CN109232574A - A kind of effective folic acid purification process - Google Patents
A kind of effective folic acid purification process Download PDFInfo
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- CN109232574A CN109232574A CN201710560074.4A CN201710560074A CN109232574A CN 109232574 A CN109232574 A CN 109232574A CN 201710560074 A CN201710560074 A CN 201710560074A CN 109232574 A CN109232574 A CN 109232574A
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- acid
- added
- folic acid
- solution
- alkali refining
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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 254
- 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 127
- 239000011724 folic acid Substances 0.000 title claims abstract description 127
- 229960000304 folic acid Drugs 0.000 title claims abstract description 127
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 127
- 238000000746 purification Methods 0.000 title claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 158
- 239000000047 product Substances 0.000 claims abstract description 89
- 238000009874 alkali refining Methods 0.000 claims abstract description 69
- 239000012043 crude product Substances 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims description 126
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 98
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 97
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- 238000001914 filtration Methods 0.000 claims description 57
- 239000000706 filtrate Substances 0.000 claims description 48
- 238000010792 warming Methods 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
- 238000005352 clarification Methods 0.000 claims description 20
- 239000003463 adsorbent Substances 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 238000012545 processing Methods 0.000 claims description 14
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000013078 crystal Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 239000000908 ammonium hydroxide Substances 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 4
- 230000000630 rising effect Effects 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 2
- 239000003610 charcoal Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 36
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 abstract description 33
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 59
- 239000012153 distilled water Substances 0.000 description 33
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- 238000000034 method Methods 0.000 description 23
- 238000001035 drying Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 13
- 239000003513 alkali Substances 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- 238000003825 pressing Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000010959 commercial synthesis reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- -1 4- aminobenzoyl Chemical group 0.000 description 1
- JOAQINSXLLMRCV-UHFFFAOYSA-N 4-{[(2-amino-4-hydroxypteridin-6-yl)methyl]amino}benzoic acid Chemical compound C1=NC2=NC(N)=NC(O)=C2N=C1CNC1=CC=C(C(O)=O)C=C1 JOAQINSXLLMRCV-UHFFFAOYSA-N 0.000 description 1
- GADGMZDHLQLZRI-VIFPVBQESA-N N-(4-aminobenzoyl)-L-glutamic acid Chemical compound NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 GADGMZDHLQLZRI-VIFPVBQESA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 206010009259 cleft lip Diseases 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 208000028831 congenital heart disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 206010048828 underweight Diseases 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000004457 water analysis 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of compound preparation, disclose a kind of purification process of folic acid, folic acid crude product be added after the first acid treating, alkali refining acid solution carry out the second acid treating it is dry folic acid finished product.The purification process of folic acid of the present invention after obtaining alkali refining product, then carries out an acid treating, can increase substantially the purity of folic acid finished product.Experiment shows to effectively reduce the content of impurity A and impurity D using the purification process of folic acid of the present invention, and yield is not substantially reduced compared with traditional folic acid purification process.
Description
Technical field
The invention belongs to field of compound preparation, and in particular to a kind of effective folic acid purification process, more particularly, to one
Kind reduces the purification process of folic acid impurity A (N- (4- aminobenzoyl)-Pidolidone) content.
Background technique
Folic acid is a kind of basic kind of vitamin, substance necessary to being body cell growth and breeding, to cell
The synthesis of merisis and nucleic acid, amino acid, protein plays an important role.Human body, which lacks folic acid, can lead to the different of red blood cell
Often, the increase of immature cell, anaemia and white blood cell are reduced；Pregnant woman's shortage folic acid is likely to result in occurring when fetal birth low
Weight, harelip, heart defect etc..
There are many food containing folic acid, but since natural folic acid is extremely unstable, influence and occur vulnerable to ultraviolet light, high temperature etc.
Oxidation, and folic acid biological availability is lower, so the folic acid that human body can really be obtained from food and few.The mankind are to folic acid
Dependent Demand is in commercial synthesis folic acid.The folic acid of commercial synthesis can keep stable within several months or several years, and it is easy to absorb,
Human body availability is about higher by one times of natural product or so.With the fast development in the fields such as medicine, food, the demand of folic acid
Also it increases sharply, has pushed the fast development of folic acid synthetic technology.
