CN114181210B - Preparation method of tetrahydrofolic acid - Google Patents
Preparation method of tetrahydrofolic acid Download PDFInfo
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- CN114181210B CN114181210B CN202111457715.6A CN202111457715A CN114181210B CN 114181210 B CN114181210 B CN 114181210B CN 202111457715 A CN202111457715 A CN 202111457715A CN 114181210 B CN114181210 B CN 114181210B
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- 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 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 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 118
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 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 59
- 239000011724 folic acid Substances 0.000 claims abstract description 59
- 229960000304 folic acid Drugs 0.000 claims abstract description 59
- 235000019152 folic acid Nutrition 0.000 claims abstract description 59
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006479 redox reaction Methods 0.000 claims abstract description 12
- 238000011049 filling Methods 0.000 claims abstract description 8
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 69
- 239000007853 buffer solution Substances 0.000 claims description 35
- 239000005460 tetrahydrofolate Substances 0.000 claims description 34
- 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 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 239000013049 sediment Substances 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 9
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 claims description 6
- 239000008055 phosphate buffer solution Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000011261 inert gas Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- 239000006171 Britton–Robinson buffer Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229960002319 barbital Drugs 0.000 claims description 3
- 229910021538 borax Inorganic materials 0.000 claims description 3
- HDFXRQJQZBPDLF-UHFFFAOYSA-L disodium hydrogen carbonate Chemical compound [Na+].[Na+].OC([O-])=O.OC([O-])=O HDFXRQJQZBPDLF-UHFFFAOYSA-L 0.000 claims description 3
- 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 description 3
- BUCIWTBCUUHRHZ-UHFFFAOYSA-K potassium;disodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O BUCIWTBCUUHRHZ-UHFFFAOYSA-K 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 239000004328 sodium tetraborate Substances 0.000 claims description 3
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 claims description 3
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000007983 Tris buffer Substances 0.000 claims 1
- VWBIJLFTDUZNDF-UHFFFAOYSA-J tetrasodium hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].[Na+].OP([O-])([O-])=O.OP([O-])([O-])=O VWBIJLFTDUZNDF-UHFFFAOYSA-J 0.000 claims 1
- 239000002244 precipitate Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 4
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical compound [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation method of tetrahydrofolic acid, which comprises the following steps: adding Pd/C catalyst and folic acid solution into a reaction kettle, filling hydrogen into the reaction kettle, placing the reaction kettle in an environment of 40-90 ℃, carrying out oxidation-reduction reaction on folic acid and hydrogen, and obtaining tetrahydrofolic acid after the reaction is finished. The preparation method of the tetrahydrofolic acid provided by the invention solves the problem of low preparation yield of the tetrahydrofolic acid under the condition of meeting the requirement of reducing the catalyst dosage.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of tetrahydrofolic acid.
Background
Tetrahydrofolate is a coenzyme for one-carbon group (including CH 3、CH2, CHO, etc.) transferases, and has the function of transferring one-carbon group, and participates in a plurality of important reactions and synthesis of nucleic acid and amino acid.
Currently, tetrahydrofolates are generally prepared from folic acid by catalytic hydrogenation reduction.
The catalysts commonly used in the catalytic hydrogenation reduction method are Pt/C (platinum carbon catalyst), rh/C (rhodium carbon catalyst), ptO 2 (platinum dioxide catalyst) and the like, the amount of the catalyst used is large, the catalytic effect is not ideal, and the preparation yield of tetrahydrofolate is low.
Disclosure of Invention
Based on the method, the invention provides a preparation method of the tetrahydrofolic acid, and solves the problem of low preparation yield of the tetrahydrofolic acid under the condition of meeting the requirement of reducing the catalyst dosage.
The invention provides a preparation method of tetrahydrofolic acid, which comprises the following steps:
Adding a Pd/C catalyst and a pH folic acid solution into a reaction kettle, filling hydrogen into the reaction kettle, placing the reaction kettle in an environment of 40-90 ℃, carrying out oxidation-reduction reaction on folic acid and hydrogen, and obtaining tetrahydrofolic acid after the reaction is finished;
the reaction equation for preparing tetrahydrofolate is as follows:
wherein, the chemical formula of folic acid is:
The chemical formula of the tetrahydrofolate is as follows:
Preferably, the catalyst Pd/C comprises 10% Pd/C, and the mass ratio of folic acid to the catalyst 10% Pd/C is 100 (0.1-20).
Preferably, in the step of oxidation-reduction reaction of folic acid and hydrogen, the pressure of the reaction kettle ranges from 20 bar to 65bar.
