CN114163440A - Method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid - Google Patents
Method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid Download PDFInfo
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- 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 title claims abstract description 148
- 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 title claims abstract description 74
- 229960000304 folic acid Drugs 0.000 title claims abstract description 74
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 74
- 239000011724 folic acid Substances 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 38
- MSTNYGQPCMXVAQ-NEPJUHHUSA-N 6R-Tetrahydrofolic acid Chemical compound C([C@@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-NEPJUHHUSA-N 0.000 title claims abstract description 32
- 230000001590 oxidative effect Effects 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000012452 mother liquor Substances 0.000 claims abstract description 15
- 230000008569 process Effects 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 238000001953 recrystallisation Methods 0.000 claims abstract description 12
- 239000002131 composite material Substances 0.000 claims abstract description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002808 molecular sieve Substances 0.000 claims abstract description 5
- 239000011148 porous material Substances 0.000 claims abstract description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000005460 tetrahydrofolate Substances 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 238000012544 monitoring process Methods 0.000 claims abstract description 3
- 229910052748 manganese Inorganic materials 0.000 claims abstract 2
- 239000011572 manganese Substances 0.000 claims abstract 2
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 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 description 13
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 claims description 5
- HDVPIMZXLWNIIP-UHFFFAOYSA-N nickel 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Ni].c1cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1ccc(n1)c(-c1ccccc1)c1ccc([nH]1)c2-c1ccccc1 HDVPIMZXLWNIIP-UHFFFAOYSA-N 0.000 claims description 3
- IPFASKMZBDWRNG-UHFFFAOYSA-N manganese 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Mn].c1cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1ccc(n1)c(-c1ccccc1)c1ccc([nH]1)c2-c1ccccc1 IPFASKMZBDWRNG-UHFFFAOYSA-N 0.000 claims description 2
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 claims description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 14
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 11
- 239000012043 crude product Substances 0.000 abstract description 6
- 238000001816 cooling Methods 0.000 abstract description 2
- RNGSTWPRDROEIW-UHFFFAOYSA-N [Ni].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Ni].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 RNGSTWPRDROEIW-UHFFFAOYSA-N 0.000 abstract 1
- -1 manganese porphyrin Chemical class 0.000 abstract 1
- 229940105150 5-methyltetrahydrofolic acid Drugs 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 229910001437 manganese ion Inorganic materials 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910001453 nickel ion Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004032 porphyrins Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention mainly relates to a method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid. The process for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid is realized according to the following method: adding a certain amount of hydrogen peroxide and a nickel porphyrin/manganese porphyrin composite catalyst loaded on a large pore molecular sieve into residual mother liquor obtained by splitting 6-S-tetrahydrofolate benzoate crystals by using benzoate as a splitting agent, reacting for a period of time at a low temperature, monitoring the reaction by TLC, and filtering and recovering the composite catalyst after the reaction is finished. And (4) concentrating the reaction solution in vacuum, cooling and standing to obtain a crude folic acid product. The purity of the crude product folic acid is more than 95.2 percent by HPLC analysis, the purity of the refined folic acid after ethanol recrystallization is more than 98.5 percent, and the yield of the refined folic acid is more than 90 percent according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Description
Technical Field
The invention relates to a process method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid, belonging to the technical field of fine chemical engineering.
Background
The 6-S-5-methyltetrahydrofolic acid is called active folic acid, has better biological activity than folic acid, overcomes a series of side effects generated in the metabolic process of folic acid, and is a new generation product of folic acid. It is commonly known as a food additive and a main ingredient of a nutritional health product. The 6-S-5-methyltetrahydrofolic acid participates in a plurality of important biochemical reactions in vivo and has important pharmacological action. The medicine can penetrate blood brain barrier, and can be used for preventing senile dementia and cell anemia. Compared with other medicines, the S-5-methyltetrahydrofolic acid has the characteristics of remarkable curative effect, complete functions and less side effects, and gradually becomes a focus of common attention in the medical and pharmaceutical research fields.
