CN109265460A - A kind of purification process of folic acid - Google Patents
A kind of purification process of folic acid Download PDFInfo
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- CN109265460A CN109265460A CN201811474195.8A CN201811474195A CN109265460A CN 109265460 A CN109265460 A CN 109265460A CN 201811474195 A CN201811474195 A CN 201811474195A CN 109265460 A CN109265460 A CN 109265460A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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Abstract
The present invention provides a kind of purification process of folic acid, comprising: mixes folic acid crude product with the first acid solution, after heating stirring, water is added, continue heating stirring, filtering is mixed with the second acid solution, after heating stirring, water is added, continues heating stirring, filtering is mixed with third acid solution, after heating stirring, water is added, continues heating stirring, filtering, it is mixed with water, pH value is adjusted to faintly acid with alkali, after adsorbent processing is added, filtering, by filtrate after adjusting acid crystal, obtains folic acid.Compared with prior art, the present invention carries out acid treating in the way of heating stirring processing to folic acid crude product by acid solution, and carries out multistage acid treating, it is possible to prevente effectively from the generation of impurity D, while impurity A and different folic acid impurity can be effectively removed；Furthermore the product after acid treating is subjected to alkali refining under weak acid benign environment, reduces the hydrolyzed possibility of folic acid, can also effectively remove impurity D, product yield and purity is made all to be greatly improved.
Description
Technical field
The invention belongs to technical field of compound preparation more particularly to a kind of purification process of folic acid.
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
Demand depends on synthetic method production.The folic acid of synthesis can keep stable within several months or several years, and it is easy to absorb, human body
Availability is high, 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.The purifying side of folic acid at present
The method that method generally uses acid treating and alkali refining to combine.The molten technique of acid of advancing first will be dissolved with acid solution dissolution crude product
Crude product afterwards obtains sour extract through elutriation, filters pressing；Alkali soluble, process for refining are carried out again, and sour extract is added into water in alkali soluble reactor tank
Stirring adjusts pH value to 9.0~9.5 with lye at 90~100 DEG C, and filters pressing obtains alkali soluble filtrate, alkali soluble filtrate adjusted acid crystal,
The process for refining such as dry are to get finished product.The folic acid purification process as disclosed in Chinese patent CN102432610A are as follows: using 25%~
35% dilute sulfuric acid dissolves folic acid crude product, and by dissolved folic acid crude product through elutriation, filters pressing obtains sour extract；Recycle lye pair
Sour extract carries out alkali soluble, is heated to 90~102 DEG C, and lye adjusts pH value to 9.0~9.5, keeps the temperature 1 hour, active carbon is added
Filters pressing obtains alkali soluble filtrate after decoloration；Diluted acid is recycled to carry out obtaining folic acid finished product at salt refining to lye；Chinese patent
(CN103102351B) folic acid purification process disclosed in are as follows: dissolved folic acid crude product using 15%~25% hydrochloric acid, to gained
In dissolved folic acid crude product solution plus water, blowing, centrifugation, directly drying obtain sour extract；In alkali soluble reaction vessel, acid
Extract is mixed with solvent, adds organic alkali solution that pH is made to be adjusted to 9.0~10.0, is heated to 65 DEG C~90 DEG C, is added
Adsorbent keeps the temperature 0.5~2 hour at 65~90 DEG C, and filters pressing obtains alkali soluble filtrate, and the clear alkali soluble filtrate of gained is added to knot
In brilliant reaction vessel, 80~90 DEG C are heated to, is 3.0~3.5 with dilute hydrochloric acid tune pH value, temperature is down to 55~60 DEG C, from
Gains in depth of comprehension folic acid finished product.
Major impurity and troublesome impurity in folic acid purification process are impurity D (pteroic acid), different folic acid and impurity A (N- (4- ammonia
Base benzoyl)-Pidolidone), content≤0.6% of folic acid lmpurities D, different leaf are required in European Pharmacopoeia EP8.0 standard
Require content≤0.4% of impurity D in content≤0.5%, EP9.5 standard of acid, content≤0.3% of different folic acid, impurity A is small
In 0.5%.Alkali refining step in traditional folic acid purification process carries out under basic conditions, folic acid Yishui River in an acidic solution
Solution is impurity D, is easier to be hydrolyzed to impurity A (N- (4- aminobenzoyl)-Pidolidone) under alkaline condition, further increases this
The content of two class impurity；And different folic acid is difficult to remove with conventional method, is unfavorable for further increasing for folic acid purity；And sour essence
It needs to dissolve folic acid crude product in system, adds water crystallization, wastewater flow rate is big, and yield is lower, complicated for operation.Therefore, in order to further mention
A kind of purity of homofolic acid, it is desirable to provide mild folic acid purification process.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing a kind of mild efficient folic acid purification process.
