Synthesis method of calcium glycerophosphate

Abstract

The invention discloses a novel synthesis method of calcium glycerophosphate. The method comprises the following steps: reacting glycidol with a sodium dihydrogen phosphate aqueous solution under an acidic condition to generate an intermediate sodium glycerophosphate, then generating disodium glycerophosphate under an alkaline condition, and finally carrying out a replacement reaction with calcium chloride to obtain a high-purity calcium glycerophosphate product. The process is high in atom economy and small in environmental pollution, the product purity can reach 99.0% or above, and the method is suitable for the fields of medicine, food, feed additives and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a novel method for synthesizing calcium glycerophosphate. Background Technology

[0002] Calcium glycerophosphate is an important organic calcium salt whose molecular structure contains both calcium ions (Ca²⁺) and glycerophosphate ions. Compared with traditional inorganic calcium salts (such as calcium carbonate and calcium phosphate), calcium glycerophosphate has significant advantages due to its unique chemical properties: (1) High bioavailability: It has good solubility in neutral or weakly alkaline environments and is more easily absorbed by the human intestine; (2) Good biocompatibility and safety: Calcium glycerophosphate is a naturally occurring metabolic intermediate in the human body and has no irritation or toxic side effects; (3) Dual nutritional function: After metabolism in the body, it can release both calcium ions and phosphate ions, both of which are essential nutrients for bone and teeth mineralization. In addition, the glycerol portion can also participate in energy metabolism. Based on the above excellent properties, calcium glycerophosphate is widely used in food and nutritional supplements, oral care, medicine, biomaterials and other fields.

[0003] Traditional methods for synthesizing calcium glycerophosphate mainly include: direct neutralization, phosphate method, and phosphorus oxychloride method. (1) Direct neutralization method: Glycerophosphate ester reacts directly with calcium hydroxide or calcium carbonate to produce calcium glycerophosphate. However, due to the high cost of glycerophosphate ester and the water solubility of the product calcium glycerophosphate, the yield of the product is low, resulting in high cost of this reaction process. (2) Phosphate method: Calcium glycerophosphate is synthesized by metathesis reaction of water-soluble glycerophosphate sodium or potassium salts with soluble calcium salts. However, the cost of purchasing sodium and potassium salts of glycerophosphate is higher than that of calcium glycerophosphate. (3) Phosphorus oxychloride method: Glycerophosphate ester is generated by phosphorus oxychloride and anhydrous glycerol under the condition of pyridine as catalyst. Then, it reacts with calcium hydroxide or calcium carbonate to finally obtain calcium glycerophosphate. However, the recovery process of the pyridine salt obtained by this reaction is relatively complicated. Compared with traditional synthesis methods, the method of synthesizing calcium glycerophosphate using glycidol, sodium dihydrogen phosphate, and calcium chloride as raw materials has the advantages of lower cost, better product quality, and environmental friendliness. Summary of the Invention

[0004] To address the shortcomings of existing glycerophosphate synthesis technologies, such as high raw material costs, harsh reaction conditions, low product purity, and significant environmental pollution, this invention proposes a novel synthesis method for glycerophosphate. This synthesis process utilizes readily available raw materials, mild reaction conditions, produces high-purity products, and is environmentally friendly.

[0005] The core of this invention is the synthesis of calcium glycerophosphate through a reaction of glycidyl phosphate with sodium dihydrogen phosphate and calcium ion exchange. The specific steps are as follows: (1) Glycidol reacts with sodium dihydrogen phosphate under acidic conditions to generate the intermediate sodium glycerophosphate. The intermediate is then reacted under alkaline conditions to generate disodium glycerophosphate.

[0006] (2) Prepare an aqueous solution of the disodium glycerophosphate obtained in step (1) and react it with calcium chloride solution to generate calcium glycerophosphate.

[0007] The reaction formula is as follows: first step:

[0008] Step Two:

[0009] In step (1), the molar ratio of sodium dihydrogen phosphate to glycidol is 1.0~1.3:1.0, preferably 1.05~1.2:1.0. The range of values ​​for the molar ratio of sodium dihydrogen phosphate to glycidol refers to any range or any value within that range.