At present, with the intensive research on the side effects caused in the folic acid metabolism process, the substitution of 6-S-5-methyltetrahydrofolic acid for natural folic acid has become the best choice in the field. Therefore, the research on the synthesis process of 6-S-5-methyltetrahydrofolic acid also becomes one of the hot spots in the field.
The synthesis of 6-S-5-methyltetrahydrofolic acid by using folic acid as a raw material mainly has two routes, one is that folic acid is reduced into tetrahydrofolic acid, the tetrahydrofolic acid is obtained by splitting, and then the tetrahydrofolic acid is methylated to obtain a product. The process produces a large amount of biologically inactive 6-R-tetrahydrofolic acid as a by-product. The other is that the reduction product racemic tetrahydrofolic acid is directly methylated to obtain racemic 6-R, S-5-methyltetrahydrofolic acid, and then the racemic 6-R, S-5-methyltetrahydrofolic acid is obtained by resolution.
Since the resolution of the latter synthetic route is carried out after methylation, the methylation reaction of 6-R-tetrahydrofolic acid results in a large increase in process cost. Therefore, the synthesis of 6-S-5-methyltetrahydrofolic acid in industry at present mainly adopts a technical route of direct resolution after reduction.
The 6-R-tetrahydrofolic acid which is a byproduct in the production process of the 6-S-5-methyltetrahydrofolic acid is a biologically-inactive substance and can only be treated as production waste at present, and the treatment process not only increases the production cost, but also brings about a great environmental problem. In order to solve the problem, the invention develops a process technology for obtaining folic acid by catalytic oxidation of 6-R-5-tetrahydrofolic acid, the obtained folic acid can be used as a production raw material to return to the production flow of 6-S-5-methyltetrahydrofolic acid, and meanwhile, the byproduct treatment process is omitted, the production cost is reduced, and the environmental risk is eliminated.
Disclosure of Invention
Tetrahydrofolic acid is a compound with poor oxidation stability, and can be oxidized into a complex mixture in air, and various common oxidants can also oxidize the tetrahydrofolic acid into the complex oxide under mild conditions. Therefore, the key to the technology of converting tetrahydrofolic acid into folic acid by using oxidation reaction is how to control the selectivity of the oxidation reaction.
Hydrogen peroxide is a mild oxidant at neutral conditions and at lower temperatures, and tetrahydrofolic acid is slowly oxidized under such conditions, but the oxidation product is also a complex mixture in the absence of a catalyst. The invention develops a catalyst which can specifically promote the oxidation of tetrahydrofolic acid to folic acid, so that the tetrahydrofolic acid can be generated with high conversion rate and high selectivity.
The supported catalyst developed by the invention takes commercial large-pore molecular sieve SBA-15 as a carrier, and nickel tetraphenylporphyrin and manganese tetraphenylporphyrin synthesized in situ are taken as active components of the catalyst. The catalysis principle is as follows: tetraphenylporphyrin rings loaded on the surface of the molecular sieve adsorb 6-R-tetrahydrofolic acid by virtue of weak intermolecular interaction to form a reaction substrate enrichment region, and the reaction substrate enrichment region is coordinated with porphyrin rings to complex divalent nickel ions and divalent manganese ions to play a synergistic role in catalyzing the oxidation of hydrogen peroxide on tetrahydrofolic acid molecules. The space limiting effect in the local micro-reaction area improves the hydrogen peroxide oxidation reaction efficiency and improves the selectivity of the oxidation reaction.
After the oxidation reaction is finished, the supported catalyst can be recycled by simple filtration, so that the production cost is reduced, and the refining process of the product is simplified.
The whole oxidation reaction is carried out under the mild condition, redundant hydrogen peroxide can be quickly decomposed under the action of a supported catalyst, and a reaction terminating reagent is not required to be additionally added, so that the method is an efficient and environment-friendly synthesis method.
The invention has the following beneficial effects:
1. the R configuration isomer in the mother liquor after the S configuration isomer is separated by the resolution of the racemic tetrahydrofolic acid can be directly subjected to oxidation reaction without separation, and the folic acid which is the production raw material of the 6-S-tetrahydrofolic acid is recovered. The recovery process is simple to operate, the production cost of the 6-S-tetrahydrofolic acid is greatly reduced, and the environmental influence generated in the byproduct treatment process is eliminated.