Preferably, the reaction time of the folic acid and the hydrogen for the oxidation-reduction reaction is 6-24h.
Preferably, after the reaction is finished, the step of obtaining the tetrahydrofolate comprises the following steps:
After the reaction is finished, a solution containing the tetrahydrofolic acid is obtained, the pH value of the solution containing the tetrahydrofolic acid is regulated to 3-3.5 by an acid solution, a solution containing the tetrahydrofolic acid sediment is obtained, the solution containing the tetrahydrofolic acid sediment is filtered, the tetrahydrofolic acid sediment is collected, and the sediment is dried, so that the tetrahydrofolic acid is obtained.
Preferably, the pH of the folic acid solution is 6-7, and the preparation of the folic acid solution comprises the following steps:
Adding solid folic acid into a flask, filling nitrogen or inert gas into the flask to form an anaerobic environment, adding a buffer solution into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH value of the mixed solution to 6-7 by using an alkali solution to obtain a folic acid solution.
Preferably, the buffer solution has a pH of 4 to 10.
Preferably, the buffer solution includes any one of disodium hydrogen phosphate-citric acid buffer solution, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, barbital sodium-hydrochloric acid buffer solution, tris-hydroxymethyl aminomethane-hydrochloric acid buffer solution, boric acid-borax buffer solution, glycine-sodium hydroxide buffer solution, borax-sodium hydroxide buffer solution, sodium carbonate-sodium bicarbonate buffer solution, britton-Robinson buffer solution, and Tris buffer salt solution.
Preferably, the alkali solution includes any one of NaOH solution and KOH solution.
Preferably, the buffer solution is used in an amount of 10-15ml/1g solid folic acid.
Compared with the prior art, the invention has the following beneficial effects:
The tetrahydrofolic acid is prepared by reducing folic acid under the catalysis of the catalyst Pd/C, the catalyst Pd/C has high catalytic efficiency and can be recycled, and the problems of large catalyst consumption and low yield in the prior art are overcome.
Drawings
FIG. 1 is a graph of experimental results of the effect of pH of folic acid solution on tetrahydrofolate yield;
FIG. 2 is a graph of experimental results of the effect of reaction time on tetrahydrofolate yield;
FIG. 3 is a graph of experimental results of the effect of reaction temperature on tetrahydrofolate yield;
FIG. 4 is a graph of experimental results of the effect of the amount of Pd/C catalyst on the productivity of tetrahydrofolate;
FIG. 5 is a nuclear magnetic resonance diagram of the product tetrahydrofolate.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials, reagents and the like used in the examples described below are commercially available unless otherwise specified. The quantitative tests in the following examples were all set up with three replicates, and the data are the mean or mean ± standard deviation of the three replicates.
In addition, "and/or" throughout this document includes three schemes, taking a and/or B as an example, including a technical scheme, a technical scheme B, and a technical scheme that both a and B satisfy; in addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be considered to be absent and not within the scope of protection claimed in the present invention.
The invention provides a preparation method of tetrahydrofolic acid, which comprises the following steps:
Adding a Pd/C catalyst and a folic acid solution into a reaction kettle, filling hydrogen into the reaction kettle, placing the reaction kettle in an environment of 40-90 ℃, carrying out oxidation-reduction reaction on folic acid and hydrogen, and obtaining tetrahydrofolic acid after the reaction is finished;
the reaction equation for preparing tetrahydrofolate is as follows:
Wherein, the chemical formula of the solid folic acid is as follows:
The chemical formula of the tetrahydrofolate is as follows:
The tetrahydrofolic acid is prepared by reducing folic acid under the catalysis of the catalyst Pd/C, the catalyst Pd/C has high catalytic efficiency and can be recycled, and the problems of large catalyst consumption and low yield in the prior art are overcome.
The carbon-nitrogen double bond in the folic acid is reduced by hydrogen, particularly, the hydrogen is adsorbed on the surface of a catalyst Pd/C, the folic acid is coordinated with the catalyst, the hydrogen molecule of the hydrogen is subjected to bond cleavage under the catalysis of the catalyst Pd/C to form active hydrogen atoms, the hydrogen atoms of the hydrogen are combined with the carbon-nitrogen double bond of the folic acid, and the carbon-nitrogen single bond is formed by reduction, so that the tetrahydrofolic acid is generated.
Pd/C refers to palladium carbon, and palladium microcrystals are uniformly soaked on a specially-made porous carbon carrier.
