool to below 20°C, and transfer to the middle Add 400.4kg of liquid sodium methoxide and 601.6kg of oxymethylisourea to body 1, heat up to 35-45°C after the addition, and react for 5 hours, remove the solvent from the reaction solution, then dissolve it in 1100kg of water, let it stand and separate, and the water phase Adjust the pH value to 3-4, cool, filter, wash, and dry to obtain 213.0kg of intermediate 2 with a y...

Embodiment 3

[0046] This embodiment provides a preparation method of 5-fluorocytosine, specifically, comprising the following steps:

[0047] Step 1: Add 600kg of toluene to the reactor, cool it, add 206.8kg of solid sodium methylate under stirring conditions, replace the air in the reactor with nitrogen, add 319.6kg of ethyl formate to the reactor, and control the temperature during the addition process 10-20°C, then add 188kg of methyl chloroacetate, control the temperature at 10-25°C during the addition process, raise the temperature to 65-75°C after the addition, and react for 10 hours to obtain intermediate 1, cool to below 20°C, and send to Add 367.1kg of liquid sodium methoxide and 564kg of oxymethylisourea to intermediate 1, raise the temperature to 35-45°C after the addition, and react for 6 hours, remove the solvent from the reaction solution, then dissolve it in 1100kg of water, let it stand for stratification, and the water phase Adjust the pH value to 3-4, cool, filter, wash, ...

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Abstract

The invention belongs to the technical field of chemical synthesis of medicines and relates to a preparation method of 5-flucytosine. The preparation method comprises the following steps: utilizing ethyl formate and methyl chloroformate to synthesize 2-chloro-3-oxo methyl propionate, then utilizing oxymethylisourea to close rings to obtain pyrimidine rings, utilizing potassium fluoride to substitute chlorine on the pyrimidine rings, utilizing phosphorus oxytrichloride to substitute hydroxyl groups on the pyrimidine rings, then adding ammonia water to lead chloride to be substituted with aminogroups, and hydrolyzing under an acid condition to obtain a product, namely the 5-flucytosine. The preparation method has the beneficial effects that the methyl chloroacetate is adopted for substituting methyl fluoroacetate to be used as a synthetic raw material of the 5-flucytosine, so that the use of highly-toxic chemicals such as the methyl fluoroacetate is avoided; simultaneously, since the price of the methyl chloroacetate is much lower than the price of the methyl fluoroacetate, the production cost can be saved; by utilization of the synthetic route provided by the invention, the higher-purity 5-flucytosine can be prepared without need of complex aftertreatment steps; simultaneously, the preparation method has higher overall yield and obvious industrial value and is worthy of being promoted and used on a large scale.

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 used as the first choice drug for the treatment of severe systemic albicans and cryptococcal infection abroad, and 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 inhibi...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 高军龙高飞飞李明陈小平魏琛辉
Owner ZHEJIANG XIANFENG TECH
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