CN108358928A - A kind of preparation method of (6S) -5-methyltetrahydrofolate calcium - Google Patents
A kind of preparation method of (6S) -5-methyltetrahydrofolate calcium Download PDFInfo
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- CN108358928A CN108358928A CN201810500346.6A CN201810500346A CN108358928A CN 108358928 A CN108358928 A CN 108358928A CN 201810500346 A CN201810500346 A CN 201810500346A CN 108358928 A CN108358928 A CN 108358928A
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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
- 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 the technical fields of organic synthesis, are related to a kind of preparation method of (6S) 5 methyl tetrahydrofolate calcium, described method includes following steps：Sodium borohydride is put under alkaline environment, the mixture of folic acid and water is added dropwise in room temperature, and heating reaction generates tetrahydrofolic acid；Formaldehyde successively is added dropwise and sodium borohydride aqueous solution is reacted, cooling after reaction stands a period of time, filters removal boron salt later；Calcium chloride solution, stirred crystallization are added dropwise in filtrate, suction filtration obtains 5 methyl tetrahydrofolate calcium；Gained crystal is mixed with water, EDTA is added and 2 aminomethyl pyrrolidine of S () N ethyls carries out resolution reaction, R types enantiomer and S type enantiomers is successively precipitated in cooling after reaction, continue that calcium chloride solution is added dropwise in obtained S type enantiomers, stirred crystallization, suction filtration obtain (6S) 5 methyl tetrahydrofolate calcium.(6S) 5 methyl tetrahydrofolate calcium product purity that preparation method provided by the invention is produced is high, and stable reaction is environmental-friendly.
Description
Technical field
The invention belongs to the technical fields of organic synthesis, are related to a kind of preparation method of (6S) -5-methyltetrahydrofolate calcium.
Background technology
(6S) -5-methyltetrahydrofolate is the principal mode of tissue and blood folic acid, it needs not move through cumbersome in human body
Enzymatic step, can a variety of important biochemical reactions (synthesis of such as purine and thymidine) directly in participant body.
(6S) -5 methyl tetrahydrofolate can be used as medicine and food additives, be used as vitamin preparation, prevent neural tube defect, treatment depression
Disease, treatment megaloblastic anemia etc., studies have shown that (6S) -5-methyltetrahydrofolate can be uniquely oozed in folic acid class drug
Through the drug of blood-brain barrier, have the function of preventing Alzheimer disease (senile dementia), therefore it has other folic acid
The incomparable superiority of class drug has huge market prospects.Since (6S) -5-methyltetrahydrofolate is highly unstable,
Easily aoxidize, thus synthesize high-purity, the tetrahydrofolic acid of high stability has the shortcomings that expensive, yield is low etc., and tetrahydrochysene leaf
Hydrochlorate has excellent stability, and experimental results demonstrate can isolate and purify out high-purity, high stable in specific aqueous slkali
The tetrahydrofolate of property, especially its calcium salt (6S) -5-methyltetrahydrofolate calcium.
Chemically synthesized 5-methyltetrahydrofolate is mainly hydrogenated and methylate acquisition by folic acid, usually at 5,6
When double-bond hydrogenation, optical activity carbon atom is formed at 6, is existed in the form of (6R)-or (6S) -5-methyltetrahydrofolate.
The existing process route of (6S) -5-methyltetrahydrofolate be using folic acid as raw material, through restore, methylate, split and etc. synthesis
And it obtains.
In the prior art there are many method of synthesis (6S) -5-methyltetrahydrofolate calcium, such as WO2008031284A1 is open
Application organic base α-phenylethylamine or the enantiomer of (+)-α-phenylethylamine or (-)-α-phenylethylamine are from racemic modification (6R, S) -5- first
Base tetrahydrofolic acid splits to obtain (6S) -5-methyltetrahydrofolate, and the hydroxide especially calcium hydroxide of alkaline-earth metal is used in combination to make
The preparation method at (6S) -5-methyltetrahydrofolate calcium salt.
It is resolving agent from outer that US5457202A, which is disclosed using organic base N- ethyl-2-aminomethylpentazaneands or its enantiomer,
The method that raceme (6R, S) -5-methyltetrahydrofolate prepares (6S) -5-methyltetrahydrofolate and its calcium salt.
