A method for synthesizing 5-fluorocytosine

A technology for flucytosine and acylcytosine, applied in the field of synthesizing 5-fluorocytosine, can solve the problems of high cost, high cost of hydrogen fluoride and formic acid, and achieve the effects of safe production process, shortened steps, and easy availability of raw materials

Active Publication Date: 2022-06-28
TUOXIN GROUP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction is more expensive to use continuous flow equipment, and the cost of formic acid is also higher
[0007] Among the above synthetic methods, the direct use of cytosine fluorination requires relatively expensive fluorine reagents or highly toxic hydrogen fluoride, or continuous flow reaction equipment, which is dangerous or costly for industrial scale-up.

Method used

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  • A method for synthesizing 5-fluorocytosine
  • A method for synthesizing 5-fluorocytosine
  • A method for synthesizing 5-fluorocytosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] The first step, N 4 -40g (0.26mol) of acetylcytosine was put into the reaction flask, 400mL of glacial acetic acid was added and then heated to 40°C, 9.9g (0.26mol) of 20% fluorine gas (80% nitrogen gas) was slowly introduced, and the liquid phase tracked the reaction to the raw material Basically disappeared, cooled and concentrated to recover glacial acetic acid, added 200 mL of methanol to the remaining oil, stirred at 20° C. for 30 min, a large amount of solid was precipitated, suction filtered to obtain the intermediate, and dried to obtain 54 g (0.23 mol) of intermediate 2.

[0027] In the second step, in the reaction kettle, 54g of intermediate 2 was added, then 200mL of ammonia methanol was added and the temperature was raised to 50°C for a closed reaction for 5h to cool down, the ammonia methanol was concentrated and recovered, and the residue was purified by adding 400mL of water to obtain 26.7g of 5-fluorocytosine ( 0.21 mol), HPLC: 99.9%. 1 HNMR...

Embodiment 2

[0029]

[0030] The first step, N 4 -40 g (0.26 mol) of acetylcytosine was put into the reaction flask, 400 mL of formic acid was added and then the temperature was raised to 40° C., 9.9 g (0.26 mol) of 20% fluorine gas (80% nitrogen gas) was slowly introduced, and the liquid phase tracked the reaction until the raw materials were basically Disappeared, cooled and concentrated to recover formic acid, added 200 mL of methanol to the remaining oil, stirred at 20° C. for 30 min, a large amount of solid was precipitated, suction filtered to obtain the intermediate, and dried to obtain 52 g (0.22 mol) of intermediate 2.

[0031] In the second step, 52g of intermediate 2 was added in the reaction kettle, then 200mL of 20% ammonia methanol was added, and the temperature was raised to 50°C for a closed reaction for 5h to cool down, the ammonia methanol was concentrated and recovered, and the residue was purified by adding 400mL of water to obtain 26g of 5-fluorocytosine (0.22 mol),...

Embodiment 3

[0033]

[0034] In the first step, 40 g (0.26 mol) of N4-acetylcytosine was put into the reaction flask, 400 mL of glacial acetic acid was added, and then the temperature was raised to 40° C. The phase tracking reaction was carried out until the raw materials basically disappeared. The glacial acetic acid was recovered by cooling and concentration. 200 mL of methanol was added to the remaining oil, and a large amount of solid was precipitated after stirring at 20° C. for 30 min.

[0035] In the second step, 54g of intermediate 2 was added in the reaction kettle, then 200 mL of 20% ammonia methanol was added, and the temperature was raised to 50 °C for a closed reaction for 5 h to cool down, the ammonia methanol was concentrated and recovered, and the residue was purified by adding 400 mL of water to obtain the product 5-fluorocytosine 26.9 g (0.21 mol), HPLC: 99.6%.

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Abstract

The invention discloses a method for synthesizing flucytosine, which belongs to the field of nucleoside synthesis in organic chemistry. Its reaction steps are as follows: adopt N 4 ‑Acyl-protected cytosine is used as raw material, organic carboxylic acid is used as solvent, one-step intermediate is obtained through direct fluorination, and 5‑fluorocytosine is obtained through removal reaction. The invention not only reduces the cost of raw materials, but also solves the equipment corrosion problem caused by the cytosine and hydrogen fluoride process, and at the same time, the purity of the 5-fluorocytosine obtained by the method can reach more than 99.9%.

Description

technical field [0001] The invention belongs to the field of organic chemistry, relates to the synthesis of pyrimidine bases, in particular to a method for synthesizing 5-fluorocytosine. Background technique [0002] 5-Fluorocytosine, chemical name: 2-carbonyl-4-amino-5-fluoro-pyrimidine, CAS number: 2022-85-7, molecular formula C 4 H 4 FN 3 O, as a very important pharmaceutical intermediate, can be used to prepare drugs such as antiviral and antitumor 5-flucytosine, lamivudine and capecitabine. The methods reported in the literature at present, in addition to the route of using 5-fluorouracil as the raw material, the other routes are mainly: direct fluorination of cytosine as the raw material to obtain 5-fluorocytosine. [0003] Tako Takahara et al. reported that cytosine was directly fluorinated at the 5th position by introducing fluorine gas at low temperature using liquid hydrogen fluoride as a solvent. After the reaction of the raw materials, the temperature of the r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 杨西宁李涛卫涛马冠军张志强刘亚利靳海燕
Owner TUOXIN GROUP
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