The present invention provides a kind of purification process of folic acid, comprising:
S1 folic acid crude product is mixed with the first acid solution), after heating stirring, water is added, continues heating stirring, filtering obtains
To primary acids item for disposal；
S2 the primary acids item for disposal is mixed with the second acid solution), after heating stirring, water is added, continues heating stirring,
Filtering, obtains second level acid item for disposal；
S3 the second level acid item for disposal is mixed with third acid solution), after heating stirring, water is added, continues heating stirring,
Filtering, obtains three-level acid item for disposal；
S4 the three-level acid item for disposal is mixed with water), adjusts pH value to faintly acid with alkali, after adsorbent processing is added,
Filtering, obtains filtrate；
S5 the filtrate) is obtained into folic acid after adjusting acid crystal.
Preferably, first acid solution, the second acid solution and third acid solution are each independently selected from hydrochloric acid and/or sulphur
Acid；The mass concentration of the hydrochloric acid is 5%~35%；The mass concentration of the sulfuric acid is 10%~50%.
Preferably, the step S1) in heating stirring temperature be 40 DEG C~60 DEG C；The time of heating stirring be 10~
60min；The temperature for continuing heating stirring is 45 DEG C~55 DEG C；The time for continuing heating stirring is 50~70min；
The step S2) in heating stirring temperature be 45 DEG C~50 DEG C；The time of heating stirring is 25~35min；After
The temperature of continuous heating stirring is 45 DEG C~50 DEG C；The time for continuing heating stirring is 50~70min；
The step S3) in heating stirring temperature be 45 DEG C~50 DEG C；The time of heating stirring is 25~35min；After
The temperature of continuous heating stirring is 45 DEG C~55 DEG C；The time for continuing heating stirring is 50~70min.
Preferably, the mass volume ratio of the folic acid crude product and the first acid solution is (1~4) g:8ml；The folic acid crude product
Mass volume ratio with the second acid solution is (1~4) g:8ml；The mass volume ratio of the folic acid crude product and third acid solution is
(1~4) g:8ml.
Preferably, the step S1) folic acid crude product and be added water mass volume ratio be (2~6) g:8ml；The folic acid
The mass volume ratio of water is added as (2~6) g:8ml in crude product and step S2)；Water is added in the folic acid crude product and step S3)
Mass volume ratio be (2~6) g:8ml.
Preferably, the step S4) in alkali be selected from one of sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide
Or it is a variety of；The adsorbent is selected from one of active carbon, diatomite and silica gel or a variety of.
Preferably, the step S4) in alkali adjust pH value to 6.0~6.5.
Preferably, the mass volume ratio of the three-level acid item for disposal and water is (0.5~2.5) g:30ml；The adsorbent
Mass ratio with three-level acid item for disposal is (0.5~2.5): 10.
Preferably, the step S5) specifically:
By the filtrate the 4th acid solution adjusting pH value to 2~4, under stirring conditions, 50 DEG C~90 DEG C are warming up to,
20~40min is kept the temperature, 50 DEG C~80 DEG C is cooled to, is filtered after 20~40min, obtain folic acid.
Preferably, the 4th acid solution is the sulfuric acid solution of 3~10wt%.