Specifically, filling hydrogen into the reaction kettle until the reaction kettle does not contain gas except hydrogen;
in the step of adding the catalyst Pd/C into the reaction kettle and adding the folic acid solution into the reaction kettle, nitrogen or inert gas is filled into the reaction kettle so as to form an anaerobic environment in the reaction kettle.
In some embodiments, the catalyst Pd/C comprises 10% Pd/C and the mass ratio of folic acid to catalyst 10% Pd/C is 100 (0.1-20).
In some embodiments, the pressure in the reaction vessel is in the range of 30-65bar during the step of oxidation-reduction of folic acid with hydrogen.
In some embodiments, the reaction time for the redox reaction of folic acid with hydrogen is between 6 and 24 hours.
In some embodiments, after the reaction is completed, the step of obtaining tetrahydrofolate includes:
After the reaction is finished, a solution containing the tetrahydrofolic acid is obtained, the pH value of the tetrahydrofolic acid-containing sediment is regulated to 3-3.5 by an acid solution, the solution containing the tetrahydrofolic acid-containing sediment is obtained, the solution containing the tetrahydrofolic acid-containing sediment is filtered, the tetrahydrofolic acid-containing sediment is collected, and the tetrahydrofolic acid-containing sediment is dried, so that the tetrahydrofolic acid is obtained.
Specifically, after the reaction is finished, the whole system is homogeneous, the tetrahydrofolate can be separated out under the acidic condition, and the pH value is 3-3.5 when the tetrahydrofolate separation yield is highest;
Tetrahydrofolate is sensitive to oxygen and is easily oxidized into dihydrofolate, so that the whole reaction process needs an anaerobic environment;
Specifically, the drying mode comprises freeze drying, vacuum drying and the like, and the drying is carried out under the anaerobic condition to prevent the tetrahydrofolic acid from being oxidized;
filtering under nitrogen or inert gas to avoid oxidation of tetrahydrofolic acid.
In some embodiments, the folic acid solution has a pH of 6 to 7 and the preparation of the folic acid solution comprises the steps of:
adding solid folic acid into a flask, filling nitrogen or inert gas into the flask to form an anaerobic environment, adding a buffer solution with the pH value of 4-7 into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH value of the mixed solution to 6-7 by using an alkali solution to obtain folic acid solution.
Specifically, folic acid solution is prepared under room temperature environment, namely 25-35 ℃.
Specifically, the buffer solution is added to control the pH of the solution, so as to avoid titration jump;
Specifically, folic acid is dissolved in an alkaline solution, and when the folic acid solution is adjusted to ph=7 by using the alkaline solution, the yield of tetrahydrofolic acid generated by folic acid reaction is maximized.
In some embodiments, the buffer solution comprises any one of disodium hydrogen phosphate-citric acid buffer solution, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, barbital sodium-hydrochloric acid buffer solution, tris-hydrochloric acid buffer solution, boric acid-borax buffer solution, glycine-sodium hydroxide buffer solution, borax-sodium hydroxide buffer solution, sodium carbonate-sodium bicarbonate buffer solution, britton-Robinson buffer solution, and Tris buffer salt solution.
In some embodiments, the alkaline solution comprises any one of NaOH solution and KOH solution.
In some embodiments, the buffer solution is used in an amount of 10-15ml/1g solid folic acid.
Specifically, the drying method comprises freeze drying, vacuum drying, etc., and drying under anaerobic condition to prevent oxidation of tetrahydrofolic acid.
In some embodiments, further comprising:
nuclear magnetic detection is carried out on tetrahydrofolic acid by taking mesitylene as an internal standard.
Example 1
Adding 1g of solid folic acid into a 100mL three-neck flask at the temperature of 25 ℃, replacing the flask with nitrogen for 3 times, adding 10mL of 0.2mol/L NaH 2PO4-Na2HPO4 buffer solution with the pH of 7 into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH of the mixed solution to 7 by using a 20% NaOH solution to obtain a folic acid solution;
Adding 0.1g of 10% Pd/C into a 50mL reaction kettle, replacing the reaction kettle with nitrogen for 3 times, adding a folic acid solution with pH of 7 into the reaction kettle, replacing the reaction kettle with hydrogen for 5 times, charging hydrogen into the reaction kettle, adjusting the pressure of the reaction kettle to 50bar, placing the reaction kettle in an environment of 60 ℃ for oxidation-reduction reaction for 15 hours, obtaining a solution containing tetrahydrofolic acid after the reaction is finished, adjusting the pH of the solution containing tetrahydrofolic acid to 3 with 1mol/L hydrochloric acid solution, precipitating tetrahydrofolic acid precipitate, filtering the precipitate, and drying the precipitate for 8 hours by using a vacuum drying box to obtain the tetrahydrofolic acid.
