CN107312004B - A kind of production method of folic acid - Google Patents
A kind of production method of folic acid Download PDFInfo
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- CN107312004B CN107312004B CN201710447629.4A CN201710447629A CN107312004B CN 107312004 B CN107312004 B CN 107312004B CN 201710447629 A CN201710447629 A CN 201710447629A CN 107312004 B CN107312004 B CN 107312004B
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- 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
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Abstract
The present invention relates to a kind of production methods of folic acid, this method in turn includes the following steps: crude product synthesis step: 2 shown in compound B in N- shown in compound A in Formulas I (p-benzoyl)-Pidolidone, Formulas I, 4, trichloroacetone shown in compound C is raw material in 5- triamido -6- hydroxy pyrimidine sulfate and Formulas I, using sodium pyrosulfite as antioxidant, it takes water as a solvent, gradation cyclization reaction is carried out by the way of feeding in batches, obtains reaction solution；The reaction solution obtains folic acid crude product through cooling, filters pressing；Folic acid crude product obtains folic acid finished product through the molten step of acid, alkali soluble step, purification step.Production method of the invention keeps the concentration of material in reaction solution in the reasonable scope, so that discharge reduction needed for making folic acid crude product synthesis phase is to the 1/4 of existing synthesis technology institute water requirement.
Description
Technical field
The invention belongs to medical material production fields, relate generally to a kind of production method of folic acid.
Background technique
Folic acid (C19H19N7O6), it is also Vitamin B9, is a kind of water soluble vitamin, is Antianemic Agents, is applied to feed
The fields such as medicine and food.Folic acid is usually a kind of greenish orange yellow crystal or thin slice, and about 250 DEG C of carbonizations are dimmed, are soluble in second
Alcohol, alkali carbonate solution etc..
Because of the rich content in plant greenery so being named as folic acid.It is most abundant containing folic acid with liver in animal tissue.
Originally it is to be extracted from liver, mostly uses synthetic method to produce now.More commonly used folic acid production technology includes three phases: thick
Product synthesis, the molten purification of acid and alkali soluble purification.Wherein, crude product synthesis is using N- (4- aminobenzoyl)-Pidolidone, trichlorine third
Ketone and 2,4,5-triamino-6-hydroxypyrimidine sulfate are reacted in crude product reactor tank, control certain reaction temperature and reaction
The pH value of feed liquid makes three kinds of materials that annulation occur and obtains folic acid crude product；Folic acid crude product is through the molten purification of acid and alkali soluble refining pure
Change obtains folic acid sterling.In above-mentioned production technology, folic acid crude product synthesis phase institute water requirement is extremely more, and thus the stage generates
Wastewater flow rate is also very big, such as 1 ton of folic acid crude product of production, probably will use 12 tons of water, generates about 13-15 tons of waste water, important
That these waste water are unable to direct emission, also can not recovery, problems demand solve.
Two patents of Publication No. CN101323614 and CN101973995 provide mixed using resin and Compositional type respectively
Solidifying destaining gel handles the waste water of each process section, achievees the purpose that recycle.But two methods not only production cost
High, complex process, and all cannot fundamentally reduce the generation of waste water.
Summary of the invention
In order to reduce the generation of waste water in folic acid production technology from the root, production cost is saved, simplifies production technology, originally
Invention provides a kind of production method of folic acid.Production method of the invention is fed in batches by using in folic acid crude product synthesis phase
Mode make material in reaction solution concentration keep in the reasonable scope, to reduce the water consumption of crude product synthesis phase.The present invention
Production method not only make the water consumption of folic acid crude product synthesis phase be reduced to existing production technology water consumption 1/4, and do not have
There is the production technology for making folic acid to complicate or increase cost.