However, chemically synthesized folic acid crude product purity is often less high, need to be further purified, qualified leaf could be obtained
Sour finished product.The method that the purification process of folic acid generally uses acid treating and alkali refining to combine at present.The molten technique of acid is carried out first,
Crude product is dissolved with acid solution, dissolved crude product is obtained into sour extract through elutriation, filters pressing；Alkali soluble technique is carried out again, it is anti-in alkali soluble
It answers and adds water and stirs sour extract in tank, adjust pH value to 9.0~9.5 with lye at 90~100 DEG C, filters pressing obtains alkali soluble filtrate；
Alkali soluble filtrate is through adjusting the process for refining such as acid crystal, drying to get finished product.Such as the Chinese patent of Publication No. CN 102432610A
Disclosed folic acid purification process are as follows: folic acid crude product is dissolved using the dilute sulfuric acid of 25%-35%, by dissolved folic acid crude product through water
Analysis, filters pressing obtain sour extract；It recycles lye to carry out alkali soluble to sour extract, is heated to 90~102 DEG C, and adjust pH value with lye
To 9.0~9.5,1 hour is kept the temperature, filters pressing obtains alkali soluble filtrate after active carbon decoloring is added；Recycle diluted acid to lye carry out at
Salt refining obtains folic acid finished product.In addition the folic acid purification process of state's patent disclosure of Publication No. CN 103102351B are as follows: utilize
The hydrochloric acid of 15%-25% dissolves folic acid crude product, and into the dissolved folic acid crude product solution of gained plus water, blowing are centrifuged, directly
Drying obtains sour extract；In alkali soluble reaction vessel, sour extract is mixed with solvent, and organic alkali solution is added to be adjusted to pH
9.0-10.0 is heated to 65-90 DEG C, adds adsorbent, keeps the temperature 0.5-2 hours at 65-90 DEG C, and filters pressing obtains alkali soluble filter
Liquid, the clear alkali soluble filtrate of gained are added in crystallization reaction container, 80~90 DEG C are heated to, with dilute hydrochloric acid tune pH
For 3.0-3.5, temperature is down to 55~60 DEG C, is centrifuged to obtain folic acid finished product.
Major impurity and troublesome impurity in folic acid purification process are impurity D (pteroic acid) and impurity A (N- (4- aminobenzoic
Acyl)-Pidolidone).Quality requirement impurity D content≤0.6% of folic acid finished product in European Pharmacopoeia, while Impurity A content≤
0.5%.And in traditional folic acid purification process, after alkali refining step, Impurity A content is often increased sour item for disposal
Greatly, the raising of folic acid finished product purity is limited.
Summary of the invention
In view of this, it is an object of the invention to provide a kind of purification process of folic acid in view of the drawbacks of the prior art.This
The purification process for inventing the folic acid after obtaining alkali refining product, then carries out an acid treating, improves the purity of folic acid finished product,
But yield is not substantially reduced.
In order to achieve the object of the present invention, the present invention adopts the following technical scheme that.
Acid solution is added after the first acid treating, alkali refining and carries out the second acid for a kind of purification process of folic acid, folic acid crude product
Refine dry folic acid finished product.
Wherein, the first acid treating is specially to dissolve folic acid crude product with acid solution, and absorption is added to after clarifying in rising temperature for dissolving
Agent is stirred, and water is added in filtering, filtrate, is stirred, and is stood, filtering, obtains acid processing wet product.
Acid solution described in the step of first acid treating can be at least one of sulfuric acid, hydrochloric acid.
Adsorbent described in the step of first acid treating can be active carbon, diatomite or silica gel.
Further, the first acid treating is specially to dissolve folic acid crude product with acid solution, and be warming up to 35~45 DEG C and be dissolved to
After clarification, adsorbent is added, stirs 25~35min, filtering, water is added in filtrate, stirs 25~35min, 40~80min is stood,
Filtering obtains acid processing wet product.