The detection of tetrahydrofolate using mesitylene as internal standard gave a yield of 93%.
Example 2
Adding 1g of solid folic acid into a 100mL three-neck flask at the temperature of 28 ℃, replacing the flask with nitrogen for 3 times, adding 10mL of 0.2mol/L NaH 2PO4-Na2HPO4 buffer solution with the pH of 7 into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH of the mixed solution to 7 by using a 20% NaOH solution to obtain a folic acid solution;
Adding 0.2g of 10% Pd/C into a 50mL reaction kettle, replacing the reaction kettle with nitrogen for 3 times, adding a folic acid solution with pH of 7 into the reaction kettle, replacing the reaction kettle with hydrogen for 5 times, charging hydrogen into the reaction kettle, adjusting the pressure of the reaction kettle to 30bar, placing the reaction kettle in a 70 ℃ environment, carrying out redox reaction for 15h, obtaining a solution containing tetrahydrofolic acid after the reaction is finished, adjusting the pH of the solution containing tetrahydrofolic acid to 3 with 1mol/L hydrochloric acid solution, precipitating tetrahydrofolic acid precipitate, filtering the precipitate, and drying the precipitate for 8h by using a vacuum drying box to obtain the tetrahydrofolic acid.
The detection of tetrahydrofolate using mesitylene as internal standard gave a yield of 91%.
Example 3
Adding 1g of solid folic acid into a 100mL three-neck flask at the temperature of 30 ℃, replacing the flask with nitrogen for 3 times, adding 10mL of 0.2mol/LpH of NaH 2PO4-Na2HPO4 buffer solution with the concentration of 7 into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH value of the mixed solution to 7 by using a 20% NaOH solution to obtain a folic acid solution;
Adding 0.1g of 10% Pd/C into a 50mL reaction kettle, replacing the reaction kettle with nitrogen for 3 times, adding a folic acid solution with pH of 7 into the reaction kettle, replacing the reaction kettle with hydrogen for 5 times, charging hydrogen into the reaction kettle, adjusting the pressure of the reaction kettle to 50bar, placing the reaction kettle in an environment with the temperature of 80 ℃ for oxidation-reduction reaction for 15 hours, obtaining a solution containing tetrahydrofolic acid after the reaction is finished, adjusting the pH of the solution containing tetrahydrofolic acid to 3.5 with 1mol/L hydrochloric acid solution, precipitating tetrahydrofolic acid precipitate, filtering the precipitate, and drying the precipitate for 8 hours by using a vacuum drying oven to obtain the tetrahydrofolic acid.
The detection of tetrahydrofolate using mesitylene as internal standard gave a yield of 91%.
Example 4
Other steps are as in example 1, the reaction time is 24 hours, the reaction temperature is 80 ℃, the pH of the folic acid solution is changed to verify the effect of the reaction pH on the yield of the tetrahydrofolate, and the experimental result is shown in FIG. 1.
As can be seen from FIG. 1, when the pH was 10, the yield of tetrahydrofolate was only 23%, when the pH was 6, the yield of tetrahydrofolate was 79%, and when the pH was 7, the yield of tetrahydrofolate reached 81% and reached the peak, indicating that the yield of reaction was the highest at pH 7.
Example 5
Other procedures were performed as in example 1, by varying the reaction time of the reaction to verify the effect of the reaction time on the yield of tetrahydrofolate, and the experimental results are shown in fig. 2.
As can be seen from FIG. 2, when the reaction time was 6 hours, the yield of tetrahydrofolic acid was 79%, when the reaction time was 12 hours, the yield of tetrahydrofolic acid was 85%, when the reaction time was 15 hours, the yield of tetrahydrofolic acid reached 90% and reached the peak, indicating that the reaction time was 15 hours, and the yield of the reaction was the highest.
Example 6
Other procedures were performed as in example 1, by varying the reaction temperature of the reaction to verify the effect of the reaction temperature on the yield of tetrahydrofolate, and the experimental results are shown in fig. 3.
As can be seen from FIG. 3, when the reaction temperature was 30 ℃, the yield of tetrahydrofolic acid was only 10%, when the reaction temperature was 50, the yield of tetrahydrofolic acid was only 79%, when the reaction temperature was 60 ℃, the yield of tetrahydrofolic acid was 90%, and when the reaction temperature was 70 ℃, the yield of tetrahydrofolic acid was 92% and reached the peak, indicating that the reaction temperature was 70 ℃, the yield of the reaction was the highest.