To achieve the above object, the invention adopts the following technical scheme:
A kind of production method of folic acid, in turn includes the following steps:
Crude product synthesis step: with chemical combination in N- shown in compound A in Formulas I (p-benzoyl)-Pidolidone, Formulas I
Trichloroacetone shown in compound C is raw material in 2,4,5-triamino-6-hydroxypyrimidine sulfate shown in object B and Formulas I, with coke
Sodium sulfite is antioxidant, is taken water as a solvent, and carries out gradation cyclization reaction using in batches plus by the way of material, is reacted
Liquid, the cyclization reaction are shown in formula I；The reaction solution obtains folic acid crude product through cooling, filters pressing；
The molten step of acid: the folic acid crude product obtains sour extract through acid dissolution, elutriation, filters pressing；
Alkali soluble step: the acid extract obtains clear alkali soluble filter through water-soluble, lye pH adjustment value, active carbon decoloring, filters pressing
Liquid；
Purification step: the clear alkali soluble filtrate is precipitated through heating, acid solution tune pH value, cooling, material, material washs,
Centrifugation and drying obtain folic acid finished product shown in compound D in Formulas I；
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, it is described in batches
Add the mode of material to refer to be added to the compound A, compound B and compound C, antioxidant in aqueous solvent in batches,
And compound A, compound B and compound C and antioxidant are added in each batch.
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, each batch is added
The raw material mole magnitude relation it is as follows: compound A: compound B: compound C=1:(1-2): (1.1-3) (such as: chemical combination
Object A: compound B: compound C=1:1:1.1；Compound A: compound B: compound C=1:1:1.5；Compound A: compound
B: compound C=1:1:2；Compound A: compound B: compound C=1:1:2.5；Compound A: compound B: compound C=1:
1:2.8；Compound A: compound B: compound C=1:1.5:1.5；Compound A: compound B: compound C=1:1.5:2.5).
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, each batch is added
The compound A and the antioxidant mole ratio be 1:(0.1-0.8).
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, each batch is added
The sum of the mole of the compound A and the solvent volume ratio be 0.08-0.28mol/L (such as 0.09mol/L,
0.10mol/L、0.12mol/L、0.15mol/L、0.18mol/L、0.20mol/L、0.22mol/L、0.25mol/L、
0.27mol/L)。
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, the cyclization is anti-
The temperature answered is 25 DEG C -45 DEG C (such as 26 DEG C, 28 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 42 DEG C, 44 DEG C)；Each cyclization reaction
Total time be 4-9h (such as 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h), each cyclization reaction it is total
Time is the summation in the reaction time for the raw material that each batch is added, i.e., the sum of the time of each secondary cyclization reaction.
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, the compound
C is trichloroacetone crystallization, purity 88-95%.
In aforementioned production method, as a preferred implementation manner, in the crude product synthesis step, it is described in batches
Adding material is secondary in two batches plus material or secondary in three batches plus material；It is described to add material to be more preferably secondary in two batches plus object in batches
Material.
It is highly preferred that described secondary in two batches plus material mode are as follows:
First batch: be added 0.5-0.7 (such as 0.51,0.52,0.54,0.56,0.58,0.60,0.62,0.64,
0.66,0.68,0.69) × integral molar quantity compound A, 0.5-0.7 (such as 0.51,0.52,0.54,0.56,0.58,0.60,
0.62,0.64,0.66,0.68,0.69) × integral molar quantity compound B, 0.5-0.7 (such as 0.51,0.52,0.54,0.56,
0.58,0.60,0.62,0.64,0.66,0.68,0.69) × integral molar quantity compound C and 0.5-0.7 (such as 0.51,
0.52,0.54,0.56,0.58,0.60,0.62,0.64,0.66,0.68,0.69) × integral molar quantity sodium pyrosulfite；
Second lot: the remaining compound A, compound B, compound C and sodium pyrosulfite is added.
It is highly preferred that the concentration for working as compound A described in the reaction system that the first batch material is formed is decreased to institute
State first batch material formation reaction system in compound A initial concentration 1/3-1/5 (such as 0.32,0.31,0.30,
0.28, when 0.25,0.22,0.21) (at this point, the pH variation of reaction system is also smaller), it is initially added into remaining second batch object
Material.
It is further preferred that the compound A, compound B, compound C and the sodium pyrosulfite that are added in first batch
Amount and second lot in the amount of corresponding material that is added it is identical.