The present invention provides a kind of purification process of folic acid, comprising: S1) folic acid crude product is mixed with the first acid solution, add
After thermal agitation, water is added, continues heating stirring, filtering obtains primary acids item for disposal；S2) by the primary acids item for disposal and
Diacid solution mixes, and after heating stirring, water is added, and continues heating stirring, and filtering obtains second level acid item for disposal；S3) by described two
The sour item for disposal of grade is mixed with third acid solution, and after heating stirring, water is added, and continues heating stirring, and filtering obtains the processing of three-level acid
Product；S4 the three-level acid item for disposal is mixed with water), pH value is adjusted with alkali and is filtered after adsorbent processing is added to faintly acid,
Obtain filtrate；S5 the filtrate) is obtained into folic acid after adjusting acid crystal.Compared with prior art, the present invention utilizes acid solution pair
Folic acid crude product carries out acid treating by the way of heating stirring processing, and carries out multistage acid treating, it is possible to prevente effectively from impurity D
Generation, while impurity A and different folic acid impurity can be effectively removed；Furthermore by the product after acid treating under weak acid benign environment into
Row alkali refining reduces the hydrolyzed possibility of folic acid, can also effectively remove impurity D, obtain product yield and purity all very
Big promotion.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
The present invention provides a kind of purification process of folic acid, comprising: S1) folic acid crude product is mixed with the first acid solution, add
After thermal agitation, water is added, continues heating stirring, filtering obtains primary acids item for disposal；S2) by the primary acids item for disposal and
Diacid solution mixes, and after heating stirring, water is added, and continues heating stirring, and filtering obtains second level acid item for disposal；S3) by described two
The sour item for disposal of grade is mixed with third acid solution, and after heating stirring, water is added, and continues heating stirring, and filtering obtains the processing of three-level acid
Product；S4 the three-level acid item for disposal is mixed with water), pH value is adjusted with alkali and is filtered after adsorbent processing is added to faintly acid,
Obtain filtrate；S5 the filtrate) is obtained into folic acid after adjusting acid crystal.
The present invention is not particularly limited the source of all raw materials, is commercially available.
Folic acid crude product is mixed with the first acid solution；The folic acid crude product is folic acid crude product well known to those skilled in the art
, having no special limitation, the preferably purity of folic acid crude product is 80%~90% in the present invention, more preferably 82%~
88%, it is further preferably 84%~86%, most preferably 85%~85.5%；The content of impurity A is preferably in the folic acid crude product
1%~5%, more preferably 2%~4%, it is further preferably 3%~4%, most preferably 3.6%；Impurity D in the folic acid crude product
Content be preferably 1%~8%, more preferably 3%~7%, be further preferably 5%~7%, be further preferably 6%~7%, it is optimal
It is selected as 6.4%；The content of different folic acid is preferably 1%~8% in the folic acid crude product, more preferably 2%~6%, further preferably for
2%~5.8%；In general the content of different folic acid is usually 2%~3% in crude product, the different smaller easier removing of folate content；
First acid solution is acid solution well known to those skilled in the art, has no special limitation, is preferably in the present invention
Sulfuric acid and/or hydrochloric acid；The mass concentration of the sulfuric acid is preferably 10%~50%, and more preferably 15%~50%；In the present invention
In some embodiments provided, the mass concentration of the sulfuric acid is preferably 15%；In some embodiments provided by the invention, institute
The mass concentration for stating sulfuric acid is preferably 30%；In other embodiments provided by the invention, the mass concentration of the sulfuric acid is excellent
It is selected as 50%；The concentration of the hydrochloric acid is preferably 5%~35%, and more preferably 10%~30%；The folic acid crude product and first
The mass volume ratio of acid solution is preferably (1~4) g:8ml, more preferably (2~4) g:8ml, is further preferably (3~4) g:8ml.
Heating stirring after mixing；The temperature of the heating stirring is preferably 40 DEG C~60 DEG C, and more preferably 45 DEG C~55 DEG C,
It is further preferably 50 DEG C；The time of the heating stirring is preferably 10~60min, more preferably 20~50min, further preferably for 30~
40min。
Then water is added, continues heating stirring, filtering obtains primary acids item for disposal；In order to reduce the influence of water intermediate ion,
It is preferably added to purified water；The folic acid crude product and the mass volume ratio that water is added are preferably (2~6) g:8ml, more preferably (3~
6) g:8ml is further preferably (4~5) g:8ml；The temperature for continuing heating stirring is preferably 45 DEG C~55 DEG C, more preferably 50
℃；The time for continuing heating stirring is preferably 50~70min, and more preferably 55~65min is further preferably 60min.