[0010] In step (1), the reaction time is 4-8 hours, preferably 4-6 hours, and the reaction temperature is 50-80℃, preferably 50-60℃. The range of reaction time and temperature refers to any range or any value within that range.

[0011] The acidic conditions in step (1) are adjusted by inorganic or organic acids, and the pH of the system is 3.0 to 6.0. The inorganic acid is hydrochloric acid, phosphoric acid or sulfuric acid; the organic acid is acetic acid or citric acid.

[0012] The pH of the system under alkaline conditions in step (1) is 7.5 to 10, with a preferred pH of 8.0 to 9.5.

[0013] In step (1), the sodium glycerophosphate is purified by removing inorganic salts using a nanofiltration membrane. The nanofiltration membrane is one of the following: NF270-200Da, NF90-200Da, ESNA-LF-200Da, ESNA-LF2-200Da, TNF-1-200Da, or TNF-4-200Da.

[0014] In step (2), the molar ratio of calcium chloride to sodium glycerophosphate is 1.0 ~ 1.5: 1.0, and the reaction temperature is 30-100℃; wherein the preferred molar ratio is 1.0 ~ 1.2: 1.0, and the preferred reaction temperature is 50 ~ 80℃.

[0015] In step (2), the crystallization temperature of calcium glycerophosphate is 10-15°C, and inorganic impurities are removed by washing with ethanol.

[0016] The synthesis process of glycerophosphate provided by this invention has the following advantages compared with existing glycerophosphate methods: (1) High atom economy: The high reactivity of the epoxy group of glycidyl phosphate is utilized to directly open the ring and esterify with sodium dihydrogen phosphate, avoiding the preparation steps of glycerophosphate in the traditional process and shortening the process route.

[0017] (2) Mild conditions: The main reaction temperatures are all below 60°C, eliminating the need for high-temperature and high-pressure equipment, thus reducing equipment investment and energy consumption.

[0018] (3) High product purity: Inorganic salt impurities (NaCl, Na3PO4, etc.) are effectively removed by nanofiltration membrane desalination and ethanol washing, and the product purity is ≥99.0% (HPLC detection).

[0019] (4) Green and environmentally friendly: The mother liquor can be recycled (NaCl solution can be used to prepare calcium chloride solution after treatment), which reduces the discharge of high-salt wastewater. Detailed Implementation

[0020] To illustrate the technical solution provided by this invention in more detail, the invention will be further explained below with reference to examples. However, the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0021] Example 1 In a 500 mL three-necked flask equipped with a stirrer, 49.2 g (0.4 mol) of sodium dihydrogen phosphate and 150 mL of deionized water were added, and the mixture was heated to 50 °C and stirred to dissolve. The pH was adjusted to a specific value using 0.1 mol / L hydrochloric acid solution (the system pH was adjusted to 1.0, 3.0, 4.5, and 6.0). 37.0 g (0.4 mol) of glycidyl phosphate was slowly added dropwise, and the mixture was heated to 50 °C and reacted for 5 hours. After the reaction was completed, a pre-prepared 10% sodium hydroxide aqueous solution was slowly added dropwise to the system at 50 °C to bring the pH of the reaction system to 8.5. After adding 1.5 g of activated carbon for decolorization for 30 minutes, the mixture was hot-filtered. The filtrate was desalted through an NF270-200 Da nanofiltration membrane and concentrated under reduced pressure to obtain wet disodium glycerophosphate. The wet product was dried in a vacuum oven at 60 °C for 12 hours to obtain a white solid disodium glycerophosphate. The purity of the obtained product was determined by liquid chromatography.

[0022] The above disodium glycerophosphate solution was heated to 55°C, and 20% calcium chloride solution (approximately 0.11 mol) was slowly added. The reaction was maintained at this temperature for 1 hour. After cooling to 10°C, the solution was crystallized, centrifuged, and the filter cake was washed with 20 mL of ice-cold ethanol. The product was then vacuum dried at 65°C to obtain calcium glycerophosphate. The purity of the calcium glycerophosphate was determined.

