CN107163051A - A kind of preparation method of folic acid - Google Patents
A kind of preparation method of folic acid Download PDFInfo
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- CN107163051A CN107163051A CN201610129238.3A CN201610129238A CN107163051A CN 107163051 A CN107163051 A CN 107163051A CN 201610129238 A CN201610129238 A CN 201610129238A CN 107163051 A CN107163051 A CN 107163051A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of preparation method of folic acid, comprise the following steps：(1) by 1,1,3 three bromacetone is added in ethanol solution, heating stirring；(2) after treating that 1,1,3 three bromacetone is completely dissolved, continue addition p-benzoyl L glutamic acid and stir to whole dissolvings, obtain the first reaction solution；(3) by 2, the hydroxy pyrimidine sulfate of 4,5 triamido 6 is dissolved in the water, and adjusts pH with saturated sodium carbonate, is completely dissolved to the hydroxy pyrimidine sulfate of 2,4,5 triamido 6, obtains the second reaction solution；(4) the second reaction solution is added in the first reaction solution, carries out insulation reaction；(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；(6) by folic acid crude product through peracid is molten, alkali soluble, it is refined after folic acid fine work is made.The preparation method of Folic Acid of the present invention, from the purpose economized on resources, changes the big shortcoming of traditional handicraft water consumption, comprehensive water-saving amount reaches more than 40%.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of preparation method of folic acid.
Background technology
Folic acid (folic acid) be also FA, is a kind of water soluble vitamin, be widely used in feed,
The field such as medicine and food.It is reported that, the synthetic method of folic acid has following several：
1st, the syntheti c route one of folic acid
By 2,4,5- triamido -6- hydroxy pyrimidines, alpha, beta-2-dibrom propionic aldehyde and p-benzoyl-Pidolidone contracting
Close and prepare.This method is reacted in acetic acid-sodium acetate buffer solution obtains folic acid crude product, is then refining to obtain two
Folic acid (the Coy W.Waller.Brian L Hutchings Synthesis of Pteroylglutamic of molecule
Acid(Liver L.casci Factor)and Pteroic Acid.I(J)J.Am.Chem.Soc.,1984,70:19-22)。
2nd, folic acid syntheti c route two
The route is with 2,4,5- triamido -6- hydroxy pyrimidines, hydroxyl MDA and p-benzoyl-L- paddy ammonia
Acid be raw material in the presence of sodium pyrosulfite using the aqueous solution as solvent, prepare folic acid crude product, the route is always received
Rate is 65.5%.
The method that both the above prepares folic acid all employ water and make solvent, and water consumption is big, produces waste water many.
The content of the invention
Invention broadly provides a kind of preparation method of folic acid, from the purpose economized on resources, change and pass
The big shortcoming of system process water consumption.Its technical scheme is as follows：A kind of preparation method of folic acid, including following step
Suddenly：
(1) by 1,1,3- tri- bromacetone is added in ethanol solution, heating stirring；
(2) after treating that 1,1,3- tri- bromacetone is completely dissolved, continue to add p-benzoyl-Pidolidone stirring
To whole dissolvings, the first reaction solution is obtained；
(3) TAHMS is dissolved in the water, and adjusted with saturated sodium carbonate
PH, is completely dissolved to TAHMS, obtains the second reaction solution；
(4) the second reaction solution is added in the first reaction solution, carries out insulation reaction；
(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；
(6) by folic acid crude product through peracid is molten, alkali soluble, it is refined after folic acid fine work is made；
Wherein, 1,1,3- tri- bromacetone, p-benzoyl-Pidolidone, 2,4,5- triamido -6- hydroxy pyrimidines
The mol ratio of sulfate and water is 0.05-0.07:0.02-0.04:0.04-0.06:5-8.
It is preferred that, 1,1,3- tri- bromacetone, p-benzoyl-Pidolidone, 2,4,5- triamido -6- hydroxyls are phonetic
The mol ratio of pyridine sulfate and water is 0.06:0.03:0.05:6.7.
It is preferred that, heating-up temperature is 40-55 DEG C in step (1), and the volumetric concentration of ethanol solution is 95%.
It is preferred that, pH is 7.5-8.5 in step (3).
It is preferred that, the insulation reaction time is 5-8h in step (4).
It is preferred that, the molten specific method of acid is to add folic acid crude product in reaction bulb in step (6), and is added
It is 1 to enter volume ratio:1 water and alcohol mixeding liquid 100g, is slowly added to the H that mass concentration is 98%2SO4It is molten
Liquid 17.3g, stirs 25-35min, and it is 1 then to add volume ratio:1 water and alcohol mixeding liquid 400g, is separated out
Crystal, temperature control at 40-55 DEG C, stir 30-50min, suction filtration obtain it is sour it is molten after folic acid crude product.
