Method for synthesizing 5-flucytosine

A technology for flucytosine and cytosine, which is applied in the field of synthesizing 5-fluorocytosine, can solve the problems of expensive reaction equipment, expensive fluorine reagents and high cost of formic acid, and achieves the advantages of avoiding the use of liquid hydrogen fluoride, reducing the risk factor and reducing the cost of raw materials. Effect

Active Publication Date: 2020-02-04
TUOXIN GROUP +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • Method for synthesizing 5-flucytosine
  • Method for synthesizing 5-flucytosine
  • Method for synthesizing 5-flucytosine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] In the first step, add 140g (0.30mol) of cytosine hydrogen fluoride and 400mL of water into the reactor, stir evenly, then raise the temperature to 40-45°C and slowly inject 12.5g (0.33mol) of 10% fluorine gas, and follow the reaction in the liquid phase After the raw materials basically disappeared, the temperature was lowered to 0°C to precipitate solids, and the filter cake was suction filtered, washed with a small amount of ice water to obtain intermediate 2, and dried to obtain 45.1 g (0.27 mol) which was put into the next reaction.

[0030] In the second step, add 45.1g (0.27mol) of intermediate 2 into the reactor, then add 300mL of methanol and 41g (0.41mol) of triethylamine, raise the temperature to reflux, then keep the temperature for 5h, and cool down to 10°C after the reaction Left and right, a large amount of solids were precipitated, and the suction filter cake was rinsed with a small amount of methanol to obtain crude 5-fluorocytosine, and then...

Embodiment 2

[0032]

[0033] In the first step, add 140g (0.30mol) of cytosine hydrogen fluoride and 400mL of water into the reactor, stir evenly, then raise the temperature to 40-45°C and slowly inject 12.5g (0.33mol) of 20% fluorine gas, and follow the reaction in the liquid phase After the raw materials basically disappeared, the temperature was lowered to 0°C to precipitate a large amount of solid, which was suction filtered, and the filter cake was washed with a small amount of ice water to obtain Intermediate 2, which was dried to obtain 47g (0.28mol).

[0034] 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 Left and right, a large amount of solids precipitated, suction filtered, and the filter cake was rinsed with a small amount of methanol to obtain crude 5-fluorocytosine, and then heated to dissolv...

Embodiment 3

[0036]

[0037] In the first step, add 44.1g (0.30mol) of cytosine hydrogen chloride salt and 400mL of water into the reaction kettle. After stirring evenly, raise the temperature to 40-45°C and slowly inject 12.5g (0.33mol) of 20% fluorine gas, and follow the liquid phase After reacting until the raw materials basically disappeared, the temperature was lowered to 0°C to precipitate a large amount of solids, and the filter cake was filtered with suction and rinsed with a small amount of ice water to obtain Intermediate 2, which was dried to obtain 40 g (0.22 mol).

[0038] 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 raise the temperature and reflux for 5h, heat up to reflux, then keep the temperature for 5h, and the reaction is over After cooling down to about 2°C, a large amount of solids precipitated. The filter cake was suction filtered and rinsed with a small amount of methano...

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Abstract

The invention discloses a method for synthesizing flucytosine and belongs to the field of nucleoside synthesis in organic chemistry. The method comprises the following reaction steps: subjecting cytosine salt 1, which serves as a raw material, to a reaction with fluorine gas by taking water as a solvent so as to obtain an intermediate 2, then, subjecting the intermediate 2 to a reaction with an organic base, carrying out dehydrating so as to obtain crude 5-flucytosine, and carrying out water refining, thereby obtaining the 5-flucytosine 3. According to the method, the operation is simple, theemploying of solvents with relatively large danger such as hydrofluoric acid is avoided, the corrosiveness to equipment is also lowered greatly, and meanwhile, the production cost is reduced, so thatthe method is relatively applicable to 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 is C 4 h 4 FN 3 O, as a very important pharmaceutical intermediate, is used to prepare antiviral and antitumor 5-fluorocytosine, lamivudine and capecitabine and other drugs. The methods currently reported in the literature are as follows: [0003] Tako Takahara et al. reported that liquid hydrogen fluoride was used as a solvent, and fluorine gas was introduced at low temperature to directly fluorinate cytosine. After the reaction of raw materials, the temperature of the reaction solution was raised to room temperature, hydrogen fluoride was removed under reduced pressure, methanol was added and concentrated under reduced pressure at room temper...

Claims

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Application Information

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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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