Further, first acid treating is preferably that acid solution is added in folic acid crude product, stirs lower dropwise addition acid solution, rises
After temperature is dissolved to clarification to 38~42 DEG C, adsorbent is added, stirs 28-32min, filtering, filtrate adds water, 28~32min is stirred,
50~70min is stood, filtering obtains acid processing wet product.
Wherein, it is preferred that based on g/ml, the mass volume ratio of the folic acid crude product and acid solution is preferably (2~4): 4；
The mass ratio of the adsorbent and folic acid crude product is (0.5~1.5): 45；Based on g/ml, the folic acid crude product is added with filtrate
Water quality volume ratio (4~8): 100.
Further, the acid solution that the step middle period acid crude of first acid treating is added and the lower acid being added dropwise of stirring are molten
The volume ratio of liquid is preferably 1:1.
Further, acid solution described in the step of the first acid treating is preferably 45%~55% sulfuric acid or 18%~36%
Hydrochloric acid.The acid solution is 50% sulfuric acid in some embodiments；In further embodiments, the acid solution is 45% sulphur
Acid；In further embodiments, the acid solution is 55% sulfuric acid；In further embodiments, the acid solution is 25% salt
Acid；In further embodiments, the acid solution is 18% hydrochloric acid；In further embodiments, the acid solution is 36% salt
Acid.
The purification process folic acid crude product of folic acid of the present invention carries out alkali refining after the first acid treating.The alkali refining
Specially acid processing wet product adds water and stirs, and heats up, and is adjusted to pH 8.0~10.0 with aqueous slkali, and adsorbent, stirring, mistake is added
Filter, obtains alkali refining filtrate, and filtrate obtains alkali refining wet product through toning acid crystal.
Wherein, the aqueous slkali can be sodium carbonate, potassium carbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide during alkali refining
At least one of.
The adsorbent is preferably active carbon, diatomite, at least one in silica gel during alkali refining of the present invention
Kind.
Further, the alkali refining is specially that acid processing wet product adds water and stirs, and is warming up to 75~85 DEG C, uses aqueous slkali
It is adjusted to pH 8.0~10.0, adsorbent is added, stirs 25~35min, filtering obtains alkali refining filtrate, alkali refining filtrate adds
Temperature adjusts pH to 3.0~4.0 to 75~85 DEG C, with acid solution, is cooled to 65~75 DEG C, stirs centrifugation, leaching after 25~35min
It washes, obtains alkali refining wet product.
Further, the alkali refining is preferably in acid processing wet product plus water, stirring are warming up to 78-82 DEG C, use alkali
Solution adjusts pH to 8.0~10.0, and adsorbent is added, and stirs 28-32min, and filtering obtains alkali refining filtrate, alkali refining filtrate
Be heated up to 78~82 DEG C, adjust pH to 3.3~3.7 with acid solution, be cooled to 68~72 DEG C, centrifugation, with 35~40 DEG C go from
Sub- water elution, obtains alkali refining wet product.
Wherein, based on g/ml, the mass volume ratio of the acid processing wet product and water is (35~50): 72；The adsorbent
Mass ratio with acid processing wet product is 1:(14~20).
Further, the aqueous slkali is preferably 5~15% sodium carbonate liquors, 5~15% solution of potassium carbonate, 5~15%
Ammonium hydroxide, 5~15% sodium hydroxide solutions or 5~15% potassium hydroxide solutions.
The aqueous slkali is 10% sodium carbonate liquor in some embodiments.The aqueous slkali is in some embodiments
10% ammonia spirit.The aqueous slkali is 10% solution of potassium carbonate in some embodiments.The alkali soluble in some embodiments
Liquid is 10% sodium hydroxide solution.The aqueous slkali is 10% potassium hydroxide solution in some embodiments.
Further, acid solution described in the alkali refining step is 3-8% dilute sulfuric acid, 7-15% hydrochloric acid or 30-40%
Acetic acid solution；The acid solution is 5% dilute sulfuric acid in some embodiments；The acid solution is 10% salt in some embodiments
Acid；The acid solution is 35% acetic acid solution in some embodiments.
The purification process of folic acid of the present invention carries out the second acid treating, dry available folic acid finished product after alkali refining.
