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Preparation method for 5-fluorocytosine

A technology of fluorocytosine and methyl fluoroacetate, which is applied in the field of preparation of 5-fluorocytosine, can solve the problems of operator injury, equipment and safety requirements, etc., and achieve the advantages of reduced injury, good purity and high yield Effect

Inactive Publication Date: 2015-02-18
SHANDONG JINCHENG PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] JP37553 / 1979 reported the method of directly using cytosine for fluorination. This method involves the use of fluorine gas. The yield and purity of 5-fluorocytosine in this method are relatively high, but the use of fluorine gas has relatively high requirements for equipment and safety. High and can cause injury to operators

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Add 200ml of xylene into a 1L reaction bottle, drop 200g of ethyl formate into the xylene, then add 5g of sodium metal and 80g of methyl fluoroacetate for condensation reaction, heat up to 20°C and stir for 2 hours, then heat up to 42°C and keep it warm 10h to obtain the intermediate; add 27g isopropylamine, 50g N-chlorosuccinimide to the intermediate, and react at 100°C for 5h to obtain the chlorinated product; Under the action of 3g of alkylphosphonamide, 3g of methine bridge phosphonium, and 2.5g of tetrabutylammonium bromide, ammoniated substitution was carried out to obtain an ammoniated product; the ammoniated product was hydrolyzed in an acidic environment of pH=5 to obtain 5- Flucytosine, 58.2 g of 5-fluorocytosine was obtained after purification, with a purity of 99.99%.

Embodiment 2

[0021] Add 200ml of xylene into a 1L reaction bottle, drop 200g of ethyl formate into the xylene, then add 5g of sodium metal and 80g of methyl fluoroacetate for condensation reaction, heat up to 20°C and stir for 2 hours, then heat up to 42°C and keep it warm 10h to obtain the intermediate; add 25g diethylamine, 50g N-chlorosuccinimide to the intermediate, and react at 95°C for 5h to obtain the chlorinated product; - Under the action of 3 g of alkylphosphonamides, 3 g of methine bridge phosphorus, and 2.5 g of tetrabutylammonium bromide, ammonium substitution is carried out to obtain an ammoniated product; the ammoniated product is hydrolyzed in an acidic environment of pH=5 to obtain 5 -Fluorocytosine, after purification, 56.1 g of 5-fluorocytosine was obtained with a purity of 99.99%.

Embodiment 3

[0023] Add 200ml of xylene into a 1L reaction bottle, drop 200g of ethyl formate into the xylene, then add 5g of sodium metal and 80g of methyl fluoroacetate for condensation reaction, heat up to 20°C and stir for 2 hours, then heat up to 42°C and keep it warm 10h to obtain the intermediate; add 28g triethylamine, 50g N-chlorosuccinimide to the intermediate, and react at 105°C for 5h to obtain the chlorinated product; - Under the action of 3 g of alkylphosphonamides, 3 g of methine bridge phosphorus, and 2.5 g of tetrabutylammonium bromide, ammonium substitution is carried out to obtain an ammoniated product; the ammoniated product is hydrolyzed in an acidic environment of pH=5 to obtain 5 -Fluorocytosine, after purification, 57.2 g of 5-fluorocytosine was obtained with a purity of 99.99%.

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Abstract

The invention belongs to the technical field of medicinal chemical synthesis, and particularly relates to a preparation method for 5-fluorocytosine. The preparation method comprises the following steps of: dropwise adding ethyl formate in xylene, carrying out a condensation reaction with methyl fluoroacetate under the action of a metal catalyst, and heating, stirring and carrying out heating heat preservation to obtain an intermediate; carrying out chlorination substitution on the intermediate with a chlorinating agent in the presence of an organic amine catalyst to obtain a chlorination product; carrying out ammoniation substitution on the chlorination product in an ammonia gas pressure environment and under the action of phase transfer catalysts (N-alkyl phosphoramide, methylene bridged phosphate and tetrabutylammonium bromide to obtain an ammoniation product; carrying out acidic hydrolysis on the ammoniation product to obtain 5-fluorocytosine. The 5-fluorocytosine prepared by the preparation method disclosed by the invention is high in yield and high in purity; use of highly-toxic fluorine is avoided during the preparation process, thus reducing damage and injury to equipment and operating personnel during a production process.

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 is used to treat fungal infections caused by cryptococcus and candida, such as fungal sepsis, endocarditis, meningitis, and antifungal drugs for lung and urinary tract infections. It is mainly used for mucocutaneous candidiasis, candida endocarditis, candida arthritis, cryptococcal meningitis and coloring fungal disease. During the period of medication, the blood picture should be checked regularly. Patients with hepatic and renal insufficiency, blood diseases and pregnant women should be used with caution; patients with severe renal insufficiency are contraindicated. 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 re...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 赵奇侯乐伟蔡会敏李珊珊宋道淮
Owner SHANDONG JINCHENG PHARMA & CHEM
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