阅读说明：本技术 一种尿嘧啶的制备方法 (Preparation method of uracil ) 是由 高飞飞 魏琛晖 戴晓楠 陈小平 高军龙 于 2019-09-28 设计创作，主要内容包括：本发明提供了一种尿嘧啶的制备方法,属于杂环化合物合成领域。本发明提供的尿嘧啶的制备方法包括以下步骤：向反应釜中加入水和亚硫酸氢钠,搅拌至完全溶解,再加入胞嘧啶,升温至45-50℃,反应12-16h；步骤一中反应液降温,搅拌,过滤,所得固定用冷水洗涤,干燥后得到中间体1；向反应釜中加入水,再向反应釜中转移步骤二中得到的中间体1,最后加入盐酸,升温至95-100℃,反应4-5h；步骤三中反应液降温,搅拌,过滤,所得固体用冷水洗涤,干燥后得到尿嘧啶。本发明在反应过程中未使用苹果酸及发烟硫酸,不会产生大量的酸性废水,环境友好,且相比于生物发酵的方法具有更高的成功率,适用于工业化生产。(the invention provides a preparation method of uracil, belonging to the field of heterocyclic compound synthesis. The preparation method of uracil provided by the invention comprises the following steps: adding water and sodium bisulfite into a reaction kettle, stirring until the water and the sodium bisulfite are completely dissolved, adding cytosine, heating to 45-50 ℃, and reacting for 12-16 h; cooling, stirring and filtering the reaction liquid in the step one, washing the obtained fixed solution with cold water, and drying to obtain an intermediate 1; adding water into the reaction kettle, transferring the intermediate 1 obtained in the second step into the reaction kettle, finally adding hydrochloric acid, heating to 95-100 ℃, and reacting for 4-5 hours; and (3) cooling the reaction liquid in the third step, stirring, filtering, washing the obtained solid with cold water, and drying to obtain the uracil. The method does not use malic acid and fuming sulfuric acid in the reaction process, does not generate a large amount of acidic wastewater, is environment-friendly, has higher success rate compared with a biological fermentation method, and is suitable for industrial production.)

1. A preparation method of uracil is characterized by comprising the following steps:

Step one, adding water and sodium bisulfite into a container, stirring until the water and the sodium bisulfite are completely dissolved, adding cytosine, heating to 45-50 ℃, and reacting for 12-16h to obtain reaction liquid;

Step two, cooling the reaction solution, stirring, filtering, taking a solid, washing with cold water, and drying to obtain an intermediate 1;

Step three: and sequentially adding water, the intermediate 1 and hydrochloric acid into a container, heating to 95-100 ℃, reacting for 4-5h, cooling, stirring, filtering, taking a solid, washing with cold water, and drying to obtain the uracil.

2. The process for producing uracil according to claim 1, wherein:

wherein the mass ratio of the cytosine to the sodium bisulfite is 1 (1.8-2.0).

3. the process for producing uracil according to claim 1, wherein:

Wherein in the second step, the temperature is reduced to 20-25 ℃ in the temperature reduction step, and the stirring time is 1-1.5 h.

4. the process for producing uracil according to claim 1, wherein:

Wherein, in the third step, the temperature is reduced to 20-25 ℃ in the temperature reduction step, and the stirring time is 1-1.5 h.

5. the process for producing uracil according to claim 1, wherein:

Wherein the drying step is performed when the pH of the washing solution obtained in the cold water washing step is 4-6.

6. the process for producing uracil according to claim 1, wherein:

Wherein the drying is reduced pressure drying, and the temperature of the reduced pressure drying is 95-100 ℃.

7. The process for producing uracil according to claim 1, wherein:

the preparation method of the cytosine comprises the following steps:

taking acetonitrile and ethyl formate as raw materials, taking sodium methoxide as alkali, and preparing 2-cyano-sodium vinyl alcohol under the reaction condition of heating and pressurizing;

And step two, reacting the 2-cyano-sodium vinyl alcohol with an ethanol solution of hydrogen chloride, adding sodium methoxide and urea after the reaction is finished, and continuing to react and close the ring to obtain the cytosine.

8. The process for producing uracil according to claim 1, wherein:

the preparation method of the cytosine comprises the following steps:

Taking acetonitrile and ethyl formate as raw materials, taking sodium methoxide as alkali, introducing carbon monoxide, and preparing 2-cyano-sodium vinyl alcohol under the reaction condition of heating and pressurizing;

and step two, reacting the 2-cyano-sodium vinyl alcohol with an ethanol solution of hydrogen chloride, adding sodium methoxide and urea after the reaction is finished, and continuing to react and close the ring to obtain the cytosine.