Second acid treating is specially acid solution to be added in alkali refining wet product, and rising temperature for dissolving, to after clarifying, stirring adds
Water stirs, and stands, dry after filtering.Wherein, acid solution described in the step of second acid treating is preferably sulfuric acid, hydrochloric acid
At least one of.
Further, second acid treating is specially acid solution to be added in alkali refining wet product, and be warming up to 35~45 DEG C
After being dissolved to clarification, 25~35min is stirred, adds water, stirs 25~35min, stands 40~80min, it is dry after filtering.
Further, second acid treating is preferably that acid solution is added in alkali refining wet product, and it is molten to stir lower dropwise addition acid
Liquid, be warming up to 38~42 DEG C be dissolved to clarification after, stir 28~32min, add water, stir 28~32min, stand 50~70min,
It is dry after filtering.
The acid solution for the lower dropwise addition of acid solution and stirring being added in alkali refining wet product in the step of second acid treating
Volume ratio is preferably 1:1.
Further, the volume ratio of alkali refining wet product described in the step of second acid treating and acid solution be (35~
50): 48；The volume ratio (7~10) of the alkali refining wet product and the water of addition: 120.
Further, acid solution described in the second acid treating step is 45%~55% sulfuric acid or 18%~36% salt
Acid.The acid solution is 50% sulfuric acid in some embodiments；In further embodiments, the acid solution is 45% sulfuric acid；
In further embodiments, the acid solution is 55% sulfuric acid；In further embodiments, the acid solution is 25% hydrochloric acid；
In further embodiments, the acid solution is 18% hydrochloric acid；In further embodiments, the acid solution is 36% hydrochloric acid.
As shown from the above technical solution, the present invention provides a kind of purification process of folic acid, and folic acid crude product is through the first acid essence
System, be added after alkali refining acid solution carry out the second acid treating it is dry folic acid finished product.The purification process of folic acid of the present invention,
After obtaining alkali refining product, then an acid treating is carried out, the purity of folic acid finished product can be increased substantially.Experiment show with it is traditional
Folic acid purification process is compared, and the content of impurity A and impurity D is effectively reduced using the purification process of folic acid of the present invention, and
Yield is not substantially reduced.
Specific embodiment
The invention discloses a kind of purification process of folic acid.Those skilled in the art can use for reference present disclosure, suitably change
Into realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications are aobvious for a person skilled in the art
And be clear to, they are considered as being included in the present invention.Method and product of the invention has passed through preferred embodiment and has carried out
Description, related personnel obviously can not depart from the content of present invention, method described herein is modified in spirit and scope or
Appropriate changes and combinations carry out implementation and application the technology of the present invention.
For a further understanding of the present invention, below in conjunction with the embodiment of the present invention, to the technical side in the embodiment of the present invention
Case is clearly and completely described, it is clear that and described embodiments are only a part of the embodiments of the present invention, rather than all
Embodiment.Based on the embodiments of the present invention, those of ordinary skill in the art institute without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Unless otherwise specified, reagent involved in the embodiment of the present invention is commercial product, can pass through business canal
Road purchase obtains.
Comparative example 1
Acid treating: using 500ml 18% hydrochloric acid by 100g folic acid crude product (pharmacopeia HPLC method detect, folic acid purity
85.86%, Impurity A content 3.5%, impurity D content 6.4%) dissolution, water is added into the dissolved folic acid crude product solution of gained,
Blowing, centrifugation, drying obtain sour extract.
Alkali refining: being added 3000ml deionized water in sour extract, ammonium hydroxide tune pH9 is added dropwise, is heated to 85 DEG C, repetition measurement
PH value is added 20g activated carbon and is cooled to 55 DEG C, filters pressing after 85-90 DEG C keeps the temperature 1 hour after pH stablizes.
It adjusts acid crystal: filtrate is heated to 80 DEG C, the hydrochloric acid tune pH for being added dropwise 10% is 3.5.83.5 DEG C are warming up to, it is multiple
PH is surveyed after 3-3.5, is cooled to 57 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted with the deionized water of 300ml 35-40 DEG C
Twice, 80 DEG C of drying, obtain folic acid fine work.Yield 81%, HPLC purity 99.2%, impurity A 0.41%, impurity D 0.10%.
