CN107312004A - A kind of production method of folic acid - Google Patents
A kind of production method of folic acid Download PDFInfo
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- CN107312004A CN107312004A CN201710447629.4A CN201710447629A CN107312004A CN 107312004 A CN107312004 A CN 107312004A CN 201710447629 A CN201710447629 A CN 201710447629A CN 107312004 A CN107312004 A CN 107312004A
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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 method of folic acid, this method in turn includes the following steps：Crude product synthesis step：With 2 shown in compound B in N (p-benzoyl) the L glutamic acid in Formulas I shown in compound A, Formulas I, 4, trichloroacetone in the hydroxy pyrimidine sulfate of 5 triamido 6 and Formulas I shown in compound C is raw material, using sodium pyrosulfite as antioxidant, using water as solvent, gradation ring-closure reaction is carried out by the way of feeding in batches, reaction solution is obtained；The reaction solution obtains folic acid crude product through cooling, press filtration；Folic acid crude product obtains folic acid finished product through sour molten step, alkali soluble step, purification step.The production method of the present invention makes the concentration holding of material in reaction solution in the reasonable scope using fed batch by the way of, so that discharge reduction needed for folic acid crude product synthesis phase is to the 1/4 of existing synthesis technique institute water requirement.
Description
Technical field
The invention belongs to medical material production field, a kind of production method of folic acid is related generally to.
Background technology
Folic acid (C19H19N7O6), FA is also, is a kind of water soluble vitamin, is Antianemic Agents, applied to feed
The field 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, it is now many using synthetic method production.The more commonly used folic acid production technology includes three phases：Slightly
Product synthesis, the molten refined and alkali soluble of acid are refined.Wherein, crude product synthesis is to use N- (4- aminobenzoyls)-Pidolidone, trichlorine third
Ketone and TAHMS react in crude product retort, the certain reaction temperature of control and reaction
The pH value of feed liquid, makes three kinds of materials occur annulation and obtains folic acid crude product；Folic acid crude product is through the molten refined and alkali soluble refining pure of acid
Change obtains folic acid sterling.In above-mentioned production technology, folic acid crude product synthesis phase institute water requirement is extremely more, thus the stage produce
Wastewater flow rate is also very big, such as produces 1 ton of folic acid crude product, can probably use 12 tons of water, produces about 13-15 tons of waste water, important
It is that these waste water can not be discharged directly, also can not recovery, problems demand solution.
Publication No. CN101323614 and CN101973995 two patents provide mixed using resin and Compositional type respectively
Solidifying destaining gel is handled the waste water of each process section, reaches the purpose recycled.But two methods not only production cost
High, complex process, and all can not fundamentally reduce the generation of waste water.
The content of the invention
For the generation of the waste water from folic acid production technology is reduced in root, production cost is saved, simplifies production technology, this
Invention provides a kind of production method of folic acid.The production method of the present invention in folic acid crude product synthesis phase by using fed batch
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 are the complex manufacturing for making folic acid or increase cost.
To achieve the above object, the present invention uses 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- (p-benzoyl)-Pidolidone in Formulas I shown in compound A, Formulas I
Trichloroacetone in TAHMS and Formulas I shown in thing B shown in compound C is raw material, with Jiao
Sodium sulfite is antioxidant, using water as solvent, carries out gradation ring-closure reaction using in batches plus by the way of material, is reacted
Liquid, the ring-closure reaction is shown in formula I；The reaction solution obtains folic acid crude product through cooling, press filtration；
The molten step of acid：The folic acid crude product obtains sour extract through sour dissolving, elutriation, press filtration；
Alkali soluble step：The sour extract obtains the alkali soluble filter of clarification through water-soluble, lye pH adjustment value, activated carbon decolorizing, press filtration
Liquid；
Purification step：The alkali soluble filtrate of the clarification through heating, acid solution adjust pH value, cooling, material separate out, material washing,
Centrifugation and drying obtain the folic acid finished product in Formulas I shown in compound D；
In aforementioned production method, as a kind of preferred embodiment, in the crude product synthesis step, it is described in batches
Plus the mode of material refers to the compound A, compound B and compound C, antioxidant being added 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 kind of preferred embodiment, 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
Thing 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 kind of preferred embodiment, in the crude product synthesis step, each batch is added
The mole ratio of the compound A and the antioxidant be 1:(0.1-0.8).
