阅读说明：本技术 一种鸟苷水解法合成鸟嘌呤的方法 (Method for synthesizing guanine by hydrolysis of guanosine ) 是由 苏华强 王育才 贾淑红 王怀江 于 2020-04-23 设计创作，主要内容包括：本发明属于化学合成领域,具体涉及一种鸟苷水解法合成鸟嘌呤的方法。本发明在反应釜中加入溶剂水和酸,然后在搅拌条件下加入鸟苷,加热反应至原料反应完毕；反应完成后冷却至20℃～35℃并用中和剂调节体系pH至中性,过滤,收集滤饼；将滤饼用去离子水浸泡、洗涤,抽滤,得到鸟嘌呤湿品,进一步干燥,得鸟嘌呤干品。该方法鸟嘌呤产品收率高,纯度高,其中,反应收率96.0～98.0％,产品纯度99.5～99.8％,操作过程简单,生产周期短,单批次反应时间低至1小时,适合工业大生产。(The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing guanine by a guanosine hydrolysis method. Adding solvent water and acid into a reaction kettle, then adding guanosine under the stirring condition, and heating for reaction until the reaction of the raw materials is finished; after the reaction is finished, cooling to 20-35 ℃, adjusting the pH value of the system to be neutral by using a neutralizing agent, filtering, and collecting a filter cake; and soaking the filter cake in deionized water, washing, performing suction filtration to obtain a wet guanine product, and further drying to obtain a dry guanine product. The method has the advantages of high yield and high purity of guanine products, wherein the reaction yield is 96.0-98.0%, the product purity is 99.5-99.8%, the operation process is simple, the production period is short, the single-batch reaction time is as short as 1 hour, and the method is suitable for industrial mass production.)

1. A method for synthesizing guanine by hydrolysis of guanosine is characterized by comprising the following steps:

(1) adding solvent water and acid into a reaction kettle, then adding guanosine under the stirring condition, and heating for reaction until the reaction of the raw materials is finished; after the reaction is finished, cooling to 20-35 ℃, adjusting the pH value of the system to be neutral by using a neutralizing agent, filtering, and collecting a filter cake;

(2) and (2) soaking the filter cake prepared in the step (1) with deionized water, washing, performing suction filtration to obtain a guanine wet product, and further drying to obtain a guanine dry product.

2. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the weight ratio of guanosine to solvent water in the step (1) is (1:7) - (1: 9).

3. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the molar ratio of guanosine to hydrogen ions in the acid in the step (1) is (1:1.4) - (1: 2).

4. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the heating reaction in the step (1) is carried out at a temperature of 80-100 ℃.

5. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the acid in the step (1) is at least one of sulfuric acid and hydrochloric acid.

6. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the neutralizing agent in the step (1) is at least one of sodium carbonate, sodium hydroxide and ammonia water.

7. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the temperature of the deionized water in the step (2) is lower than 25 ℃.

8. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

and (3) soaking and washing for 2-3 times.

9. The method for the hydrolysis of guanosine to synthesize guanine according to claim 1, wherein:

the drying in the step (2) is drying.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a method for synthesizing guanine by a guanosine hydrolysis method.

Background

Guanine (guanine), also known as guanylin, 2-amino-6-hydroxypurine, 2-aminohypoxanthine, having a relative molecular weight of 151.13 and a molecular formula C₅H₅N₅O, with the structure as shown in formula I, is colorless square crystalline or amorphous powder with relative density of 2.19g/cm³Melting Point>300 ℃; it is soluble in ammonia water, caustic alkali and dilute mineral acid solution, slightly soluble in ethanol and diethyl ether, insoluble in water, and has strong absorption to ultraviolet, and is a component of guanosine and guanylic acid. Its hydrochloride salt isMonohydrate powder crystal, losing water at 100 deg.C and hydrogen chloride at 200 deg.C.

Guanine is an important medical intermediate, and can be used for synthesizing a series of high-efficiency low-toxicity antiviral drugs, such as acyclovir and famciclovir. At present, methods for producing guanine include chemical synthesis, extraction of natural raw materials, and microbial fermentation.