In aforementioned production method, as a preferred implementation manner, when the material secondary addition in two batches, described point
Secondary cyclization reaction specifically:, will be described under 25 DEG C -45 DEG C (such as 26 DEG C, 28 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 42 DEG C, 44 DEG C)
First batch material is added the solvent and mixes to form the first reaction system, then uses 10wt% aqueous sodium carbonate tune institute
State the first pH value of reaction system and control first reaction system pH be maintained at 3.0-3.5 (such as 3.1,3.2,3.3,
3.4) between, the concentration of the compound A described in first reaction system is decreased to compound A in first reaction system
Initial concentration 1/3-1/5 (such as 0.32,0.31,0.30,0.28,0.25,0.22,0.21) when (at this point, reaction system
PH variation it is also smaller), be initially added into remaining second batch materials and be uniformly mixed to form the second reaction system, then proceed to
Using 10wt% aqueous sodium carbonate adjust the pH value of second reaction system to 3.0-3.5 (such as 3.1,3.2,3.3,
3.4), later under conditions of keeping the pH value of second reaction system in 3.0-3.5 (such as 3.1,3.2,3.3,3.4) after
Continuous reaction 5-8h (such as 5.5h, 6h, 6.5h, 7h, 7.5h, 7.8h).The first batch material before second lot material is added
Reaction time experienced is 40-70min；Before second lot material is added, the first batch material is experienced anti-
It is to be added dropwise to count since 10wt% aqueous sodium carbonate between seasonable, until compound A's described in first reaction system is dense
Degree is decreased to terminate when the 1/3-1/5 of the initial concentration of compound A in first reaction system, and compound A is in reaction process
In concentration variation can according to LC-MS detect result be determined: the first reaction system is repeatedly sampled, according to
The testing result of LC-MS determines the appearance time and integral area of compound A；The opportunity of first sub-sampling is that sodium carbonate is added dropwise
Before solution；Then the first reaction system is repeatedly sampled with the dropwise addition of aqueous sodium carbonate, until sample detection knot
Fruit shows that the integral area of compound A is the 1/3-1/5 of the first sub-sampling sample compound A integral area.
In aforementioned production method, as a preferred implementation manner, when the material secondary addition in three batches, described point
Secondary cyclization reaction specifically:, will be described under 25 DEG C -45 DEG C (such as 26 DEG C, 28 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 42 DEG C, 44 DEG C)
First batch material is added the solvent and mixes to form the first reaction system, then uses 10wt% aqueous sodium carbonate tune institute
State the first pH value of reaction system and control first reaction system pH be maintained at 3.0-3.5 (such as 3.1,3.2,3.3,
3.4) between, the concentration of the compound A described in first reaction system is decreased to compound A in first reaction system
Initial concentration 1/3-1/5 (such as 0.32,0.31,0.30,0.28,0.25,0.22,0.21) when (at this point, reaction system
PH variation it is also smaller), be initially added into the second batch materials and be uniformly mixed to form the second reaction system, then proceed to use
10wt% aqueous sodium carbonate adjusts the pH value of second reaction system to 3.0-3.5 (such as 3.1,3.2,3.3,3.4) simultaneously
Keep the pH value of second reaction system to 3.0-3.5, the concentration of the compound A described in second reaction system reduces
To the initial concentration of compound A in second reaction system 1/3-1/5 (such as 0.32,0.31,0.30,0.28,0.25,
0.22, when, 0.21) (at this point, the pH variation of reaction system is also smaller), third batch materials is initially added into and are uniformly mixed to be formed
Third reaction system then proceedes to the pH value for using 10wt% aqueous sodium carbonate to adjust the third reaction system to 3.0-
3.5 (such as 3.1,3.2,3.3,3.4), later keep the pH value of the third reaction system 3.0-3.5 (such as 3.1,
3.2,3.3,3.4) under conditions of the reaction was continued 5-8h (such as 5.5h, 6h, 6.5h, 7h, 7.5h, 7.8h).Second batch is being added
The first batch material reaction time experienced is 40-70min before secondary material；It is described before second lot material is added
The first batch material reaction time experienced is to be added dropwise to count since 10wt% aqueous sodium carbonate, until first reaction
The concentration of compound A described in system is decreased to knot when the 1/3-1/5 of the initial concentration of compound A in first reaction system
Beam.Before third batches are added, the second lot material reaction time experienced is 40-70min；Third batch is being added
Before secondary material, the second lot material reaction time experienced is to be added dropwise to calculate since 10wt% aqueous sodium carbonate
It rises, until the concentration of compound A described in second reaction system is decreased to the initial of compound A in second reaction system