In aforementioned production method, as a kind of preferred embodiment, in the crude product synthesis step, each batch is added
The compound A mole sum and the solvent volume ratio for 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 kind of preferred embodiment, 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 ring-closure reaction
Total time be 4-9h (such as 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h), each ring-closure reaction it is total
Time is the summation in the reaction time for the raw material that each batch is added, i.e., the time sum of each time ring-closure reaction.
In aforementioned production method, a kind of preferred embodiment, in the crude product synthesis step, the compound are used as
C crystallizes for trichloroacetone, and purity is 88-95%.
In aforementioned production method, as a kind of preferred embodiment, in the crude product synthesis step, it is described in batches
Plus 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 thing in batches
Material.
It is highly preferred that the material mode that adds secondary in two batches is：
First batch：Add 0.5-0.7 (such as 0.51,0.52,0.54,0.56,0.58,0.60,0.62,0.64,
0.66th, 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,
0.62nd, 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,
0.58th, 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,
0.52nd, 0.54,0.56,0.58,0.60,0.62,0.64,0.66, the 0.68, sodium pyrosulfite of 0.69) × integral molar quantity；
Second lot：Add the remaining compound A, compound B, compound C and sodium pyrosulfite.
It is highly preferred that the compound A concentration described in the reaction system of first batch material formation 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,
When the 0.28th, 0.25,0.22,0.21) (now, the pH changes of reaction system are also smaller), remaining second batch thing is initially added into
Material.
It is further preferred that the compound A, compound B, compound C and the sodium pyrosulfite that are added in first batch
Amount material corresponding with what is added in second lot amount it is identical.
In aforementioned production method, a kind of preferred embodiment, when the material secondary addition in two batches, described point are used as
Secondary ring-closure reaction is specially：In 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), by described in
First batch material adds the solvent and mixes to form the first reaction system, then adjusts institute using 10wt% aqueous sodium carbonates
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, when the concentration of 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 (now, reaction system
PH changes it is also smaller), be initially added into remaining second batch materials and well mixed to form the second reaction system, then proceed to
Using 10wt% aqueous sodium carbonates adjust the pH value of second reaction system to 3.0-3.5 (such as 3.1,3.2,3.3,
3.4), afterwards keep the pH value of second reaction system under conditions of 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
The reaction time undergone is 40-70min；Before second lot material is added, it is anti-that the first batch material is undergone
It is that dropwise addition is counted since 10wt% aqueous sodium carbonates between seasonable, compound A's is dense extremely described in first reaction system
Degree is decreased to terminate during the 1/3-1/5 of compound A initial concentration in first reaction system, and compound A is in course of reaction
In the result that can be detected according to LC-MS of change in concentration be determined：Many sub-samplings are carried out to the first reaction system, according to
LC-MS testing result determines compound A appearance time and integral area；The opportunity of first sub-sampling is dropwise addition sodium carbonate
Before solution；Then as the dropwise addition of aqueous sodium carbonate carries out many sub-samplings to the first reaction system, until sample detection knot
Fruit shows that compound A integral area is the 1/3-1/5 of the first sub-sampling sample compound A integral areas.
