Preparation method of beta-sodium glycerophosphate

Abstract

The invention relates to a preparation method of beta-sodium glycerophosphate. According to the method, glycerol and bis (dimethylamino) sodium phosphate react to construct a five-membered lactone ring, a product mainly containing beta-sodium glycerophosphate is obtained after hydrolysis, and beta-sodium glycerophosphate with high purity can be obtained through refining. The method provided by the invention has high product yield and purity, and is suitable for industrial application.

Description

Technical Field

[0001] The invention relates to the field of chemical industry, and in particular to a method for preparing sodium beta-glycerophosphate. Background Art

[0002] Sodium glycerophosphate is an intravenous phosphorus supplement used to prevent and treat osteoporosis and osteomalacia. It contains both α- and β-forms, but it is β-sodium glycerophosphate that plays an effective role in human metabolism.

[0003] Since the sodium glycerophosphate currently produced on the market is a mixture, there are also many literatures on the synthesis of single β-sodium glycerophosphate, usually in two types:

[0004] The first method is to protect the α-hydroxyl group of glycerol first, then react with chlorinated phosphine, deprotect and obtain β-sodium glycerophosphate. However, this method requires protection and deprotection, and the purity of the obtained β-sodium glycerophosphate is also poor, only about 80%.

[0005]

[0006] The second method is to convert α-glycerophosphate into β-glycerophosphate under the catalysis of glucose phosphate translocase. The cost of the raw materials is relatively high, and the reaction conversion is not complete. After purification, there may be protein residues.

[0007]

[0008] Therefore, there is still a need to provide more preparation methods of sodium β-glycerophosphate. Summary of the invention

[0009] The purpose of the present invention is to overcome the shortcomings of expensive raw materials, low yield and poor purity in the prior art, and to provide a preparation method of sodium β-glycerophosphate with easy-to-obtain raw materials and low cost.

[0010] The technical solution adopted by the present invention to achieve the above-mentioned purpose is:

[0011] A method for preparing sodium β-glycerophosphate, comprising:

[0012]

[0013] The bis(dimethylamino)phosphoryl chloride is converted into sodium bis(dimethylamino)phosphate, which reacts with glycerol to form five-membered heterocyclic sodium glycerophosphate, which is then hydrolyzed to obtain sodium β-glycerophosphate.

[0014] In one embodiment, the method comprises:

[0015] a. Hydrolysis: Add bis(dimethylamino)phosphoryl chloride to a sodium hydroxide solution and react at 0-40°C for 1-5h to obtain sodium bis(dimethylamino)phosphate;

[0016] b. Cyclization: adding the sodium bis(dimethylamino)phosphate prepared above, glycerol and an organic tin catalyst to an organic solvent, reacting at 50 to 100° C. for 5 to 15 hours to obtain a five-membered heterocyclic sodium glycerophosphate; the organic tin catalyst is a mixture of dialkyltin dichloride and dialkyltin oxide;

[0017] c. Hydrolysis: Add five-membered heterocyclic sodium glycerophosphate to sodium hydroxide solution and react at 50-120°C for 8-20 hours to obtain β-sodium glycerophosphate.

[0018] In one embodiment, the method further comprises:

[0019] d. Crystallization: Add an appropriate amount of magnesium oxide to the reaction mixture in step c, stir for 2 to 4 hours, filter, add alcohol solvent dropwise to the filtrate, crystallize at 0 to 25 ° C for 10 to 20 hours, filter, and obtain a crude sodium β-glycerophosphate;

[0020] e. Refining: Dissolve the crude product of step d in water, add alcohol solvent dropwise, crystallize at 0-15°C for 10-20h, filter and wash to obtain a refined product.

[0021] Further, in step a: the molar ratio of bis(dimethylamino)phosphoryl chloride to sodium hydroxide is 1:2.0-3.0, preferably 1:2.05-2.4;

[0022] The concentration of sodium hydroxide is 5 to 20%, preferably 5 to 10%;

[0023] The temperature for adding bis(dimethylamino)phosphoryl chloride is 0 to 10° C., preferably 0 to 5° C.; when adding, bis(dimethylamino)phosphoryl chloride is slowly added to the sodium hydroxide solution;

[0024] The reaction temperature is preferably 10 to 35° C., more preferably room temperature; the reaction time is preferably 2 to 4 h.

[0025] Furthermore, in step a, after the reaction is completed, the solvent is evaporated under reduced pressure, ethanol is added to dissolve, the mixture is filtered, and the filtrate is evaporated under reduced pressure to obtain sodium bis(dimethylamino)phosphate.