[0023] Adjusting the pH of the reaction system to different values ​​using hydrochloric acid in step 1 of the reaction has the following beneficial effects: Table 1: Effect of pH on the reaction in step 1

[0024] As shown in Table 1, the purity and yield of the glycerophosphate disodium salt obtained by adjusting the pH of the reaction system to 3.0-6.0 using 0.1 mol / L hydrochloric acid in step 1 are better than those obtained under other acidic conditions. Therefore, the optimal pH of 3.0-6.0 obtained by adjusting the pH using acid in step 1 of this invention is shown to be better.

[0025] Example 2 In a 500 mL three-necked flask equipped with a stirrer, 49.2 g (0.4 mol) of sodium dihydrogen phosphate and 150 mL of deionized water were added. The mixture was heated to specific temperatures (30℃, 50℃, 80℃, and 100℃) and stirred until dissolved. The pH of the system was adjusted to 4.5 using 0.1 mol / L hydrochloric acid solution. 37.0 g (0.4 mol) of glycidyl phosphate was slowly added dropwise over 5 hours. After the reaction was complete, a pre-prepared 10% sodium hydroxide aqueous solution was slowly added dropwise to bring the pH of the reaction system to 8.5. 1.5 g of activated carbon was added for decolorization for 30 minutes, followed by hot filtration. The filtrate was desalted using an NF270-200Da nanofiltration membrane and concentrated under reduced pressure to obtain wet disodium glycerophosphate. The wet product was dried in a vacuum oven at 60℃ for 12 hours to obtain a white solid disodium glycerophosphate. The purity of the obtained product was determined by liquid chromatography.

[0026] The above disodium glycerophosphate solution was heated to 55°C, and 20% calcium chloride solution (approximately 0.11 mol) was slowly added. The reaction was maintained at this temperature for 1 hour. After cooling to 10°C, the solution was crystallized, centrifuged, and the filter cake was washed with 20 mL of ice-cold ethanol. The product was then vacuum dried at 65°C to obtain calcium glycerophosphate. The purity of the calcium glycerophosphate was determined.

[0027] The following benefits are observed when reacting step 1 at different reaction temperatures: Table 2: Effect of reaction temperature on the reaction in step 1

[0028] As shown in Table 2, when the reaction temperature in step 1 is 30-100℃, the yield and purity of disodium glycerophosphate are both good.

[0029] Example 3 In a 500 mL three-necked flask equipped with a stirrer, 49.2 g (0.4 mol) of sodium dihydrogen phosphate and 150 mL of deionized water were added, and the mixture was heated to 50 °C and stirred to dissolve. The pH of the system was adjusted to 4.5 with 0.1 mol / L hydrochloric acid solution. 37.0 g (0.4 mol) of glycidyl phosphate was slowly added dropwise, and the reaction was carried out for 5 hours. After the reaction was completed, a pre-prepared 10% sodium hydroxide aqueous solution was slowly added dropwise to the system to bring the pH of the reaction system to 8.5. After adding 1.5 g of activated carbon for decolorization for 30 minutes, the mixture was hot filtered. The filtrate (desalted by NF270-200Da, ESNA-LF-200Da, TNF-1-200Da nanofiltration membranes or without nanofiltration membranes) was concentrated under reduced pressure to obtain wet disodium glycerophosphate. The product was dried in a vacuum oven at 60 °C for 12 hours to obtain a white solid disodium glycerophosphate. The purity of the obtained product was determined by liquid chromatography.

[0030] The above disodium glycerophosphate solution was heated to 55°C, and 20% calcium chloride solution (approximately 0.11 mol) was slowly added. The reaction was maintained at this temperature for 1 hour. After cooling to 10°C, the solution was crystallized, centrifuged, and the filter cake was washed with 20 mL of ice-cold ethanol. The product was then vacuum dried at 65°C to obtain calcium glycerophosphate. The purity of the calcium glycerophosphate was determined.

[0031] Whether or not the system in reaction step 1 is treated with a nanofiltration membrane has the following beneficial effects: Table 3: Effect of nanofiltration membrane on the reaction in step 1

[0032] Table 3 shows that the product yield obtained without nanofiltration membrane desalination in step 1 is higher than that obtained with nanofiltration membrane treatment, but the product purity is lower. Therefore, nanofiltration membrane treatment is necessary after the reaction is completed.

