A method for preparing a nitroimidazole phosphate compound

Abstract

The application aims to provide a preparation method of high-purity phosphonic acid levonikosazol ester disodium hydrate, which has the advantages of controllable reaction condition, stable quality, high yield and suitability for industrial production, etc.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a method for preparing nitroimidazole phosphate compounds. Background Technology

[0002] Levonidazole phosphate disodium hydrate, chemically named S-(-)-3-chloro-1-(2-methyl-5-nitro-1H-imidazol-1-yl)propane-2-yl phosphate sodium hydrate, belongs to the nitroimidazole class of antibacterial drugs. It is mainly used to treat anaerobic bacterial infections and protozoan infections, and has wide clinical applications. The synthesis of this product typically uses levonidazole as the starting material, reacting it with phosphorus oxychloride followed by post-processing to obtain levonidazole phosphate hydrate.

[0003] Chinese patent CN114075242B discloses an industrial production method for disodium levonitroazole phosphate. The method involves reacting levonitroazole with phosphorus oxychloride in an organic solvent, quenching the reaction with a large amount of water, adjusting the pH to 3-6 with an alkaline aqueous solution, followed by nanofiltration, and then adjusting the pH again to 9.0-13.5 with alkali to induce crystallization and obtain the target product. This process removes chloride ions through direct nanofiltration, thereby achieving desalination and to some extent avoiding excessive inorganic salt levels. Studies have shown that a large amount of phosphorus oxychloride exists in the phosphorus oxychloride reaction system. After the reaction is completed, excess phosphorus oxychloride remains. Directly adjusting the pH of the system to 3-6 without concentration will produce a large amount of inorganic salts such as sodium chloride and phosphate. The nanofiltration process is too cumbersome. Adjusting the pH of the ethanol aqueous solution after nanofiltration to 9.0-13.5 will precipitate disodium levonornidazole phosphate, but the yield is low, about 70%. If recrystallization is carried out in a GMP clean area, the total yield will be less than 60%, and there is still a risk of excessive phosphate after nanofiltration.

[0004] Chinese patent CN116535440A discloses a method for preparing levonornidazole phosphate disodium methanol hydrate. The method involves adding levonornidazole phosphate disodium hydrate to 6-10 times its volume (w / w) of anhydrous methanol, decolorizing with 0.1%-1% (w / v) of activated carbon, then adding 0.1-2.0 times its volume (w / w) of water, followed by adding 5-15 times its volume (w / w) of an antisolvent for crystallization. The antisolvent is selected from dichloromethane, ethanol, acetone, and ethyl acetate, thereby obtaining levonornidazole phosphate disodium methanol tetrahydrate. The purpose of this patent application is to provide a levonornidazole phosphate disodium methanol hydrate with low free phosphate content, controlled to a limit of no more than 0.5%. In Example 2, the phosphate content of levonornidazole phosphate disodium methanol hydrate was 0.008%, with a yield of 76%. In Example 8, the phosphate content was 0.009%, with a yield of less than 50%. The phosphate content in other examples ranged from 0.01% to 0.02%. Therefore, the phosphate content of levonornidazole phosphate disodium methanol hydrate prepared using this method is approximately 0.01% to 0.02%, and both the quality and yield are unstable, making it unsuitable for industrial production.

[0005] Levonidazole phosphate disodium hydrate is a prodrug of levonitrozine. It has good water solubility. As an injectable active pharmaceutical ingredient (API), its quality control includes not only properties, related substances, and content, but also the control of inorganic salts. The 2020 edition of the Chinese Pharmacopoeia controls chloride and sulfate content in levonitrozine API, with limits not exceeding 0.02%. Based on the synthesis process and structural characteristics of levonitrozine phosphate disodium hydrate, its molecular weight is approximately 445, while levonitrozine is approximately 219. Therefore, 1g of levonitrozine phosphate disodium hydrate is approximately equivalent to 0.5g of levonitrozine. Marketed levonitrozine phosphate disodium injections are available in 1.0g, 0.5g, and 0.25g strengths, while levonitrozine injections are available in 0.5g, 0.25g, and 0.125g strengths, with a clear dosing ratio between the strengths. Based on the control of the total intake of impurities, the phosphate limit in levonornidazole phosphate disodium hydrate should not exceed 0.01%. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing high-purity levofloxacin phosphate disodium hydrate, which has the advantages of mild reaction conditions, high yield, stable quality, and suitability for industrial production.