WO2013025203A discloses a kind of method preparing (6S) -5-methyltetrahydrofolate salt, and this method includes as follows
Step：Folic acid obtains tetrahydrofolic acid through Borohydride reduction, then obtains N-5- methyl tetrahydrofolates with formaldehyde reduction amination, then uses
N- alkyl-D-Glucose amine is split as (6S) -5-methyltetrahydrofolate and (6R) -5-methyltetrahydrofolate, last (6S) -5- first
Base tetrahydrofolic acid obtains product (6S) -5-methyltetrahydrofolate calcium with calcium salt at salt again.
Equal resolution racemic modification (6R, the S) -5-methyltetrahydrofolate of patent documents above, obtains (6S) -5- methyl four
Then hydrogen folic acid regenerates (6S) -5-methyltetrahydrofolate calcium, since the property of (6S) -5-methyltetrahydrofolate is extremely active,
Therefore impurity is easily generated when splitting, it is difficult to split out (6S) -5-methyltetrahydrofolate of high-purity, while also contributes to produce
The yield and cost of product.
CN103214487A discloses a kind of synthesis work of important medicine chemical material (6S) -5-methyltetrahydrofolate salt
Folic acid is suspended in the water that 5-7 times is measured by skill, and 1N-2N aqueous alkalis are added, and under nitrogen protection, sulphite is added,
Reaction 0.5-1.5h is kept at 60-75 DEG C, with activated carbon decolorizing, filters, antioxidant is added in filtrate, is adjusted with the acid of 2N-3N
PH to 2.5-3.5 is filtered, and is washed solid, is dried in vacuo to obtain tetrahydrofolic acid, tetrahydrofolic acid is suspended in the water that 5-7 times is measured, is added
Enter the formalin of 35%-40%, maintain 35-45 DEG C under nitrogen protection, reducing agent (being added in 45min) is added, keeps anti-
1-1.5h is answered, 3N-5N acetic acid tune pH6-7 are used after having reacted, 8%-11% calcium chloride solutions, filtering is added, filtrate adds chlorine
Change calcium solution, stir at room temperature, filter, is added in the 5-7 times of alcoholic solution measured after insoluble matter decoloration, filters, be dried in vacuo to obtain 5-
5-methyltetrahydrofolate calcium is mixed with organic base and anhydrous alcohol reflux 0.3-0.6h is added, is cooled to room by methyl tetrahydrofolate calcium
Temperature filters, and filter cake is recrystallized with alcohol, the solid recrystallized is added to the water, and adjusts pH to 1-2 with acid, is cooled to 0-5 DEG C, mistake
Filter, is washed to neutrality, is dried in vacuo (6S) -5-methyltetrahydrofolate calcium.5-methyltetrahydrofolate calcium is being torn open in this patent
Timesharing may dissociate, and influence the purity and yield of product；In addition resolution reaction uses organic base ((±)-α-phenylethylamine),
Entire reaction carries out in organic system, and production cost is high, and environmental pollution is big.
Invention content
It is this in view of the deficiencies of the prior art, the present invention provides a kind of preparation method of (6S) -5-methyltetrahydrofolate calcium
Preparation method is at low cost, high income, and product purity is high, and stable reaction is environmental-friendly.
The purpose of the present invention is achieved through the following technical solutions：
A kind of preparation method of (6S) -5-methyltetrahydrofolate calcium, including step as shown below：
(1) sodium borohydride is put under alkaline environment, the mixture of folic acid and water is added dropwise in room temperature, and heating reaction generates tetrahydrochysene
Folic acid；
(2) formaldehyde is successively added dropwise in the reaction solution of step (1) and sodium borohydride aqueous solution is reacted, after reaction
Cooling stands a period of time, filters removal boron salt later, obtains 5-methyltetrahydrofolate；
(3) calcium chloride solution, stirred crystallization are added dropwise in the filtrate of step (2), suction filtration obtains 5-methyltetrahydrofolate calcium；
(4) the 5-methyltetrahydrofolate calcium obtained in step (3) is mixed with water, EDTA and S- (-)-N- ethyls-is added
2- aminomethyl pyrrolidines, heating carry out resolution reaction, and R types enantiomer and S type enantiomers is precipitated in cooling priority after reaction, obtains
Continue that calcium chloride solution, stirred crystallization is added dropwise in S type enantiomers, suction filtration obtains (6S) -5-methyltetrahydrofolate calcium.