[0033] Example 4 In a 500 mL three-necked flask equipped with a stirrer, 49.2 g (0.4 mol) of sodium dihydrogen phosphate and 150 mL of deionized water were added, and the mixture was heated to 50 °C and stirred to dissolve. The pH of the system was adjusted to 4.5 with 0.1 mol / L hydrochloric acid solution. 37.0 g (0.4 mol) of glycidyl phosphate was slowly added dropwise, and the mixture was heated to 50 °C for a period of time (3 h, 5 h, and 7 h, respectively). After the reaction was completed, a pre-prepared 10% sodium hydroxide aqueous solution was slowly added dropwise to the system at 50 °C to bring the pH of the reaction system to 8.5. After adding 1.5 g of activated carbon for decolorization for 30 minutes, the mixture was hot-filtered. The filtrate was desalted through an NF270-200 Da nanofiltration membrane and concentrated under reduced pressure to obtain wet disodium glycerophosphate. The wet product was dried in a vacuum oven at 60 °C for 12 h to obtain a white solid disodium glycerophosphate. The purity of the obtained product was determined by liquid chromatography.

[0034] The above disodium glycerophosphate solution was heated to 55°C, and 20% calcium chloride solution (approximately 0.11 mol) was slowly added. The reaction was maintained at this temperature for 1 hour. After cooling to 10°C, the solution was crystallized, centrifuged, and the filter cake was washed with 20 mL of ice-cold ethanol. The product was then vacuum dried at 65°C to obtain calcium glycerophosphate. The purity of the calcium glycerophosphate was determined.

[0035] Different reaction times for reaction step 1 have the following beneficial effects: Table 4: Effect of reaction time in step 1 on the reaction

[0036] As shown in Table 4, the product yield of disodium glycerophosphate was improved when the reaction time was 3-7 hours.

[0037] Those skilled in the art will readily understand that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for the synthesis of glycerophosphocholine, characterized in that, The method comprises the following steps: (1) reacting glycidol with sodium dihydrogen phosphate in an aqueous solution under acidic conditions to form monosodium glycerophosphate, and then converting the monosodium glycerophosphate into disodium glycerophosphate under alkaline conditions; (2) subjecting the disodium glycerophosphate obtained in step (1) to a double decomposition reaction with calcium chloride to form calcium glycerophosphate.

2. The method of claim 1, wherein, The molar ratio of sodium dihydrogen phosphate to glycidol in step (1) is 1.0-1.3:1.0, preferably the molar ratio is 1.05-1.2:1.

0.

3. The method of claim 1, wherein, The reaction temperature in step (1) is 50-80°C, and the reaction time is 4-8 hours.

4. The method of claim 3, wherein, The reaction temperature is 50-60°C, and the reaction time is 4-6 hours.

5. The method of claim 1, wherein, The acidic conditions in step (1) are adjusted by an inorganic acid or an organic acid, and the pH of the system is 3.0-6.0; the inorganic acid is hydrochloric acid, phosphoric acid or sulfuric acid; and the organic acid is acetic acid or citric acid.

6. The method of claim 1, wherein, The alkaline conditions in step (1) are adjusted by a lye, and the pH of the system is 7.5-10.0, preferably the pH is 8.0-9.

5.

7. The method of claim 1, wherein, In step (2), after adjusting to an alkaline pH, a step of purifying the disodium glycerophosphate solution is further included; the purification includes removing inorganic salt impurities in the solution by using a membrane separation technology.

8. The method of claim 1, wherein, The nanofiltration membrane used for purifying the sodium glycerophosphate is selected from one of NF270-200Da, NF90-200Da, ESNA-LF-200Da, ESNA-LF2-200Da, TNF-1-200Da and TNF-4-200Da.

9. The method of claim 1, wherein, The molar ratio of calcium chloride to sodium glycerophosphate in step (2) is 1.0-1.5:1.0, and the reaction temperature is 30-100°C; preferably the molar ratio is 1.0-1.2:1.0, and preferably the reaction temperature is 50-80°C. The post-treatment includes cooling the system to 5-20°C for crystallization after the reaction is completed, separating the precipitate, and washing the precipitate with a low-carbon alcohol; preferably the crystallization temperature is 10-15°C, and the low-carbon alcohol is ethanol.

10. The method of claim 1, wherein, ​

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