A kind of method for synthesizing 5-fluorocytosine by cytosine fluorination

A technology for flucytosine and cytosine, which is applied in the field of cytosine fluorination to synthesize 5-flucytosine, can solve problems such as unfavorable industrial production, unstable product quality, use of organic solvents, etc., and achieves easy control of raw material temperature and avoidance of fluorine The effect of high gas concentration and many reaction steps

Active Publication Date: 2016-09-14
SHANGYU HUALUN CHEM
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] This method mainly has the following disadvantages: first, the route with 5-fluorouracil as raw material has high cost and low yield (not including refining 56.4%), and the route with 5-fluorouracil precursor as raw material needs pressurized ammonia Chemical reaction and use a large amount of anhydrous methanol as a solvent, which is not conducive to industrial production. In addition, the last step of hydrolysis is easy to convert the amino group on the pyrimidine ring into a hydroxyl group, and then back to 5-fluorouracil, resulting in unstable product quality
[0014] Although the above two preparation methods can increase the yield, there are still problems of complex reaction, long synthetic route, and the use of organic solvents in the reaction process, causing environmental pollution.

Method used

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  • A kind of method for synthesizing 5-fluorocytosine by cytosine fluorination
  • A kind of method for synthesizing 5-fluorocytosine by cytosine fluorination
  • A kind of method for synthesizing 5-fluorocytosine by cytosine fluorination

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Embodiment 1

[0043] (1) Under the protection of nitrogen, add 1150g of cytosine to the anhydrous hydrogen fluoride with a temperature of 0°C and a mass of 3450g, and at a temperature of -15°C, feed a mixed gas of fluorine and nitrogen with a fluorine content of 15%, The flow rate is 40g / h, and the fluorination reaction is carried out;

[0044] (2) After reacting for 4 hours, feed nitrogen gas to remove excess fluorine gas, vacuum distill anhydrous hydrogen fluoride from the reaction solution to dryness at -20°C, add 8L of water, and then add calcium carbonate to adjust the pH value to 8;

[0045](3) Heat the reaction solution to 90°C and keep it warm for 1 hour. After hot filtration, add 100g of activated carbon, keep warm at 90°C for 0.5 hour, heat and filter again, cool down to 25°C and stir for 0.5 hour, then cool down to 0°C and stir for 1 hour , filtered to obtain white 5-fluorocytosine wet product;

[0046] (4) After drying the wet product of 5-fluorocytosine at 70° C. for 16 hours,...

Embodiment 2

[0049] (1) Under the protection of nitrogen, add 1150g of cytosine to the anhydrous hydrogen fluoride with a temperature of 0°C and a mass of 4600g, and at a temperature of -15°C, feed a mixed gas of fluorine and nitrogen with a fluorine content of 15%, The flow rate is 40g / h, and the fluorination reaction is carried out;

[0050] (2) After reacting for 3 hours, feed nitrogen to remove excess fluorine gas, vacuum distill anhydrous hydrogen fluoride from the reaction solution to dryness at -20°C, add 8L of water, and then add calcium carbonate to adjust the pH value to 7;

[0051] (3) Heat the reaction solution to 90°C and keep it warm for 1 hour. After hot filtration, add 100g of activated carbon, keep warm at 90°C for 0.5 hour, heat and filter again, cool down to 25°C and stir for 0.5 hour, then cool down to 0°C and stir for 1 hour , filtered to obtain white 5-fluorocytosine wet product;

[0052] (4) After drying the wet product of 5-fluorocytosine at 70° C. for 16 hours, th...

Embodiment 3

[0055] (1) Under the protection of nitrogen, add 1150g of cytosine to the anhydrous hydrogen fluoride with a temperature of 0°C and a mass of 2300g, and at a temperature of -15°C, feed a mixed gas of fluorine and nitrogen with a fluorine content of 20%, The flow rate is 50g / h, and the fluorination reaction is carried out;

[0056] (2) After reacting for 3 hours, feed nitrogen gas to remove excess fluorine gas, vacuum distill anhydrous hydrogen fluoride from the reaction solution to dryness at -20°C, add 8L of water, and then add calcium carbonate to adjust the pH value to 8;

[0057] (3) Heat the reaction solution to 90°C and keep it warm for 1 hour. After hot filtration, add 100g of activated carbon, keep warm at 90°C for 0.5 hour, heat and filter again, cool down to 25°C and stir for 0.5 hour, then cool down to 0°C and stir for 1 hour , filtered to obtain white 5-fluorocytosine wet product;

[0058] (4) After drying the wet product of 5-fluorocytosine at 70° C. for 16 hours...

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Abstract

The invention discloses a method for fluoridating and synthesizing 5-flucytosine by cytosine, which comprises the following steps: 1)under inert gas protection, adding cytosine in anhydrous hydrogen fluoride, introducing fluorine containing gas for a fluorination reaction under -5--20 DEG C, and 2)after reacting for 3-5 hours, distilling and concentrating the reaction solution, adding water for dissolving, adding alkali to adjust the pH value of the reaction solution, and separating to obtain the 5-flucytosine by cytosine. The method has the advantages of short synthesis route and good technology selectivity, no organic solvent is used during the production process, and the synthesized 5-flucytosine by cytosine has the advantages of high purity and high synthesis yield.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 5-fluorocytosine by fluorination of cytosine. Background technique [0002] In the prior art, 5-fluorocytosine (Fluorocytosine), also known as: 4-amino-5-fluoro-2(1H)-pyrimidinone, structural formula: CAS: 2022-85-7, molecular formula: C 4 h 4 FN 3 O, is white or off-white crystalline powder, odorless or slightly odorous, molecular weight: 129.09, melting point: 295-297°C. Slightly soluble in water, the solubility in water is 1.2% (20°C), slightly soluble in ethanol; almost insoluble in chloroform and ether; easily soluble in dilute hydrochloric acid or dilute sodium hydroxide solution. It is stable at room temperature, and crystallizes when it is cold, and partly turns into 5-fluorouracil when it is heated. [0003] 5-fluorocytosine is mainly used as an antifungal agent for mucocutaneous candidiasis, candida endocarditis, candida arthritis, crypto...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 李典正何光明孙刚姜嘉宝
Owner SHANGYU HUALUN CHEM
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