Embodiment 1
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 18% hydrochloric acid of 240mL is added, continue that 18% hydrochloric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, active carbon 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, stands
1h, filtering obtain 456g acid and handle wet product.
Alkali refining: 456g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, with 10% ammonia spirit tune
PH 9.0 is saved, active carbon 25g is added, stirs 30min, filtering.Filtrate is heated to 80 DEG C, 5% sulfuric acid tune pH is added dropwise
It is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted twice with 35~40 DEG C of 300ml of deionized water, obtained
To 442g alkali refining wet product.
Second acid treating: being added 18% hydrochloric acid of 240mL in 442g alkali refining wet product, stirs 18% hydrochloric acid of lower dropwise addition
240mL, be warming up to 40 DEG C be dissolved to clarification after, stir 30min, then be added distilled water about 6L, stir 30min, stand 1h, mistake
Filter, 50 DEG C of dryings obtain folic acid finished product.Yield 80%, HPLC detect folic acid purity 99.6%, and impurity A is not detected, impurity D
0.07%.
Comparative example 2
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 50% sulfuric acid of 240mL, continue under stirring be added dropwise 50% sulfuric acid about 240mL, be warming up to 40 DEG C it is molten
Active carbon 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, filtering
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, is adjusted with 10% sodium hydroxide solution
Active carbon 25g is added in pH10.0, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 79%, HPLC detect folic acid purity 98.7%, impurity A
0.71%, impurity D 0.35%.
Embodiment 2
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 50% sulfuric acid of 240mL is added, continue that 50% sulfuric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, active carbon 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, stands
1h, filtering obtain 453g acid and handle wet product.
Alkali refining: 453g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, molten with 10% sodium hydroxide
Liquid adjusts pH 10, and active carbon 25g is added, and stirs 30min, filtering.Filtrate is heated to 80 DEG C, 10% hydrochloric acid is added dropwise
Adjusting pH is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then elutes two with 35~40 DEG C of 300ml of deionized water
It is secondary, obtain 441g alkali refining wet product.
Second acid treating: being added 50% sulfuric acid of 240mL in 441g alkali refining wet product, stirs 50% sulfuric acid of lower dropwise addition
240mL, be warming up to 40 DEG C be dissolved to clarification after, stir 30min, then be added distilled water about 6L, stir 30min, stand 1h, mistake
Filter, 50 DEG C of dryings obtain folic acid finished product.Yield 78%, HPLC detect folic acid purity 99.5%, impurity A 0.01%, impurity D
0.29%.
Comparative example 3
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 45% sulfuric acid of 240mL, continue under stirring be added dropwise 45% sulfuric acid about 240mL, be warming up to 40 DEG C it is molten
Silica gel 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, and filtering obtains
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, is adjusted with 10% sodium hydroxide solution
Silica gel 25g is added in pH 9, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 80%, HPLC detect folic acid purity 98.7%, impurity A
0.66%, impurity D 0.25%.
Embodiment 3
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 45% sulfuric acid of 240mL is added, continue that 45% sulfuric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, silica gel 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, 1h is stood,
Filtering obtains 458g acid and handles wet product.
Alkali refining: 458g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, molten with 10% sodium hydroxide
Liquid adjusts pH 9, and silica gel 25g is added, and stirs 30min, filtering.Filtrate is heated to 80 DEG C, 35% acetic acid tune pH is added dropwise
It is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted twice with 35~40 DEG C of 300ml of deionized water, obtained
To 439g alkali refining wet product.
Second acid treating: being added 45% sulfuric acid of 240mL in 439g alkali refining wet product, stirs 45% sulfuric acid of lower dropwise addition
240mL, be warming up to 40 DEG C be dissolved to clarification after, stir 30min, then be added distilled water about 6L, stir 30min, stand 1h, mistake
Filter, 50 DEG C of dryings obtain folic acid finished product.Yield 79%, HPLC detect folic acid purity 99.4%, and impurity A is not detected, impurity D
0.21%.