The primary acids item for disposal is mixed with the second acid solution；Second acid solution is known to those skilled in the art
Acid solution, have no special limitation, preferably sulfuric acid and/or hydrochloric acid in the present invention；The mass concentration of the sulfuric acid is excellent
It is selected as 10%~50%, more preferably 15%~50%；In some embodiments provided by the invention, the quality of the sulfuric acid is dense
Degree preferably 15%；In some embodiments provided by the invention, the mass concentration of the sulfuric acid is preferably 30%；In the present invention
In other embodiments provided, the mass concentration of the sulfuric acid is preferably 50%；The concentration of the hydrochloric acid is preferably 5%~
35%, more preferably 10%~30%；The mass volume ratio of the folic acid crude product and the second acid solution is preferably (1~4) g:
8ml, more preferably (2~4) g:8ml are further preferably (3~4) g:8ml.
Heating stirring after mixing；The temperature of the heating stirring is preferably 40 DEG C~60 DEG C, and more preferably 45 DEG C~55 DEG C,
It is further preferably 50 DEG C；The time of the heating stirring is preferably 10~60min, more preferably 20~50min, further preferably for 30~
40min。
Then water is added, continues heating stirring, filtering obtains second level acid item for disposal；In order to reduce the influence of water intermediate ion,
It is preferably added to purified water；The folic acid crude product and the mass volume ratio that water is added are preferably (2~6) g:8ml, more preferably (3~
6) g:8ml is further preferably (4~5) g:8ml；The temperature for continuing heating stirring is preferably 45 DEG C~55 DEG C, more preferably 50
℃；The time for continuing heating stirring is preferably 50~70min, and more preferably 55~65min is further preferably 60min.
The second level acid item for disposal is mixed with third acid solution；The third acid solution is known to those skilled in the art
Acid solution, have no special limitation, preferably sulfuric acid and/or hydrochloric acid in the present invention；The mass concentration of the sulfuric acid is excellent
It is selected as 10%~50%, more preferably 15%~50%；In some embodiments provided by the invention, the quality of the sulfuric acid is dense
Degree preferably 15%；In some embodiments provided by the invention, the mass concentration of the sulfuric acid is preferably 30%；In the present invention
In other embodiments provided, the mass concentration of the sulfuric acid is preferably 50%；The concentration of the hydrochloric acid is preferably 5%~
35%, more preferably 10%~30%；The mass volume ratio of the folic acid crude product and third acid solution is preferably (1~4) g:
8ml, more preferably (2~4) g:8ml are further preferably (3~4) g:8ml.
Heating stirring after mixing；The temperature of the heating stirring is preferably 40 DEG C~60 DEG C, and more preferably 45 DEG C~55 DEG C,
It is further preferably 50 DEG C；The time of the heating stirring is preferably 10~60min, more preferably 20~50min, further preferably for 30~
40min。
Then water is added, continues heating stirring, filtering obtains three-level acid item for disposal；In order to reduce the influence of water intermediate ion,
It is preferably added to purified water；The folic acid crude product and the mass volume ratio that water is added are preferably (2~6) g:8ml, more preferably (3~
6) g:8ml is further preferably (4~5) g:8ml；The temperature for continuing heating stirring is preferably 45 DEG C~55 DEG C, more preferably 50
℃；The time for continuing heating stirring is preferably 50~70min, and more preferably 55~65min is further preferably 60min.
The three-level acid item for disposal is mixed with water；The water is preferably purified water；The three-level acid item for disposal and water
Mass volume ratio is preferably (0.5~2.5) g:30ml, more preferably (1~2.5) g:30ml, is further preferably (1~2) g:30ml,
It is further preferably (1.5~2) g:30ml, most preferably (1.6~1.8) g:30ml；The mixing preferably carries out at room temperature.
After mixing, pH value is adjusted to weak acid with alkali；The alkali is alkali well known to those skilled in the art, and it is special to have no
Limitation, preferably one of sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide or a variety of in the present invention；The alkali
It is preferred that being added in the form of aqueous slkali；The mass concentration of the aqueous slkali is preferably 5%~15%, and more preferably 8%~12%,
It is further preferably 10%；PH value is preferably adjusted with alkali to 6~6.5.
After adjusting pH value, adsorbent is added；The adsorbent is adsorbent well known to those skilled in the art, is had no
Special limitation, preferably one of active carbon, diatomite and silica gel or a variety of in the present invention；The adsorbent and three-level acid
The mass ratio of item for disposal is preferably (0.5~2.5): 10, more preferably (0.5~2): 10, be further preferably (0.5~1.5): 10,
Further preferably it is (0.5~1): 10, most preferably (0.7~0.8): 10.