[0007] To achieve the above objectives, this law adopts the following technical solution, including the following steps:

[0008] Step (1): Preparation of crude levofloxacin phosphate disodium hydrate: Levofloxacin was dissolved in an organic solvent, phosphorus oxychloride was slowly added, and after the reaction was completed, the reaction was concentrated to remove a large amount of phosphorus oxychloride. Water was then added to quench the reaction, the pH was adjusted to 4-5, the water was concentrated to remove the water, ethanol was added to dissolve the product, the mixture was filtered, the pH was adjusted to 8-10 with alkaline solution, the product was precipitated, and the mixture was filtered to obtain crude levofloxacin phosphate disodium hydrate.

[0009] The mass ratio of levonornidazole to phosphorus oxychloride is 1:1~2; the organic solvent is acetonitrile, and the mass ratio of levonornidazole to acetonitrile is 1:1.5~4; the mass ratio of levonornidazole to ethanol is 1:5~10.

[0010] Step (2): Preparation of disodium levonidazole phosphate methanol hydrate: The crude disodium levonidazole phosphate hydrate obtained in step (1) is dissolved in 8-10 times (w / w) of methanol. After filtration, 16-20 times (w / w) of acetonitrile and 0.2-0.6 times (w / w) of water are added to the filtrate. After filtration and drying, disodium levonidazole phosphate methanol hydrate is obtained.

[0011] Studies have shown that when acetonitrile is used as the antisolvent, its phosphate removal ability is significantly better than that of organic solvents such as acetone and dichloromethane. The phosphate detection amount is far below 0.01%, and the quality yield in large-scale production is greater than 80%.

[0012] Meanwhile, studies have shown that when water is not added, the precipitation effect of the antisolvent is too obvious, with a mass yield of over 90%, close to the theoretical conversion mass yield of 94%, and the removal effect of free phosphate is reduced. Therefore, the addition of water is necessary.

[0013] Step (3): Preparation of disodium levonornidazole phosphate hydrate: Disodium levonornidazole phosphate methanol hydrate was dissolved in water, filtered, and then ethanol was added to precipitate it. After filtration and drying, disodium levonornidazole phosphate hydrate was obtained.

[0014] The mass ratio of disodium levonornidazole phosphate methanol hydrate to water to ethanol is 1:1.2~1.5:3~6, and the drying temperature is 15~25℃.

[0015] The beneficial effects of this invention are as follows: Step (1) prepares crude disodium levonitrozole phosphate, and step (2) removes excess phosphate from the disodium levonitrozole phosphate. Then, step (3) recrystallizes the product to obtain disodium levonitrozole phosphate hydrate. The product quality is stable and controlled, and the total yield of the three steps is high. Based on levonitrozole, the yield is 140% (the molecular weight of levonitrozole is 219, the molecular weight of disodium levonitrozole phosphate hydrate is 445, and the theoretical yield is 203%). Moreover, the free phosphate content is significantly lower than 0.01%, which meets the quality requirements for injectable raw materials and is suitable for industrial production. Attached Figure Description

[0016] Figure 1 The graphs show the free phosphate levels in Example 1 and Comparative Examples 1-2.

[0017] Figure 2 Figures showing the free phosphate levels in Comparative Examples 3-5

[0018] Figure 3 Figures showing the free phosphate test results for Examples 2-7 Detailed Implementation

[0019] Comparative Example 1: Preparation of crude levonornidazole phosphate disodium hydrate

[0020] Referring to Examples 1-3 of CN114075242, crude levonornidazole phosphate disodium hydrate was prepared and desalted using sodium filtration. The results are as follows:

[0021] Add 330g acetonitrile and 90g levonidazole to the reactor, start stirring, add 100g phosphorus oxychloride, raise to room temperature and stir until the reaction is complete, add 250g water, and stir at 40℃ for 1h. Adjust the pH to 4 with 30% potassium hydroxide, transfer the solution (1ml by weight) to a nanofiltration device, after nanofiltration, transfer the solution to the reactor, add 30% potassium hydroxide, adjust the solution to pH 9.5, stir at room temperature to crystallize for 2h, filter, collect the filter cake, add 50g water and the above filter cake to the reactor, stir to dissolve, add 100g ethanol and 100g acetone respectively, stir to crystallize for 4h, filter and dry to obtain 49.5g of product (No.: LO-0500437-09-S02), with a mass yield of approximately 55%.

