CN106432241A - New folic acid preparation method - Google Patents
New folic acid preparation method Download PDFInfo
- Publication number
- CN106432241A CN106432241A CN201510481287.9A CN201510481287A CN106432241A CN 106432241 A CN106432241 A CN 106432241A CN 201510481287 A CN201510481287 A CN 201510481287A CN 106432241 A CN106432241 A CN 106432241A
- Authority
- CN
- China
- Prior art keywords
- folic acid
- reaction
- acid
- ionic liquid
- acid preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a new folic acid preparation method, wherein folic acid is subjected to one-pot low temperature synthesis by using an ion liquid as a solvent. According to the present invention, the reaction condition is mild, the problems of more side reactions, high water consumption and complex refining process of the existing folic acid preparation method using the water as the solvent are solved, and the good foundation is established for the production capacity improving in the industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology field is and in particular to a kind of new preparation method of Folic Acid.
Background technology
Also known as FA, vitamin(e) M, it, as a kind of water-soluble B vitamin, extensively deposits Folic Acid (Folic Acid)
It is in fresh green vegetable fruit, nineteen forty-one, American scholar H.K.Mitchell et al. is extracted this first in the leaf of spinach
Plant the compound with anti-anemia action effect, therefore be named as Folic Acid.1945, Angier et al. was complete synthesis with the method for chemistry
Folic Acid is simultaneously determined to its structure.The structure of pteridine, para-amino benzoic acid, L-Glutamic Acid is comprised in the molecular structure of Folic Acid
Unit, so Folic Acid is referred to as pteroylglutamic acid, research finds that Folic Acid plays the role of to promote juvenile cell maturation in bone marrow, and the mankind are as lacked
Weary Folic Acid can cause megaloblastic anemia and leukopenia, and anemia of pregnant woman is even more important, and is clinically mainly used in anti-eliminate-poverty
The diseases such as blood, inappetence and hypoevolutism.
The food containing Folic Acid in nature is a lot, but due to natural Folic Acid extremely unstable, easy light, the impact of heat and occur
Oxidation, so the Folic Acid that human body really can obtain from food is simultaneously few, if the Folic Acid in food is through boiling for a long time, can lose
50%～90%.When human body Folic Acid Deficiency of Intake, multiple deficiency diseases can be caused：Newborn teratogenesis, senile dementia, class wind
Wet arthritis etc., therefore human body are taken in necessary during a certain amount of Folic Acid.
Folic Acid as the valuable source being related to national economy, also paid close attention to by vast researcher, at present by its synthetic method
The acquisition of Folic Acid relies primarily on chemosynthesis, and existing Folic Acid preparation method is with N- NSC 71042,1,1,3- trichlorine
Acetone, TAHMS are initiation material, with water as solvent, in the work of sodium pyrosulfite and Sodium Acetate Trihydrate
With lower generation ring-closure reaction, prepared Folic Acid crude product, be then passed through acid carry, refine, decolouring, re-refine after obtain Folic Acid.
The pH value that existing Folic Acid preparation method adjusts reaction system with Sodium Acetate Trihydrate maintains 3.0 about, because this course of reaction generates
Hydrochloric acid, acidity is too strong, and Sodium Acetate Trihydrate belongs to strong base-weak acid salt, and amount ratio is larger, and price comparison is high, virtually increased
The labor intensity of workman and production cost.In addition, with water as solvent, side reaction is many for existing preparation method, and follow-up subtractive process is loaded down with trivial details,
Lead to total recovery not high, and produce substantial amounts of waste water, bring very big pressure to environment.
Content of the invention
The present invention is directed to the technical deficiency that existing Folic Acid refines, there is provided a kind of method of new preparation Folic Acid, should ionic liquid
Use i.e. with ionic liquid for the solvent reacting in the preparation technology of Folic Acid, one kettle way prepares Folic Acid crude product, after simply refined i.e.