Comparative example 4
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 55% sulfuric acid of 240mL, continue under stirring be added dropwise 55% sulfuric acid about 240mL, be warming up to 40 DEG C it is molten
Diatomite 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, filtering
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, adjusts pH with 10% sodium carbonate liquor
8.0, diatomite 25g is added, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 80%, HPLC detect folic acid purity 98.9%, impurity A
0.67%, impurity D 0.28%.
Embodiment 4
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 55% sulfuric acid of 240mL is added, continue that 55% sulfuric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, diatomite 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, stands
1h, filtering obtain 459g acid and handle wet product.
Alkali refining: 459g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, with 10% sodium carbonate liquor
PH 8.0 is adjusted, diatomite 25g is added, stirs 30min, filtering.Filtrate is heated to 80 DEG C, 10% hydrochloric acid tune is added dropwise
PH is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted twice with 35~40 DEG C of 300ml of deionized water,
Obtain 441g alkali refining wet product.
Second acid treating: being added 55% sulfuric acid of 240mL in 441g alkali refining wet product, stirs 55% sulfuric acid of lower dropwise addition
240mL, be warming up to 40 DEG C be dissolved to clarification after, stir 30min, then be added distilled water about 6L, stir 30min, stand 1h, mistake
Filter, 50 DEG C of dryings obtain folic acid finished product.Yield 79%, HPLC detect folic acid purity 99.5%, impurity A 0.03%, impurity D
0.25%.
Comparative example 5
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 25% hydrochloric acid of 240mL, continue under stirring be added dropwise 25% hydrochloric acid about 240mL, be warming up to 40 DEG C it is molten
Active carbon 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, filtering
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, is adjusted with 10% potassium hydroxide solution
Active carbon 25g is added in pH 10.0, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 80%, HPLC detect folic acid purity 98.7.1%, impurity A
0.61%, impurity D 0.31%.
Embodiment 5
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 25% hydrochloric acid of 240mL is added, continue that 25% hydrochloric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, active carbon 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, stands
1h, filtering obtain 457g acid and handle wet product.
Alkali refining: 457g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, molten with 10% potassium hydroxide
Liquid adjusts pH 10.0, and active carbon 25g is added, and stirs 30min, filtering.Filtrate is heated to 80 DEG C, 10% salt is added dropwise
It is 3.5 that acid, which adjusts pH, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted with 35~40 DEG C of 300ml of deionized water
Twice, 443g alkali refining wet product is obtained.
Second acid treating: being added 25% hydrochloric acid of 240mL in 443g alkali refining wet product, stirs 25% hydrochloric acid of lower dropwise addition
240mL after being warming up to 40 DEG C of dissolved clarifications, stirs 30min, distilled water about 6L is then added, stir 30min, stand 1h, filters, 50
DEG C drying, obtains folic acid finished product.Yield 79%, HPLC detect folic acid purity 99.5%, and impurity A is not detected, impurity D 0.26%.
Comparative example 6
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 18% hydrochloric acid of 240mL, continue under stirring be added dropwise 18% hydrochloric acid about 240mL, be warming up to 40 DEG C it is molten
Silica gel 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, and filtering obtains
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, is adjusted with 10% potassium hydroxide solution
Silica gel 25g is added in pH 9.0, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 81%, HPLC detect folic acid purity 98.6.1%, impurity A
0.67%, impurity D 0.33%.
Embodiment 6
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 18% hydrochloric acid of 240mL is added, continue that 18% hydrochloric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, silica gel 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, 1h is stood,
Filtering obtains 457g acid and handles wet product.
Alkali refining: 454g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, molten with 10% potassium hydroxide
Liquid adjusts pH 9.0, and silica gel 25g is added, and stirs 30min, filtering.Filtrate is heated to 80 DEG C, 10% hydrochloric acid tune is added dropwise
PH is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted twice with 35~40 DEG C of 300ml of deionized water,
Obtain 441g alkali refining wet product.