After adsorbent is added, preferably 20~40min of stirring, more preferably stirring 30min, filtering obtain filtrate.
The filtrate is subjected to tune acid crystal, obtains folic acid；The method for adjusting acid crystal is that those skilled in the art are ripe
The method known has no special limitation, preferably follows the steps below in the present invention: the filtrate is molten with tetracid
Liquid adjusts pH value to 2~4, is preferably adjusted to 3~3.5, under stirring conditions, is warming up to 50 DEG C~90 DEG C, is preferably warming up to
60 DEG C~90 DEG C, 70 DEG C~90 DEG C are more preferably warming up to, is further preferably warming up to 75 DEG C~85 DEG C, is preferably warming up to 80 DEG C, heat preservation
20~40min, preferably heat preservation 25~35min, more preferably heat preservation 30min, be cooled to 50 DEG C~80 DEG C, be preferably cooled to 65 DEG C~
It 70 DEG C, after 20~40min, is filtered after preferably 30min；It is preferably dried after filtering, obtains folic acid；The temperature of the drying is preferably
40 DEG C~60 DEG C, more preferably 45 DEG C~55 DEG C, be further preferably 50 DEG C；4th acid solution is known to those skilled in the art
Acid solution, have no special limitation, the preferably sulfuric acid solution of 3~10wt% in the present invention, more preferably 5~
The sulfuric acid solution of 8wt%.
The present invention carries out acid treating to folic acid crude product by acid solution in the way of heating stirring processing, and carries out more
Grade acid treating, it is possible to prevente effectively from the generation of impurity D, while impurity A and different folic acid impurity can be effectively removed；Furthermore by acid treating
Product afterwards carries out alkali refining under weak acid benign environment, reduces the hydrolyzed possibility of folic acid, can also effectively remove impurity D,
Product yield and purity is set all to be greatly improved, impurity A, impurity D and different folic acid all meet EP standard after purifying.
In order to further illustrate the present invention, with reference to embodiments to a kind of purification process of folic acid provided by the invention into
Row detailed description.
Reagent used in following embodiment is commercially available.
Embodiment 1
Acid treating:
(1) 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 30% sulfuric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product 451g.
(2) primary acids item for disposal is then added in 30% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product 439g.
(3) second level acid item for disposal is added in 30% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product 427g.
Alkali refining:
7200mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusts pH with 10% sodium carbonate liquor
6.0~6.5, active carbon 30g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 58.5%, HPLC inspection
Folic acid purity 99.6%, Impurity A content 0.18% are surveyed, impurity D content is 0.07%, and different folic acid is not detected.
Embodiment 2
Acid treating:
(1) 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 15% sulfuric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product 437g.
(2) primary acids item for disposal is then added in 15% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product 411g.
(3) second level acid item for disposal is added in 15% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product 398g.
Alkali refining:
7200mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusts pH with 10% sodium carbonate liquor
6.0~6.5, active carbon 30g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 58.1%, HPLC inspection
Folic acid purity 99.5%, Impurity A content 0.22% are surveyed, impurity D content is 0.11%, and different folic acid is not detected.
Embodiment 3
Acid treating:
(1) 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 50% sulfuric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product 435g.
(2) primary acids item for disposal is then added in 50% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product 407g.
(3) second level acid item for disposal is added in 50% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product 393g.
Alkali refining:
7200mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, is adjusted with 10% sodium hydroxide solution
Active carbon 30g is added in pH6.0~6.5, stirs 30min, and filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilute hydrochloric acid solution, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 57.9%, HPLC inspection
Folic acid purity 99.5%, Impurity A content 0.15 are surveyed, impurity D content is 0.14%, different folate content 0.03%.
Embodiment 4
Acid treating:
(1) 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 30% hydrochloric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product 442g.
(2) primary acids item for disposal is then added in 30% hydrochloric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product 421g.
(3) second level acid item for disposal is added in 30% hydrochloric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product 403g.
Alkali refining:
7200mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusts pH with 10% potassium hydroxide solution
6.0~6.5, diatomite 30g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 58.3%, HPLC inspection
Folic acid purity 99.4%, Impurity A content 0.34% are surveyed, impurity D content is 0.14%, different folate content 0.04%.