The Folic Acid finished product meeting standards of pharmacopoeia can be obtained.Side reaction is few during the course of the reaction for the method, and product purity is high, preparation technology letter
Single, effectively improve the product quality of Folic Acid, reduce the production cost of Folic Acid.
The present invention is to solve its technical problem to adopt the following technical scheme that：
A kind of new method preparing Folic Acid is it is characterised in that comprise the following steps：
(1) by N- NSC 71042, TAHMS, 1,1,3- trichloroacetone, pyrosulfurous acid
Sodium is added in reaction bulb according to certain proportioning, and with ionic liquid as solvent, controlling reaction temperature is 15～50 DEG C, is adjusted with alkali
Section system pH maintains 2～5, and stirring reaction, to terminating, obtains Folic Acid crude product after filtration.Obtain highly purified after refined
Folic Acid.
(2) step 1) in the weight ratio of involved each material be：
(3) step 1) in ionic liquid used be mainly imidazoles, pyridines two big class, specifically can use general formula be indicated：
Wherein：
X is BF4 -、PF6 -、CF3COO-、CF3SO3 -、CH3COO-、Cl-、Br-、HSO4 -、NO3 -Deng；
R1、R2、R3For-(CH2)nCH3(wherein n is 0～10), benzyl, isopropyl, pi-allyl etc.；
(4) step 1) in alkali used be：Sodium hydroxide, potassium hydroxide, Sodium Acetate Trihydrate, sodium carbonate, sodium bicarbonate, potassium carbonate, phosphorus
Sour sodium, preferably sodium hydroxide, potassium hydroxide.
Beneficial effects of the present invention are as follows：
(1) with ionic liquid for reaction dissolvent carry out Folic Acid synthesis when, can effectively reduce the generation of side reaction, improve the purity of product,
And react and carry out under mild conditions, reaction is easily operated, and the response time is shorter, and reaction rate faster, reduces cost,
Also mitigate the labor intensity of workman, improve production capacity for later industrialized production and lay a good foundation.
(2) with ionic liquid as reaction dissolvent, it is to avoid a large amount of waste water producing in Conventional process, reduce environmental pollution, reduce
Environmental protection production cost.
Specific embodiment
Contribute to understanding the present invention by following embodiments, but be not intended to limit present disclosure.
Embodiment one
Charge ratio：
Operating procedure：
100g N- NSC 71042,120g TAHMS, 160g is added in reaction bulb
1,1,3- trichloroacetone, 140g sodium pyrosulfite, 100g 1- ethyl-3-methylimidazole tetrafluoroborate ([emim] BF4), stirring
20～30 DEG C of stirring reactions 2h of temperature control, use sodium hydroxide regulation system pH value 3.0～3.5 during reaction, reaction stops after terminating
Stirring, filters, obtains Folic Acid crude product.
The Folic Acid obtaining crude product and 4.5L purified water are added in reaction bulb, under stirring, are heated to 80～90 DEG C, then use hydrogen-oxygen
Change sodium solution (2N) regulation system pH to 8～9, add 15g activated carbon insulated and stirred to decolour 30 minutes, heat filter.Filtrate
80～90 DEG C of temperature control, adds dilute hydrochloric acid (2N) to adjust pH to 3.0～3.5, slow cooling to room temperature, filters, filter cake is placed in baking
60～65 DEG C of drying under reduced pressure 5h of temperature control in case, obtain Folic Acid sterling 138g, yield 83.2%, and HPLC purity 99.7% is wherein miscellaneous
Matter pteroic acid content 0.09%.
Embodiment two
Charge ratio：
Operating procedure：
100g N- NSC 71042,120g TAHMS, 160g is added in reaction bulb
1,1,3- trichloroacetone, 140g sodium pyrosulfite, 150g 1- butyl -3- Methylimidazole. hexafluorophosphate ([bmim] PF6), stirring
30-40 DEG C of stirring reaction 1h30min of temperature control, uses potassium hydroxide regulation system pH value 4.0～5.0, after reaction terminates during reaction
Stop stirring, filter, obtain Folic Acid crude product.