Terminate when the 1/3-1/5 of concentration.The result that the concentration variation of compound A during the reaction can be detected according to LC-MS carries out
It determines, such as: it determines that the concentration variation of compound A in the first reaction system can carry out as follows: reacting first
System is repeatedly sampled, and the appearance time and integral area of compound A are determined according to the testing result of LC-MS；It takes for the first time
The opportunity of sample is before aqueous sodium carbonate is added dropwise；Then the first reaction system is carried out with the dropwise addition of aqueous sodium carbonate more
Sub-sampling, until the integral area of sample detection compound A as the result is shown is the first sub-sampling sample compound A integral area
1/3-1/5.Determine that the concentration variation of compound A in the second reaction system can carry out as follows: to the second reactant
System is repeatedly sampled, and the appearance time and integral area of compound A are determined according to the testing result of LC-MS；First sub-sampling
Opportunity be added dropwise aqueous sodium carbonate before；Then the second reaction system is carried out with the dropwise addition of aqueous sodium carbonate multiple
Sampling, until sample detection as the result is shown compound A integral area be the first sub-sampling sample compound A integral area 1/
3-1/5。
Inventor is according to long-term experiment empirical discovery, when using material is added in batches, controls in addition to first batch
Other batches the addition time it is particularly important, the concentration of the compound A described in each secondary response system is decreased to this time
When being initially added into next batch material when the 1/3-1/5 of compound A initial concentration in reaction system, compound A's is converted into leaf
The conversion ratio highest of acid, the yield of crude product folic acid also highest, while water consumption has also been saved from source.
In aforementioned production method, as a preferred implementation manner, in the molten step of acid, using 30-38wt%
Aqueous sulfuric acid carries out the acid dissolution.
In aforementioned production method, as a preferred implementation manner, in the alkali soluble step: at 90-100 DEG C (91
DEG C, 92 DEG C, 94 DEG C, 96 DEG C, 98 DEG C, 99 DEG C) with 10-30wt% sodium hydroxide solution tune pH value to 9.0-9.5 (such as 9.1,
9.2、9.3、9.4)。
In aforementioned production method, as a preferred implementation manner, in the purification step, the clear alkali soluble
Filtrate is warming up to 98 ± 2 DEG C (such as 96 DEG C, 97 DEG C, 98 DEG C, 99 DEG C, 100 DEG C), with CP hydrochloric acid tune pH value to 3.0-3.5 (such as
3.1,55 ± 2 DEG C (such as 53 DEG C, 54 DEG C, 55 DEG C, 56 DEG C, 57 DEG C) then 3.2,3.3,3.4), are cooled to.
In aforementioned production method, as a preferred implementation manner, in the purification step, the material washing is
It is washed to pH=6-7 (such as 6.1,6.2,6.4,6.6,6.8,6.9).
Compared with prior art, technical effect of the invention is as follows:
Acidum folicum production method of the invention makes the concentration of material in reaction solution be maintained at reasonable by the way of being fed in batches
In range, so that discharge reduction needed for making folic acid crude product synthesis phase is to the 1/4 of existing synthesis technology institute water requirement；The present invention adopts
It reduces the generation of waste water in folic acid production technology from the root with the mode of fed batch, reduces wastewater discharge, be at sewage
Reason system eases off the pressure, and has saved production cost, to improve productivity effect.
Specific embodiment
Combined with specific embodiments below, a kind of production method of folic acid of the invention is further described.It should be understood that
These embodiments are only used for the present invention rather than limit the scope of the invention.Externally it should be understood that reading in of the invention
After appearance, those skilled in the art make various changes or modifications the present invention, and such equivalent forms are equally fallen within appended by the application
Claims limited range.
Embodiment 1
For the present embodiment in crude product synthesis step, the total dosage relation of material is as follows:
N- (p-benzoyl)-Pidolidone: 26.6kg；
2,4,5- triamido -6- hydroxy pyrimidine sulfate: 23.9kg；
Trichloroacetone crystallizes (purity 92%): 25.6kg；
Sodium pyrosulfite: 9.5kg；
Water 700L；
Wherein, molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxyls
Pyrimidine sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:1:1.6:0.5；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.14mol/L；
Material N- (p-benzoyl)-Pidolidone, 2,4,5- triamido -6- hydroxy pyrimidine sulfate, trichloroacetone
By secondary addition in two batches, the 1/2 of corresponding material total amount is added in first batch for crystallization and sodium pyrosulfite, and second lot is added surplus
Excess material.