Embodiment 5
Acid treating:
(1) 360g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 10% hydrochloric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product 431g.
(2) primary acids item for disposal is then added in 10% hydrochloric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product 411g.
(3) second level acid item for disposal is added in 10% hydrochloric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product 386g.
Alkali refining:
7200mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusts pH with 10% sodium bicarbonate solution
6.0~6.5, silica gel 30g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 58.1%, HPLC inspection
Folic acid purity 99.4%, Impurity A content 0.31% are surveyed, impurity D content is 0.18%, different folate content 0.05%.
Comparative example 1
Acid treating:
(detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D contain 360g folic acid crude product
Amount 6.4%, different folate content 5.8%) it is added in 30% sulfuric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains sour processing wet product 451g.
Alkali refining:
7200mL purified water is added in acid processing wet product, 30min is stirred at room temperature, adjusts pH 6.0 with 10% sodium carbonate liquor
~6.5, active carbon 30g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 53.5%, HPLC inspection
Folic acid purity 98.7%, Impurity A content 0.23% are surveyed, impurity D content is 0.15%, and different folate content is 0.61%.
Comparative example 2
Acid treating:
(1) 150g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 30% sulfuric acid of 1000mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 1200mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product.
(2) primary acids item for disposal is then added in 30% sulfuric acid of 1000mL, and stirring stirs 30min after being warming up to 50 DEG C,
Purified water 1200mL is added, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product.
(3) second level acid item for disposal is added in 30% sulfuric acid of 1000mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 1200mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains three-level acid processing wet product.
Alkali refining:
Three-level acid, which is handled, is added 4000mL purified water in wet product, 30min is stirred at room temperature, and adjusting pH with 10% ammonium hydroxide is 8.0,
Active carbon 10g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% acetic acid solution, then heats to 80 DEG C, stirs 30min, drop
Temperature filters after standing 30min to 65~70 DEG C, obtains folic acid finished product, 80 DEG C of drying obtain product.Yield 51.5%, HPLC detection
Folic acid purity 98.3%, Impurity A content 0.14%, impurity D content are 0.47%, and different folate content is 0.23%.
Comparative example 3
Acid treating:
(1) 300g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 55% sulfuric acid of 960mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product.
(2) primary acids item for disposal is then added in 55% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 720mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product.
(3) second level acid item for disposal is added in 55% sulfuric acid of 960mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Purified water 720mL keeps the temperature 50 DEG C, and mashing stirring 1 hour, filtering obtains three-level acid processing wet product.
Alkali refining:
2000mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusts pH with 10% sodium carbonate liquor
6.0~6.5, active carbon 5g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
Alkali refining filtrate is adjusted into pH 3.0~3.5 with 5% dilution heat of sulfuric acid, 80 DEG C is then heated to, stirs 30min,
65~70 DEG C are cooled to, is filtered after standing 30min, obtains folic acid finished product, 50 DEG C of drying obtain product.Yield 31.7%, HPLC inspection
Folic acid purity 98.1%, Impurity A content 0.48% are surveyed, impurity D content is 0.35%, and different folate content is 0.08%.
Comparative example 4
Acid treating:
(1) 150g folic acid crude product (detection of pharmacopeia HPLC method, folic acid purity 85.17%, Impurity A content 3.6%, impurity D
Content 6.4%, different folate content 5.8%) it is added in 30% sulfuric acid of 1000mL, stirring stirs 30min after being warming up to 50 DEG C, adds
Enter purified water 500mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains primary acids processing wet product.
(2) primary acids item for disposal is then added in 30% sulfuric acid of 1000mL, and stirring stirs 30min after being warming up to 50 DEG C,
Purified water 500mL is added, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains second level acid processing wet product.
(3) second level acid item for disposal is added in 30% sulfuric acid of 1000mL, and stirring stirs 30min after being warming up to 50 DEG C, is added
Enter purified water 500mL, keeps the temperature 50 DEG C, mashing stirring 1 hour, filtering obtains three-level acid processing wet product.
Alkali refining:
2000mL purified water is added in three-level acid item for disposal, 30min is stirred at room temperature, adjusting pH with 20% sodium carbonate liquor is
9.0, zeolite molecular sieve 50g is added, stirs 30min, filtering obtains alkali refining filtrate.
Adjust acid crystal:
It is 4.0 that alkali refining filtrate, which is adjusted pH with 10% dilution heat of sulfuric acid, then heats to 80 DEG C, stirs 30min, cooling
To 65~70 DEG C, is filtered after standing 30min, obtain folic acid finished product, 50 DEG C of drying obtain product.Yield 50.7%, HPLC detect leaf
Sour purity 97.9%, Impurity A content 0.44%, impurity D content are 1.11%, and different folate content is 0.05%.
In conclusion compared with traditional folic acid purification process (comparative example 1~4), using the pure of folic acid of the present invention
Change method (Examples 1 to 5) effectively reduces the content of impurity A, impurity D and different folic acid, improves the yield of folic acid finished product
And purity.
Claims (10)
1. a kind of purification process of folic acid characterized by comprising
S1 folic acid crude product is mixed with the first acid solution), after heating stirring, water is added, continues heating stirring, filtering obtains one
The sour item for disposal of grade；
S2 the primary acids item for disposal is mixed with the second acid solution), after heating stirring, water is added, continues heating stirring, mistake
Filter, obtains second level acid item for disposal；
S3 the second level acid item for disposal is mixed with third acid solution), after heating stirring, water is added, continues heating stirring, mistake
Filter, obtains three-level acid item for disposal；
S4 the three-level acid item for disposal is mixed with water), pH value is adjusted with alkali and is filtered after adsorbent processing is added to faintly acid,
Obtain filtrate；
S5 the filtrate) is obtained into folic acid after adjusting acid crystal.
2. purification process according to claim 1, which is characterized in that first acid solution, the second acid solution and third
Acid solution is each independently selected from hydrochloric acid and/or sulfuric acid；The mass concentration of the hydrochloric acid is 5%~35%；The matter of the sulfuric acid
Measuring concentration is 10%~50%.
3. purification process according to claim 1, which is characterized in that the step S1) in heating stirring temperature be 40
DEG C~60 DEG C；The time of heating stirring is 10~60min；The temperature for continuing heating stirring is 45 DEG C~55 DEG C；Continue heating to stir
The time mixed is 50~70min；
The step S2) in heating stirring temperature be 45 DEG C~50 DEG C；The time of heating stirring is 25~35min；Continue to add
The temperature of thermal agitation is 45 DEG C~50 DEG C；The time for continuing heating stirring is 50~70min；
The step S3) in heating stirring temperature be 45 DEG C~50 DEG C；The time of heating stirring is 25~35min；Continue to add
The temperature of thermal agitation is 45 DEG C~55 DEG C；The time for continuing heating stirring is 50~70min.
4. purification process according to claim 1, which is characterized in that the mass body of the folic acid crude product and the first acid solution
Product is than being (1~4) g:8ml；The mass volume ratio of the folic acid crude product and the second acid solution is (1~4) g:8ml；The folic acid
The mass volume ratio of crude product and third acid solution is (1~4) g:8ml.
5. purification process according to claim 1, which is characterized in that the step S1) folic acid crude product and be added water matter
Amount volume ratio is (2~6) g:8ml；The mass volume ratio of water is added as (2~6) g:8ml in the folic acid crude product and step S2)；
The mass volume ratio of water is added as (2~6) g:8ml in the folic acid crude product and step S3).
6. purification process according to claim 1, which is characterized in that the step S4) in alkali be selected from sodium carbonate, bicarbonate
One of sodium, sodium hydroxide and potassium hydroxide are a variety of；The adsorbent is selected from one of active carbon, diatomite and silica gel
Or it is a variety of.
7. purification process according to claim 1, which is characterized in that the step S4) in alkali adjust pH value to 6.0~
6.5。
8. purification process according to claim 1, which is characterized in that the mass volume ratio of the three-level acid item for disposal and water
For (0.5~2.5) g:30ml；The mass ratio of the adsorbent and three-level acid item for disposal is (0.5~2.5): 10.
9. purification process according to claim 1, which is characterized in that the step S5) specifically:
The filtrate is adjusted into pH value to 2~4 with the 4th acid solution, under stirring conditions, is warming up to 50 DEG C~90 DEG C, heat preservation
20~40min is cooled to 50 DEG C~80 DEG C, filters after 20~40min, obtain folic acid.
10. purification process according to claim 9, which is characterized in that the 4th acid solution is the sulfuric acid of 3~10wt%
Solution.
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