2. The supported catalyst has high catalytic efficiency and good selectivity, can be simply recycled after being used, reduces the production cost and has no problem of waste gas catalyst treatment.
3. The hydrogen peroxide is used as an oxidant, and the oxidant generates water in the reaction without other byproducts. The residual hydrogen peroxide in the reaction can be decomposed under the action of a reaction catalyst, so that the product separation process is simplified.
4. The synthesis process is simple, convenient to operate, free of byproduct generation and environment-friendly.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following examples describe the specific implementation processes of the present invention, but the present invention is not limited to the specific implementation modes listed below, and includes any combinations of the specific implementation modes.
Example 1 racemic tetrahydrofolate 9g (20mmol) was dissolved in 50ml water, 3.8g (22mmol) of p-toluic acid was added as a resolving agent, and about 50ml of mother liquor remained after isolation of 6-S-tetrahydrofolate benzoate crystals (of which tetrahydrofolate was about 4.6 g). Adjusting the pH value to 7, adding 140mg of supported composite catalyst, stirring at 25 ℃, slowly dropwise adding 40ml of 5% hydrogen peroxide, reacting for 6 hours, monitoring the total consumption of raw materials by TLC (thin layer chromatography), continuously stirring for 60min, and filtering to recover the composite catalyst. The reaction solution is concentrated to 50ml in vacuum, the pH value is adjusted to 3-4 by dilute hydrochloric acid, and 4.5g of crude folic acid is obtained after cooling, standing and filtering. The purity of the crude folic acid product is 95.2 percent by HPLC analysis, and 4.13g of refined folic acid with the purity of 98.5 percent is obtained after ethanol recrystallization. The yield of the refined folic acid is 90.6 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 2 the charging amount and operation process of example 1 were followed except that the amount of hydrogen peroxide was changed to 27 ml. Filtration gave 4.0g of crude folic acid. The purity of folic acid of the crude product is 91.2 percent by HPLC analysis, and the folic acid of 3.52g is refined after ethanol recrystallization, and the purity is 98.4 percent. The yield of the refined folic acid is 76.7 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 3 the charging amount and operation process of example 1 were followed except that the amount of hydrogen peroxide was changed to 50 ml. The crude folic acid product was obtained in an amount of 4.4g by filtration. The purity of folic acid of the crude product is 94.9 percent by HPLC analysis, 4.02g of refined folic acid is obtained after ethanol recrystallization, and the purity is 98.6 percent. The yield of the refined folic acid is 88.1 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 4. the charge and operation of example 1 were followed except that the amount of supported catalyst was changed to 50 mg. Filtration gave 3.8g of crude folic acid. The purity of folic acid of the crude product is 90.7 percent by HPLC analysis, and the purity of folic acid is 98.1 percent by refining 3.34g of folic acid after ethanol recrystallization. The refined folic acid yield is 73.2 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 5 the charge and the procedure of example 1 were followed except that the amount of supported catalyst was changed to 90 mg. The crude folic acid product was obtained in an amount of 4.3g by filtration. The purity of the crude folic acid product is 95.1 percent by HPLC analysis, and the purity of the refined folic acid is 98.5 percent by 3.94g after ethanol recrystallization. The yield of the refined folic acid is 86.5 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 6 the charge and the procedure of example 1 were followed except that the amount of supported catalyst was changed to 180 mg.
Filtration gave 4.5g of crude folic acid. The purity of the crude folic acid product is 95.3 percent by HPLC analysis, and 4.14g of refined folic acid with the purity of 98.5 percent is obtained after ethanol recrystallization. The yield of the refined folic acid is 90.7 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 7 the charge and procedure of example 1 was followed except that the amount of supported catalyst was changed to 230 mg.