[0022] Free phosphate test: Levofloxacin disodium hydrate, the UV absorbance of the test sample's free phosphate was lower than that of the reference solution, but it was still detectable. Sodium filtration can remove a large amount of free phosphate, but a small amount remains, less than 0.01%, but the yield is low.

[0023] Comparative Example 2: Preparation of Levonidazole Phosphate Disodium Methanol Hydrate

[0024] Referring to Example 2 of CN116535440A, which is the optimal example for phosphate residue, the process was reproduced, and the residual free phosphoric acid in the obtained disodium levonornidazole methanol hydrate and the yield were investigated as follows:

[0025] Take 50g of crude levofloxacin phosphate disodium hydrate, add 380g of anhydrous methanol and dissolve at room temperature, add 1.5g of activated carbon and decolorize at room temperature for 20min, filter, stir the filtrate, add 750g of acetone dropwise, crystallize for 3 hours after addition, filter, dry the filter cake at 30℃ for 3 hours to obtain 36.5g of product (No.: LO-0500437-09-S03), with a yield of about 73%.

[0026] Test for free phosphate: The UV absorbance of the test sample free phosphate disodium methanol hydrate was lower than that of the reference solution, indicating that the yield was low when using 7.6 times the amount of methanol for dissolution and 15 times the amount of acetone as the antisolvent. Although a large amount of free phosphate could be removed and the free phosphate residue was less than 0.01%, there was still a risk of residue.

[0027] Comparative Example 3: Preparation of Levonidazole Phosphate Disodium Methanol Hydrate

[0028] Referring to Example 11 of CN116535440A, which yielded the best results, the process was reproduced. The residual free phosphoric acid in the obtained disodium levonornidazole methanol hydrate and the yield were investigated, and the results are as follows:

[0029] Take 100g of crude disodium levonidazole phosphate, dissolve it in 800g of methanol and 10g of acetone, stir and dissolve at room temperature, add 3.0g of activated carbon for decolorization, add 100g of water, and then add 800g of anhydrous ethanol dropwise. Continue stirring to induce crystallization. After crystallization is complete, filter and air dry the filter cake at 25℃ to obtain 81.5g of product (No.: LO-0500437-09-S04), with a yield of approximately 81.5%.

[0030] Test for free phosphate: The UV absorbance of the free phosphate in the test sample was higher than that in the reference solution, indicating that the phosphate exceeded the limit. This suggests that using 8 times the amount of methanol to dissolve the sample, adding 1 times the amount of water, and then using 8 times the amount of ethanol as the antisolvent resulted in a higher yield and could remove a large amount of free phosphate. However, there were still residues, which were greater than 0.01%. The impurity removal effect was slightly worse than that of acetone.

[0031] Comparative Example 4: Preparation of Levonidazole Phosphate Disodium Methanol Hydrate

[0032] Referring to the technical solution of claim 5 in CN116535440A, the residual free phosphoric acid and yield in the obtained disodium levonornidazole methanol hydrate were investigated, and the results are as follows:

[0033] Take 100g of crude disodium levonidazole phosphate, dissolve it in 1000g of anhydrous methanol, add 0.5% (w / v) activated carbon for decolorization for 20min, filter, stir the filtrate, add 40g of water dropwise, then add 500g of acetone dropwise to precipitate crystals for 1-4 hours, filter, and air dry the filter cake at 25℃ to obtain 46.2g of product (No.: LO-0500437-09-S05), with a yield of approximately 46.2%.

[0034] Free phosphate test: The UV absorbance of the free phosphate in the test sample was lower than that in the reference solution, indicating that the yield was low when 10 times the amount of methanol was used for dissolution and 5 times the amount of acetone was used as the antisolvent. Although a large amount of free phosphate could be removed, there was still a residue of about 0.01%.

[0035] Comparative Example 5: Preparation of Levonidazole Phosphate Disodium Methanol Hydrate

[0036] Referring to the technical solution of claim 5 in CN116535440A, the residual free phosphoric acid and yield in the obtained disodium levonornidazole methanol hydrate were investigated, and the results are as follows:

[0037] Take 100g of crude disodium levonidazole phosphate, dissolve it in 600g of anhydrous methanol, add 0.5% (w / v) activated carbon for decolorization for 20min, filter, stir the filtrate, add 30g of water dropwise, then add 1000g of acetone dropwise to precipitate crystals for 1-4 hours, filter, and air dry the filter cake at 25℃ to obtain 82.9g of product (No.: LO-0500437-09-S06), with a yield of approximately 82.9%.