The following detailed description of the preparation method of the present embodiment folic acid:
1) crude product synthesis step:
First batch N- (4- aminobenzoyl)-Pidolidone 13.3kg is added in 700L water, after stirring 15 minutes
First batch 2,4,5-triamino-6-hydroxypyrimidine sulfate 11.95kg is added, it is burnt sub- to stir 15 minutes addition first batchs
Sodium sulphate 4.75kg, stirring add first batch trichloroacetone crystallization 12.8kg and are stirred after so that material is evenly distributed
It is even, keep system temperature at 32-35 DEG C when material is added, above-mentioned charging process lasts about 45min altogether；Then 10wt% carbonic acid is used
Sodium solution adjusts pH value between 3.0-3.5, and controls reaction system pH during the reaction between 3.0-3.5, LC-MS
Above-mentioned system is detected, when the concentration of N- (4- aminobenzoyl)-Pidolidone drops to the 1/4 of initial concentration, is lasted
40min；Then remaining N- (4- aminobenzoyl)-Pidolidone is sequentially added according to the Adding Way of first batch material
13.3kg, 2,4,5-triamino-6-hydroxypyrimidine sulfate 11.95kg and sodium pyrosulfite 1.9kg, add after mixing evenly
Remaining trichloroacetone crystallizes 12.8kg, continues to adjust pH to 3.5 with the sodium carbonate liquor of 10wt% after mixing evenly, last
45min, then at 35 DEG C and under conditions of the pH of guarantee reaction system is 3.5, the reaction was continued 6 hours, and LC-MS detects N- (4- ammonia
Base benzoyl)-Pidolidone conversion ratio be 92%.It is then turned on cooling water valve goalkeeper's reaction solution and is cooled to 20-25 DEG C, pass through
Sheet frame carries out filters pressing, and filter cake is folic acid crude product (wet product 120kg), for the molten use of lower workshop section's acid.The waste liquid generated after filters pressing can
To carry out decolorization adsorption processing, utilized for following cycle；It can also be discharged into sewage disposal system, leaf is synthesized using the above method
1 ton of acid crude, only generate 7-8 tons of waste water.
2) the molten step of acid:
(amount of aqueous sulfuric acid is added with folic acid crude product in the aqueous sulfuric acid that 35wt% is added into 1/3 folic acid crude product
All until dissolution), remaining folic acid crude product is added, after stirring 3-5 minutes, Sufficient purified water is added and (purified water is added
Volume is about 6 times of aqueous sulfuric acid), it stirs 3-5 minutes, after standing 1 hour, solid is precipitated, above-mentioned system is pressed into plate
Frame, filter cake are sour extract.The waste liquid generated after filters pressing enters the absorption of bleacher carbon decoloring, logical ammonia neutralizes, and then enters back into
The molten elutriation of acid, which fills, is used as process water；As the concentration 20%-25%kg/m of the ammonium sulfate in the waste water in bleacher3Afterwards, to waste water
Evaporation and concentration obtains ammonium sulfate.
3) alkali soluble step:
The sour extract that step 2) is obtained is added in 90 ± 2 DEG C of purified water that (every 60-90kg acid extract needs 2500L
Purified water), PH to 9.0-9.5 then is adjusted with the sodium hydrate aqueous solution of 15wt%, continues to be heated to 98 ± 2 DEG C, 10 minutes
Repetition measurement afterwards, pH value are stablized between 9.0-9.5, and active carbon decoloring is added, and then stir 1 hour for 98 ± 2 DEG C, by above-mentioned alkali soluble
Liquid carries out filters pressing, and primary filtrate returns in alkali soluble reactor tank, then carries out filters pressing until filtrate clarification, is refined into salt for clear be transferred to
In pot；The complete backward alkali soluble reactor tank of filters pressing adds 200kg purified water, is heated to 90-95 DEG C, cleans the sheet frame of filters pressing, washing lotion
Indentation is refined into salt pan together.
4) purification step:
Unlatching is refined into salt pan stirring, and alkali soluble filtrate is heated separately to 98 ± 2 DEG C, the C.P of mass concentration 10% is added dropwise
Dilute hydrochloric acid, until material liquid pH value is 3.0-3.5 in pot, then repetition measurement after ten minutes cools down until pH value is between 3.0-3.5
To 55 ± 2 DEG C, after material precipitation, material is put into quiet filter tank and is filtered, then with washings material is purified, until with examination extensively
Until paper detects PH=6-7；After having washed, material is transferred in centrifuge and dries, and obtains filter cake, and filter cake is folic acid finished product；
Filtrate enters resin treatment tank decolorization adsorption, and waste liquid enters alkali soluble reactor tank and uses as process water after decolorization adsorption.