The present invention uses sodium borohydride reduction folic acid synthesis high-purity tetrahydrofolic acid (raceme) under alkaline condition, uses formaldehyde
It methylates to the tetrahydrofolic acid of synthesis, adds calcium chloride and generate 5-methyltetrahydrofolate calcium (raceme), EDTA is added
With S- (-)-N- ethyl-2-aminomethylpentazaneands, 5-methyltetrahydrofolate calcium (raceme) is split to obtain (6S) -5- first
Base tetrahydrofolic acid is eventually adding calcium chloride and obtains (6S) -5-methyltetrahydrofolate calcium at calcium salt.
The sodium hydroxide solution that alkaline environment in above-mentioned steps (1) is 25%, the heating reaction temperature are 80-
100℃。
The reaction of above-mentioned steps (2) carries out in the environment of pH is 8-10.
Dwell temperature in above-mentioned steps (2) is 0-10 DEG C, time of repose 5-12h.
The temperature of above-mentioned steps (3) and the stirred crystallization in step (4) is 0-10 DEG C, crystallization time 4-8h.
The temperature of heating reaction is 70-85 DEG C in above-mentioned steps (4), and the temperature that R type enantiomers are precipitated is 55-60 DEG C, after
The temperature that S type enantiomers are precipitated in continuous cooling is 15-25 DEG C.
The mass ratio of folic acid and water is 1 in above-mentioned steps (1)：3.
Above-mentioned dropwise addition calcium chloride solution at the reaction of salt is carried out in the environment that pH is 7.5, chlorine in the step (3)
A concentration of 5-15% for changing calcium solution, a concentration of 30-50% of calcium chloride solution in the step (4).
The adjusting solution of above-mentioned solution ph is concentrated hydrochloric acid.
Further, above-mentioned steps further include：(6S) -5-methyltetrahydrofolate calcium that step (4) obtains is mixed with water,
It is heated to flowing back, (6S) -5-methyltetrahydrofolate calcium crystallization after being refined after suction filtration.
The improvement of the present invention compared with the existing technology is as follows：
The maturation process of existing production (6S) -5-methyltetrahydrofolate calcium is, using folic acid as raw material, through reduction, methyl
Change, split, at salt and etc. be synthesized into, entire technique gross production rate is relatively low.The technique of the present invention is using folic acid as raw material, through also
It is former, methylate, calcium chloride at salt, fractionations, adding calcium chloride salt again, (6S) -5-methyltetrahydrofolate calcium is unstable and solves to prevent
From products therefrom is stablized, and purity is high.
Resolution reagent used in the technique of existing production (6S) -5-methyltetrahydrofolate calcium is mostly organic base ((±) -
α-phenylethylamine either (+)-α-phenylethylamine or (-)-α-phenylethylamine), the present invention uses water-soluble S- (-)-N- ethyl -2- ammonia
Crassitude is resolving agent, is avoided using organic solvent system, not only cost-effective, but also reduces environmental pollution.
The present invention carries out salt-forming reaction by the further investigation to salt-forming reaction, using the calcium chloride solution of two kinds of concentration,
Salt-forming reaction is carried out using the calcium chloride solution of low concentration in step (3), the generation of impurity can be reduced, make the 5- methyl of generation
Calcium leucovorin purity higher, and since resolution reaction has been completed in step (4), at salt during be difficult generate again it is new
Impurity can improve the yield of product so the calcium chloride solution using high concentration carries out salt-forming reaction.
The present invention replaces potassium borohydride using sodium borohydride so that reaction is milder, and reaction is more thorough, and yield is more
It is high.
By above technological means, (6S) -5-methyltetrahydrofolate calcium its total impurities prepared by the present invention can reach
1.0% hereinafter, total recovery can reach 40%-45%.
Description of the drawings
Fig. 1 is the nuclear magnetic resonance spectroscopy that the present invention prepares (6S) -5-methyltetrahydrofolate calcium；
Fig. 2 is the carbon-13 nmr spectra that the present invention prepares (6S) -5-methyltetrahydrofolate calcium.