In aforementioned production method, a kind of preferred embodiment, when the material secondary addition in three batches, described point are used as
Secondary ring-closure reaction is specially：In 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), by described in
First batch material adds the solvent and mixes to form the first reaction system, then adjusts institute using 10wt% aqueous sodium carbonates
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, when the concentration of 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 (now, reaction system
PH changes it is also smaller), be initially added into the second batch materials and well mixed to form the second reaction system, then proceed to use
10wt% aqueous sodium carbonates adjust the pH value of second reaction system to 3.0-3.5 (such as 3.1,3.2,3.3,3.4) simultaneously
The pH value of second reaction system is kept to 3.0-3.5, the concentration of the compound A described in second reaction system reduces
To compound A initial concentration in second reaction system 1/3-1/5 (such as 0.32,0.31,0.30,0.28,0.25,
When the 0.22nd, 0.21) (now, the pH changes of reaction system are also smaller), the 3rd batch materials are initially added into and well mixed with formation
3rd reaction system, then proceedes to adjust the pH value of the 3rd reaction system to 3.0- using 10wt% aqueous sodium carbonates
3.5 (such as 3.1,3.2,3.3,3.4), afterwards keep the pH value of the 3rd reaction system 3.0-3.5 (such as 3.1,
3.2nd, 3.3,3.4) under conditions of continue to react 5-8h (such as 5.5h, 6h, 6.5h, 7h, 7.5h, 7.8h).Adding second batch
The reaction time that first batch material is undergone before secondary material is 40-70min；It is described before second lot material is added
The reaction time that first batch material is undergone is that dropwise addition is counted since 10wt% aqueous sodium carbonates, to the described first reaction
The concentration of compound A described in system is decreased to tie during the 1/3-1/5 of compound A initial concentration in first reaction system
Beam.Before the 3rd batches are added, the reaction time that second lot material is undergone is 40-70min；Adding the 3rd batch
Before secondary material, the reaction time that the second lot material is undergone is to be added dropwise to calculate since 10wt% aqueous sodium carbonates
Rise, the concentration to compound A described in second reaction system is decreased to the initial of compound A in second reaction system
Terminate during the 1/3-1/5 of concentration.The result that the change in concentration of compound A during the course of the reaction can be detected according to LC-MS is carried out
It is determined that, such as：Determining the change in concentration of compound A in the first reaction system can be carried out as follows：React first
System carries out many sub-samplings, and compound A appearance time and integral area is determined according to LC-MS testing result；Take for the first time
Before the opportunity of sample is dropwise addition aqueous sodium carbonate；It is then many to the progress of the first reaction system with the dropwise addition of aqueous sodium carbonate
Sub-sampling, until sample detection result shows that compound A integral area is the first sub-sampling sample compound A integral areas
1/3-1/5.Determining the change in concentration of compound A in the second reaction system can be carried out as follows：To the second reactant
System carries out many sub-samplings, and compound A appearance time and integral area is determined according to LC-MS testing result；First sub-sampling
Opportunity for be added dropwise aqueous sodium carbonate before；Then the second reaction system is carried out repeatedly with the dropwise addition of aqueous sodium carbonate
Sampling, until sample detection result shows that compound A integral area is the 1/ of the first sub-sampling sample compound A integral areas
3-1/5。
Inventor when using material is added in batches, is controlled in addition to first batch according to long-term experiment empirical discovery
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 during the 1/3-1/5 of compound A initial concentrations 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 also having saved water consumption from source.
In aforementioned production method, as a kind of preferred embodiment, in the sour molten step, using 30-38wt%
Aqueous sulfuric acid carries out the acid dissolving.
In aforementioned production method, as a kind of preferred embodiment, 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 solutions adjust pH value to 9.0-9.5 (such as 9.1,
9.2、9.3、9.4)。
In aforementioned production method, a kind of preferred embodiment, in the purification step, the alkali soluble of the clarification are used as
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 adjust pH value to 3.0-3.5 (such as
3.1st, 3.2,3.3,3.4), then it is cooled to 55 ± 2 DEG C (such as 53 DEG C, 54 DEG C, 55 DEG C, 56 DEG C, 57 DEG C).
In aforementioned production method, as a kind of preferred embodiment, 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, technique effect of the invention is as follows：
The Acidum folicum production method of the present invention makes the concentration of material in reaction solution be maintained at reasonable by the way of fed batch
In the range of, so that discharge reduction needed for folic acid crude product synthesis phase is to the 1/4 of existing synthesis technique institute water requirement；The present invention is adopted
With the generation of mode waste water from folic acid production technology is reduced in root of fed batch, wastewater discharge is reduced, is at sewage
Reason system eases off the pressure, and has saved production cost, so as to improve productivity effect.
Embodiment
With reference to specific embodiment, the production method to a kind of folic acid of the present invention is further described.It should be understood that
These embodiments are only used for the present invention rather than limitation the scope of the present invention.Externally it should be understood that reading in the present invention
After appearance, those skilled in the art are made various changes or modifications to the present invention, and these equivalent form of values are equally fallen within appended by the application
Claims limited range.