Folic acid finished product 30.2kg, purity 99%, yield 69%, the present embodiment middle period acid crude are obtained in the present embodiment
Synthesis step water consumption is the 45% of prior art water consumption.
Embodiment 2
For the present embodiment in crude product synthesis step, material relationships are as follows:
Molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxy pyrimidine
Sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:1.3:2:0.5；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.1mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, 2,4,5-triamino-6-hydroxypyrimidine sulfate and coke
For three kinds of materials of sodium sulfite by secondary addition in two batches, first batch adds the 2/3 of corresponding material total amount, and second lot is added remaining
Material.
First batch material uses 10wt% sodium carbonate liquor to adjust pH value between 3.0-3.5 after being added, and is reacting
Reaction system pH is controlled in journey between 3.0-3.5, LC-MS detects above-mentioned system, when N- (4- aminobenzoyl)-L- paddy ammonia
The second batch materials are added when dropping to the 1/3 of initial concentration in the concentration of acid, last 45min.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
The molten step of acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 1.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 3
For the present embodiment in crude product synthesis step, material relationships are as follows:
Molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxy pyrimidine
Sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:2:3:0.8；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.08mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, 2,4,5-triamino-6-hydroxypyrimidine sulfate and coke
For three kinds of materials of sodium sulfite by secondary addition in three batches, the 1/2 of corresponding material total amount is added in first batch, and second lot is added surplus
Surplus material is added in the 1/2 of excess material, third batch.
35 DEG C of first batch reaction temperature, first batch material be added after with 10wt% sodium carbonate liquor adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The second batch materials are added when dropping to the 1/5 of initial concentration in the concentration of N- (4- aminobenzoyl)-Pidolidone, last 55min；
35 DEG C of second lot reaction temperature, second lot material be added after with 10wt% sodium carbonate liquor adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyl)-Pidolidone drops to N- (4- aminobenzoyl)-L- paddy when second lot material is added
The initial concentration of propylhomoserin 1/4 when be added third batch materials, last 50min；
Third batch adjusts pH value between 3.0-3.5, in 35 DEG C and pH value of reaction system with 10wt% sodium carbonate liquor
Under conditions of between 3.0-3.5, the reaction was continued 5h.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
The molten step of acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 1.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 4
For the present embodiment in crude product synthesis step, material relationships are as follows:
Molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxy pyrimidine
Sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:1.7:2.2:0.6；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.25mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, 2,4,5-triamino-6-hydroxypyrimidine sulfate and coke
The 1/3 of corresponding material total amount, second lot and first is added by secondary addition in three batches, first batch in three kinds of materials of sodium sulfite
Batch additional amount is identical, and surplus material is added in third batch.
35 DEG C of first batch reaction temperature, first batch material be added after with 10wt% sodium carbonate liquor adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The second batch materials are added when dropping to the 1/5 of initial concentration in the concentration of N- (4- aminobenzoyl)-Pidolidone, last 70min；
35 DEG C of second lot reaction temperature, second lot material be added after with 10wt% sodium carbonate liquor adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyl)-Pidolidone drops to N- (4- aminobenzoyl)-L- paddy when second lot material is added
The initial concentration of propylhomoserin 1/3 when be added third batch materials, last 60min；
Third batch adjusts pH value between 3.0-3.5, in 35 DEG C and pH value of reaction system with 10wt% sodium carbonate liquor
Under conditions of between 3.0-3.5, the reaction was continued 6.5h.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
The molten step of acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 1.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 5
In the present embodiment, in addition to the addition opportunity of second lot material is different from embodiment 1, the present embodiment crude product is closed
It is same as Example 1 at step, the molten step of acid, alkali soluble step and purification step concrete operations and other parameters.In the present embodiment
The second batch materials are added when the concentration of N- (4- aminobenzoyl)-Pidolidone drops to the 1/8 of initial concentration, first object
The reaction time of material is 150min.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
In the present embodiment, the time reacted due to extending first batch, side reaction is caused to increase, the decline of folic acid yield.