Wherein, the chemical synthesis method mainly uses sulfate of 2, 4, 5-triamino-6-hydroxypyrimidine (TAHP sulfate) or 2, 4-diamino-5-formamido-6-hydroxypyrimidine (DAFHP) and the like as raw materials to prepare guanine. DE3729471 discloses the preparation of guanine by reacting TAHP sulfate with formamide at 200 ℃, which, although in high yield, leads to poor quality and dark yellow color of the product due to partial decomposition of formamide at high temperature, and in addition, 2, 4, 5-triamino-6-hydroxypyrimidine needs to be introduced in the form of its sulfate, so that a large amount of inorganic salts are present in the product, increasing the purification cost. EP0415028 discloses the preparation of guanine by reacting TAHP sulfate, an alkali metal formate and formic acid at 200 ℃. The method avoids the disadvantages caused by using formamide, but the existence of TAHP sulfate and alkali metal formate also makes the purification process complicated and increases the purification cost. DE4136114 discloses the reaction of DAFHP, formamide and formic acid as reactants at over 140 deg.C to obtain guanine, and this process avoids the use of TAHP sulfate, but also has the disadvantages of poor product quality and dark yellow color, and needs further purification. EP1010700 discloses that DAFHP and concentrated formic acid are used as raw materials, guanine is obtained by a high pressure (4-5 bar) reaction, which is a great improvement over the aforementioned reaction, avoids the disadvantages caused by formamide and TAHP sulfate, and has a high yield, but this method requires the addition of expensive catalysts such as Pd/C, and the reaction has a high requirement on equipment, such as industrial production, and has a large potential safety hazard. The domestic research on guanine is less, and the application number 'CN200510110536. X' discloses that guanidine nitrate and ethyl cyanoacetate are subjected to cyclization reaction, the obtained compound 2, 4-diamino-6-hydroxypyrimidine is added with a mixed solution of sodium nitrite, formamide and concentrated formic acid and a reducing agent in a formamide solvent of the compound in sequence to carry out nitrosation and reduction reaction, and then the cyclization reaction is further carried out to prepare guanine. Application number "CN 200810019347.5" discloses that urea reacts with formic acid, 2, 4, 5-triamino-6-hydroxypyrimidine sulfate is added after the reaction is finished, and formic acid is added for continuous reaction to obtain guanine. This process also suffers from the disadvantages and problems associated with the above-mentioned 2, 4, 5-triamino-6-hydroxypyrimidinesulfates.

The natural raw material extraction method is mainly to extract the guano from the bird droppings and the fish scales, has wide sources and easily obtained raw materials, but has complex extraction process, low yield and high cost, for example, the process and the quality research of guanine extraction from the scales of grass carp by Zangdan et al (Zangdan, Zhangying, Xicheng, et al. the process and the quality research of guanine extraction from the scales of grass carp [ J ] modern agricultural science and technology, 2012,000(001):15-16.) have shown that: the extraction rate is 0.39% at most.

Application No. CN201611160505.X discloses adding cytidine and guanosine into a culture medium respectively, inoculating Clavicipitaceae strains, performing shake culture, and performing static culture at room temperature to obtain cytosine and guanine. The method has the problems of long time consumption, low efficiency, difficult product separation and the like.

Disclosure of Invention

In order to overcome the defects of complex reaction, low efficiency, difficult separation of products, high purification difficulty and the like in the prior art, the invention aims to provide a method for synthesizing guanine by a guanosine hydrolysis method.

The purpose of the invention is realized by the following technical scheme:

a method for synthesizing guanine by hydrolysis of guanosine comprises the following steps:

(1) adding solvent water and acid into a reaction kettle, then adding guanosine under the stirring condition, and heating for reaction until the reaction of the raw materials is finished; after the reaction is finished, cooling to 20-35 ℃, adjusting the pH value of the system to be neutral by using a neutralizing agent, filtering, and collecting a filter cake;

(2) soaking the filter cake prepared in the step (1) with deionized water, washing, performing suction filtration to obtain a wet guanine product, and further drying to obtain a dry guanine product;

the weight ratio of guanosine to solvent water in the step (1) is preferably (1:7) - (1: 9);

the molar ratio of guanosine to hydrogen ions in the acid in the step (1) is preferably (1:1.4) to (1: 2);

the heating reaction temperature in the step (1) is preferably 80-100 ℃;

the acid in the step (1) is preferably at least one of sulfuric acid and hydrochloric acid;

the neutralizing agent in the step (1) is preferably at least one of sodium carbonate, sodium hydroxide and ammonia water, and the pH value of the adjusting system is 7;

the temperature of the deionized water in the step (2) is preferably lower than 25 ℃;

the soaking and washing times in the step (2) are preferably 2-3 times;

the drying in the step (2) is preferably drying;

the reaction scheme of the invention is as follows:

compared with the prior art, the invention has the following advantages and effects:

(1) the method for synthesizing guanine by using the guanosine hydrolysis method provided by the invention uses guanosine as a raw material, and the guanine is obtained under the acidic hydrolysis condition, and the method has high yield and high purity of the guanine product, wherein the reaction yield is 96.0-98.0%, and the product purity is 99.5-99.8%.

(2) The invention takes water as a reaction solvent, is green and mild, and is nontoxic and harmless.

(3) The invention uses inorganic acid (hydrochloric acid, sulfuric acid) as hydrolysis medium, and has low cost and easy obtaining.

(4) The invention adopts proper solvent and hydrolysis medium, and optimizes the dosage proportion of reactants, thereby greatly improving the reaction rate and yield and leading the reaction to be more complete and thorough.

(5) The method for synthesizing guanine by the guanosine hydrolysis method provided by the invention has the advantages of simple operation process and short production period (the single batch reaction time is as short as 1 hour), and is suitable for industrial mass production.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.