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Synthesis method of cytosine

A synthesis method, cytosine technology, applied in the direction of organic chemistry, etc., can solve the problems of cytosine, such as expensive raw materials, long production cycle, cumbersome operation, etc., to reduce labor operation and energy consumption, low production cost, and process steps simple effect

Active Publication Date: 2014-06-25
ZHEJIANG XIANFENG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The existing synthetic methods of cytosine mainly include functional group conversion method and Pinner synthesis method; functional group conversion method is to synthesize cytosine with 2-mercapto-6-pyrimidinone as raw material, or use uracil or 2,4-dithiopyrimidine as Substrate, synthesize cytosine through processes such as hydrolysis; This synthesis method has the disadvantages of complicated operation, long production cycle, many by-products and serious environmental pollution; Pinner synthesis method is based on 3-alkoxyacrylonitrile or 3-alkoxyacrylonitrile , 3-alkoxypropionitrile is used as a raw material to synthesize cytosine, which is the main method for industrial production of cytosine at present. 3-alkoxyacrylonitrile or 3,3-alkoxypropionitrile is generally passed through the action of acetonitrile on sodium alkoxide It is synthesized by reacting with CO to generate 3-hydroxyacrylonitrile sodium salt, and then reacting with hydrochloric acid alcohol solution; however, its raw material price of cytosine produced by this method is relatively expensive, and the total yield is relatively low; therefore it is necessary to improve

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  • Synthesis method of cytosine

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Effect test

Embodiment 1

[0015] Example 1: A synthetic method of cytosine, the preparation process steps are as follows: put sodium methoxide (24.3g, 0.45mol) and 180mL methanol into the reaction kettle and stir evenly; add 3-hydroxyacrylonitrile sodium salt (27.3 g, 0.3mol) and thiourea (24.0g, 0.315mol); the temperature was raised to 60°C and the ring-closure reaction was carried out for 10 hours to obtain a ring-closure reaction solution; methanol was distilled off under normal pressure, and 80mL of water and 95mL of concentrated Hydrochloric acid to obtain an intermediate solution; add 30% hydrogen peroxide (40.8g, 0.36mol) dropwise to the intermediate solution, and the mass fraction of hydrogen peroxide is 30% to achieve better results, of course, as long as the mass fraction is between 20% and 30% A similar effect can also be obtained if the dropwise addition is completed; after the dropwise addition, raise the temperature to 60°C for 24 hours; cool to room temperature, add 10mol / L sodium hydroxi...

Embodiment 2

[0016] Example 2: Put sodium methoxide (24.3g, 0.45mol) and 180mL methanol into the reaction kettle and stir evenly; add 3-hydroxyacrylonitrile sodium salt (27.3g, 0.3mol) and thiourea (34.2g, 0.45mol) in sequence ), heated to 60°C and cyclization reaction for 8 hours; methanol was distilled off under normal pressure, and 50mL water and 95mL concentrated hydrochloric acid were slowly added to obtain an intermediate solution; 30% hydrogen peroxide (68.0g , 0.6mol), after the dropwise addition, raise the temperature to 90°C and keep it warm for 18 hours; cool to room temperature, add 10mol / L sodium hydroxide solution dropwise to adjust the pH value, when the pH is 7.0, cool to 15°C; after cooling After filtering, washing with water, and drying, 30.9 g of cytosine can be obtained, with a yield of 92.8% and an HPLC content of 99.0%.

Embodiment 3

[0017] Example 3: Put sodium ethoxide (25.5g, 0.375mol) and 180mL ethanol into the reaction kettle and stir evenly; add 3-hydroxyacrylonitrile sodium salt (27.3g, 0.3mol) and thiourea (24.0g, 0.315mol ), heated to 70°C and cyclized for 8 hours; evaporated ethanol under normal pressure, and slowly added 85mL water and 80mL concentrated hydrochloric acid to obtain an intermediate solution; added dropwise 30% hydrogen peroxide (51.0g , 0.45mol), the dropwise addition is completed, heat up to 80°C and keep warm for 20 hours; cool to room temperature, add 10mol / L sodium hydroxide solution dropwise to adjust the pH value, when the pH is 7.5, cool to 10°C; filter after cooling , washed with water, and dried to obtain 30.7 g of cytosine, with a yield of 92.1% and an HPLC content of 99.1%.

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Abstract

The invention discloses a synthesis method of cytosine. The preparation process comprises the following steps: selecting 3-hydroxy acrylonitrile sodium salt and thiourea as raw materials; when preparing, adding a catalyst and an organic solvent to a reaction kettle, uniformly stirring, and sequentially adding the 3-hydroxy acrylonitrile sodium salt and the thiourea; raising temperature to 50-90 DEG C and carrying out a cyclization reaction for 6-10 hours to obtain a cyclization reaction solution; evaporating out the solvent in the cyclization reaction solution, and adding water and hydrochloric acid to obtain an intermediate product solution; dropping hydrogen peroxide to the intermediate product solution, raising temperature to 60-90 DEG C and preserving heat for 18-24 hours; regulating pH value through a sodium hydroxide solution, and cooling to 10-15 DEG C when the pH value is 7.0-7.5; and after cooling, filtering, washing and drying to obtain the cytosine. The synthesis method disclosed by the invention has the advantages that the process is simple in step, short in production cycle and low in cost; moreover, a raw material conversion rate is high, and the synthesized product is good in quality, high in yield, convenient in post-treatment and applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and in particular relates to a synthesis method of cytosine. Background technique [0002] Cytosine is 4-amino-2-hydroxypyrimidine, which is one of the pyrimidine bases in nucleic acid, and is also an important intermediate in fine chemicals, pesticides and medicine; especially in the field of medicine, it is mainly used to synthesize anti-AIDS drugs and anti-hepatitis B drugs Mivudine, anticancer drugs gemcitabine, enoxitabine, and 5-fluorocytosine, etc. The existing synthetic methods of cytosine mainly include functional group conversion method and Pinner synthesis method; functional group conversion method is to synthesize cytosine with 2-mercapto-6-pyrimidinone as raw material, or use uracil or 2,4-dithiopyrimidine as Substrate, synthesize cytosine through processes such as hydrolysis; This synthesis method has the disadvantages of complicated operation, lon...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 高飞飞魏琛晖郭国胜朱善龙卢娓
Owner ZHEJIANG XIANFENG TECH