[0038] Free phosphate: disodium levonornidazole phosphate methanol complex. The UV absorbance of the test sample free phosphate was slightly greater than that of the reference solution, indicating that using 6 times the amount of methanol for dissolution and then using 10 times the amount of acetone as the antisolvent can remove a large amount of free phosphate, but there is still a residue of about 0.01%.

[0039] Example 1: Preparation of crude levonornidazole phosphate disodium hydrate

[0040] Weigh 20 kg of acetonitrile and 10 kg of levonidazole and add them to the reaction vessel, stirring. Add 15 kg of phosphorus oxychloride at a controlled temperature of 0-30℃. Heat to 40-50℃ and react. After the reaction is complete, concentrate the reaction solution under reduced pressure to remove phosphorus oxychloride and acetonitrile. Slowly add the concentrate to 50 kg of water, stirring. Adjust the pH to 4-5 with 30% sodium hydroxide aqueous solution at 0-10℃, and concentrate at 40-50℃ until the reaction solution becomes viscous. Add 60 kg of anhydrous ethanol to the concentrate, heat to 40-50℃, and stir to dissolve until there is no obvious viscous substance. Filter to remove inorganic salts. Cool the filtrate to 0-10℃, adjust the pH to 8-10 with 30% sodium hydroxide aqueous solution, and crystallize at 0-10℃. Filter to obtain 16.3 kg of crude levonidazole phosphate disodium hydrate (No.: LO-0500437-09-S01), with a yield of 163%.

[0041] Free phosphate test: The UV absorbance of the crude disodium levonornidazole phosphate was significantly greater than that of the control solution, and the free phosphate content was significantly greater than 0.01%, indicating that there was a large amount of free phosphate in the crude product.

[0042] Example 2 Preparation of disodium levonornidazole phosphate methanol hydrate

[0043] The crude product obtained in Example 1 was subjected to desalination treatment using 8 times the amount of methanol as the dissolution agent, 20 times the amount of acetonitrile as the antisolvent, and 0.6 times the amount of water. The amount of free phosphate residue in the resulting solvate was investigated.

[0044] 6.4 kg of methanol was weighed and added to a reaction vessel, stirred, and cooled to 0-10℃. 0.8 kg of crude levonornidazole disodium hydrate was added, stirred to dissolve, and filtered. A mixed solution of 16 kg acetonitrile and 0.48 kg purified water was added to the filtrate. After the addition was complete, the mixture was kept at 0-10℃ and stirred for 3-4 hours. The solution was filtered and dried to obtain 0.67 kg of product (product number: APILO-0500437-20-S01), with a yield of 83.7%.

[0045] Free phosphate test: Levofloxacin disodium methyl phosphate methanol compound. The UV absorbance of the free phosphate in the test sample was comparable to that in the blank. After the desalting step, the phosphate level decreased significantly to undetectable.

[0046] Example 3 Preparation of disodium levonornidazole phosphate methanol hydrate

[0047] The crude product obtained in Example 1 was subjected to desalination treatment using 10 times the amount of methanol as the dissolution agent, 20 times the amount of acetonitrile as the antisolvent, and 0.4 times the amount of water. The amount of free phosphate residue in the resulting solvate was investigated.

[0048] Weigh 8 kg of methanol and add it to the reaction vessel. Stir and cool to 0-10℃. Add 0.8 kg of crude levonidazole disodium hydrate, stir to dissolve, and filter. Add a mixed solution of 16 kg acetonitrile and 0.32 kg purified water to the filtrate. After the addition is complete, keep the mixture at 0-10℃ and stir for 3-4 hours. Filter and dry to obtain 0.66 kg of product (product number: APILO-0500437-20-S02), with a yield of 82.2%.

[0049] Free phosphate test: Levofloxacin disodium methyl phosphate methanol compound. The UV absorbance of the free phosphate in the test sample was comparable to that in the blank. After the desalting step, the phosphate level decreased significantly to undetectable.

[0050] Example 4: Preparation of disodium levonornidazole phosphate methanol hydrate

[0051] The crude product obtained in Example 1 was subjected to desalination treatment using 10 times the amount of methanol as the dissolution agent, 16 times the amount of acetonitrile as the antisolvent, and 0.2 times the amount of water. The amount of free phosphate residue in the resulting solvate was investigated.

