CN114315934A - Synthesis and refining method of citicoline important intermediate cytidylic acid - Google Patents
Synthesis and refining method of citicoline important intermediate cytidylic acid Download PDFInfo
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- CN114315934A CN114315934A CN202111577952.6A CN202111577952A CN114315934A CN 114315934 A CN114315934 A CN 114315934A CN 202111577952 A CN202111577952 A CN 202111577952A CN 114315934 A CN114315934 A CN 114315934A
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Abstract
The invention discloses a method for synthesizing and refining citicoline important intermediate cytidylic acid, which comprises the following steps: s1, adding 4-5Kg/Kg of trimethyl phosphate into a reaction kettle, wherein the weight ratio is based on the weight of cytidine, the following materials are in the same ratio, uniformly stirring with the cytidine, replacing nitrogen in the reaction system for 3 times, introducing a cooling medium to cool the reaction system, and dropwise adding 1-2Kg/Kg of phosphorus oxychloride into the reaction system through an overhead dropwise adding device; a high-activity phosphorylation reagent of phosphorus oxychloride is adopted, cytidine is acylated by phosphorus oxychloride and then quenched by hydrolysis, the obtained reactant is dissolved by adding organic alkali, a mixed solution of hydrochloric acid and ethanol is dripped to carry out neutralization crystallization, and the steps are repeated to recrystallize for three times to remove impurities, so that cytidylic acid with the content of more than 95% is obtained, better selectivity and higher reaction yield are shown, and the method has the process characteristics of lower cost and less pollution.
Description
Technical Field
The invention relates to the field of preparation equipment of cytidine acid, an important intermediate of citicoline, in particular to a method for synthesizing and refining cytidine acid, an important intermediate of citicoline.
Background
The citicoline important intermediate cytidine acid at present has the disadvantages of low yield, difficult separation and the like due to the limitation of reaction selectivity.
Disclosure of Invention
The invention aims to provide a method for synthesizing and refining cytidine monophosphate serving as an important intermediate of citicoline, which adopts a high-activity phosphorylation reagent of phosphorus oxychloride, is used for acylating cytidine by phosphorus oxychloride and then is quenched by hydrolysis, an obtained reactant is dissolved by adding organic alkali, a mixed solution of hydrochloric acid and ethanol is dripped to perform neutralization and crystallization, and the steps are repeated for recrystallization and three times for impurity removal, so that cytidine monophosphate with the content of more than 95% is obtained, better selectivity and higher reaction yield are shown, and the method has the process characteristics of lower cost and less pollution.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing and refining cytidine monophosphate serving as an important intermediate of citicoline comprises the following steps:
s1, adding 4-5Kg/Kg of trimethyl phosphate into a reaction kettle, wherein the weight ratio is based on the weight of cytidine, the following materials are in the same ratio, uniformly stirring with the cytidine, replacing nitrogen in the reaction system for 3 times, introducing a cooling medium to cool the reaction system, and dropwise adding 1-2Kg/Kg of phosphorus oxychloride into the reaction system through an overhead dropwise adding device;
s2, adding the reaction solution in the previous step into 4-6Kg/Kg of purified water through an overhead tank, keeping the temperature at 40-60 ℃ after the addition, stirring for 3-4 h, adding 1-2Kg/Kg of organic base under stirring, continuing to stir for 1.0-1.5 h after the addition, continuing to dropwise add 0.5-1Kg/Kg of organic base, and finishing dropwise adding 1.0-2.0 h;
s3, centrifugally separating the reaction liquid, collecting solids, directly adding the obtained solid into a mixed liquid of 1.2-1.8Kg/Kg of absolute ethyl alcohol and purified water, controlling the temperature to be 10-30 ℃, and stirring for 0.5-1.0 h;
s4, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into purified water, adding 0.3-0.5Kg/Kg of organic alkali until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.1-0.3Kg/Kg of hydrochloric acid, continuing stirring for reaction for 1.0-1.5 h, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.2-2.5Kg/Kg of absolute ethyl alcohol under stirring, and finishing the addition for 3.0-5.0 h;
s5, centrifugally separating the reaction liquid in the previous step, collecting solids, adding 2.5-3.0Kg/Kg of purified water into the obtained wet product, adding 0.3-0.4Kg/Kg of organic base into the obtained wet product, stirring the obtained mixture until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.09-0.11Kg/Kg of hydrochloric acid into the obtained mixture, continuously stirring the obtained mixture for 1.0-1.5 hours, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.0-2.5Kg/Kg of ethanol into the obtained mixture under stirring, and finishing the adding of the obtained mixture for 3.0-5.0 hours;
s6, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into a mixed solution of 1.2-1.3Kg/Kg of absolute ethyl alcohol and 1.5-2.0Kg/Kg of purified water, controlling the temperature to 15-25 ℃, and stirring for 0.5-1.0 h;
s7, centrifugally separating the reaction solution, washing with 20kg of absolute ethyl alcohol, collecting a filter cake, transferring the filter cake into a hot air circulation oven, controlling the temperature to be 55-60 ℃, and drying for 6-8 hours to obtain the citicoline important intermediate cytidine monophosphate.
As a further scheme of the invention: and S1, cooling the reaction system to-15 to-5 ℃ by using the cooling medium, dropwise adding phosphorus oxychloride, controlling the internal temperature to-15 to-5 ℃, controlling the temperature to-15 to-5 ℃ after the dropwise adding is finished, and keeping the temperature for reaction for 1 hour.
As a further scheme of the invention: and (S2) dropwise adding the organic alkali, then keeping the temperature and stirring for 2.0-3.0 h, then cooling to 10-30 ℃, and stirring for 3.0-5.0 h.
As a further scheme of the invention: and S4, dropwise adding a mixed solution of hydrochloric acid and absolute ethyl alcohol, keeping the temperature, stirring for 1.0-2.0 h, cooling to 15-25 ℃, and stirring for 3.0-5.0 h.
As a further scheme of the invention: and (S5) adding a mixed solution of hydrochloric acid and ethanol in the step, keeping the temperature, stirring for 1.0-2.0 h, cooling to 15-25 ℃, and stirring for 3.0-5.0 h.
The invention has the beneficial effects that: a high-activity phosphorylation reagent of phosphorus oxychloride is adopted, cytidine is acylated by phosphorus oxychloride and then quenched by hydrolysis, the obtained reactant is dissolved by adding organic alkali, a mixed solution of hydrochloric acid and ethanol is dripped to carry out neutralization crystallization, and the steps are repeated to recrystallize for three times to remove impurities, so that cytidylic acid with the content of more than 95% is obtained, better selectivity and higher reaction yield are shown, and the method has the process characteristics of lower cost and less pollution.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A method for synthesizing and refining cytidine monophosphate serving as an important intermediate of citicoline comprises the following steps:
s1, adding 4-5Kg/Kg of trimethyl phosphate into a reaction kettle, wherein the weight ratio is based on the weight of cytidine, the following materials are in the same ratio, uniformly stirring with the cytidine, replacing nitrogen in the reaction system for 3 times, introducing a cooling medium to cool the reaction system, and dropwise adding 1-2Kg/Kg of phosphorus oxychloride into the reaction system through an overhead dropwise adding device;
s2, adding the reaction solution in the previous step into 4-6Kg/Kg of purified water through an overhead tank, keeping the temperature at 40-60 ℃ after the addition, stirring for 3-4 h, adding 1-2Kg/Kg of organic base under stirring, continuing to stir for 1.0-1.5 h after the addition, continuing to dropwise add 0.5-1Kg/Kg of organic base, and finishing dropwise adding 1.0-2.0 h;
s3, centrifugally separating the reaction liquid, collecting solids, directly adding the obtained solid into a mixed liquid of 1.2-1.8Kg/Kg of absolute ethyl alcohol and purified water, controlling the temperature to be 10-30 ℃, and stirring for 0.5-1.0 h;
s4, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into purified water, adding 0.3-0.5Kg/Kg of organic alkali until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.1-0.3Kg/Kg of hydrochloric acid, continuing stirring for reaction for 1.0-1.5 h, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.2-2.5Kg/Kg of absolute ethyl alcohol under stirring, and finishing the addition for 3.0-5.0 h;
s5, centrifugally separating the reaction liquid in the previous step, collecting solids, adding 2.5-3.0Kg/Kg of purified water into the obtained wet product, adding 0.3-0.4Kg/Kg of organic base into the obtained wet product, stirring the obtained mixture until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.09-0.11Kg/Kg of hydrochloric acid into the obtained mixture, continuously stirring the obtained mixture for 1.0-1.5 hours, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.0-2.5Kg/Kg of ethanol into the obtained mixture under stirring, and finishing the adding of the obtained mixture for 3.0-5.0 hours;
s6, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into a mixed solution of 1.2-1.3Kg/Kg of absolute ethyl alcohol and 1.5-2.0Kg/Kg of purified water, controlling the temperature to 15-25 ℃, and stirring for 0.5-1.0 h;
s7, centrifugally separating the reaction solution, washing with 20kg of absolute ethyl alcohol, collecting a filter cake, transferring the filter cake into a hot air circulation oven, controlling the temperature to be 55-60 ℃, and drying for 6-8 hours to obtain citicoline important intermediate cytidine monophosphate;
s1, cooling the reaction system to-15-5 ℃ by using a cooling medium, dropwise adding phosphorus oxychloride, controlling the internal temperature to-15-5 ℃, controlling the temperature to-15-5 ℃ after dropwise adding, and keeping the temperature for reaction for 1 hour; step S2, dropwise adding the organic base, keeping the temperature, stirring for 2.0-3.0 h, cooling to 10-30 ℃, and stirring for 3.0-5.0 h; s4, dropwise adding a mixed solution of hydrochloric acid and absolute ethyl alcohol, keeping the temperature, stirring for 1.0-2.0 h, cooling to 15-25 ℃, and stirring for 3.0-5.0 h; and S5, adding a mixed solution of hydrochloric acid and ethanol, keeping the temperature, stirring for 1.0-2.0 h, cooling to 15-25 ℃, and stirring for 3.0-5.0 h.
The working principle of the invention is as follows: a high-activity phosphorylation reagent of phosphorus oxychloride is adopted, cytidine is acylated by phosphorus oxychloride and then quenched by hydrolysis, the obtained reactant is dissolved by adding organic alkali, a mixed solution of hydrochloric acid and ethanol is dripped to carry out neutralization crystallization, and the steps are repeated to recrystallize for three times to remove impurities, so that cytidylic acid with the content of more than 95% is obtained, better selectivity and higher reaction yield are shown, and the method has the process characteristics of lower cost and less pollution.
Example 2
A synthetic method for citicoline crystallization purification comprises the following steps: dissolving the citicoline crude product with purified water, filtering the feed liquid into a clean-zone reaction kettle through a 0.22-micron filter element of a titanium pump filter twice, controlling the temperature in the reaction kettle to be 28-35 ℃, adding 1.2-1.5Kg/Kg of methanol, wherein the weight ratio is based on the weight of the citicoline crude product, the following materials are in the same ratio, and continuously stirring for 1.0-2.0 hours after the addition is finished;
dropwise adding 8-10 Kg/Kg of methanol into the reaction kettle, controlling the temperature in the reaction kettle to be 28-35 ℃, dropwise adding for 8-10 h, and after adding, keeping the temperature and stirring for 5-10 h;
after the heat preservation is finished, cooling to 0-5 ℃, and stirring for 3-5 h;
centrifuging, washing the filter cake for 2 times, using 2-4Kg/Kg of anhydrous methanol each time, and collecting the obtained filter cake;
and transferring the filter cake obtained in the previous step into a vacuum drying oven, controlling the temperature to be 40-60 ℃, controlling the vacuum degree to be-0.065 MPa-0.09 MPa, and drying for 4-6 hours to obtain a citicoline finished product.
Citicoline has the property of being very soluble in water and hardly soluble in methanol. By utilizing the characteristic, a refining and purifying process of citicoline is designed, purified water is used for dissolving citicoline in a general area, then mechanical impurity removal is carried out through a filter, the citicoline enters a reaction kettle in a clean area, methanol is dripped for crystallization, the temperature is controlled to be 28-35 ℃, the crystal habit form can be influenced by overhigh or overlow temperature, the dripping speed of the methanol also needs to be strictly controlled, and the crystal habit form can be influenced by overhigh speed;
citicoline is a thermally unstable substance, and when the temperature is too high, a product is degraded to generate cytidylic acid, so that the content of the cytidylic acid is higher; the temperature is low, the solvent residue will exceed the standard, the drying temperature is kept at 20-30 ℃, and the abnormal situation can be effectively avoided;
the process technology has the characteristics of high product yield, small solvent residue and excellent crystallization form.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (5)
1. A method for synthesizing and refining cytidine monophosphate serving as an important intermediate of citicoline is characterized by comprising the following steps:
s1, adding 4-5Kg/Kg of trimethyl phosphate into a reaction kettle, wherein the weight ratio is based on the weight of cytidine, the following materials are in the same ratio, uniformly stirring with the cytidine, replacing nitrogen in the reaction system for 3 times, introducing a cooling medium to cool the reaction system, and dropwise adding 1-2Kg/Kg of phosphorus oxychloride into the reaction system through an overhead dropwise adding device;
s2, adding the reaction solution in the previous step into 4-6Kg/Kg of purified water through an overhead tank, keeping the temperature at 40-60 ℃ after the addition, stirring for 3-4 h, adding 1-2Kg/Kg of organic base under stirring, continuing to stir for 1.0-1.5 h after the addition, continuing to dropwise add 0.5-1Kg/Kg of organic base, and finishing dropwise adding 1.0-2.0 h;
s3, centrifugally separating the reaction liquid, collecting solids, directly adding the obtained solid into a mixed liquid of 1.2-1.8Kg/Kg of absolute ethyl alcohol and purified water, controlling the temperature to be 10-30 ℃, and stirring for 0.5-1.0 h;
s4, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into purified water, adding 0.3-0.5Kg/Kg of organic alkali until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.1-0.3Kg/Kg of hydrochloric acid, continuing stirring for reaction for 1.0-1.5 h, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.2-2.5Kg/Kg of absolute ethyl alcohol under stirring, and finishing the addition for 3.0-5.0 h;
s5, centrifugally separating the reaction liquid in the previous step, collecting solids, adding 2.5-3.0Kg/Kg of purified water into the obtained wet product, adding 0.3-0.4Kg/Kg of organic base into the obtained wet product, stirring the obtained mixture until the solids are dissolved, controlling the temperature to be 40-50 ℃, adding 0.09-0.11Kg/Kg of hydrochloric acid into the obtained mixture, continuously stirring the obtained mixture for 1.0-1.5 hours, slowly dropwise adding a mixed solution of 0.2-0.3Kg/Kg of hydrochloric acid and 2.0-2.5Kg/Kg of ethanol into the obtained mixture under stirring, and finishing the adding of the obtained mixture for 3.0-5.0 hours;
s6, centrifugally separating the reaction liquid, collecting solids, adding the obtained wet product into a mixed solution of 1.2-1.3Kg/Kg of absolute ethyl alcohol and 1.5-2.0Kg/Kg of purified water, controlling the temperature to 15-25 ℃, and stirring for 0.5-1.0 h;
s7, centrifugally separating the reaction solution, washing with 20kg of absolute ethyl alcohol, collecting a filter cake, transferring the filter cake into a hot air circulation oven, controlling the temperature to be 55-60 ℃, and drying for 6-8 hours to obtain the citicoline important intermediate cytidine monophosphate.
2. The method for synthesizing and refining citicoline important intermediate cytidine acid according to claim 1, characterized in that, in the step S1, the cooling medium cools the reaction system to-15 to-5 ℃, the internal temperature is controlled to-15 to-5 ℃ after the phosphorus oxychloride is dripped, the temperature is controlled to-15 to-5 ℃ after the dripping, and the temperature is kept at-15 to-5 ℃ for 1 hour of heat preservation reaction.
3. The method for synthesizing and refining citicoline important intermediate cytidylic acid according to claim 1, wherein in step S2, the organic base is added dropwise, stirred for 2.0-3.0 hours under heat preservation, then cooled to 10-30 ℃, and stirred for 3.0-5.0 hours.
4. The method for synthesizing and refining citicoline important intermediate cytidylic acid according to claim 1, wherein a mixed solution of hydrochloric acid and absolute ethyl alcohol is dropwise added in the step of S4, the mixture is stirred for 1.0-2.0 hours under heat preservation, then the temperature is reduced to 15-25 ℃, and the mixture is stirred for 3.0-5.0 hours.
5. The method for synthesizing and refining citicoline important intermediate cytidylic acid according to claim 1, wherein the mixed solution of hydrochloric acid and ethanol is added in the step of S5, and then the mixture is stirred for 1.0-2.0 hours under heat preservation, cooled to 15-25 ℃ and stirred for 3.0-5.0 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114751949A (en) * | 2022-05-26 | 2022-07-15 | 南京工业大学 | 5' -cytidine monophosphate monohydrate crystal and preparation method thereof |
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| CN116425815A (en) * | 2023-04-18 | 2023-07-14 | 江苏金亿嘉医药科技有限公司 | Cytidine acid production process |
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| CN1616475A (en) * | 2004-09-21 | 2005-05-18 | 苏州工业园区赛康德万马化工有限公司 | Process for preparing cytidine-S'-phosphate |
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| CN114751949A (en) * | 2022-05-26 | 2022-07-15 | 南京工业大学 | 5' -cytidine monophosphate monohydrate crystal and preparation method thereof |
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