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A method for synthesizing 5-fluorocytosine

A technology of fluorocytosine and cytosine, which is applied in the field of synthesizing 5-fluorocytosine, can solve problems such as high cost of formic acid, expensive fluorine reagents, and expensive reaction equipment, and achieve the goal of simplifying production operations, reducing risk factors, and reducing raw material costs Effect

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 synthesis of 2,5-difluoro-4-chloropyrimidine is cumbersome and not suitable for industrial production
The reaction is more expensive to use continuous flow equipment, and the cost of formic acid is also higher
[0007] In the above synthetic methods, there are disadvantages such as expensive fluorine reagents, difficult to obtain raw materials, ultra-low temperature or expensive reaction equipment, etc., which are not conducive to 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

[0027]

[0028] In the first step, 140g (0.30mol) of cytosine hydrogen fluoride and 400mL of water were added in the reactor, and after stirring evenly, the temperature was raised to 40-45°C, and 12.5g (0.33mol) of 10% fluorine gas was slowly introduced into the liquid phase to track the reaction. When the raw materials basically disappeared, the temperature was lowered to 0° C. to separate out solids, the filter cake was suction filtered, and then rinsed with a small amount of ice water to obtain Intermediate 2, which was dried to obtain 45.1 g (0.27 mol) and put into the next reaction.

[0029] In the second step, 45.1 g (0.27 mol) of intermediate 2 was added in the reaction kettle, then 300 mL of methanol and 41 g (0.41 mol) of triethylamine were added, the temperature was raised to reflux, and then the reaction was incubated for 5 h. After the reaction was completed, the temperature was lowered to 10° C. A large amount of solid was precipitated, and the suction filtratio...

Embodiment 2

[0031]

[0032] In the first step, 140g (0.30mol) of cytosine hydrogen fluoride and 400mL of water were added in the reactor, and after stirring evenly, the temperature was raised to 40-45°C, and 12.5g (0.33mol) of 20% fluorine gas was slowly introduced into the reaction vessel, and the liquid phase tracked the reaction. When the raw materials basically disappeared, the temperature was lowered to 0° C. to separate out a large amount of solid, suction filtration, and the filter cake was rinsed with a small amount of ice water to obtain Intermediate 2, which was dried to obtain 47 g (0.28 mol).

[0033] In the second step, in the reactor, add 47g (0.28mol) of Intermediate 2, then add 300mL of methanol and 42.4g (0.42mol) of triethylamine, heat up to reflux, then keep the temperature for 5h, and cool down to 10°C after the reaction is complete A large amount of solid was precipitated, suction filtration, and the filter cake was rinsed with a small amount of methanol to obtain c...

Embodiment 3

[0035]

[0036] In the first step, 44.1g (0.30mol) of cytosine hydrochloride and 400mL of water were added to the reactor, and after stirring, the temperature was raised to 40-45°C, and 12.5g (0.33mol) of 20% fluorine gas was slowly introduced into the reactor, and the liquid phase tracked. The reaction was carried out until the raw materials basically disappeared, and the temperature was lowered to 0° C. to precipitate a large amount of solids. The filter cake was suction filtered and washed with a small amount of ice water to obtain Intermediate 2, which was dried to obtain 40 g (0.22 mol).

[0037] In the second step, in the reactor, add 40g (0.22mol) of intermediate 2, then add 300mL of methanol and 33.3g (0.33mol) of triethylamine to heat up and reflux for 5h, heat up to reflux, then heat for 5h, and the reaction ends After cooling to about 2 ℃, a large amount of solids precipitated, and the filter cake was suction filtered and washed with a small amount of methanol to ...

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Abstract

The invention discloses a method for synthesizing flucytosine, which belongs to the field of nucleoside synthesis in organic chemistry. The reaction steps are as follows: use cytosine salt 1 as raw material, use water as solvent, react with fluorine gas to obtain intermediate 2, then react with organic base, obtain 5-fluorocytosine crude product after dehydration, and obtain 5‑fluorocytosine3. The method is simple to operate, avoids the use of dangerous solvents such as hydrofluoric acid, greatly reduces the corrosion to equipment, and reduces production costs at the same time, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemistry and 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, used to prepare drugs such as antiviral and antitumor 5-flucytosine, lamivudine and capecitabine. The methods currently reported in the literature are as follows: [0003] Tako Takahara et al. reported that cytosine was directly fluorinated by introducing fluorine gas at low temperature by using liquid hydrogen fluoride as a solvent. After the reaction of the raw materials, the temperature of the reaction solution was raised to room temperature, the hydrogen fluoride was removed under reduced pressure, and methanol was added at room temperature and concentrated under reduced press...

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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