[0052] Weigh 8 kg of methanol and add it to the reaction vessel. Stir and cool to 0-10℃. Add 0.8 kg of crude levonornidazole disodium hydrate, stir to dissolve, and filter. Add a mixed solution of 12.8 kg acetonitrile and 0.16 kg purified water to the filtrate. After the addition is complete, keep the mixture at 0-10℃ and stir for 3-4 hours. Filter and dry to obtain 0.64 kg of product (product number: APILO-0500437-20-S03), with a yield of 80.1%.

[0053] Free phosphate test: Levofloxacin disodium methyl phosphate methanol compound. The UV absorbance of the free phosphate in the test sample was comparable to that in the blank. After the desalting step, the phosphate level decreased significantly to undetectable.

[0054] Example 5 Preparation of disodium levonornidazole phosphate methanol hydrate

[0055] The crude product obtained in Example 1 was subjected to desalination treatment using 10 times the amount of methanol as the dissolution agent and 20 times the amount of acetonitrile as the antisolvent, without adding water. The amount of free phosphate residue in the resulting solvate was investigated.

[0056] Weigh 8 kg of methanol and add it to the reaction vessel. Stir and cool to 0-10℃. Add 0.8 kg of crude levonornidazole disodium hydrate, stir to dissolve, and filter. Add 16 kg of a mixed solution of acetonitrile to the filtrate. After the addition is complete, keep the temperature at 0-10℃ and stir for 3-4 hours. Filter and dry to obtain 0.73 kg of product (product number: LO-0500369-16-S01), with a yield of 91.2%.

[0057] Free phosphate test: The UV absorbance of the free phosphate in the test sample was significantly greater than that in the control solution. After the desalting step, some free phosphate can be removed, but there is still a residue exceeding 0.01%.

[0058] Example 6 Preparation of disodium levonornidazole phosphate hydrate

[0059] The solvate obtained in Example 2 was recrystallized to investigate the amount of free phosphate residue in the resulting disodium levonidazole phosphate hydrate.

[0060] Weigh 1.2 kg of purified water, stir, cool to 0-10℃, add 1 kg of levonornidazole phosphate disodium methanol hydrate, stir to dissolve, filter, add 3.5 kg of anhydrous ethanol dropwise to the reaction vessel, after the addition is complete, control the temperature at 0-10℃ and stir for 3-4 h, filter, and dry to obtain 1.38 kg of levonornidazole phosphate disodium hydrate (No.: LO-0500369-16-S02), with a yield of 102.2%.

[0061] Free phosphate test: The UV absorbance of the free phosphate of the test sample was comparable to that of the blank, and it was almost undetectable, which meets the quality control standards for raw materials.

[0062] Example 7 Preparation of disodium levonornidazole phosphate hydrate

[0063] The solvate obtained in Example 2 was recrystallized to investigate the amount of free phosphate residue in the resulting disodium levonidazole phosphate hydrate.

[0064] Weigh 1.5 kg of purified water, stir, cool to 0-10℃, add 1.0 kg of levonornidazole phosphate disodium methanol hydrate, stir to dissolve, filter, add 5 kg of anhydrous ethanol dropwise to the reaction vessel, after the addition is complete, control the temperature at 0-10℃ and stir for 3-4 hours, filter, and dry to obtain 0.98 kg of levonornidazole phosphate disodium hydrate (No.: LO-0500369-16-S03), with a yield of 98%.

[0065] Free phosphate test: The UV absorbance of the free phosphate of the test sample was comparable to that of the blank, and it was almost undetectable, which meets the quality control standards for raw materials.

[0066] Example 8 Determination of Phosphate

[0067] Referring to Chapter 0401 of the Chinese Pharmacopoeia, Part IV, the free phosphate content of the samples in each example was determined using the following steps:

[0068] Accurately weigh 2g of this product into a 25ml volumetric flask and add 15ml of water to dissolve it. Accurately add 5ml of ammonium molybdate sulfuric acid test solution and 2ml of 1-amino-2-naphthol-4-sulfonic acid solution (take 5g of anhydrous sodium sulfite, 94.3g of sodium bisulfite and 0.7g of 1-amino-2-naphthol-4-sulfonic acid, mix thoroughly, and add 1.5g of this mixture to 10ml of water to dissolve it before use; filter if necessary). Add water to the mark, shake well, and place at 20℃ for 30-50 minutes.