Embodiment 6
For the present embodiment in crude product synthesis step, material relationships are as follows:
Molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxy pyrimidine
Sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:2.5:3.5:1；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.5mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, 2,4,5-triamino-6-hydroxypyrimidine sulfate and coke
For three kinds of materials of sodium sulfite by secondary addition in two batches, first batch adds the 1/2 of corresponding material total amount, and second lot is added remaining
Amount.In the present embodiment, second is added when the concentration of N- (4- aminobenzoyl)-Pidolidone drops to the 1/4 of initial concentration
Batch materials last 120min.
Except the addition opportunity of above-mentioned second batch materials be different from embodiment 1 in addition to, in this implementation crude product synthesis step its
He operates and parameter is same as Example 1.
The molten step of acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 1 in the present embodiment.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 7
The present embodiment one batch of material in embodiment 1 is added, 35 DEG C of reaction temperature, always in crude product synthesis step
Reaction time 7h20min (reaction time refers to the time terminated from being added aqueous sodium carbonate to reaction).
The other parameters of the present embodiment crude product synthesis step are same as Example 1.
The molten step of the present embodiment acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 1.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Comparative example
Comparative example is prior art, and in crude product synthesis step, material relationships are as follows:
Molar ratio of material relationship is as follows: N- (p-benzoyl)-Pidolidone: 2,4,5- triamido -6- hydroxy pyrimidine
Sulfate: trichloroacetone crystallization: sodium pyrosulfite=1:1:1.3:0.2；
The volume ratio of N- (p-benzoyl)-Pidolidone integral molar quantity and water is 0.06mol/L；
Comparative example crude product synthesis step concrete operations and other parameters are same as Example 7.
The molten step of comparative example acid, the concrete operations of alkali soluble step and purification step and other parameters are the same as embodiment 7.
N- (p-benzoyl)-Pidolidone conversion ratio, folic acid yield and purity, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Table 1 compares folic acid yield etc. under different technical parameters
Claims (11)
1. a kind of production method of folic acid, which is characterized in that in turn include the following steps:
Crude product synthesis step: with compound B institute in N- shown in compound A in Formulas I (p-benzoyl)-Pidolidone, Formulas I
Trichloroacetone shown in compound C is raw material in the 2,4,5-triamino-6-hydroxypyrimidine sulfate and Formulas I shown, with burnt sulfurous
Sour sodium is antioxidant, is taken water as a solvent, and carries out gradation cyclization reaction using in batches plus by the way of material, obtains reaction solution,
The cyclization reaction is shown in formula I；The reaction solution obtains folic acid crude product through cooling, filters pressing；
The molten step of acid: the folic acid crude product obtains sour extract through acid dissolution, elutriation, filters pressing；
Alkali soluble step: the acid extract obtains clear alkali soluble filtrate through water-soluble, lye pH adjustment value, active carbon decoloring, filters pressing；
Purification step: the clear alkali soluble filtrate is precipitated through heating, acid solution tune pH value, cooling, material, material washing, is centrifuged
Folic acid finished product shown in compound D in Formulas I is obtained with drying；
It is described to add the mode of material to refer to the compound A, compound B and change in batches in the crude product synthesis step
Object C, antioxidant is closed to be added in aqueous solvent in batches, and be added in each batch compound A, compound B and compound C and
Antioxidant；Mole magnitude relation for the raw material that each batch is added is as follows: compound A: compound B: compound C=1:
(1-2): (1.1-3)；The mole ratio of the compound A and the antioxidant that each batch is added are 1:(0.1-0.8)；Institute
Compound C is stated as trichloroacetone crystallization, purity 88-95%；
In the crude product synthesis step, volume of the sum of the mole of the compound A that each batch is added with the solvent
Ratio is 0.08-0.28mol/L；
In the crude product synthesis step, the temperature of the cyclization reaction is 25 DEG C -45 DEG C；Each cyclization reaction it is total when
Between be 4-9h, total time of each cyclization reaction is the summation in the reaction time of the raw material of each batch addition.
2. the production method of folic acid according to claim 1, which is characterized in that described in the crude product synthesis step
In batches plus material is secondary in two batches plus material or secondary in three batches plus material.
