CN109970825A - A method of preparing magnesium fructose-diphosphate - Google Patents
A method of preparing magnesium fructose-diphosphate Download PDFInfo
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- CN109970825A CN109970825A CN201910215912.3A CN201910215912A CN109970825A CN 109970825 A CN109970825 A CN 109970825A CN 201910215912 A CN201910215912 A CN 201910215912A CN 109970825 A CN109970825 A CN 109970825A
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- fructose
- magnesium
- diphosphate
- diphosphonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
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Abstract
The invention discloses a kind of methods for preparing magnesium fructose-diphosphate, comprising: reacts fructose, sodium dihydrogen phosphate in the presence of magnesium chloride and fixed yeast, purifies, ester of Harden Young is made；2) fructose -1 for preparing step 1), 6- diphosphonic acid is configured to fructose -1,6- diphosphonic acid aqueous solution, under agitation to fructose -1, powdered magnesium hydroxide is added in 6- diphosphonic acid aqueous solution in batches, reacts, is made, ester of Harden Young is excessive relative to the inventory of magnesium hydroxide；The present invention, which can have both, obtains the product with high-purity, and simple process in high yield, is suitable for industrialized production.
Description
Technical field
The invention belongs to chemical medicine more particularly to ester of Harden Youngs and its derivative, and in particular to a kind of
The method for preparing magnesium fructose-diphosphate.
Background technique
Fructose-1,6-diphosphonic acid (fructose-1,6-diphosphate, FDP) is just identified early in the 1930s
For the important intermediate of glycometabolism.And (the structure such as following formula I of the derivative magnesium fructose-diphosphate made of fructose-1,6-diphosphonic acid
It is shown, a magnesium salts) it is the active drug for treating myocardial ischemia disease and cerebral ischemia diseases；
Such as Chinese patent CN95100068.3 discloses a kind of preparation method of magnesium fructose-diphosphate, with sucrose, phosphoric acid
Disodium hydrogen and yeast are that raw material carries out microorganism anerobic glycolysis, 41 ± 2 DEG C of fermentation temperature, fermentation time 4 hours, are examined with magnesium mixture
Survey keeps its phosphorylation reaction complete to confirm, then promotes it to be converted into bismuth salt precipitating with bismuth nitrate, finally makes to precipitate with magnesium chloride
It is fully converted into magnesium fructose-diphosphate, referring to embodiment, we could be aware that its yield very low about 9%, while by Shen
It asks someone to repeat to test, purity is not highly desirable, and the special work that it has its unexpected as treatment of myocardial infarction medicine yet
Property, it is confirmed through pharmacological testing, diphosphofructose magnesium is injected when ischaemic occurs for cardiac muscle, cardiac muscle can be made not by its subsequent office
Portion's ischemia injury is medically referred to as have pre- restrictive function, moreover regardless of the age bracket of patient, all preventabilitys are treated, because
Urgently those skilled in the art seeks a kind of methods to solve the above problems for this, and then can make magnesium fructose-diphosphate
Preparation can be with industrialized production, and large-scale application is in field of medicaments.
Summary of the invention
The technical problem to be solved by the present invention is to overcome deficiency in the prior art, provides and a kind of improved prepare fructose
The method of biphosphate magnesium can have both and obtain the product with high-purity, and simple process in high yield, be suitable for industrialized production.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:
A method of magnesium fructose-diphosphate being prepared, the preparation method includes the following steps:
(1) it reacts fructose, sodium dihydrogen phosphate in the presence of magnesium chloride and fixed yeast, purifies, fructose -1 is made,
6- diphosphonic acid；
(2) ester of Harden Young prepared by step (1) is configured to ester of Harden Young aqueous solution, in stirring bar
Powdered magnesium hydroxide is added in batches into the ester of Harden Young aqueous solution under part, reacts, the fructose is made
Biphosphate magnesium, the ester of Harden Young are excessive relative to the inventory of the magnesium hydroxide.
Some preferred aspects according to the present invention, in step (1), in terms of mass percentage, control starting reaction system
The mass percentage of middle fructose is 10-30%.
Some preferred aspects according to the present invention, in step (1), mole of sodium dihydrogen phosphate in control starting reaction system
Concentration is 0.2-0.6mol/L.
Some preferred aspects according to the present invention, in step (1), the molar concentration of magnesium chloride in control starting reaction system
For 0.02-0.03mol/L.
Some preferred aspects according to the present invention, in step (1), the fixed yeast by by saccharomycete be adsorbed on from
It is formed on sub-exchange resin.
Some preferred aspects according to the present invention, in step (2), the ester of Harden Young and the magnesium hydroxide
Molar ratio be 1.01-1.03: 1.
It is highly preferred that in step (2), the molar ratio of the ester of Harden Young and the magnesium hydroxide is
1.01-1.02∶1。
Some preferred aspects according to the present invention in step (2), carry out the reaction at 20-35 DEG C.
Some preferred aspects according to the present invention, in step (2), the preparation method further includes after said reaction
Separating-purifying step, the separating-purifying include: to carry out reaction mixture resulting after the reaction using micron membrane filter
Crude product is made in filter, and then the crude product and ethanol solution are mixed, filtering, then plus ethanol solution stirred crystallization, mistake
Filter, it is dry, obtain the magnesium fructose-diphosphate.
Some preferred aspects according to the present invention, in step (2), the aperture of the nanofiltration membrane is 0.2-0.25 μm.
Some preferred aspects according to the present invention, in step (2), controlling each input amount of the magnesium hydroxide, to account for it total
The 1/50-1/200 of inventory.
Some preferred aspects according to the present invention, in step (2), fructose -1 in the ester of Harden Young aqueous solution,
The molar concentration of 6- diphosphonic acid is 0.1-0.3mol/L.It is highly preferred that in step (2), the ester of Harden Young aqueous solution
The molar concentration of middle fructose-1,6-diphosphonic acid is 0.2-0.3mol/L.
Due to the use of above technical scheme, the invention has the following advantages over the prior art:
The present invention uses fixed yeast by fructose converting for ester of Harden Young, overcomes in the prior art individually
Yeast is excessive using consuming, and the defect of complex process is conducive to Produce on a large scale.The present invention innovatively uses fructose -1 simultaneously,
6- diphosphonic acid, which is directly reacted with magnesium hydroxide, prepares magnesium fructose-diphosphate, not only makes the final product purity of preparation higher, and receives
Rate is also more satisfactory, and post-processing is also simple, is conducive to industrialized production.
Specific embodiment
Above scheme is described further below in conjunction with specific embodiment；It should be understood that these embodiments are for illustrating
The basic principles, principal features and advantages of the present invention, and the present invention is not by the scope limitation of following embodiment；It is used in embodiment
Implementation condition further adjustment can be done according to specific requirement, the implementation condition being not specified is usually the item in routine experiment
Part.
In following, unless otherwise specified, all raw materials are substantially from conventional method that is commercially available or passing through this field
It is prepared.
Embodiment 1 prepares fructose-1,6-diphosphonic acid
Saccharomyces cerevisiae is placed in culture medium and cultivates and collect fermentation liquid, then makes it through anion exchange resin, quilt
Anion exchange resin adsorbs and fixed yeast is made；
Fructose aqueous solution 10L is selected, sodium dihydrogen phosphate, magnesium chloride are added in fructose aqueous solution and form reaction system,
The mass percentage that middle fructose accounts for reaction system is 30%, and the molar concentration of sodium dihydrogen phosphate is 0.25mol/L, magnesium chloride
Molar concentration is 0.025mol/L, and then flowing through fixed yeast at 40 DEG C or so makes reaction system connect with fixed yeast
Touching, obtains crude product after outflow, and using active carbon decoloring, column chromatography (uses Chioro-anion exchange resin chromatographic column), is made
Ester of Harden Young, 386.8g, yield 91%, purity 99.5%.
Embodiment 2 prepares magnesium fructose-diphosphate
The fructose-1,6-diphosphonic acid (1.01mol) prepared according to method shown in embodiment 1 is dissolved in water (4L), fruit is made
Sugar -1,6- diphosphonic acid aqueous solution adds into the ester of Harden Young aqueous solution of preparation by 100 times in batches under agitation
Enter powdered magnesium hydroxide (0.01mol is added in total 1mol every time), reacts at room temperature, by reaction resulting after reaction
Mixture is filtered using 0.22 μm of micron membrane filter, and crude product is made, is then with mass fraction by the crude product
95% ethanol water is mixed, and the additional amount of ethanol water is about 3-4 times of crude product quality, and stirring makes fructose two
Magnesium phosphate precipitation, filtering, then plus mass fraction be 95% ethanol water, stirred crystallization filters, dry, obtains purification
Magnesium fructose-diphosphate 282.6g, yield is about 78%, and purity is about 97.8%.
Embodiment 3 prepares magnesium fructose-diphosphate
The fructose-1,6-diphosphonic acid (1.02mol) prepared according to method shown in embodiment 1 is dissolved in water (4L), fruit is made
Sugar -1,6- diphosphonic acid aqueous solution is added portionwise into the ester of Harden Young aqueous solution of preparation by 80 times under agitation
Powdered magnesium hydroxide (0.0125mol is added in total 1mol every time), reacts, at room temperature by reaction resulting after reaction
Mixture is filtered using 0.22 μm of micron membrane filter, and crude product is made, is then with mass fraction by the crude product
95% ethanol water is mixed, and the additional amount of ethanol water is about 3-4 times of crude product quality, and stirring makes fructose two
Magnesium phosphate precipitation, filtering, then plus mass fraction be 95% ethanol water, stirred crystallization filters, dry, obtains purification
Magnesium fructose-diphosphate 261.9g, yield is about 72.3%, and purity is about 96%.
Embodiment 4 prepares magnesium fructose-diphosphate
The fructose-1,6-diphosphonic acid (2.02mol) prepared according to method shown in embodiment 1 is dissolved in water (8L), fruit is made
Sugar -1,6- diphosphonic acid aqueous solution adds into the ester of Harden Young aqueous solution of preparation by 200 times in batches under agitation
Enter powdered magnesium hydroxide (0.01mol is added in total 2mol every time), reacts at room temperature, by reaction resulting after reaction
Mixture is filtered using 0.22 μm of micron membrane filter, and crude product is made, is then with mass fraction by the crude product
95% ethanol water is mixed, and the additional amount of ethanol water is about 3-4 times of crude product quality, and stirring makes fructose two
Magnesium phosphate precipitation, filtering, then plus mass fraction be 95% ethanol water, stirred crystallization filters, dry, obtains purification
Magnesium fructose-diphosphate 581.1g, yield is about 80.2%, and purity is about 96.5%.
Comparative example 1
Substantially with embodiment 2, difference is only that, directly mixes ester of Harden Young with magnesium hydroxide in reaction
It is stirred to react, magnesium fructose-diphosphate 219.6g, yield 60.6%, purity 94% is made.
Comparative example 2
Substantially with embodiment 2, difference is only that, magnesium hydroxide is replaced with magnesium carbonate, and magnesium fructose-diphosphate is made
280.8g, yield 77.5%, purity 88%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention, it is all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of method for preparing magnesium fructose-diphosphate, which is characterized in that the preparation method includes the following steps:
(1) it reacts fructose, sodium dihydrogen phosphate in the presence of magnesium chloride and fixed yeast, purifies, fructose -1,6- bis- is made
Phosphoric acid；
(2) ester of Harden Young prepared by step (1) is configured to ester of Harden Young aqueous solution, under agitation
Powdered magnesium hydroxide is added in batches into the ester of Harden Young aqueous solution, reacts, two phosphorus of fructose is made
Sour magnesium, the ester of Harden Young are excessive relative to the inventory of the magnesium hydroxide.
2. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (1), with quality hundred
Divide content meter, the mass percentage of fructose is 10-30% in control starting reaction system；And/or it in step (1), controls
The molar concentration of sodium dihydrogen phosphate is 0.2-0.6mol/L in beginning reaction system, mole of magnesium chloride in control starting reaction system
Concentration is 0.02-0.03mol/L, and the fixed yeast is formed and saccharomycete is adsorbed on ion exchange resin.
3. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), the fruit
The molar ratio of sugar -1,6- diphosphonic acid and the magnesium hydroxide is 1.01-1.03: 1.
4. the method according to claim 3 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), the fruit
The molar ratio of sugar -1,6- diphosphonic acid and the magnesium hydroxide is 1.01-1.02: 1.
5. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), make described anti-
It should be carried out at 20-35 DEG C.
6. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), the preparation
Method further includes separating-purifying step after said reaction, and the separating-purifying includes: will be resulting anti-after the reaction
It answers mixture to be filtered using micron membrane filter, crude product is made, then the crude product and ethanol solution are mixed, mistake
Filter, then plus ethanol solution stirred crystallization, filter, it is dry, obtain the magnesium fructose-diphosphate.
7. the method according to claim 6 for preparing magnesium fructose-diphosphate, which is characterized in that the aperture of the nanofiltration membrane
It is 0.2-0.25 μm.
8. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), described in control
The each input amount of magnesium hydroxide accounts for the 1/50-1/200 of its total amount of feeding.
9. the method according to claim 1 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), the fruit
The molar concentration of fructose-1,6-diphosphonic acid is 0.1-0.3mol/L in sugar -1,6- diphosphonic acid aqueous solution.
10. the method according to claim 9 for preparing magnesium fructose-diphosphate, which is characterized in that in step (2), the fruit
The molar concentration of fructose-1,6-diphosphonic acid is 0.2-0.3mol/L in sugar -1,6- diphosphonic acid aqueous solution.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910215912.3A CN109970825A (en) | 2019-03-21 | 2019-03-21 | A method of preparing magnesium fructose-diphosphate |
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| CN201910215912.3A CN109970825A (en) | 2019-03-21 | 2019-03-21 | A method of preparing magnesium fructose-diphosphate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123794A (en) * | 1995-07-10 | 1996-06-05 | 广州科阳工贸有限公司 | Magnesium hexose diphosphate and its production |
| CN1265397A (en) * | 2000-01-17 | 2000-09-06 | 欧阳平凯 | Preparation of magnesium fructose-1,6-diphosphate |
| CN1519245A (en) * | 2003-01-20 | 2004-08-11 | 赵建安 | Diabetin-1, 6-diphosphonie acid as well as preparation method and application |
-
2019
- 2019-03-21 CN CN201910215912.3A patent/CN109970825A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123794A (en) * | 1995-07-10 | 1996-06-05 | 广州科阳工贸有限公司 | Magnesium hexose diphosphate and its production |
| CN1265397A (en) * | 2000-01-17 | 2000-09-06 | 欧阳平凯 | Preparation of magnesium fructose-1,6-diphosphate |
| CN1519245A (en) * | 2003-01-20 | 2004-08-11 | 赵建安 | Diabetin-1, 6-diphosphonie acid as well as preparation method and application |
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