It is preferred that, the specific method of alkali soluble is in step (6), and folic acid crude product of the acid after molten is added into reaction bulb
In, and the 530g that adds water, 95-105 DEG C is heated to, sodium hydroxide solution and tune of the mass concentration for 20% is added
Section pH is 8-9, until folic acid crude product is completely dissolved.
It is preferred that, the specific method refined in step (6) is that activity is added in the aqueous slkali of folic acid crude product
Charcoal 1.2g, stirs 30-40min, be incubated under the conditions of suction filtration, 60-70 DEG C of filtrate obtained by suction filtration,
Temperature in pH to 2.5-3.0, reaction bulb is adjusted with concentrated hydrochloric acid and continues cool to 40-50 DEG C, and press filtration, filter cake is used
700mL purifies water washing, dry folic acid fine work.
Using the preparation method of above-mentioned folic acid, the present invention has advantages below：
It is existing to prepare that folic acid process water consumption is big, produce that waste water is more, the present invention using second alcohol and water mixed liquor
As reaction dissolvent, ethanol can be recycled by recycling, greatly reduce the cost of folic acid preparation,
And the wastewater flow rate in production is reduced, comprehensive water-saving amount reaches more than 40%, is conducive to environmental protection.Together
When, the yield of acetic acid reaches more than 55%, and comprehensive yied is high.
Embodiment
Embodiment 1
A kind of preparation method of folic acid, specifically includes following steps：
(1) by 18g1,1,3- tri- bromacetone is added in 600mL ethanol solutions, is heated with stirring to 55 DEG C；
(2) after treating that 1,1,3- tri- bromacetone is completely dissolved, continue to add 10g p-benzoyls-Pidolidone
Stirring obtains the first reaction solution to whole dissolvings；
(3) water 120g is added in other reaction bulb, the triamido -6- hydroxy pyrimidine sulphur of 12g 2,4,5- is weighed
Hydrochlorate is added portionwise into reaction bulb, and is 8 with saturated sodium carbonate regulation pH, to 2,4,5- triamido -6- hydroxyls
Yl pyrimidines sulfate is completely dissolved, and obtains the second reaction solution；
(4) the second reaction solution is added portionwise into the first reaction solution, carries out insulation reaction 5h；
(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；
(6) folic acid crude product is added in reaction bulb, and it is 1 to add volume ratio:1 water and alcohol mixeding liquid
100g, is slowly added into the H that mass concentration is 98%2SO4Solution 17.3g, stirs 30min；
(7) above-mentioned material is transferred in big reaction bulb, it is 1 to add volume ratio:1 water and ethanol mixing
Liquid 400g, separates out crystal；
(8) 40 DEG C of temperature control, stir 30min, suction filtration obtain it is sour it is molten after folic acid crude solid；
(9) under normal temperature, solid obtained by above-mentioned suction filtration is added in reaction bulb, and the 530g that adds water, it is heated to
100 DEG C, it is 8 to add the sodium hydroxide solution regulation pH that mass concentration is 20%, until solid all dissolves；
(10) activated carbon 1.2g all is added after dissolving, stirs 40min, carry out suction filtration, filtrate obtained by suction filtration
It is transferred in other reaction bulb, is incubated under the conditions of 65 DEG C, pH to 3.0 is adjusted with concentrated hydrochloric acid；
(11) temperature continues cool to 40 DEG C in reaction bulb, press filtration, and filter cake 700mL purifies water washing,
It is dried to obtain 9.2g folic acid fine work.
The yield of above-mentioned folic acid fine work is 56%.
Above-mentioned preparation method reactive chemistry formula is shown below：
Wherein, formula (1) is TAHMS, and formula (2) is 1,1,3- tribromo third
Ketone, formula (3) is p-benzoyl-Pidolidone, and formula (4) is folic acid.