Example 4
Other procedures as in example 1, experiments were performed to verify the effect of the amount of Pd/C as a catalyst for the reaction on the productivity of tetrahydrofolate, and the experimental results are shown in FIG. 4.
As can be seen from FIG. 4, when the mass of Pd/C as the catalyst is 0.5% of the mass of folic acid, the yield of tetrahydrofolic acid is only 13%, the catalyst amount is increased, and when the mass of Pd/C as the catalyst is more than 5% of the mass of folic acid, the yield tends to be stable, and the reaction yield is more than 90%
FIG. 5 is a nuclear magnetic resonance diagram of the product tetrahydrofolate, the results of which are as follows:
1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝7.7Hz,1H),7.66(d,J＝8.5Hz,2H),6.63(d,J＝8.5Hz,2H),6.42(s,1H),6.18(s,1H),5.74(s,2H),4.35(ddd,J＝9.7,7.6,4.9Hz,1H),3.36(d,J＝11.3Hz,1H),3.13(s,3H),3.06–2.91(m,1H),2.33(t,J＝7.5Hz,2H),2.05(ddd,J＝12.9,9.4,5.3Hz,1H),1.93(ddd,J＝13.8,9.6,6.9Hz,1H)..
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (8)
1. A method for preparing tetrahydrofolic acid, comprising the steps of:
Adding a Pd/C catalyst and a folic acid solution into a reaction kettle, filling hydrogen into the reaction kettle, placing the reaction kettle in an environment of 60-80 ℃, carrying out oxidation-reduction reaction on folic acid and hydrogen, and obtaining tetrahydrofolic acid after the reaction is finished;
the reaction equation for preparing tetrahydrofolate is as follows:
wherein, the chemical formula of folic acid is:
The chemical formula of the tetrahydrofolate is as follows:
the Pd/C of the catalyst is 10% Pd/C, and the mass ratio of folic acid to the 10% Pd/C of the catalyst is 100 (5-20);
The reaction time of the folic acid and the hydrogen for oxidation-reduction reaction is 15h;
The pH of the folic acid solution is 6-7.
2. The method for preparing tetrahydrofolate of claim 1, wherein in the step of oxidation-reduction reaction of folic acid with hydrogen, the pressure of the reaction vessel is in the range of 20-65bar.
3. The method for preparing tetrahydrofolic acid of claim 1, wherein the step of obtaining tetrahydrofolic acid after the reaction is completed comprises:
After the reaction is finished, a solution containing the tetrahydrofolic acid is obtained, the pH value of the solution containing the tetrahydrofolic acid is regulated to 3-3.5 by an acid solution, a solution containing the tetrahydrofolic acid sediment is obtained, the solution containing the tetrahydrofolic acid sediment is filtered, the tetrahydrofolic acid sediment is collected, and the sediment is dried, so that the tetrahydrofolic acid is obtained.
4. The method for preparing tetrahydrofolate according to claim 1, wherein the preparation of the folic acid solution comprises the steps of:
Adding solid folic acid into a flask, filling nitrogen or inert gas into the flask to form an anaerobic environment, adding a buffer solution into the flask, stirring uniformly to obtain a mixed solution, and regulating the pH value of the mixed solution to 6-7 by using an alkali solution to obtain a folic acid solution.
5. The method for producing tetrahydrofolate according to claim 4, wherein the pH of the buffer solution is 4 to 10.
6. The method for preparing tetrahydrofolic acid of claim 4, wherein the buffer solution comprises any one of disodium hydrogen phosphate-citric acid buffer solution, disodium hydrogen phosphate-disodium hydrogen phosphate buffer solution, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, barbital sodium-hydrochloric acid buffer solution, tris buffer solution, boric acid-borax buffer solution, glycine-sodium hydroxide buffer solution, borax-sodium hydroxide buffer solution, sodium carbonate-sodium bicarbonate buffer solution, britton-Robinson buffer solution and Tris buffer salt solution.
7. The method for producing tetrahydrofolic acid of claim 4, wherein the alkaline solution comprises any one of NaOH solution and KOH solution.
8. The method for preparing tetrahydrofolate according to claim 4, wherein the buffer solution is used in an amount of 10-15ml/1g solid folic acid.
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| A Continuous Flow Strategy for the Facile Synthesis and Elaboration of Semi-Saturated Heterobicyclic Fragments;Nicola Luise et al.;《Eur. J. Org. Chem.》;Scheme 1、表1、1347页左栏 * |
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