Second acid treating: being added 18% hydrochloric acid of 240mL in 441g alkali refining wet product, stirs 18% hydrochloric acid of lower dropwise addition
240mL after being warming up to 40 DEG C of dissolved clarifications, stirs 30min, distilled water about 6L is then added, stir 30min, stand 1h, filters, 50
DEG C drying, obtains folic acid finished product.Yield 80%, HPLC detect folic acid purity 99.4%, and impurity A is not detected, impurity D 0.27%.
Comparative example 7
Acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content 3.5%,
Impurity D content 6.4%) be added 36% hydrochloric acid of 240mL, continue under stirring be added dropwise 36% hydrochloric acid about 240mL, be warming up to 40 DEG C it is molten
Diatomite 8g is added to after clarifying in solution, stirs 30min, filtering, and distilled water 6L is added in filtrate, stirs 30min, stands 1h, filtering
Obtain sour item for disposal.
Alkali refining: being added 7.2L distilled water in sour item for disposal, stirring is warming up to 80 DEG C, adjusts pH with 10% solution of potassium carbonate
8.0, diatomite 25g is added, stirs 30min, filtering.
It adjusts acid crystal: filtrate is heated to 80 DEG C, adjust pH 3.5 with 5% dilution heat of sulfuric acid, stirring is cooled to 70
DEG C, it is filtered after about 30min, 50 DEG C of drying obtain folic acid finished product.Yield 80%, HPLC detect folic acid purity 98.7%, impurity A
0.60%, impurity D 0.35%.
Embodiment 7
First acid treating: 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.86%, Impurity A content
3.5%, impurity D content 6.4%) 36% hydrochloric acid of 240mL is added, continue that 36% hydrochloric acid about 240mL is added dropwise under stirring, is warming up to
After 40 DEG C are dissolved to clarification, diatomite 8g is added, stirs 30min, filtering, distilled water 6L is added in filtrate, stirs 30min, stands
1h, filtering obtain 458g acid and handle wet product.
Alkali refining: 458g acid handles and 7.2L distilled water is added in wet product, and stirring is warming up to 80 DEG C, with 10% solution of potassium carbonate
PH 8.0 is adjusted, diatomite 25g is added, stirs 30min, filtering.Filtrate is heated to 80 DEG C, 10% hydrochloric acid tune is added dropwise
PH is 3.5, is cooled to 70 DEG C.It is discharged to centrifuge to be directly centrifuged, then is eluted twice with 35~40 DEG C of 300ml of deionized water,
Obtain 440g alkali refining wet product.
Second acid treating: being added 36% hydrochloric acid of 240mL in 440g alkali refining wet product, stirs 36% hydrochloric acid of lower dropwise addition
240mL after being warming up to 40 DEG C of dissolved clarifications, stirs 30min, distilled water about 6L is then added, stir 30min, stand 1h, filters, 50
DEG C drying, obtains folic acid finished product.Yield 79%, HPLC detect folic acid purity 99.4%, and impurity A is not detected, impurity D 0.26%.
In conclusion compared with traditional folic acid purification process (comparative example 1-7), using the purifying of folic acid of the present invention
Method (embodiment 1-7) effectively reduces the content of impurity A and impurity D, improves in the case where not being substantially reduced yield
The purity of folic acid finished product.
Claims (10)
1. a kind of purification process of folic acid, which is characterized in that folic acid crude product be added after the first acid treating, alkali refining acid solution into
The second acid treating of row it is dry folic acid finished product.
2. purification process according to claim 1, which is characterized in that first acid treating is specially to be dissolved with acid solution
Folic acid crude product, and adsorbent is added to after clarifying in rising temperature for dissolving, stirs, water is added in filtering, filtrate, stirs, and stands, and filtering obtains
Obtain sour processing wet product；Wherein, the acid solution is preferably at least one of sulfuric acid, hydrochloric acid；The adsorbent is preferably lived
At least one of property charcoal, diatomite, silica gel.