[0026] Further, in step b: the molar ratio of sodium bis(dimethylamino)phosphate to glycerol is 0.9-1.2:1, preferably 1:1;

[0027] The dialkyltin dichloride is selected from at least one of dimethyltin dichloride, diethyltin dichloride, and dibutyltin dichloride, preferably dimethyltin dichloride; the dialkyltin oxide is selected from at least one of dimethyltin oxide and dibutyltin oxide, preferably dibutyltin oxide;

[0028] The molar ratio of dialkyltin dichloride to dialkyltin oxide is 1-2:2-1, preferably 1-1.5:1;

[0029] The amount of the organic tin catalyst, calculated as the molar amount of tin, is in a ratio of 0.05 to 0.2:1 to the molar amount of sodium bis(dimethylamino)phosphate, preferably 0.08 to 0.12:1;

[0030] The organic solvent is selected from at least one of N-methylpyrrolidone and DMSO, preferably N-methylpyrrolidone;

[0031] The reaction temperature is preferably 80-100°C. If the temperature is too low, the reaction rate is slow, and if the temperature is too high, the product is easy to gelatinize. The reaction time is preferably 6-10 hours.

[0032] Further, in step b, after the reaction is completed, the reaction mixture is cooled to room temperature, an equal volume of water is added, and then purified using an ion exchange column Sephadex A-25 with an eluent of 0.1-0.3M NaHCO3 solution to obtain five-membered heterocyclic sodium glycerophosphate.

[0033] Further, in step c: the concentration of sodium hydroxide is 10-30%, preferably 30%;

[0034] The molar ratio of five-membered heterocyclic sodium glycerophosphate to sodium hydroxide is 1:1-4, preferably 1:1.5-3;

[0035] The reaction temperature is preferably 80-100°C; the reaction time is preferably 8-12h.

[0036] Further, in step d: magnesium oxide is used to remove free phosphate, and its amount is not limited, as long as the free phosphate can be completely removed; preferably, the mass ratio of magnesium oxide to five-membered heterocyclic sodium glycerophosphate is 0.01 to 0.2:1, preferably 0.05 to 0.1:1;

[0037] The alcohol solvent is selected from at least one of methanol and ethanol;

[0038] The crystallization temperature is preferably 5 to 15°C.

[0039] Further, in step e: the alcohol solvent is selected from at least one of methanol and ethanol;

[0040] The crystallization temperature is preferably 0 to 5°C.

[0041] The useful technology of the present invention: The present invention provides a method for preparing sodium β-glycerophosphate. The method of the present invention constructs a five-membered lactone ring by reacting glycerol with sodium bis(dimethylamino)phosphate, and obtains a product mainly composed of sodium β-glycerophosphate after hydrolysis, and can obtain sodium β-glycerophosphate with high purity by refining. The core of the present invention is to construct a five-membered lactone ring, and the use of a specific organic tin catalyst composition can greatly improve the degree of lactonization, thereby improving the yield and purity of sodium β-glycerophosphate in the final hydrolyzate. DETAILED DESCRIPTION

[0042] The present invention is described in more detail hereinafter to facilitate understanding of the present invention.

[0043] It should be understood that the terms or words used in the specification and claims should not be understood as having the meaning defined in the dictionary, but should be understood as having the meaning consistent with their meaning in the context of the present invention based on the following principle: the concept of the term can be appropriately defined by the inventor for the best explanation of the present invention.

[0044] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0045] Example 1

[0046] Weigh 33.6 g (0.84 mol) of sodium hydroxide, add it to 400 g of water to prepare a solution, cool it to 0-5°C, then add 68.24 g (0.4 mol) of bis(dimethylamino)phosphoryl chloride dropwise. After the addition is complete, warm the temperature to room temperature and react for 2 h. Evaporate the solvent under reduced pressure, add ethanol to dissolve, filter, and evaporate the filtrate under reduced pressure to obtain 67.86 g of sodium bis(dimethylamino)phosphate, with a yield of 98.0%.

[0047] Example 2

[0048] Add 27.6 g (0.3 mol) of glycerol, 51.93 g (0.3 mol) of sodium bis(dimethylamino)phosphate, 3.30 g (0.015 mol) of dimethyltin dichloride and 3.73 g (0.015 mol) of dibutyltin oxide to 200 ml of N-methylpyrrolidone, heat to 90°C and react for 8 hours; cool the reaction mixture to room temperature, add an equal volume of water, and then purify it with an ion exchange column Sephadex A-25 (eluent: 0.2 M NaHCO3 solution) to obtain 49.2 g of five-membered heterocyclic sodium glycerophosphate with a yield of 93.2%.