Filtration gave 4.6g of crude folic acid. The purity of the crude folic acid is 95.6 percent by HPLC analysis, and 4.24g of refined folic acid with the purity of 98.6 percent is obtained after ethanol recrystallization. The yield of the refined folic acid is 92.9 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 8 the charge and procedure of example 1 were followed except that the reaction temperature was changed to 5 c in a chilled salt bath. The reaction was extended to 12 hours and filtered to obtain 4.5g of crude folic acid. The purity of folic acid of the crude product is 96.4 percent by HPLC analysis, and 4.17g of refined folic acid with the purity of 98.8 percent is obtained after ethanol recrystallization. The yield of the refined folic acid is 91.5 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Example 9 the procedure of example 1 was followed except that the reaction temperature was changed to 15 ℃ and the reaction was carried out in a constant temperature water bath. The reaction was extended to 8 hours and filtered to obtain 4.5g of crude folic acid. The purity of the crude folic acid product is 95.8 percent by HPLC analysis, and 4.15g of refined folic acid with the purity of 98.6 percent is obtained after ethanol recrystallization. The yield of the refined folic acid is 91.1 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
EXAMPLE 10 the procedure of example 1 was followed except that the reaction temperature was changed to 40 ℃ and TLC was used to monitor the complete consumption of the reactants for 4 hours. After the reaction, 4.0g of crude folic acid was obtained by filtration. The purity of folic acid of the crude product is 93.3 percent by HPLC analysis, and the folic acid of 3.67g is refined after ethanol recrystallization, and the purity is 96.5 percent. The yield of the refined folic acid is 80.6 percent calculated according to the content of the 6-R-tetrahydrofolic acid in the split mother liquor.
Claims (8)
1. A method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid. The method is characterized in that the process for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid is realized according to the following method: adding a certain amount of hydrogen peroxide and a tetraphenylporphyrin nickel/tetraphenylporphyrin manganese composite catalyst loaded on a large-pore molecular sieve into residual mother liquor obtained by splitting 6-S-tetrahydrofolate benzoate crystals by using benzoate as a splitting agent, reacting for a period of time at a low temperature, monitoring the reaction by TLC, and filtering and recovering the composite catalyst after the reaction is finished. The reaction liquid is subjected to vacuum concentration, cooled and placed to obtain a crude folic acid product, and the refined folic acid with the purity of more than 98.5 percent is obtained after ethanol recrystallization.
2. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the 6-R-tetrahydrofolic acid is obtained by separating 6-S-tetrahydrofolic acid benzoate crystals from racemic tetrahydrofolic acid by benzoate resolution.
3. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the dosage of hydrogen peroxide is 2-4 times of the mole number of 6-R-tetrahydrofolic acid.
4. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the method is used for loading folic acidThe large-pore molecular sieve of the composite catalyst is SBA-15 sold in the market, and the basic structural parameters are as follows: pore diameter of 6-11nm, BET specific surface area of 550-600m2Relative degree of crystallinity in g>90％。
5. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the ratio of nickel tetraphenylporphyrin to manganese tetraphenylporphyrin in the composite catalyst is 1: 2.
6. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the dosage of the supported composite catalyst is 1-5% of the weight of 6-R-tetrahydrofolic acid.
7. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the temperature of the oxidation reaction is 5-40 ℃.
8. The method for synthesizing folic acid by oxidizing 6-R-tetrahydrofolic acid according to claim 1, characterized in that the oxidation reaction time is 4-12 hours.
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| CN114957257A (en) * | 2022-03-21 | 2022-08-30 | 河北冀衡药业股份有限公司 | Preparation method of calcium 5-methyltetrahydrofolate |
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| JP2001302665A (en) * | 2000-04-19 | 2001-10-31 | Shiratori Pharmaceutical Co Ltd | Method for producing l-biopterin or d-neopterin |
| CN103664945A (en) * | 2012-09-07 | 2014-03-26 | 南京莱因医药科技有限公司 | Preparation method of L-5-methyl tetrahydrofolate amino acid salt |
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| CN114957257A (en) * | 2022-03-21 | 2022-08-30 | 河北冀衡药业股份有限公司 | Preparation method of calcium 5-methyltetrahydrofolate |
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