CN111635405A - Production process of calcium tetrahydrofolate preparation - Google Patents
Production process of calcium tetrahydrofolate preparation Download PDFInfo
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- CN111635405A CN111635405A CN202010633024.6A CN202010633024A CN111635405A CN 111635405 A CN111635405 A CN 111635405A CN 202010633024 A CN202010633024 A CN 202010633024A CN 111635405 A CN111635405 A CN 111635405A
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- WUPYWCAWYJNPBS-GOHZCRCRSA-L calcium (4S)-4-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-3H-pteridin-6-yl)methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca+2].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NCC2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NCC2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-] WUPYWCAWYJNPBS-GOHZCRCRSA-L 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000001914 filtration Methods 0.000 claims abstract description 35
- 238000003756 stirring Methods 0.000 claims abstract description 35
- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 claims abstract description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000007787 solid Substances 0.000 claims abstract description 21
- 239000012153 distilled water Substances 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 16
- 235000019152 folic acid Nutrition 0.000 claims abstract description 13
- 239000011724 folic acid Substances 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 12
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960000304 folic acid Drugs 0.000 claims abstract description 11
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 239000011591 potassium Substances 0.000 claims abstract description 6
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000001035 drying Methods 0.000 claims description 27
- 239000012295 chemical reaction liquid Substances 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 125000003929 folic acid group Chemical group 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000012535 impurity Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 238000002386 leaching Methods 0.000 claims description 9
- 238000012216 screening Methods 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 8
- 239000002244 precipitate Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940014144 folate Drugs 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 5
- 239000000203 mixture Substances 0.000 claims 5
- 239000000047 product Substances 0.000 claims 2
- 238000000746 purification Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 235000011148 calcium chloride Nutrition 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 239000005515 coenzyme Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- VWNLXEPGSWIPMG-MMFRDWCLSA-N (2s)-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;calcium Chemical compound [Ca].C1NC=2NC(N)=NC(=O)C=2NC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VWNLXEPGSWIPMG-MMFRDWCLSA-N 0.000 description 1
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- 108700007696 Tetrahydrofolate Dehydrogenase Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
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.
Description
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.
Example 1
Referring to fig. 1, a production process of a calcium tetrahydrofolate 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, namely washing the solid obtained by the reaction with distilled water, then filtering and drying to obtain tetrahydrofolic acid, wherein 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;
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.
The amount of folic acid unit substance in S1 of the invention is 0.01-0.06N, the folic acid unit substance is heated while being stirred in S2, the heating temperature is controlled at 30-40 ℃, the reaction efficiency can be improved by heating, the folic acid unit substance is washed twice when being washed by distilled water in S4, then the folic acid unit substance is filtered by a 100-mesh sieve, the tetrahydrofolic acid can be thoroughly washed away without damaging the tetrahydrofolic acid by the washing operation of the distilled water, and the tetrahydrofolic acid can be fully filtered by the 100-mesh sieve.
Particularly, the amount concentration of HCL in S5 is 1.2-3.5C, the reaction is carried out for 18-20h under the condition of room temperature in S5, the solution is filtered after precipitation is generated, vacuum drying is carried out after the filtration, the solution is placed for 8-15h after being cooled in S6, then NaOH is used for adjusting the pH value to 7.1-7.8, the solution is heated to 50-70 ℃, CaCl2 of 3-7mL0.01-0.03C is added, the reaction is carried out for 15-40min under stirring, crushing is carried out before drying in S7, a 1000-mesh filter screen is used for screening after crushing, large particle impurities after screening are removed, and the large particle impurities which meet the requirements are collected for later use.
Example 2
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 0.8-2g 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 3-3.5 with HCl to obtain light yellow solid;
s4; washing and filtering, namely washing the solid obtained by the reaction with distilled water, then filtering and drying to obtain tetrahydrofolic acid, wherein 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;
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 20-45mL of absolute ethyl alcohol, standing at room temperature to generate a precipitate, performing suction filtration, leaching by using diluted HCL for 2 times, then performing suction filtration, and drying;
s6: purification, 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 6.2-7.6h, 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.
The amount of folic acid unit substance in S1 of the invention is 0.01-0.06N, the folic acid unit substance is heated while being stirred in S2, the heating temperature is controlled at 28-35 ℃, the reaction efficiency can be improved by heating, the folic acid unit substance is washed twice when being washed by distilled water in S4, then the folic acid unit substance is filtered by a 100-mesh sieve, the tetrahydrofolic acid can be thoroughly washed away without damaging the tetrahydrofolic acid by the washing operation of the distilled water, and the tetrahydrofolic acid can be fully filtered by the 100-mesh sieve.
Particularly, the amount concentration of HCL in S5 is 1.2-3.5C, the reaction is carried out for 18-20h under the condition of room temperature in S5, the solution is filtered after precipitation is generated, vacuum drying is carried out after the filtration, the solution is placed for 8-15h after being cooled in S6, then NaOH is used for adjusting the pH value to 7.1-7.8, the solution is heated to 50-70 ℃, CaCl2 of 3-7mL0.01-0.03C is added, the reaction is carried out for 15-40min under stirring, crushing is carried out before drying in S7, a 1000-mesh filter screen is used for screening after crushing, large particle impurities after screening are removed, and the large particle impurities which meet the requirements are collected for later use.
Example 3
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 10-20min, adding 0.5-2g of potassium borohydride, and stirring for full reaction;
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, namely washing the solid obtained by the reaction with distilled water, then filtering and drying to obtain tetrahydrofolic acid, wherein 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;
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 50-60mL 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.
The amount of folic acid unit substance in S1 of the invention is 0.01-0.06N, the folic acid unit substance is heated while being stirred in S2, the heating temperature is controlled at 30-40 ℃, the reaction efficiency can be improved by heating, the folic acid unit substance is washed twice when being washed by distilled water in S4, then the folic acid unit substance is filtered by a 100-mesh sieve, the tetrahydrofolic acid can be thoroughly washed away without damaging the tetrahydrofolic acid by the washing operation of the distilled water, and the tetrahydrofolic acid can be fully filtered by the 100-mesh sieve.
Particularly, the amount concentration of HCL in S5 is 1.2-3.5C, the S5 is stirred and reacted for 12-18h at room temperature, the precipitate is subjected to suction filtration after being generated, vacuum drying is performed after the suction filtration, the S6 is cooled and then placed for 8-15h, then the pH is adjusted to 6.9.1-7.5 by NaOH, the solution is heated to 50-70 ℃ after being adjusted, 3-7mL0.015-0.04C CaCl2 is added, stirring and reaction is performed for 15-40min, crushing is performed before drying in the S7, the crushed solution is screened by a 1000-mesh filter screen, large particle impurities after screening are removed, and the large particle impurities which meet the requirements are collected for later use.
In the description herein, it is noted that relational terms such as first and second, and the like, are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
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.
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| CN114130097A (en) * | 2021-12-09 | 2022-03-04 | 连云港冠昕医药科技有限公司 | Purification method and device for preparing L-5-methyl tetrahydrocalcium folate |
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