[0049] Example 3

[0050] 30.8 g (0.2 mol) of five-membered heterocyclic sodium glycerophosphate was added to 60 g (0.45 mol) of 30% sodium hydroxide solution, and the mixture was reacted at 90°C for 10 h. After the reaction was completed, 2 g of magnesium oxide was added and stirring was continued for 2 h according to the detection content of free phosphate. The mixture was cooled and filtered, 100 ml of methanol was added to the filtrate, and the mixture was stirred and crystallized at 10°C for 12 h. The mixture was filtered, 20 ml of water was added to the filter cake to dissolve it, 40 ml of methanol was added dropwise, and the mixture was crystallized at 0-5°C for 5 h. The mixture was filtered and dried to obtain 52.63 g of sodium β-glycerophosphate (containing five crystal waters), with a yield of 86.0% (discounted water), a sodium β-glycerophosphate content of 99.5% (external standard method), and the free phosphate was qualified.

[0051] Comparative Example 1

[0052] Add 27.6 g (0.3 mol) of glycerol, 51.93 g of sodium bis(dimethylamino)phosphate (0.3 mol), and 6.6 g (0.03 mol) of dimethyltin dichloride to 200 ml of N-methylpyrrolidone, heat to 90°C, and react for 10 hours; cool the reaction mixture to room temperature, add an equal volume of water, and then purify it with an ion exchange column Sephadex A-25 (eluent: 0.2 M NaHCO3 solution) to obtain 40.3 g of five-membered heterocyclic sodium glycerophosphate with a yield of 76.4%.

[0053] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing sodium β-glycerophosphate, comprising: The bis(dimethylamino)phosphoryl chloride is converted into sodium bis(dimethylamino)phosphate, which reacts with glycerol to form five-membered heterocyclic sodium glycerophosphate, which is then hydrolyzed to obtain sodium β-glycerophosphate.

2. The method according to claim 1, characterized in that The method comprises: a. Hydrolysis: Add bis(dimethylamino)phosphoryl chloride to a sodium hydroxide solution and react at 0-40°C for 1-5h to obtain sodium bis(dimethylamino)phosphate; b. Cyclization: adding the sodium bis(dimethylamino)phosphate prepared above, glycerol and an organic tin catalyst to an organic solvent, reacting at 50 to 100° C. for 5 to 15 hours to obtain a five-membered heterocyclic sodium glycerophosphate; the organic tin catalyst is a mixture of dialkyltin dichloride and dialkyltin oxide; c. Hydrolysis: Add five-membered heterocyclic sodium glycerophosphate to sodium hydroxide solution and react at 50-120°C for 8-20 hours to obtain β-sodium glycerophosphate.

3. The method according to claim 2, characterized in that The method further comprises: d. Crystallization: Add an appropriate amount of magnesium oxide to the reaction mixture in step c, stir for 2 to 4 hours, filter, add alcohol solvent dropwise to the filtrate, crystallize at 0 to 25 ° C for 10 to 20 hours, filter, and obtain a crude sodium β-glycerophosphate; e. Refining: Dissolve the crude product of step d in water, add alcohol solvent dropwise, crystallize at 0-15°C for 10-20h, filter and wash to obtain a refined product.

4. The method according to claim 2, characterized in that: In step a: the molar ratio of bis(dimethylamino)phosphoryl chloride to sodium hydroxide is 1:2.0-3.0, preferably 1:2.05-2.

4.

5. The method according to claim 2, characterized in that: In step b: the molar ratio of sodium bis(dimethylamino)phosphate to glycerol is 0.9-1.2:1, preferably 1:

1.

6. The method according to claim 2, characterized in that In step b: the dialkyltin dichloride is selected from at least one of dimethyltin dichloride, diethyltin dichloride, and dibutyltin dichloride, preferably dimethyltin dichloride; the dialkyltin oxide is selected from at least one of dimethyltin oxide and dibutyltin oxide, preferably dibutyltin oxide; the molar ratio of the dialkyltin dichloride to the dialkyltin oxide is 1-2:2-1, preferably 1-1.5:

1.

7. The method according to claim 2, characterized in that In step b: the ratio of the amount of the organic tin catalyst used, calculated on the molar amount of tin, to the molar amount of sodium bis(dimethylamino)phosphate is 0.05 to 0.2:1, preferably 0.08 to 0.12:

1.

8. The method according to claim 2, characterized in that: In step c: the molar ratio of five-membered heterocyclic sodium glycerophosphate to sodium hydroxide is 1:1-4, preferably 1:1.5-3.

9. The method according to claim 3, characterized in that: In step d: the alcohol solvent is selected from at least one of methanol and ethanol.

10. The method according to claim 3, characterized in that: In step e: the alcohol solvent is selected from at least one of methanol and ethanol.

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