Technical Field

the invention relates to a preparation method of uracil, and belongs to the field of heterocyclic compound synthesis.

background

Uracil, named by the chemical system 2,4- (1H,3H) -pyrimidinedione or 2, 4-dihydroxylpyrimidine radical, molecular formula C₄H₄N₂O₂. Uracil is used as a pharmaceutical agent for the treatment of digestive system cancer, breast cancer, thyroid cancer, etc., and is used in combination with mitomycin for the treatment of advanced gastric cancer. When used as a medical intermediate, uracil can be used for synthesizing a series of important compounds such as 5-fluorouracil, tegafur, bifurofluorouracil, deoxyfluorouracil, carmofur, 5-iodo-2' -deoxyuridine and the like.

disclosure of Invention

the present invention has been made to solve the above problems, and an object of the present invention is to provide a green and environmentally friendly method for preparing uracil.

the invention provides a preparation method of uracil, which is characterized by comprising the following steps: step one, adding water and sodium bisulfite into a container, stirring until the water and the sodium bisulfite are completely dissolved, adding cytosine, heating to 45-50 ℃, and reacting for 12-16h to obtain reaction liquid; step two, cooling the reaction solution, stirring, filtering, taking a solid, washing with cold water, and drying to obtain an intermediate 1; step three: and sequentially adding water, the intermediate 1 and hydrochloric acid into a container, heating to 95-100 ℃, reacting for 4-5h, cooling, stirring, filtering, taking a solid, washing with cold water, and drying to obtain the uracil.

the method for producing uracil provided by the present invention may further include: wherein the mass ratio of the cytosine to the sodium bisulfite is 1 (1.8-2.0).

The method for producing uracil provided by the present invention may further include: wherein, in the second step, the temperature is reduced to 20-25 ℃ in the temperature reduction step, and the stirring time is 1-1.5 h.

The method for producing uracil provided by the present invention may further include: wherein, in the third step, the temperature is reduced to 20-25 ℃ in the temperature reduction step, and the stirring time is 1-1.5 h.

the method for producing uracil provided by the present invention may further include: wherein, when the pH value of the washing liquid obtained in the cold water washing step is 4-6, the drying step is carried out.

The method for producing uracil provided by the present invention may further include: wherein the drying is reduced pressure drying at 95-100 deg.C.

The method for producing uracil provided by the present invention may further include: the preparation method of the cytosine comprises the following steps: taking acetonitrile and ethyl formate as raw materials, taking sodium methoxide as alkali, and preparing 2-cyano-sodium vinyl alcohol under the reaction condition of heating and pressurizing; and step two, reacting the 2-cyano-sodium vinyl alcohol with an ethanol solution of hydrogen chloride, adding sodium methoxide and urea after the reaction is finished, and continuing to react and close the ring to obtain the cytosine.

The method for producing uracil provided by the present invention may further include: the preparation method of the cytosine comprises the following steps: taking acetonitrile and ethyl formate as raw materials, taking sodium methoxide as alkali, introducing carbon monoxide, and preparing 2-cyano-sodium vinyl alcohol under the reaction condition of heating and pressurizing; and step two, reacting the 2-cyano-sodium vinyl alcohol with an ethanol solution of hydrogen chloride, adding sodium methoxide and urea after the reaction is finished, and continuing to react and close the ring to obtain the cytosine.

Specifically, the preparation method of uracil provided by the invention has the following process route:

specifically, the cytosine synthesis process route provided by the invention is as follows:

Action and Effect of the invention

According to the uracil preparation method, cytosine and sodium bisulfite are used for replacing traditional concentrated sulfuric acid and malic acid as raw materials, so that a large amount of acidic wastewater containing concentrated sulfuric acid is not generated in the production process, the method is environment-friendly, the reaction process is stable and reliable, the method is suitable for industrial production, and the washing liquid containing sodium bisulfite obtained in the production process can be recycled, so that the method conforms to the green environmental protection principle.

Drawings

FIG. 1 is a hydrogen spectrum of uracil obtained by the process for preparing uracil in example 1 of the present invention;

FIG. 2 is a carbon spectrum of uracil obtained by the method for preparing uracil in example 1 of the present invention;

FIG. 3 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 1 of the present invention;

FIG. 4 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 2 of the present invention; and

FIG. 5 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 3 of the present invention.

Detailed Description

In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.

the cytosines used in the following examples are either commercially available cytosines or synthesized by the following method:

Taking acetonitrile and ethyl formate as raw materials, taking sodium methoxide as alkali, introducing carbon monoxide, and preparing 2-cyano-sodium vinyl alcohol under the reaction condition of heating and pressurizing; and step two, reacting the 2-cyano-sodium vinyl alcohol with an ethanol solution of hydrogen chloride, adding sodium methoxide and urea after the reaction is finished, and continuing to react and close the ring to obtain the cytosine.

Other chemical reagents were purchased from conventional biochemical reagent stores unless otherwise specified.