Embodiment 1
The present embodiment is in crude product synthesis step, and material is always as follows with magnitude relation：
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 relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxyls
Pyrimidine sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:1:1.6:0.5；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.14mol/L；
Material N- (p-benzoyl)-Pidolidone, 2,4,5- triamido -6- hydroxy pyrimidines sulfate, trichloroacetone
Crystallization and sodium pyrosulfite are added by secondary in two batches, and first batch adds the 1/2 of corresponding material total amount, and second lot adds 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- aminobenzoyls)-Pidolidone 13.3kg is added in 700L water, after stirring 15 minutes
First batch TAHMS 11.95kg is added, stirs and adds within 15 minutes the burnt Asia of first batch
Sodium sulphate 4.75kg, stirring makes material add first batch trichloroacetone crystallization 12.8kg after being evenly distributed and stirs mixing
It is even, keep system temperature at 32-35 DEG C when adding material, 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 course of the reaction between 3.0-3.5, LC-MS
Above-mentioned system is detected, when the concentration of N- (4- aminobenzoyls)-Pidolidone drops to the 1/4 of initial concentration, is lasted
40min；Then remaining N- (4- aminobenzoyls)-Pidolidone is sequentially added according to the Adding Way of first batch material
13.3kg, TAHMS 11.95kg and sodium pyrosulfite 1.9kg, are added after stirring
Remaining trichloroacetone crystallizes 12.8kg, and continuation 10wt% sodium carbonate liquor adjusts pH to 3.5 after stirring, and lasts
45min, then at 35 DEG C and ensure reaction system pH be 3.5 under conditions of continue react 6 hours, LC-MS detection 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, passes through
Sheet frame carries out press filtration, and filter cake is folic acid crude product (wet product 120kg), is used for lower workshop section acid is molten.The waste liquid generated after press filtration can
To carry out decolorization adsorption processing, utilized for following cycle；Sewage disposal system can also be discharged into, leaf is synthesized using the above method
1 ton of acid crude, only produces 7-8 tons of waste water.
2) sour molten step：
The aqueous sulfuric acid that 35wt% is added into 1/3 folic acid crude product (adds the amount of aqueous sulfuric acid with folic acid crude product
All untill dissolving), remaining folic acid crude product is added, after stirring 3-5 minutes, Sufficient purified water is added and (adds purified water
Volume is about 6 times of aqueous sulfuric acid), stir 3-5 minutes, after standing 1 hour, separate out solid, above-mentioned system is pressed into plate
Frame, filter cake is sour extract.The waste liquid generated after press filtration is adsorbed into bleacher with carbon decoloring, logical ammonia is neutralized, and is then entered back into
The molten elutriation of acid, which is filled, 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：
By step 2) obtained sour extract is added in 90 ± 2 DEG C of purified water that (sour extract needs 2500L per 60-90kg
Purified water), PH then is adjusted to 9.0-9.5 with 15wt% sodium hydrate aqueous solution, continues to be heated to 98 ± 2 DEG C, 10 minutes
Repetition measurement afterwards, its pH value is stable between 9.0-9.5, adds activated carbon decolorizing, and then 98 ± 2 DEG C are stirred 1 hour, by above-mentioned alkali soluble
Liquid carries out press filtration, and primary filtrate is returned in alkali soluble retort, then carries out press filtration until filtrate clarification, salt is refined into by being transferred to for clarification
In pot；The complete backward alkali soluble retort of press filtration adds 200kg purified waters, is heated to 90-95 DEG C, cleans the sheet frame of press filtration, washing lotion
Press-in is refined into salt pan in the lump.
4) purification step：
Unlatching is refined into salt pan stirring, and alkali soluble filtrate is heated separately into 98 ± 2 DEG C, and the C.P of mass concentration 10% is added dropwise
Watery hydrochloric acid, until material liquid pH value is 3.0-3.5 in pot, repetition measurement after 10 minutes, until pH value is between 3.0-3.5, then cools
To 55 ± 2 DEG C, after after material precipitation, material is put into quiet filter tank and filtered, then with purified water washing material, until using examination extensively
Untill paper detection PH=6-7；After having washed, material is transferred in centrifuge and dried, and obtains filter cake, filter cake is folic acid finished product；
Filtrate enters waste liquid after resin treatment tank decolorization adsorption, decolorization adsorption and used into alkali soluble retort as process water.