Embodiment 2
A kind of preparation method of folic acid, specifically includes following steps：
(1) by 14.74g1,1,3- tri- bromacetone is added in 600mL ethanol solutions, is heated with stirring to 50 DEG C；
(2) after treating that 1,1,3- tri- bromacetone is completely dissolved, continue to add 10.65g p-benzoyl-L- paddy ammonia
Acid stirring obtains the first reaction solution to whole dissolvings；
(3) water 90g is added in other reaction bulb, the triamido -6- hydroxy pyrimidine sulphur of 9.49g 2,4,5- is weighed
Hydrochlorate is added portionwise into reaction bulb, and is 8.5 with saturated sodium carbonate regulation pH, to 2,4,5- triamido -6-
Hydroxy pyrimidine sulfate is completely dissolved, and obtains the second reaction solution；
(4) the second reaction solution is added portionwise into the first reaction solution, carries out insulation reaction 6h；
(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；
(6) folic acid crude product is added in reaction bulb, and it is 1 to add volume ratio:1 water and alcohol mixeding liquid
100g, is slowly added to the H that mass concentration is 98%2SO4Solution 17.3g, stirs 25min；
(7) above-mentioned material is transferred in big reaction bulb, it is 1 to add volume ratio:1 water and ethanol mixing
Liquid 400g, separates out crystal；
(8) 50 DEG C of temperature control, stir 40min, suction filtration obtain it is sour it is molten after folic acid crude solid；
(9) under normal temperature, solid obtained by above-mentioned suction filtration is added in reaction bulb, and the 550g that adds water, it is heated to
105 DEG C, it is 8.5 to add the sodium hydroxide solution regulation pH that mass concentration is 20%, until solid all dissolves；
(10) activated carbon 1.2g all is added after dissolving, stirs 35min, carry out suction filtration, filtrate obtained by suction filtration
It is transferred in other reaction bulb, is incubated under the conditions of 70 DEG C, pH to 3.0 is adjusted with concentrated hydrochloric acid；
(11) temperature continues cool to 45 DEG C in reaction bulb, press filtration, and filter cake 700mL purifies water washing,
It is dried to obtain 10.2g folic acid fine work.
The yield of above-mentioned folic acid fine work is 58%.
Embodiment 3
A kind of preparation method of folic acid, specifically includes following steps：
(1) by 20.63g1,1,3- tri- bromacetone is added in 600mL ethanol solutions, is heated with stirring to 40 DEG C；
(2) after treating that 1,1,3- tri- bromacetone is completely dissolved, continue to add 5.33g p-benzoyl-L- paddy ammonia
Acid stirring obtains the first reaction solution to whole dissolvings；
(3) water 144g is added in other reaction bulb, the triamido -6- hydroxy pyrimidines of 14.23g 2,4,5- are weighed
Sulfate is added portionwise into reaction bulb, and is 7.5 with saturated sodium carbonate regulation pH, to 2,4,5- triamido -6-
Hydroxy pyrimidine sulfate is completely dissolved, and obtains the second reaction solution；
(4) the second reaction solution is added portionwise into the first reaction solution, carries out insulation reaction 8h；
(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；
(6) folic acid crude product is added in reaction bulb, and it is 1 to add volume ratio:1 water and alcohol mixeding liquid 100
G, is slowly added to the H that mass concentration is 98%2SO4Solution 17.3g, stirs 35min；
(7) above-mentioned material is transferred in big reaction bulb, it is 1 to add volume ratio:1 water and ethanol mixing
Liquid 400g, separates out crystal；
(8) 55 DEG C of temperature control, stir 50min, suction filtration obtain it is sour it is molten after folic acid crude solid；
(9) under normal temperature, solid obtained by above-mentioned suction filtration is added in reaction bulb, and the 530g that adds water, it is heated to
95 DEG C, it is 9 to add the sodium hydroxide solution regulation pH that mass concentration is 20%, until solid all dissolves；
(10) activated carbon 1.2g all is added after dissolving, stirs 30min, carry out suction filtration, filtrate obtained by suction filtration
It is transferred in other reaction bulb, is incubated under the conditions of 60 DEG C, pH to 2.5 is adjusted with concentrated hydrochloric acid；
(11) temperature continues cool to 50 DEG C in reaction bulb, press filtration, and filter cake 700mL purifies water washing,
It is dried to obtain 5.3g folic acid fine work.
The yield of above-mentioned folic acid fine work is 60%.
It will be apparent to those skilled in the art that technical scheme that can be as described above and design, make it
Its various corresponding changes and deformation, and all these change and deformation should all belong to power of the present invention
Within the protection domain that profit is required.
Claims (8)
1. a kind of preparation method of folic acid, it is characterised in that：Comprise the following steps：
(1) by 1,1,3- tri- bromacetone is added in ethanol solution, heating stirring；
(2) after treating that 1,1,3- tri- bromacetone is completely dissolved, continue to add p-benzoyl-Pidolidone stirring
To whole dissolvings, the first reaction solution is obtained；
(3) TAHMS is dissolved in the water, and adjusted with saturated sodium carbonate
PH, is completely dissolved to TAHMS, obtains the second reaction solution；
(4) the second reaction solution is added in the first reaction solution, carries out insulation reaction；
(5) after the completion of reacting, suction filtration is carried out, folic acid crude product is obtained；
(6) by folic acid crude product through peracid is molten, alkali soluble, it is refined after folic acid fine work is made；
Wherein, 1,1,3- tri- bromacetone, p-benzoyl-Pidolidone, 2,4,5- triamido -6- hydroxy pyrimidines
The mol ratio of sulfate and water is 0.05-0.07:0.02-0.04:0.04-0.06:5-8.