The Folic Acid obtaining crude product and 4.5L purified water are added in reaction bulb, under stirring, are heated to 80～90 DEG C, then use hydrogen-oxygen
Change potassium solution (2N) regulation system pH to 8～9, add 15g activated carbon insulated and stirred to decolour 30 minutes, heat filter.Filtrate
80～90 DEG C of temperature control, adds dilute hydrochloric acid (2N) to adjust pH to 3.0～3.5, slow cooling to room temperature, filters, filter cake is placed in baking
60～65 DEG C of drying under reduced pressure 5h of temperature control in case, obtain Folic Acid sterling 131g, yield 79.0%, HPCL purity 99.6%, wherein
Impurity pteroic acid content 0.11%.
Embodiment three
Charge ratio：
Operating procedure：
100g N- NSC 71042,160g TAHMS, 150g is added in reaction bulb
1,1,3- trichloroacetone, 150g sodium pyrosulfite, 80g N- butyl-pyridinium hexafluorophosphate (BPyPF6), stir 40-50 DEG C of temperature control
Stirring reaction 2h15min, uses sodium hydroxide regulation system pH value 2.0～3.0 during reaction, reaction stops stirring, mistake after terminating
Filter, obtains Folic Acid crude product.
The Folic Acid obtaining crude product and 4.5L purified water are added in reaction bulb, under stirring, are heated to 80～90 DEG C, then use sodium carbonate molten
Liquid (1N) regulation system pH, to 8～9, adds 15g activated carbon insulated and stirred to decolour 30 minutes, heat filter.Filtrate temperature control 80～
90 DEG C, add dilute hydrochloric acid (2N) to adjust pH to 3.0～3.5, slow cooling to room temperature, filter, filter cake is placed in temperature control in baking oven
60～65 DEG C of drying under reduced pressure 5h, obtain Folic Acid sterling 125g, yield 75.4%, HPLC purity 99.4%, wherein impurity pteroic acid
Content 0.12%.
Example IV
Charge ratio：
Operating procedure：
100g N- NSC 71042,120g TAHMS, 180g is added in reaction bulb
1,1,3- trichloroacetone, 100g sodium pyrosulfite, 150g 1- ethyl-3-methylimidazole fluoroform sulphonate, stirs 25-35 DEG C of temperature control
Stirring reaction 3h, uses sodium hydroxide regulation system pH value 2.5～3.5 during reaction, reaction stops stirring after terminating, and filters,
Obtain Folic Acid crude product.
The Folic Acid obtaining crude product and 4.5L purified water are added in reaction bulb, under stirring, are heated to 80～90 DEG C, then use potassium carbonate molten
Liquid (1N) regulation system pH, to 8～9, adds 15g activated carbon insulated and stirred to decolour 30 minutes, heat filter.Filtrate temperature control 80～
90 DEG C, add dilute hydrochloric acid (2N) to adjust pH to 3.0～3.5, slow cooling to room temperature, filter, filter cake is placed in temperature control in baking oven
60～65 DEG C of drying under reduced pressure 5h, obtain Folic Acid sterling 129g, yield 77.8%, HPLC purity 99.5%, wherein impurity pteroic acid
Content 0.10%.
Claims (6)
1. a kind of new method preparing Folic Acid, is primarily characterized in that and comprises the following steps：
By N- NSC 71042,2,4,5- triamido -6- hydroxy pyrimidine sulfate, 1,1,3- trichloroacetone, sodium pyrosulfite are added in reaction bulb according to certain proportioning, with ionic liquid as solvent, controlling reaction temperature is 15～50 DEG C, maintain 2～5 with alkali regulation system pH value, stirring reaction, to terminating, obtains Folic Acid crude product after filtration.Obtain highly purified Folic Acid after refined.
2. method according to claim 1 it is characterised in that：The weight ratio of each material is：
.