Folic acid finished product 30.2kg is obtained in the present embodiment, purity is 99%, and yield is 69%, the present embodiment middle period acid crude
Synthesis step water consumption is the 45% of prior art water consumption.
Embodiment 2
The present embodiment is in crude product synthesis step, and material relationships are as follows：
Molar ratio of material relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxy pyrimidines
Sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:1.3:2:0.5；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.1mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, TAHMS and Jiao
Three kinds of materials of sodium sulfite are added by secondary in two batches, and first batch adds the 2/3 of corresponding material total amount, and second lot adds remaining
Material.
First batch material adjusts pH value between 3.0-3.5 after adding with 10wt% sodium carbonate liquors, and is reacting
Reaction system pH is controlled in journey between 3.0-3.5, LC-MS detects above-mentioned system, when N- (4- aminobenzoyls)-L- paddy ammonia
The concentration of acid adds the second batch materials when dropping to the 1/3 of initial concentration, lasts 45min.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
Concrete operations and the other parameters be the same as Example 1 of the molten step of acid, alkali soluble step and purification step.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 3
The present embodiment is in crude product synthesis step, and material relationships are as follows：
Molar ratio of material relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxy pyrimidines
Sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:2:3:0.8；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.08mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, TAHMS and Jiao
Three kinds of materials of sodium sulfite are added by secondary in three batches, and first batch adds the 1/2 of corresponding material total amount, and second lot adds surplus
The 1/2 of excess material, the 3rd batch adds leftover materials.
35 DEG C of first batch reaction temperature, first batch material add after with 10wt% sodium carbonate liquors adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the course of the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyls)-Pidolidone adds the second batch materials when dropping to the 1/5 of initial concentration, lasts 55min；
35 DEG C of second lot reaction temperature, second lot material add after with 10wt% sodium carbonate liquors adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the course of the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyls)-Pidolidone drops to N- (4- aminobenzoyls)-L- paddy when second lot material is added
The initial concentration of propylhomoserin 1/4 when add the 3rd batch materials, last 50min；
3rd batch, adjusts pH value between 3.0-3.5, in 35 DEG C and pH value of reaction system with 10wt% sodium carbonate liquors
Under conditions of between 3.0-3.5, continue to react 5h.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
Concrete operations and the other parameters be the same as Example 1 of the molten step of acid, alkali soluble step and purification step.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Embodiment 4
The present embodiment is in crude product synthesis step, and material relationships are as follows：
Molar ratio of material relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxy pyrimidines
Sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:1.7:2.2:0.6；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.25mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, TAHMS and Jiao
Three kinds of materials of sodium sulfite are added by secondary in three batches, and first batch adds the 1/3 of corresponding material total amount, second lot and first
Batch addition is identical, and the 3rd batch adds leftover materials.
35 DEG C of first batch reaction temperature, first batch material add after with 10wt% sodium carbonate liquors adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the course of the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyls)-Pidolidone adds the second batch materials when dropping to the 1/5 of initial concentration, lasts 70min；
35 DEG C of second lot reaction temperature, second lot material add after with 10wt% sodium carbonate liquors adjust pH value to
Between 3.0-3.5, and reaction system pH is controlled during the course of the reaction between 3.0-3.5, LC-MS detects above-mentioned system, when
The concentration of N- (4- aminobenzoyls)-Pidolidone drops to N- (4- aminobenzoyls)-L- paddy when second lot material is added
The initial concentration of propylhomoserin 1/3 when add the 3rd batch materials, last 60min；
3rd batch, adjusts pH value between 3.0-3.5, in 35 DEG C and pH value of reaction system with 10wt% sodium carbonate liquors
Under conditions of between 3.0-3.5, continue to react 6.5h.
In addition to above-mentioned technique, other operations of crude product synthesis step and parameter are same as Example 1.
Concrete operations and the other parameters be the same as Example 1 of the molten step of acid, alkali soluble step and purification step.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, 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 into step, sour molten step, 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- aminobenzoyls)-Pidolidone drops to the 1/8 of initial concentration, first thing
The reaction time of material is 150min.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, 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, due to the time of extension first batch reaction, side reaction is caused to increase, folic acid yield declines.
Embodiment 6
The present embodiment is in crude product synthesis step, and material relationships are as follows：
Molar ratio of material relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxy pyrimidines
Sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:2.5:3.5:1；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.5mol/L；
Wherein, material N- (p-benzoyl)-Pidolidone, TAHMS and Jiao
Three kinds of materials of sodium sulfite are added by secondary in two batches, and first batch adds the 1/2 of corresponding material total amount, and second lot adds remaining
Amount.In the present embodiment, second is added when the concentration of N- (4- aminobenzoyls)-Pidolidone drops to the 1/4 of initial concentration
Batch materials, last 120min.
Except above-mentioned second batch materials addition opportunity 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.
Sour molten step, the concrete operations of alkali soluble step and purification step and other parameters be the same as Example 1 in the present embodiment.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, 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 adds the batch of material one in embodiment 1,35 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.
Concrete operations and the other parameters be the same as Example 1 of the molten step of the present embodiment acid, alkali soluble step and purification step.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, 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 existing process, and in crude product synthesis step, material relationships are as follows：
Molar ratio of material relation is as follows：N- (p-benzoyl)-Pidolidone：2,4,5- triamido -6- hydroxy pyrimidines
Sulfate：Trichloroacetone is crystallized：Sodium pyrosulfite=1:1:1.3:0.2；
The integral molar quantity of N- (p-benzoyl)-Pidolidone and the volume ratio of water are 0.06mol/L；
Comparative example crude product synthesis step concrete operations and other parameters are same as Example 7.
Concrete operations and the other parameters be the same as Example 7 of the molten step of comparative example acid, alkali soluble step and purification step.
Conversion ratio, folic acid yield and the purity of N- (p-benzoyl)-Pidolidone, folic acid crude product synthesis step water
The ratio of amount and prior art water consumption is referring to table 1.
Folic acid yield etc. under the contrast different technical parameters of table 1
Claims (10)
1. a kind of production method of folic acid, it is characterised in that in turn include the following steps：
Crude product synthesis step：With compound B institutes in N- (p-benzoyl)-Pidolidone in Formulas I shown in compound A, Formulas I
Trichloroacetone in the TAHMS and Formulas I that show shown in compound C is raw material, with burnt sulfurous
Sour sodium is antioxidant, using water as solvent, carries out gradation ring-closure reaction using in batches plus by the way of material, obtains reaction solution,
The ring-closure reaction is shown in formula I；The reaction solution obtains folic acid crude product through cooling, press filtration；
The molten step of acid：The folic acid crude product obtains sour extract through sour dissolving, elutriation, press filtration；
Alkali soluble step：The sour extract obtains the alkali soluble filtrate of clarification through water-soluble, lye pH adjustment value, activated carbon decolorizing, press filtration；
Purification step：The alkali soluble filtrate of the clarification is through heating, acid solution adjust pH value, cooling, material is separated out, material is washed, centrifugation
The folic acid finished product in Formulas I shown in compound D is obtained with drying；
2. the production method of folic acid according to claim 1, it is characterised in that described in the crude product synthesis step
In batches plus the mode of material refers to the compound A, compound B and compound C, antioxidant being added to solvent in batches
Compound A, compound B and compound C and antioxidant are added in water, and in each batch；Preferably, 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)；Preferably, respectively
The mole ratio of the compound A that batch is added and the antioxidant is 1:(0.1-0.8)；Preferably, the compound C
Crystallized for trichloroacetone, purity is 88-95%.
3. the production method of folic acid according to claim 1 or 2, it is characterised in that in the crude product synthesis step, respectively
The mole sum for the compound A that batch is added is 0.08-0.28mol/L with the volume ratio of the solvent.
4. the production method of the folic acid according to claim any one of 1-3, it is characterised in that in the crude product synthesis step
In, the temperature of the ring-closure reaction is 25 DEG C -45 DEG C；The total time of each ring-closure reaction is 4-9h, each cyclization
The total time of reaction is the summation in the reaction time for the raw material that each batch is added.
5. the production method of the folic acid according to claim any one of 1-4, it is characterised in that in the crude product synthesis step
In, it is described to add material to be secondary in two batches plus material or secondary in three batches plus material in batches；It is described to add material to be more preferably in batches
Secondary in two batches plus material；
It is highly preferred that the material mode that adds secondary in two batches is：
First batch：Add compound B, 0.5- of compound A, 0.5-0.7 × integral molar quantity of 0.5-0.7 × integral molar quantity
The compound C of 0.7 × integral molar quantity and the sodium pyrosulfite of 0.5-0.7 × integral molar quantity；
Second lot：Add the remaining compound A, compound B, compound C and sodium pyrosulfite；
It is highly preferred that the concentration of the compound A described in the reaction system of first batch material formation is decreased to described the
One batch material shape into reaction system in the compound A initial concentration 1/3-1/5 when, be initially added into remaining
Two batch materials；
It is further preferred that the amount of the compound A, compound B, compound C and the sodium pyrosulfite added in first batch
The amount of material corresponding with what is added in second lot is identical.
6. the production method of the folic acid according to claim any one of 1-5, it is characterised in that when the material is secondary in two batches
During addition, the gradation ring-closure reaction is specially：In at 25 DEG C -45 DEG C, the first batch material is added into the solvent simultaneously
Mix and form the first reaction system, first pH value of reaction system is then adjusted using 10wt% aqueous sodium carbonates and institute is controlled
The pH for stating the first reaction system is maintained between 3.0-3.5, and the concentration of the compound A described in first reaction system reduces
Into first reaction system during 1/3-1/5 of compound A initial concentration, it is initially added into remaining second batch materials and mixes
Close uniform to form the second reaction system, then proceed to adjust second reaction system using 10wt% aqueous sodium carbonates
PH value is keeping the pH value of second reaction system to continue to react 5-8h under conditions of 3.0-3.5 afterwards to 3.0-3.5.
7. the production method of the folic acid according to claim any one of 1-5, it is characterised in that when the material is secondary in three batches
During addition, the gradation ring-closure reaction is specially：In at 25 DEG C -45 DEG C, the first batch material is added into the solvent simultaneously
Mix and form the first reaction system, first pH value of reaction system is then adjusted using 10wt% aqueous sodium carbonates and institute is controlled
The pH for stating the first reaction system is maintained between 3.0-3.5, and the concentration of the compound A described in first reaction system reduces
Into first reaction system during 1/3-1/5 of compound A initial concentration, it is initially added into the second batch materials and is well mixed
To form the second reaction system, then proceed to using 10wt% aqueous sodium carbonates adjust the pH value of second reaction system to
3.0-3.5 simultaneously keeps the pH value of second reaction system to 3.0-3.5, the compound A described in second reaction system
Concentration when being decreased to the 1/3-1/5 of compound A initial concentration in second reaction system, be initially added into the 3rd batch materials
And it is well mixed to form the 3rd reaction system, then proceed to adjust the 3rd reactant using 10wt% aqueous sodium carbonates
The pH value of system is keeping the pH value of the 3rd reaction system to continue to react 5- under conditions of 3.0-3.5 afterwards to 3.0-3.5
8h。
8. the production method of the folic acid according to claim any one of 1-7, it is characterised in that in the sour molten step,
The acid dissolving is carried out using 30-38wt% aqueous sulfuric acids.
9. the production method of the folic acid according to claim any one of 1-8, it is characterised in that in the alkali soluble step：
PH value is adjusted to 9.0-9.5 with 10-30wt% sodium hydroxide solutions at 90-100 DEG C.
10. the production method of the folic acid according to claim any one of 1-9, it is characterised in that in the purification step,
The alkali soluble filtrate of the clarification is warming up to 98 ± 2 DEG C, adjusts pH value to 3.0-3.5 with CP hydrochloric acid, is then cooled to 55 ± 2 DEG C；It is excellent
Selection of land, in the purification step, the material washing is to be washed to pH=6-7.
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