2. the preparation method of folic acid according to claim 1, it is characterised in that：The bromacetones of 1,1,3- tri-,
The mol ratio of p-benzoyl-Pidolidone, 2,4,5- triamidos -6- hydroxy pyrimidines sulfate and water is
0.06:0.03:0.05:6.7。
3. the preparation method of folic acid according to claim 1, it is characterised in that：Add in step (1)
Hot temperature is 40-55 DEG C, and the volumetric concentration of ethanol solution is 95%.
4. the preparation method of folic acid according to claim 1, it is characterised in that：PH in step (3)
For 7.5-8.5.
5. the preparation method of folic acid according to claim 1, it is characterised in that：Protected in step (4)
The warm reaction time is 5-8h.
6. the preparation method of folic acid according to claim 1, it is characterised in that：It is sour in step (6)
Molten specific method is to add folic acid crude product in reaction bulb, and it is 1 to add volume ratio:1 water and ethanol is mixed
Liquid 100g is closed, the H that mass concentration is 98% is slowly added to2SO4Solution 17.3g, stirs 25-35min, so
It is 1 to add volume ratio afterwards:1 water and alcohol mixeding liquid 400g, separate out crystal, temperature control at 40-55 DEG C,
Stir 30-50min, suction filtration obtain it is sour it is molten after folic acid crude product.
7. the preparation method of folic acid according to claim 1, it is characterised in that：Alkali in step (6)
Molten specific method is to add folic acid crude product of the acid after molten in reaction bulb, and the 530g that adds water, and is heated to
95-105 DEG C, add sodium hydroxide solution that mass concentration is 20% and to adjust pH be 8-9, until folic acid is thick
Product are completely dissolved.
8. the preparation method of folic acid according to claim 1, it is characterised in that：It is smart in step (6)
The specific method of system is that activated carbon 1.2g is added in the aqueous slkali of folic acid crude product, stirs 30-40min, enters
It is incubated under the conditions of row suction filtration, 60-70 DEG C of filtrate obtained by suction filtration, pH is adjusted to 2.5-3.0 with concentrated hydrochloric acid,
Temperature continues cool to 40-50 DEG C in reaction bulb, press filtration, and filter cake 700mL purifies water washing, dry
Folic acid fine work.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108676006A (en) * | 2018-06-29 | 2018-10-19 | 常州制药厂有限公司 | A kind of process for purification of high-purity folic acid |
| CN109535083A (en) * | 2018-12-26 | 2019-03-29 | 浙江本立科技股份有限公司 | The preparation method of 2,4,5-triamino-6-hydroxypyrimidine sulfate and folic acid |
| CN109678858A (en) * | 2018-11-03 | 2019-04-26 | 黄红军 | A kind of preparation method of folic acid |
| CN112010856A (en) * | 2019-05-29 | 2020-12-01 | 威海中腾医药科技有限公司 | Telescoping process method for preparing folic acid by using microchannel reaction |
| CN113816961A (en) * | 2021-08-17 | 2021-12-21 | 北京斯利安药业有限公司 | Folic acid synthesis method |
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| CN101973995A (en) * | 2010-07-20 | 2011-02-16 | 上海华理生物医药有限公司 | Method for recycling waste water in production of folic acid |
| CN102399224A (en) * | 2011-10-21 | 2012-04-04 | 湖州展望药业有限公司 | Preparation method of low-iron methotrexate |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108676006A (en) * | 2018-06-29 | 2018-10-19 | 常州制药厂有限公司 | A kind of process for purification of high-purity folic acid |
| CN109678858A (en) * | 2018-11-03 | 2019-04-26 | 黄红军 | A kind of preparation method of folic acid |
| CN109535083A (en) * | 2018-12-26 | 2019-03-29 | 浙江本立科技股份有限公司 | The preparation method of 2,4,5-triamino-6-hydroxypyrimidine sulfate and folic acid |
| CN112010856A (en) * | 2019-05-29 | 2020-12-01 | 威海中腾医药科技有限公司 | Telescoping process method for preparing folic acid by using microchannel reaction |
| CN112010856B (en) * | 2019-05-29 | 2023-05-16 | 威海中腾医药科技有限公司 | Folic acid telescoping process method by utilizing microchannel reaction |
| CN113816961A (en) * | 2021-08-17 | 2021-12-21 | 北京斯利安药业有限公司 | Folic acid synthesis method |
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