3. method according to claim 1 is it is characterised in that step 1) species of described ionic liquid is：
Wherein：
X is BF4 -、PF6 -、CF3COO-、CF3SO3 -、CH3COO-、Cl-、Br-、HSO4 -、NO3 -Deng；
R1、R2、R3For-(CH2)nCH3(wherein n is 0～10), benzyl, isopropyl, pi-allyl etc..
4. method according to claim 1 is it is characterised in that step 1) described reaction temperature is preferably 20～30 DEG C.
5. method according to claim 1 is it is characterised in that step 1) the pH value span of control of described course of reaction system is optimal between 3.0～3.5.
6. method according to claim 1 is it is characterised in that step 1) described in response time be 0.5～5h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510481287.9A CN106432241B (en) | 2015-08-04 | 2015-08-04 | A method of preparing folic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510481287.9A CN106432241B (en) | 2015-08-04 | 2015-08-04 | A method of preparing folic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106432241A true CN106432241A (en) | 2017-02-22 |
| CN106432241B CN106432241B (en) | 2019-07-12 |
Family
ID=58093677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510481287.9A Active CN106432241B (en) | 2015-08-04 | 2015-08-04 | A method of preparing folic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106432241B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101182323A (en) * | 2007-12-26 | 2008-05-21 | 潘福星 | Method for preparing folic acid |
| CN102558180A (en) * | 2011-05-13 | 2012-07-11 | 河北冀衡（集团）药业有限公司 | Preparation method for folic acid |
-
2015
- 2015-08-04 CN CN201510481287.9A patent/CN106432241B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101182323A (en) * | 2007-12-26 | 2008-05-21 | 潘福星 | Method for preparing folic acid |
| CN102558180A (en) * | 2011-05-13 | 2012-07-11 | 河北冀衡（集团）药业有限公司 | Preparation method for folic acid |
Non-Patent Citations (1)
| Title |
|---|
| 李汝雄: "《绿色溶剂—离子液体的合成与应用》", 29 February 2004, 化学工业出版社 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106432241B (en) | 2019-07-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101434608B (en) | Preparation of high-purity ellagic acid | |
| CN102976917B (en) | Aqueous-phase refining method of long-chain dibasic acid | |
| CN108017535B (en) | Method for extracting long-chain dicarboxylic acid from fermentation liquor | |
| CN1800000A (en) | Barium metaphosphorate production process | |
| KR20120041208A (en) | Process for preparing ammonium metatungstate | |
| CN105712887B (en) | A kind of production method of long-chain nylon salt | |
| CN108191688A (en) | A kind of method synthesized and crystallize D-VB5 calcium | |
| CN103804172A (en) | Method for improving organic acid product quality | |
| CN103804173B (en) | A kind of process for purification of fermentation organic acid | |
| CN102828036B (en) | Method of preparing potassium metavanadate solution from vanadium slag | |
| CN101298445A (en) | Method for directly preparing vitamin C with sodium gulonate | |
| CN106146560A (en) | A kind of process for purification of high-purity phosphoric acid specially azoles amine | |
| CN102910681A (en) | Preparation method of Mn3O4 nano particles | |
| CN106432241A (en) | New folic acid preparation method | |
| CN104086466A (en) | Preparation method of 2-chloro-4-methylsulfonylbenzoic acid | |
| CN104478974B (en) | A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide | |
| CN104310471B (en) | A kind of method of synthesizing bismuth oxychloride pearlescent pigment | |
| CN104591999A (en) | Long chain organic acid purifying method | |
| CN104418729A (en) | Soluble citrate preparation method | |
| CN103896232B (en) | Raffinate twice neutralisation prepares the method for industrial grade monoammonium phosphate | |
| CN101891171A (en) | Method for preparing food-grade anhydrous disodium hydrogen phosphate | |
| CN105859542A (en) | Preparing method for high-purity lithium oxalate | |
| CN106432547A (en) | Method for preparing enoxaparin sodium through heparin benzyl ester | |
| CN105481771B (en) | A kind of preparation process of ozagrel intermediate (E) -4- (imidazolyl methyl) methyl cinnamate | |
| CN108774231A (en) | A kind of environment-protection production method of folic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |