CN109970824B - Preparation method of high-stability fructose calcium diphosphate - Google Patents
Preparation method of high-stability fructose calcium diphosphate Download PDFInfo
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- CN109970824B CN109970824B CN201910215911.9A CN201910215911A CN109970824B CN 109970824 B CN109970824 B CN 109970824B CN 201910215911 A CN201910215911 A CN 201910215911A CN 109970824 B CN109970824 B CN 109970824B
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- C07—ORGANIC CHEMISTRY
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- 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 preparation method of fructose diphosphate calcium, which comprises the steps of reacting fructose-1,6-diphosphate with calcium chloride to prepare fructose diphosphate calcium, and carrying out the reaction in a mixed solvent in the presence of mixed acid, wherein the mixed solvent comprises 0.5-1.5% of ethanol and 98.5-99.5% of water in percentage by volume, and the mixed acid comprises concentrated nitric acid and hydrochloric acid in a mass ratio of 1: 0.1-0.5, wherein the concentrated nitric acid is a nitric acid aqueous solution with the mass fraction of 68-98%; the method can avoid yellowing of the product, obtain the product with high yield and high purity, has simple process and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical medicine, particularly relates to fructose-1,6-diphosphate and derivatives thereof, and particularly relates to a preparation method of fructose diphosphate calcium.
Background
Fructose-1,6-diphosphate (FDP) was identified as an important intermediate in sugar metabolism as early as 30 in the 20 th century. After experimental animals and clinical researches of the American Markov and the like discovered that FDP sodium salt has the curative effect on tissue ischemia and hypoxia diseases such as myocardial infarction, shock and the like since the 80 th century, FDP sodium salt (injection grade freeze-dried powder, the trade name is Efafosfina) and fructose diphosphate calcium (calcium fructose diphosphate-1, 6-diphosphonate, CaFDP, shown as the following formula (1), tablets are developed by Foscama pharmaceutical company of Italy,
the fructose diphosphate calcium can be used for the adjuvant treatment of various metabolic diseases such as brain metabolic diseases, ossification diseases, skeletal muscle metabolic disorder, diabetes and the like.
The dietary structure of China is mainly cereals, the calcium content is low, the vegetable supply amount is high, the intake of phytic acid, oxalic acid, plant fiber and the like is relatively large, and all the substances can influence the absorption of calcium in intestinal tracts. The intake of calcium-rich milk products is small, and the dietary structure has been improved in recent years, but it is not sufficient. The daily requirement of calcium for adults, 1000mg for teenagers and 1500mg for pregnant women and the elderly, which are formulated by the Chinese academy of nutrition in 1988, is 800 mg. At present, the average daily calcium intake of each person in China is 500mg, which is not yet achieved.
30-50 mg of calcium is lost every day from the age of 35, and the total amount of bones is reduced to about 0.7kg after the age of 50. The head of the middle-aged and the elderly becomes short, which is related to the short of the decalcification of the spine.
As bone calcium "migrates", the calcium content in bones is reduced, and the calcium content in soft tissues and blood is increased, so that people are easy to fatigue, lack of strength in the whole body, waist soreness and back pain. Therefore, calcium salt is supplemented, and fatigue of susceptible people can be better relieved. Besides strengthening bones and teeth, calcium also has the functions of improving the endurance and explosive power of human bodies, treating and preventing osteoporosis and the like. Calcium deficiency can lead to osteoporosis. Osteoporosis is a common senile disease, and the total number of people suffering from osteoporosis is more than 2 hundred million in the world at present, which is the sixth most common disease and frequently encountered disease. The pathogenesis of the disease is that due to calcium deficiency, PTH secretion of the body is accelerated, bone calcium is promoted to enter blood, and calcium deposits in soft tissues, particularly in arterial walls, are increased. In addition, the change at the cellular level is membrane permeability increase, Ca2+The concentration of the protein entering the cells is increased, thereby causing osteoporosis.
However, the existing preparation method of fructose diphosphate mainly has the problem of yellowing of the product, and a way for solving the problem is urgently needed by those skilled in the art.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art, and provide an improved method for preparing fructose diphosphate, which can avoid yellowing of products, obtain products with high yield and high purity, has simple process and is suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the preparation method of fructose diphosphate calcium comprises the step of reacting fructose-1,6-diphosphate with calcium chloride to prepare fructose diphosphate calcium, and the preparation method further comprises the step of carrying out the reaction in a mixed solvent in the presence of a mixed acid, wherein the mixed solvent comprises 0.5-1.5% of ethanol and 98.5-99.5% of water in percentage by volume, and the mixed acid comprises concentrated nitric acid and hydrochloric acid according to the mass ratio of 1: 0.1-0.5, wherein the concentrated nitric acid is a nitric acid water solution with the mass fraction of 68-98%.
According to some preferred aspects of the invention, the feeding mass ratio of the mixed acid to the fructose-1, 6-bisphosphate is 0.1-0.6: 1.
According to some preferred aspects of the invention, the feeding mass ratio of the mixed acid to the fructose-1, 6-bisphosphate is 0.3-0.6: 1.
According to some preferred aspects of the present invention, the mixed solvent is composed of 0.5% to 1.0% of ethanol and 99 to 99.5% of water.
According to some preferred aspects of the invention, the feed molar ratio of the calcium chloride to the fructose-1, 6-bisphosphate is 1.01-1.05: 1.
According to some specific aspects of the invention, the hydrochloric acid is a 10-38% aqueous solution of hydrogen chloride in mass fraction.
According to some preferred aspects of the invention, the mixed acid consists of concentrated nitric acid and hydrochloric acid in a mass ratio of 1: 0.25-0.5.
According to some preferred aspects of the invention, the specific embodiments for preparing the fructose bisphosphate are: dissolving the fructose-1,6-diphosphate in the water, and then sequentially adding the mixed acid, the calcium chloride and the ethanol into the water for reaction.
According to some specific and preferred aspects of the present invention, the preparation method further comprises adding ethanol to the mixed solution obtained after the reaction, precipitating to obtain a syrup, and drying to obtain the fructose diphosphate.
According to some preferred aspects of the invention, in the preparation method, 90-95% by mass of ethanol water is added firstly, then water is added to adjust the mass fraction of ethanol to 60-65%, the syrup is obtained by precipitation, and the fructose diphosphate calcium is prepared by drying.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the invention, the fructose-1,6-diphosphate and calcium chloride are controlled to react in a specific mixed solvent, and the specific mixed acid is adopted for catalysis, so that the occurrence of side reactions is reduced, the selectivity is improved, the finally prepared fructose diphosphate keeps a good color, the problem of yellowing of products in the prior art is avoided, the yield and the purity are extremely high, and the preparation method can meet the requirements of industrial mass production.
Detailed Description
Through a large amount of research, the following findings are obtained: the yellowing of the final product fructose diphosphate calcium is caused by excessive impurities due to more side reactions in the reaction process, so that the yellowing of the final product is caused, and the inventor of the application finds that the yellowing problem of the final product can be solved when the purity of the final product is controlled to be more than 99.5 percent.
Based on the above, the application provides a preparation method of fructose diphosphate, the preparation method comprises the step of reacting fructose-1,6-diphosphate with calcium chloride to prepare the fructose diphosphate, the preparation method further comprises the step of carrying out the reaction in a mixed solvent in the presence of a mixed acid, wherein the mixed solvent comprises 0.5-1.5% of ethanol and 98.5-99.5% of water in percentage by volume, the mixed acid comprises concentrated nitric acid and hydrochloric acid according to a mass ratio of 1: 0.1-0.5, and the concentrated nitric acid is a nitric acid aqueous solution with a mass fraction of 68-98%.
In the invention, a small amount of ethanol is added to be capable of complexing with calcium chloride and further combining part of calcium chloride, so that fructose-1, 6-diphosphonic acid is always in an excessive state in the reaction process, a monocalcium salt is basically generated in the reaction, only a trace amount of dicalcium salt can be generated, and the combined calcium chloride can be slowly released by the complex in the continuous reaction process, so that the fructose-1, 6-diphosphonic acid can be ensured to be basically reacted completely, the cost is greatly saved, and the purity and the yield are improved. Meanwhile, under the action of the specific mixed acid, the generation of monocalcium salt is further ensured, the occurrence of side reactions is reduced, the yield is improved, and the purity is extremely high.
Preferably, the feeding mass ratio of the mixed acid to the fructose-1,6-diphosphate is 0.1-0.6: 1. More preferably, the feeding mass ratio of the mixed acid to the fructose-1,6-diphosphate is 0.3-0.6: 1.
Preferably, the mixed solvent is composed of 0.5% -1.0% of ethanol and 99-99.5% of water.
Preferably, the feeding molar ratio of the calcium chloride to the fructose-1,6-diphosphate is 1.01-1.05: 1.
Preferably, the hydrochloric acid is a 10-38% aqueous solution of hydrogen chloride in mass fraction.
Preferably, the mixed acid consists of concentrated nitric acid and hydrochloric acid according to the mass ratio of 1: 0.25-0.5.
Preferably, the specific embodiment for preparing the fructose diphosphate calcium is as follows: dissolving the fructose-1,6-diphosphate in the water, and then sequentially adding the mixed acid, the calcium chloride and the ethanol into the water for reaction.
In some embodiments of the present invention, the preparation method further comprises adding ethanol to the mixed solution obtained after the reaction, precipitating to obtain syrup, and drying to obtain the fructose diphosphate. Preferably, in the preparation method, 90-95% by mass of ethanol aqueous solution is added firstly, then water is added to adjust the mass fraction of ethanol to 60-65%, the syrup is obtained by precipitation, and the fructose diphosphate calcium is prepared by drying.
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments. In the following, all starting materials are essentially obtained commercially or prepared by conventional methods in the art, unless otherwise specified.
EXAMPLE 1 preparation of fructose diphosphate calcium
Dissolving fructose-1,6-diphosphate (1mol) in water to form a water (178.2ml) solution, adding 114g of concentrated nitric acid (mass percentage content), 56g of hydrochloric acid (mass percentage content is 36%), 1.02mol of calcium chloride and 1.8ml of ethanol into the water solution formed in the previous step, adding an ethanol water solution with the mass fraction of 95%, adding water to adjust the mass fraction of the ethanol to 60%, precipitating to obtain syrup, and performing spray drying to obtain 366.7g of fructose diphosphate, wherein the yield is 97% and the purity is 99.8%.
EXAMPLE 2 preparation of fructose diphosphate calcium
Dissolving fructose-1,6-diphosphate (2mol) in water to form a water (475.2ml) solution, adding 210g of concentrated nitric acid (mass percentage content), 62g of hydrochloric acid (mass percentage content is 36%), 2.06mol of calcium chloride and 4.8ml of ethanol, adding an ethanol water solution with the mass fraction of 95%, adding water to adjust the mass fraction of the ethanol to 60%, precipitating to obtain syrup, and performing spray drying to obtain 740.9g of fructose diphosphate, wherein the yield is 98% and the purity is 99.6%.
EXAMPLE 3 preparation of fructose diphosphate calcium
Dissolving fructose-1,6-diphosphate (1mol) in water to form a water (178.2ml) solution, adding 114g of concentrated nitric acid (mass percentage content), 56g of hydrochloric acid (mass percentage content is 36%), 1.01mol of calcium chloride and 1.8ml of ethanol into the water solution formed in the previous step, adding an ethanol water solution with the mass fraction of 95%, adding water to adjust the mass fraction of the ethanol to 60%, precipitating to obtain syrup, and performing spray drying to obtain 363g of fructose diphosphate calcium, wherein the yield is 96% and the purity is 99.7%.
Comparative example 1
Essentially the same as example 1 except that only a single hydrochloric acid was added to produce 332.6g of fructose diphosphate having a yield of 88% and a purity of 94%.
Comparative example 2
Essentially the same as example 1, except that only a single amount of concentrated nitric acid was added, 340g of fructose diphosphate was obtained in a yield of 90% and a purity of 96%.
Comparative example 3
Basically the same as example 1, except that 321g of fructose diphosphate was obtained in 85% yield and 98% purity by adding only a single amount of water as a solvent.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. The preparation method of fructose diphosphate monocalcium comprises the step of reacting fructose-1,6-diphosphate with calcium chloride to prepare fructose diphosphate monocalcium, and is characterized by further comprising the step of carrying out the reaction in a mixed solvent in the presence of a mixed acid, wherein the mixed solvent comprises 0.5-1.0% of ethanol and 99-99.5% of water in percentage by volume, the mixed acid comprises concentrated nitric acid and hydrochloric acid in a mass ratio of 1: 0.1-0.5, and the concentrated nitric acid is a nitric acid aqueous solution with the mass fraction of 68%;
the specific implementation mode for preparing the fructose diphosphate monocalcium is as follows: dissolving the fructose-1,6-diphosphate in the water, and then sequentially adding the mixed acid, the calcium chloride and the ethanol into the water for reaction.
2. The method for preparing fructose diphosphate monocalcium according to claim 1, wherein the feeding mass ratio of the mixed acid to the fructose-1,6-diphosphate is 0.1-0.6: 1.
3. The method for preparing fructose diphosphate monocalcium according to claim 2, wherein the feeding mass ratio of the mixed acid to the fructose-1,6-diphosphate is 0.3-0.6: 1.
4. The method for preparing fructose diphosphate monocalcium according to claim 1, wherein the feeding molar ratio of calcium chloride to fructose-1,6-diphosphate is 1.01-1.05: 1.
5. The method for producing fructose diphosphate monocalcium according to claim 1, wherein the hydrochloric acid is an aqueous solution of hydrogen chloride having a mass fraction of 10 to 38%.
6. The method for preparing fructose diphosphate monocalcium according to claim 1, wherein the mixed acid consists of concentrated nitric acid and hydrochloric acid at a mass ratio of 1: 0.25-0.5.
7. The method according to claim 1, further comprising adding ethanol to the mixed solution obtained after the reaction, precipitating to obtain a syrup, and drying to obtain the fructose diphosphate monocalcium.
8. The method for preparing fructose diphosphate monocalcium according to claim 7, wherein the fructose diphosphate monocalcium is prepared by first adding an aqueous solution of ethanol with a mass fraction of 90-95%, then adding water to adjust the mass fraction of ethanol to 60-65%, precipitating to obtain the syrup, and drying.
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| RU2278164C2 (en) * | 2003-09-15 | 2006-06-20 | Общество с ограниченной ответственностью ООО "ЭЛЕСТ" | Method for production of calcium fructose diphosphate |
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