The liquid phase conditions used to examine uracil purity in the following examples are as follows:

the uracil liquid chromatography detection instrument is an Shimadzu high performance liquid chromatograph LC-2030, the chromatographic column is an Agilent HC-C18 type chromatographic column with the size of 4.6mm multiplied by 250mm, and the filler particle size is 5 mu m; the column temperature was 40 ℃; detector wavelength UV259 nm; the sample injection amount is 10 mu L; the running time is 40 min; the mobile phase is trifluoroacetic acid water solution with mass fraction of 0.05% and trifluoroacetic acid acetonitrile solution with mass fraction of 0.05%, and the specific gradient is shown in table 1.

TABLE 1 gradient elution Table

Time/min	Aqueous 0.05% TFA	0.05% TFA acetonitrile solution
			0	100	0
30.0	5	95
			34.0	5	95
34.1	100	0
			40	100	0

< example 1>

a preparation method of uracil comprises the following steps:

step one, adding 200kg of water and 72kg of sodium bisulfite into a 300L reaction kettle, stirring until the water and the 72kg of sodium bisulfite are completely dissolved, adding 40kg of cytosine, heating to 45 ℃, and reacting for 12 hours to obtain a reaction solution;

Step two, cooling the reaction liquid to 20 ℃, stirring for 1h, centrifuging, filtering, taking solid, washing with 80kg of cold water, and drying to obtain white crystal powder, namely an intermediate 1;

Step three: adding 200kg of water into a 300L enamel reaction kettle, transferring the intermediate 1 into the reaction kettle, finally adding 55kg of hydrochloric acid with the mass fraction of 36%, heating to 95 ℃, reacting for 4h, cooling to 20 ℃, stirring for 1h, centrifuging, filtering, taking the solid, washing with cold water, monitoring the pH value of a washing solution by using a pH test paper in the washing process until the pH value of the washing solution is 4, stopping washing, drying the washed solid at 95 ℃ under reduced pressure to obtain 33.9kg of uracil with the total yield of 84.0%,

FIG. 1 is a hydrogen spectrum of uracil obtained by the method for producing uracil in example 1 of the present invention. FIG. 2 is a carbon spectrum of uracil obtained by the method for preparing uracil in example 1 of the present invention.

As shown in FIG. 1-2, the product obtained in this example was identified as uracil by confirmation of the hydrogen spectrum and the carbon spectrum (the solvents used in the hydrogen spectrum and the carbon spectrum were DMSO-d)⁶)。

FIG. 3 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 1 of the present invention.

As shown in FIG. 3, the uracil obtained in this example was 99.982% pure as measured by liquid chromatography.

< example 2>

A preparation method of uracil comprises the following steps:

step one, adding 200kg of water and 80kg of sodium bisulfite into a 300L reaction kettle, stirring until the water and the sodium bisulfite are completely dissolved, adding 40kg of cytosine, heating to 50 ℃, and reacting for 16 hours to obtain a reaction solution;

step two, cooling the reaction liquid to 25 ℃, stirring for 1.5h, centrifuging, filtering, taking solid, washing with 80kg of cold water, and drying to obtain white crystal powder, namely an intermediate 1;

Step three: adding 200kg of water into a 300L enamel reaction kettle, transferring the intermediate 1 into the reaction kettle, finally adding 55kg of hydrochloric acid with the mass fraction of 36%, heating to 100 ℃, reacting for 5h, cooling to 25 ℃, stirring for 1h, centrifuging, filtering, taking the solid, washing with cold water, monitoring the pH value of a washing solution by using a pH test paper in the washing process until the pH value of the washing solution is 6, stopping washing, and drying the washed solid at 100 ℃ under reduced pressure to obtain 33.4kg of uracil with the total yield of 82.8%.

FIG. 4 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 2 of the present invention.

As shown in FIG. 4, the uracil obtained in this example was 99.978% pure as measured by liquid chromatography.

< example 3>

a preparation method of uracil comprises the following steps:

Step one, adding 200kg of water and 75kg of sodium bisulfite into a 300L reaction kettle, stirring until the water and the sodium bisulfite are completely dissolved, adding 40kg of cytosine, heating to 48 ℃, and reacting for 14 hours to obtain a reaction solution;

step two, cooling the reaction liquid to 22 ℃, stirring for 1.2h, centrifuging, filtering, taking solid, washing with 80kg of cold water, and drying to obtain white crystal powder, namely an intermediate 1;

step three: adding 200kg of water into a 300L enamel reaction kettle, transferring the intermediate 1 into the reaction kettle, finally adding 55kg of hydrochloric acid with the mass fraction of 36%, heating to 98 ℃, reacting for 4.5h, cooling to 22 ℃, stirring for 1.2h, centrifugally filtering, taking the solid, washing with cold water, monitoring the pH value of a washing solution by using a pH test paper in the washing process until the pH value of the washing solution is 5, stopping washing, drying the washed solid at 98 ℃ under reduced pressure to obtain 34.1kg of uracil, wherein the total yield is 84.5%.

FIG. 5 is a liquid chromatogram of uracil obtained by the method for producing uracil in example 3 of the present invention.

as shown in FIG. 5, the uracil obtained in this example was 99.983% pure as measured by liquid chromatography.