Specific implementation mode
Below by the description of specific implementation mode, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art's basic thought according to the present invention, various modifications may be made or improves, but without departing from
The basic thought of the present invention, is all within the scope of the present invention.
Various raw materials and reagents used in the embodiment of the present invention are commercially available purchase unless otherwise instructed.
Detection method in the embodiment of the present invention is using Calcium L-5- specified in USP40
Methyltetrahydrofolate detection methods and standard, standard require total impurities to be not more than 2.5%.
Detecting instrument used in the present invention is Agilent 1100.
Embodiment 1：
(a concentration of 25% NaOH solution) puts into 22.4 grams of sodium borohydride under alkaline environment, is added dropwise at 25 DEG C of temperature
(mass ratio of folic acid and water is for mixture that 128g is made of folic acid and water：1：3), anti-at 85~90 DEG C after completion of dropwise addition
Answer 1 hour, adjust pH to 9.0 with concentrated hydrochloric acid after reaction, after having adjusted at 5~10 DEG C dropwise addition formaldehyde 16ml and in the temperature
Lower reaction 0.5 hour, is added dropwise the sodium borohydride aqueous solution of 27.2g a concentration of 40% after reaction, and insulation reaction 1 hour rises
Temperature to 55 DEG C react 0.5 hour, add 160ml water, with concentrated hydrochloric acid adjust pH to 7.5, stands 5 hours at 0~10 DEG C, filter removing
9% calcium chloride solution 64ml is added dropwise with hydrochloric acid tune pH to 7.5 in boron salt, filtrate, and stirred crystallization 4 hours at 0~10 DEG C are taken out
Filter to obtain 5-methyltetrahydrofolate calcium wet-milling.
After the 5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with water, 16.8gEDTA and 16g S- are added
(-)-N- ethyl-2-aminomethylpentazaneands are warming up to 80 DEG C, and stirring is cooled to 55 DEG C again after 0.5 hour, continues stirring 1 hour
After filter, remove R type enantiomers, filtrate is cooled to 15 DEG C, and suction filtration obtains S type enantiomers, and obtained S type enantiomers are stirred with water
It mixes uniformly, with concentrated hydrochloric acid tune pH to 7.5, a concentration of 34% calcium chloride solution 16ml is added dropwise, stirred crystallization 4 is small at 0~10 DEG C
When, suction filtration obtains (6S) -5-methyltetrahydrofolate calcium crude product.
(6S) -5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with 80ml water, is heated to flowing back, is stirred
It is filtered while hot after 1 hour, (6S) -5-methyltetrahydrofolate calcium 7.9g is obtained after dry.Total recovery is 43.7%, by detecting,
Its total impurities is 1.0%.Its nuclear magnetic resonance spectroscopy and carbon spectrum are shown in that attached drawing, data are：1H NMR(600MHz,D2O)δ7.42-
7.47(m,4H),6.51-6.55(m,4H),4.04-4.07(m,2H),3.20-3.22(m,2H),2.89-3.00(m,2H),
2.85(m,2H),2.77-2.81(m,2H),2.67-2.71(m,2H),2.28(s,6H),2.05-2.13(m,4H),1.88-
1.93(m,2H),1.75-1.80(m,2H)；13C NMR(150MHz,D2O)δ182.3,179.3,170.6,169.7,159.2,
153.6,151.9,129.0,121.4,112.4,112.7,102.3,55.7,54.8,43.3,42.6,35.6,34.2,28.4。
Embodiment 2：
(a concentration of 25% NaOH solution) puts into 22.4 grams of sodium borohydride under alkaline environment, is added dropwise at 25 DEG C of temperature
(ratio of folic acid and water is for mixture that 96ml is made of folic acid and water：1：3), reaction 1 is small at 80-85 DEG C after completion of dropwise addition
When, pH to 8.0 is adjusted with concentrated hydrochloric acid after reaction, formaldehyde 16ml is added dropwise at 5-10 DEG C after having adjusted and reacts at such a temperature
0.5 hour, the sodium borohydride aqueous solution of 27.2g a concentration of 40% is added dropwise after reaction, insulation reaction 1 hour is warming up to 50
DEG C reaction 0.5 hour, add 160ml water, with concentrated hydrochloric acid adjust pH to 7.5, stands 8 hours at 0-10 DEG C, filter remove boron salt, filter
5% calcium chloride solution 110ml is added dropwise in liquid hydrochloric acid tune pH to 7.5, and stirred crystallization 8 hours at 0~10 DEG C filter to obtain 5-
Methyl tetrahydrofolate calcium wet-milling.