3. the production method of folic acid according to claim 2, which is characterized in that described that material is added to be secondary in two batches in batches
Add material；
Described secondary in two batches plus material mode are as follows:
First batch: 0.5-0.7 × integral molar quantity compound A, 0.5-0.7 × integral molar quantity compound B, 0.5- is added
The compound C and 0.5-0.7 × integral molar quantity sodium pyrosulfite of 0.7 × integral molar quantity；
Second lot: the remaining compound A, compound B, compound C and sodium pyrosulfite is added.
4. the production method of folic acid according to claim 3, which is characterized in that when the first batch material formed it is anti-
The concentration of compound A described in system is answered to be decreased to the compound A in the reaction system that the first batch material is formed
Initial concentration 1/3-1/5 when, be initially added into remaining second batch materials.
5. the production method of folic acid according to claim 4, which is characterized in that the compound being added in first batch
A, the amount for the corresponding material being added in the amount to second lot of compound B, compound C and sodium pyrosulfite is identical.
6. the production method of folic acid according to claim 1, which is characterized in that when the material secondary addition in two batches,
The gradation cyclization reaction specifically: at 25 DEG C -45 DEG C, the first batch material is added the solvent and is mixed to be formed
Then first reaction system uses the first pH value of reaction system described in 10wt% aqueous sodium carbonate tune and controls described first instead
The pH of system is answered to be maintained between 3.0-3.5, the concentration of the compound A described in first reaction system is decreased to described
In one reaction system when the 1/3-1/5 of the initial concentration of compound A, be initially added into remaining second batch materials and be uniformly mixed with
Form the second reaction system, then proceed to adjust using 10wt% aqueous sodium carbonate the pH value of second reaction system to
3.0-3.5, the reaction was continued under conditions of keeping the pH value of second reaction system in 3.0-3.5 later 5-8h.
7. the production method of folic acid according to claim 1, which is characterized in that when the material secondary addition in three batches,
The gradation cyclization reaction specifically: at 25 DEG C -45 DEG C, the first batch material is added the solvent and is mixed to be formed
Then first reaction system uses the first pH value of reaction system described in 10wt% aqueous sodium carbonate tune and controls described first instead
The pH of system is answered to be maintained between 3.0-3.5, the concentration of the compound A described in first reaction system is decreased to described
In one reaction system when the 1/3-1/5 of the initial concentration of compound A, it is initially added into the second batch materials and is uniformly mixed to form the
Two reaction systems then proceed to the pH value for using 10wt% aqueous sodium carbonate to adjust second reaction system to 3.0-3.5
And keeping the pH value of second reaction system to 3.0-3.5, the concentration of the compound A described in second reaction system subtracts
In as low as described second reaction system when 1/3-1/5 of the initial concentration of compound A, it is initially added into third batch materials and mixes equal
It is even to form third reaction system, then proceed to adjust the pH value of the third reaction system using 10wt% aqueous sodium carbonate
To 3.0-3.5, the reaction was continued under conditions of keeping the pH value of the third reaction system in 3.0-3.5 later 5-8h.
8. the production method of folic acid according to claim 1, which is characterized in that in the molten step of acid, using 30-
38wt% aqueous sulfuric acid carries out the acid dissolution.
9. the production method of folic acid according to claim 1, which is characterized in that in the alkali soluble step: in 90-100
DEG C with 10-30wt% sodium hydroxide solution tune pH value to 9.0-9.5.
10. the production method of folic acid according to claim 1, which is characterized in that in the purification step, the clarification
Alkali soluble filtrate be warming up to 98 ± 2 DEG C, with CP hydrochloric acid tune pH value to 3.0-3.5, be then cooled to 55 ± 2 DEG C.
11. the production method of folic acid according to claim 1, which is characterized in that preferably, in the purification step,
The material washing is to be washed to pH=6-7.
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| CN108084185A (en) * | 2017-12-29 | 2018-05-29 | 常州市新鸿医药化工技术有限公司 | A kind of environment-friendly type folic acid process for purification |
| CN108676006B (en) * | 2018-06-29 | 2019-06-04 | 常州制药厂有限公司 | A kind of refining methd of high-purity folic acid |
| CN109761985B (en) * | 2019-01-28 | 2020-07-21 | 河北冀衡（集团）药业有限公司 | Method for purifying folic acid |
| CN115772172B (en) * | 2022-12-08 | 2024-04-09 | 浙江圣达生物药业股份有限公司 | Preparation method of folic acid |
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