3. purification process according to claim 2, which is characterized in that first acid treating is specially that folic acid crude product is added
Acid solution, stir it is lower acid solution is added dropwise, be warming up to 35~45 DEG C be dissolved to clarification after, adsorbent is added, stirs 25~35min,
Filtering, filtrate add water, stir 25~35min, stand 40~80min, and filtering obtains acid processing wet product；Wherein, based on g/ml,
The mass volume ratio of the folic acid crude product and acid solution is (2~4): 4；The mass ratio of the adsorbent and folic acid crude product is (0.5
~1.5): 45；Based on g/ml, the mass volume ratio (4~8) of the water of the folic acid crude product and filtrate addition: 100；The acid is molten
Liquid be 45%~55% sulfuric acid or 18%~36% hydrochloric acid, preferably 45% sulfuric acid, 50% sulfuric acid, 55% sulfuric acid, 18% hydrochloric acid,
25% hydrochloric acid or 36% hydrochloric acid.
4. purification process according to claim 1, which is characterized in that the alkali refining is specially that acid processing wet product adds water to stir
It mixes, and heats up, adjust pH to 8.0~10.0 with aqueous slkali, adsorbent is added, stir, filtering obtains alkali refining filtrate, filtrate
Through toning acid crystal, alkali refining wet product is obtained；Wherein, the aqueous slkali be preferably sodium carbonate, potassium carbonate, ammonium hydroxide, sodium hydroxide,
At least one of potassium hydroxide；The adsorbent is preferably at least one of active carbon, diatomite, silica gel.
5. purification process according to claim 4, which is characterized in that the alkali refining is specially to add in acid processing wet product
Water, stirring are warming up to 75~85 DEG C, adjust pH to 8.0~10.0 with aqueous slkali, adsorbent is added, stir 25~35min, mistake
Filter, obtains alkali refining filtrate, and filtrate is heated up to 75~85 DEG C, adjusts pH to 3.0~4.0 with acid solution, is cooled to 65~75 DEG C,
Centrifugation, elution obtain alkali refining wet product；Wherein, based on g/ml, it is described acid processing wet product and water mass volume ratio be (35~
50):72；The adsorbent and the mass ratio of acid processing wet product are 1:(14~20)；The aqueous slkali is that 5~15% sodium carbonate are molten
Liquid, 5~15% solution of potassium carbonate, 5~15% ammonium hydroxide, 5~15% sodium hydroxide solutions or 5~15% potassium hydroxide solutions, it is excellent
It is molten to be selected as 10% sodium carbonate liquor, 10% solution of potassium carbonate, 10% ammonium hydroxide, 10% sodium hydroxide solution or 10% potassium hydroxide
Liquid；The acid solution is 3-8% dilute sulfuric acid, 7-15% hydrochloric acid or 30-40% acetic acid solution；Preferably 5% dilute sulfuric acid, 10% salt
Acid or 35% acetic acid solution.
6. purification process according to claim 1, which is characterized in that second acid treating is specially in alkali refining wet product
Acid solution is added, and rising temperature for dissolving, to after clarifying, stirring adds water, stirs, and stands, dry after filtering.
7. purification process according to claim 6, which is characterized in that acid solution described in the step of second acid treating
For at least one of sulfuric acid, hydrochloric acid.
8. purification process according to claim 6, which is characterized in that second acid treating is specially in alkali refining wet product
Acid solution is added, stir it is lower acid solution is added dropwise, be warming up to 35~45 DEG C be dissolved to clarification after, stir 25~35min, add water, stir
25~35min is mixed, 40~80min is stood, it is dry after filtering.
9. purification process according to any one of claims 6 to 8, which is characterized in that institute in the step of the second acid treating
The volume ratio for stating alkali refining wet product and acid solution is (35~50): 48；The volume ratio (7 of the alkali refining wet product and the water of addition
~10): 120.
10. according to purification process described in claim 6~9 any one, which is characterized in that institute in the step of the second acid treating
State acid solution be 45%~55% sulfuric acid or 18%~36% hydrochloric acid, preferably 50% sulfuric acid, 45% sulfuric acid, 55% sulfuric acid,
25% hydrochloric acid, 18% hydrochloric acid or 36% hydrochloric acid.
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| CN109761985A (en) * | 2019-01-28 | 2019-05-17 | 河北冀衡（集团）药业有限公司 | A method of purifying folic acid |
| CN113816961A (en) * | 2021-08-17 | 2021-12-21 | 北京斯利安药业有限公司 | Folic acid synthesis method |
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