After the 5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with water, 16.8gEDTA and 16g S- are added
(-)-N- ethyl-2-aminomethylpentazaneands are warming up to 70 DEG C, and stirring is cooled to 50 DEG C again after 0.5 hour, continues stirring 1 hour
After filter, remove R type enantiomers, filtrate is cooled to 20 DEG C, and suction filtration obtains S type enantiomers, and obtained S type enantiomers are stirred with water
It mixes uniformly, with concentrated hydrochloric acid tune pH to 7.5, a concentration of 50% calcium chloride solution 12ml is added dropwise, stirred crystallization 6 is small at 0-10 DEG C
When, suction filtration obtains (6S) -5-methyltetrahydrofolate calcium crude product.
(6S) -5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with 80ml water, is heated to flowing back, is stirred
It is filtered while hot after 1 hour, (6S) -5-methyltetrahydrofolate calcium 8.1g is obtained after dry.Total recovery is passed through for 44.8% to be detected,
Total impurities are 0.9%.
Embodiment 3：
(a concentration of 25% NaOH solution) puts into 22.4 grams of sodium borohydride under alkaline environment, is added dropwise at 25 DEG C of temperature
(ratio of folic acid and water is for mixture that 96ml is made of folic acid and water：1：3), 1 is reacted at 95-100 DEG C after completion of dropwise addition
Hour, adjust pH to 10.0 with concentrated hydrochloric acid after reaction, after having adjusted at 5-10 DEG C dropwise addition formaldehyde 16ml and at such a temperature
The sodium borohydride aqueous solution of 27.2g a concentration of 40%, insulation reaction 1 hour, heating is added dropwise in reaction 0.5 hour after reaction
It is reacted 0.5 hour to 60 DEG C, adds 160ml water, adjusted pH to 7.5 with concentrated hydrochloric acid, 12 hours are stood at 0-10 DEG C, filter and remove boron
15% calcium chloride solution 40ml is added dropwise with hydrochloric acid tune pH to 7.5 in salt, filtrate, and stirred crystallization 6 hours at 0-10 DEG C filter
Obtain 5-methyltetrahydrofolate calcium wet-milling.
After the 5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with water, 16.8gEDTA and 16g S- are added
(-)-N- ethyl-2-aminomethylpentazaneands are warming up to 85 DEG C, and stirring is cooled to 55 DEG C again after 0.5 hour, continues stirring 1 hour
After filter, remove R type enantiomers, filtrate is cooled to 25 DEG C, and suction filtration obtains S type enantiomers, and obtained S type enantiomers are stirred with water
It mixes uniformly, with concentrated hydrochloric acid tune pH to 7.5, a concentration of 30% calcium chloride solution 18ml is added dropwise, stirred crystallization 6 is small at 0-10 DEG C
When, suction filtration obtains (6S) -5-methyltetrahydrofolate calcium crude product.
(6S) -5-methyltetrahydrofolate calcium that above-mentioned steps obtain is stirred evenly with 80ml water, is heated to flowing back, is stirred
It is filtered while hot after 1 hour, (6S) -5-methyltetrahydrofolate calcium 7.6g is obtained after dry.Total recovery is 42.1%, by detecting,
Its total impurities is 1.0%.
Claims (10)
1. a kind of preparation method of (6S) -5-methyltetrahydrofolate calcium, which is characterized in that described method includes following steps：
(1) sodium borohydride is put under alkaline environment, the mixture of folic acid and water is added dropwise in room temperature, and heating carries out reaction and generates tetrahydrochysene
Folic acid；
(2) formaldehyde is successively added dropwise in the reaction solution of step (1) and sodium borohydride aqueous solution is reacted, stand after reaction
For a period of time, removal boron salt is filtered later, obtains 5-methyltetrahydrofolate；
(3) calcium chloride solution, stirred crystallization are added dropwise in the filtrate of step (2), suction filtration obtains 5-methyltetrahydrofolate calcium；
(4) the 5-methyltetrahydrofolate calcium obtained in step (3) is mixed with water, EDTA and S- (-)-N- ethyl -2- ammonia is added
Crassitude, heating carry out resolution reaction, and R types enantiomer and S type enantiomers, obtained S types is precipitated in cooling priority after reaction
Continue that calcium chloride solution, stirred crystallization is added dropwise in enantiomer, suction filtration obtains (6S) -5-methyltetrahydrofolate calcium.
2. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(1) sodium hydroxide solution that the alkaline environment in is 25%, the heating reaction temperature are 80-100 DEG C.
3. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(2) reaction carries out in the environment of pH is 8-10.
4. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(2) dwell temperature in is 0-10 DEG C, time of repose 5-12h.
5. the preparation method of (6s) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(3) temperature of the stirred crystallization and in step (4) is 0-10 DEG C, crystallization time 4-8h.
6. the preparation method of (6s) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(4) temperature of heating reaction is 70-85 DEG C in, and the temperature that R type enantiomers are precipitated is 55-60 DEG C, continues cooling and S type mappings are precipitated
The temperature of body is 15-25 DEG C.
7. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
(1) mass ratio of folic acid and water is 1 in：3.
8. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the dropwise addition
Calcium chloride solution at the reaction of salt is carried out in the environment that pH is 7.5, and calcium chloride solution is a concentration of in the step (3)
5-15%, a concentration of 30-50% of calcium chloride solution in the step (4).
9. according to claim 3 or the preparation method of (6S) -5-methyltetrahydrofolate calcium according to any one of claims 8, feature
It is, the adjusting solution of solution ph is concentrated hydrochloric acid.
10. the preparation method of (6S) -5-methyltetrahydrofolate calcium according to claim 1, which is characterized in that the step
Further include：(6S) -5-methyltetrahydrofolate calcium that step (4) obtains is mixed with water, is heated to flowing back, be refined after suction filtration
(6S) -5-methyltetrahydrofolate calcium crystallization afterwards.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627244A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | Enzyme process prepares L-5- methyl tetrahydrofolate calcium |
| CN113769694A (en) * | 2021-10-09 | 2021-12-10 | 连云港冠昕医药科技有限公司 | Preparation method and preparation device of safe L-5-methyl tetrahydrocalcium folate |
| CN114130097A (en) * | 2021-12-09 | 2022-03-04 | 连云港冠昕医药科技有限公司 | Purification method and device for preparing L-5-methyl tetrahydrocalcium folate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5350850A (en) * | 1991-10-10 | 1994-09-27 | Apr Applied Pharma Research S.A. | Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N5 diastereoisomers in form of alkali and alkaline earth metal salts |
| US5457202A (en) * | 1991-11-11 | 1995-10-10 | Knoll Aktiengesellschaft | Resolution of 5-methyltetrahydrofolic acid |
| CN103214487A (en) * | 2013-04-12 | 2013-07-24 | 张家港威胜生物医药有限公司 | Synthesis of important medical chemical raw material (6S)-5-methyl tetrahydrofolate |
-
2018
- 2018-05-23 CN CN201810500346.6A patent/CN108358928A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5350850A (en) * | 1991-10-10 | 1994-09-27 | Apr Applied Pharma Research S.A. | Process for the preparation of substituted tetrahydrofolico derivatives in the [6(R,S)(-)] forms and of their active [6(S)(-)] N5 diastereoisomers in form of alkali and alkaline earth metal salts |
| US5457202A (en) * | 1991-11-11 | 1995-10-10 | Knoll Aktiengesellschaft | Resolution of 5-methyltetrahydrofolic acid |
| CN103214487A (en) * | 2013-04-12 | 2013-07-24 | 张家港威胜生物医药有限公司 | Synthesis of important medical chemical raw material (6S)-5-methyl tetrahydrofolate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627244A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | Enzyme process prepares L-5- methyl tetrahydrofolate calcium |
| CN113769694A (en) * | 2021-10-09 | 2021-12-10 | 连云港冠昕医药科技有限公司 | Preparation method and preparation device of safe L-5-methyl tetrahydrocalcium folate |
| CN114130097A (en) * | 2021-12-09 | 2022-03-04 | 连云港冠昕医药科技有限公司 | Purification method and device for preparing L-5-methyl tetrahydrocalcium folate |
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