阅读说明：本技术 一种四氢叶酸钙制剂生产工艺 (Production process of calcium tetrahydrofolate preparation ) 是由 葛月兰 文佺佺 于 2020-07-02 设计创作，主要内容包括：本发明涉及四氢叶酸钙生产技术领域,且公开了一种四氢叶酸钙制剂生产工艺,包括以下步骤：S1：初步混合,在氮气的保护气氛下,取柠檬酸-磷酸氢二钠30-60mL、叶酸0.3-0.7g放入烧瓶中,然后加入30-55mL的蒸馏水,0.4-2g的保险粉进行混合；S2：搅拌溶解,静置10-30min后加入硼氢化钾0.5-2g,搅拌使其充分反应；S3：脱色过滤,通过活性炭进行脱色、过滤,用HCL调反应液PH至3-4,产生淡黄色固体。本发明的工艺制得的四氢叶酸纯度和产出率更高,而且不会产生有害物质,相对于其他方法更加有效,而且提纯效果好。(The invention relates to the technical field of calcium tetrahydrofolate production, and discloses a production process of a calcium tetrahydrofolate preparation, which comprises the following steps: s1: primarily mixing, under the protection atmosphere of nitrogen, putting 30-60mL of citric acid-disodium hydrogen phosphate and 0.3-0.7g of folic acid into a flask, and then adding 30-55mL of distilled water and 0.4-2g of sodium hydrosulfite for mixing; s2: stirring for dissolving, standing for 10-30min, adding 0.5-2g of potassium borohydride, and stirring for fully reacting; s3: decolorizing and filtering, decolorizing by active carbon, filtering, and adjusting pH of the reaction solution to 3-4 with HCl to obtain light yellow solid. The tetrahydrofolic acid prepared by the process has higher purity and yield, does not generate harmful substances, is more effective compared with other methods, and has good purification effect.)

1. The production process of the tetrahydrocalcium folate preparation is characterized by comprising the following steps:

s1: primarily mixing, under the protection atmosphere of nitrogen, putting 30-60mL of citric acid-disodium hydrogen phosphate and 0.3-0.7g of folic acid into a flask, and then adding 30-55mL of distilled water and 0.4-2g of sodium hydrosulfite for mixing;

s2: stirring for dissolving, standing for 10-30min, adding 0.5-2g of potassium borohydride, and stirring for fully reacting;

s3: decolorizing and filtering, decolorizing with active carbon, filtering, and adjusting pH of the reaction solution to 3-4 with HCl to obtain light yellow solid;

s4; washing and filtering, washing the solid obtained by the reaction with distilled water, then filtering and drying to obtain tetrahydrofolic acid;

s5: transferring tetrahydrofolic acid into a flask, continuously introducing nitrogen for 15-20min, adding DMSO/ET3N, stirring at room temperature until the tetrahydrofolic acid is dissolved, adding 40-60mL of ethyl formate into reaction liquid, stirring at room temperature for reaction, then adding 20-50mL of absolute ethyl alcohol, standing at room temperature to generate a precipitate, performing suction filtration, leaching by using diluted HCL, leaching for 2-3 times, then draining, and drying;

s6: purifying, namely adding the solid obtained in the S5 into 50-70mL of boiling water, stirring in a nitrogen environment, slowly adding NaOH to gradually clarify the reaction liquid until the reaction liquid is completely dissolved, adjusting the pH of the reaction liquid to 6-6.5, performing reflux reaction for 6.2-8h, and then cooling the reaction liquid to room temperature;

s7: filtering, drying, filtering, adding 80-130mL of absolute ethyl alcohol into the filtrate, cooling for 40-70min to separate out a light yellow solid, and drying to obtain the calcium tetrahydrofolate.

2. The process for producing a calcium tetrahydrofolate formulation according to claim 1, wherein the amount of folic acid units in S1 is 0.01 to 0.06N.

3. The process for producing a calcium tetrahydrofolate formulation according to claim 1, wherein said S2 is heated while stirring, and the heating temperature is controlled to 30-40 ℃.

4. The process for producing a calcium tetrahydrofolate formulation according to claim 3, wherein said washing with distilled water in S4 is performed twice, and then the product is filtered through a 100-mesh screen.

5. The process for producing a calcium tetrahydrofolate formulation according to claim 1, wherein the amount of said substance of HCL in S5 is 1.2-3.5C.

6. The process for producing a calcium tetrahydrofolate preparation according to claim 5, wherein the reaction in S5 is carried out at room temperature for 18-20h with stirring, and after the precipitate is formed, the precipitate is filtered with suction and dried under vacuum.

7. The process for producing a calcium tetrahydrofolate formulation according to claim 1, wherein said S6 is cooled and left for 8-15 hours, then the pH is adjusted to 7.1-7.8 with NaOH, the solution is heated to 50-70 ℃, and 3-7ml0.01-0.03C CaCl is added₂And stirring to react for 15-40 min.

8. The process for producing a calcium tetrahydrofolate preparation according to claim 7, wherein the step of S7 is crushing before drying, the crushed product is screened by a 1000-mesh filter screen, and large-particle impurities after screening are removed and collected for later use.

Technical Field

The invention relates to the technical field of calcium tetrahydrofolate production, and in particular relates to a production process of a calcium tetrahydrofolate preparation.

Background

Tetrahydrofolic acid is a reduced folic acid, also known as coenzyme F, which is the parent compound of folic acid in the form of a coenzyme. When folic acid is deficient or some drugs inhibit folic acid reductase, folic acid can not be converted into tetrahydrofolic acid, which can affect the development and maturation of blood cells to cause megaloblastic anemia, calcium tetrahydrofolate is an important folic acid derivative, which can be prepared by using folic acid as a reactant, and has many advantages in the aspects of biological activity, medicinal value and the like.

The general calcium tetrahydrofolate needs many compounds to carry out the steps of reaction dissolution, precipitation, filtration, drying and the like during production, and the production yield of the current calcium tetrahydrofolate is low, so that the production efficiency is reduced in the process of large-scale production, the popularization of the calcium tetrahydrofolate is affected, and the requirements of people cannot be met.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a production process of a calcium tetrahydrofolate preparation, which mainly solves the problems that the production efficiency is reduced and the requirements of people cannot be met in the process of large-scale production of the existing calcium tetrahydrofolate.

(II) technical scheme

In order to achieve the purpose, the invention provides the following technical scheme:

a production process of a tetrahydrocalcium folate preparation comprises the following steps:

s1: primarily mixing, under the protection atmosphere of nitrogen, putting 30-60mL of citric acid-disodium hydrogen phosphate and 0.3-0.7g of folic acid into a flask, and then adding 30-55mL of distilled water and 0.4-2g of sodium hydrosulfite for mixing;

s2: stirring for dissolving, standing for 10-30min, adding 0.5-2g of potassium borohydride, and stirring for fully reacting;

s3: decolorizing and filtering, decolorizing with active carbon, filtering, and adjusting pH of the reaction solution to 3-4 with HCl to obtain light yellow solid;

s4; washing and filtering, washing the solid obtained by the reaction with distilled water, then filtering and drying to obtain tetrahydrofolic acid;

s5: transferring tetrahydrofolic acid into a flask, continuously introducing nitrogen for 15-20min, adding DMSO/ET3N, stirring at room temperature until the tetrahydrofolic acid is dissolved, adding 40-60mL of ethyl formate into reaction liquid, stirring at room temperature for reaction, then adding 20-50mL of absolute ethyl alcohol, standing at room temperature to generate a precipitate, performing suction filtration, leaching by using diluted HCL, leaching for 2-3 times, then draining, and drying;

s6: purifying, namely adding the solid obtained in the S5 into 50-70mL of boiling water, stirring in a nitrogen environment, slowly adding NaOH to gradually clarify the reaction liquid until the reaction liquid is completely dissolved, adjusting the pH of the reaction liquid to 6-6.5, performing reflux reaction for 6.2-8h, and then cooling the reaction liquid to room temperature;

s7: filtering, drying, filtering, adding 80-130mL of absolute ethyl alcohol into the filtrate, cooling for 40-70min to separate out a light yellow solid, and drying to obtain the calcium tetrahydrofolate.

Further, the amount of folic acid unit substance in the S1 is 0.01-0.06N.

On the basis of the scheme, the S2 is heated while stirring, and the heating temperature is controlled to be 30-40 ℃.

In a still further aspect of the present invention, the washing with distilled water in S4 is performed twice, and then the filtrate is filtered through a 100-mesh sieve.

Further, the substance amount concentration of the HCL in the S5 is 1.2-3.5C.

On the basis of the scheme, the S5 is stirred and reacted for 18-20h at room temperature, and after precipitation is generated, suction filtration is carried out, and vacuum drying is carried out after suction filtration.

In a further scheme of the invention, the S6 is cooled and then placed for 8-15h, then the PH value is adjusted to 7.1-7.8 by NaOH, the solution is heated to 50-70 ℃ after adjustment, 3-7mL0.01-0.03C CaCl2 is added, and the stirring reaction is carried out for 15-40 min.

Further, crushing is performed before drying in S7, screening is performed with a 1000-mesh filter screen after crushing, and large-particle impurities after screening are removed, and collected for later use according to requirements.

(III) advantageous effects

Compared with the prior art, the invention provides a production process of a calcium tetrahydrofolate preparation, which has the following beneficial effects:

1. the citric acid-disodium hydrogen phosphate is used as a raw material, the tetrahydrofolic acid prepared by the process has higher purity and yield, does not generate harmful substances, and is more effective compared with other methods.

2. In S2, the reaction mixture is heated while being stirred, the heating temperature is controlled to be 30-40 ℃, and the reaction efficiency can be improved by heating the reaction mixture.

3. And (3) slowly adding NaOH into S6 to gradually clarify the reaction solution until the reaction solution is completely dissolved, adjusting the pH of the reaction solution to 6-6.5, performing reflux reaction for 6.2-8h, cooling the reaction solution to room temperature, and improving the conditioning effect and the purification efficiency through the reflux reaction.

4. Through the washing operation of distilled water, abundant washing off impurity when can not harm tetrahydrofolic acid, and 100 mesh sieves can fully filter tetrahydrofolic acid moreover, obtain crushing before drying it behind the tetrahydrofolic acid calcium in S7, screen with 1000 mesh filter sieve after smashing, the large granule impurity after the screening is got rid of, the collection that accords with the requirement is got up and is reserved, facilitates the use.

Drawings

Fig. 1 is a schematic flow structure diagram of a production process of a calcium tetrahydrofolate preparation provided by the invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious 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.