[0069] For the reference solution, take 4.0 ml of standard phosphate solution [accurately weigh 0.35 g of potassium dihydrogen phosphate dried at 105℃ for 2 hours, place it in a 1000 ml volumetric flask, add 10 ml of sulfuric acid solution (3→10) and an appropriate amount of water to dissolve it, dilute with water to the mark, and shake well; dilute 5 times again before use], place it in a 25 ml volumetric flask, and add 11 ml of water; from “accurately add 5 ml of ammonium molybdate sulfuric acid test solution” onwards, the preparation method is the same as the test solution.

[0070] The test solution and the control solution were measured at a wavelength of 740 nm. The results are as follows:

[0071] Serial Number Sample number Absorbance of control solution (0.01%) absorbance of the test sample result Example 1 LO-0500437-09-S01 0.164 / 0.163 1.127 Much greater than 0.01% Example 2 LO-0500437-20-S01 0.183 / 0.186 0.002 Not detected Example 3 LO-0500437-20-S02 0.183 / 0.186 0.007 Not detected Example 4 LO-0500437-20-S03 0.183 / 0.186 0.006 Not detected Example 5 LO-0500369-16-S01 0.183 / 0.186 0.194 ＞0.01% Example 6 LO-0500369-16-S02 0.183 / 0.186 0.003 Not detected Example 7 LO-0500369-16-S03 0.183 / 0.186 0.004 Not detected Comparative Example 1 LO-0500437-09-S02 0.164 / 0.163 0.131 ＜0.01% Comparative Example 2 LO-0500437-09-S03 0.164 / 0.163 0.162 ≈0.01% Comparative Example 3 LO-0500437-09-S04 0.175 / 0.173 0.199 ＞0.01% Comparative Example 4 LO-0500437-09-S05 0.175 / 0.173 0.171 ≈0.01% Comparative Example 5 LO-0500437-09-S06 0.175 / 0.173 0.217 ＞0.01%

Claims

1. A method for preparing high-purity levonornidazole phosphate disodium hydrate, comprising the following steps: Step (1): Preparation of crude levofloxacin phosphate disodium hydrate: Dissolve levofloxacin in an organic solvent, slowly add phosphorus oxychloride, after the reaction is complete, concentrate to remove a large amount of phosphorus oxychloride, then add water to quench the reaction, adjust the pH to 4-5, concentrate to remove water, then add ethanol to dissolve, filter, adjust the pH to 8-10, filter, and obtain crude levofloxacin phosphate disodium hydrate. Step (2): Preparation of disodium levonidazole phosphate methanol hydrate: Dissolve the crude disodium levonidazole phosphate hydrate from step (1) in 8-10 times (w / w) of methanol, filter, add 16-20 times (w / w) of acetonitrile and 0.2-0.6 times (w / w) of water to the filtrate, filter, and dry to obtain disodium levonidazole phosphate methanol hydrate; Step (3): Preparation of disodium levonornidazole phosphate hydrate: Dissolve the disodium levonornidazole phosphate methanol hydrate from step (2) in water, filter, add ethanol to precipitate, filter, and dry to obtain disodium levonornidazole phosphate hydrate.

2. The method for preparing levonornidazole phosphate disodium hydrate according to claim 1, characterized in that: In step (1), the mass ratio of levonornidazole to phosphorus oxychloride is 1:1~2; the organic solvent is acetonitrile, and the mass ratio of levonornidazole to acetonitrile is 1:1.5~4; the mass ratio of levonornidazole to ethanol is 1:5~10.

3. The method for preparing levonornidazole phosphate disodium hydrate according to claim 1, characterized in that: In step (2), the crude product of levonidazole phosphate disodium hydrate was dissolved in 10 times (w / w) methanol, filtered, and 20 times (w / w) acetonitrile and 0.4 times (w / w) water were added to the filtrate. The mixture was then filtered and dried to obtain levonidazole phosphate disodium methanol hydrate.

4. The method for preparing levonornidazole phosphate disodium hydrate according to claim 1, characterized in that: Step (3) The mass ratio of disodium levonornidazole phosphate methanol hydrate to water to ethanol is 1:1.2~1.5:3~6, and the drying temperature is 15~25℃.

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