Preparation method of S-ornidazole disodium phosphate
By esterification, hydrolysis and pH adjustment during the preparation process of disodium levonidazole phosphate, and crystallization steps using an ethanol aqueous solution, the problems of low yield and high impurity content in the prior art are solved, and the preparation effect of high purity and high yield is achieved.
Patent Information
- Application Number
- CN202411850346.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-16
- Publication Date
- 2025-03-25
AI Technical Summary
The existing preparation method for disodium levonidazole phosphate has problems with low yield and high impurity content.
By esterification and hydrolysis of l-oonidazole and inorganic phosphorus salt in an organic solvent, the pH value is adjusted to remove impurities, and crystallization is performed using aqueous ethanol solution to obtain high-purity disodium l-oonidazole phosphate.
The yield and purity of disodium levonidazole phosphate is improved, the content of chloride ions and impurities is reduced, the production process is simplified, the waste liquid is discharged, and the production cost is reduced.
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Figure BDA0005190410720000081
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of pharmaceutical engineering, and in particular to a method for preparing levornidazole disodium phosphate. Background Art
[0002] Ornidazole is a nitroimidazole derivative, a powerful drug against anaerobic and antiprotozoal infections, and a third-generation nitroimidazole derivative developed after metronidazole, with higher efficacy, shorter course of treatment, better tolerance, and wider distribution in the body. In further research on ornidazole, it was found that after use, ornidazole will produce a certain degree of central toxicity, and the central toxicity of its single left-handed enantiomer is much lower than that of its racemic form, which has pointed out a new direction for the research of ornidazole, and the research on left-handed ornidazole and its derivatives has become a new hotspot.
[0003] Left ornidazole disodium phosphate is the sodium salt of the phosphate derivative of the left-isomer of ornidazole, belongs to nitroimidazole antibiotics, and is the prodrug of the listed left ornidazole. Left ornidazole disodium phosphate is mainly used for anti-infection treatment, and has the effect of preventing and treating infections caused by sensitive bacteria. Therefore, it is of great significance to study the synthesis method of left ornidazole disodium phosphate. At present, the synthesis method of left ornidazole disodium phosphate mainly uses nanofiltration method to remove phosphate and chloride, but the left ornidazole disodium phosphate prepared using the method also has the problems of low yield and high chloride ion content, and the production is cumbersome, the production cycle is long, and the amount of waste liquid is high. Therefore, it is urgent to provide a preparation method of left ornidazole disodium phosphate, so as to solve the problems of low yield and high impurity content in the preparation method of existing left ornidazole disodium phosphate. Summary of the invention
[0004] Aiming at the problems of low yield and high impurity content in the existing preparation method of levornidazole disodium phosphate, the present invention provides a preparation method of levornidazole disodium phosphate.
[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:
[0006] The present invention provides a method for preparing levornidazole disodium phosphate, comprising the following steps:
[0007] S1, adding L-ornidazole and an inorganic phosphate salt to a first organic solvent, performing an esterification reaction at 40° C. to 80° C., and concentrating under reduced pressure to obtain a concentrate; adding water and a second organic solvent to the concentrate, performing a hydrolysis reaction at 40° C. to 80° C., and concentrating under reduced pressure to obtain L-ornidazole phosphate;
[0008] S2, adding the levornidazole phosphate to the third organic solvent, then adjusting the pH to 4-5, filtering, adjusting the pH of the filtrate to 8-10, filtering, and obtaining a crude product of levornidazole disodium phosphate;
[0009] S3. Add the crude product of levornidazole disodium phosphate to an ethanol aqueous solution, filter, add an alcohol solvent to the filtrate, crystallize at 0° C. to 25° C., filter, and dry to obtain levornidazole disodium phosphate.
[0010] Compared with the prior art, the preparation method of levornidazole disodium phosphate provided by the present invention can remove impurities such as phosphate and sodium chloride by adjusting the pH value to 4-5 in S2, thereby reducing the content of chloride ions and impurities in levornidazole disodium phosphate and improving the purity of levornidazole disodium phosphate; further, by adjusting the pH value to 8-10, the crude levornidazole disodium phosphate is completely precipitated, which is beneficial to improve the yield of levornidazole disodium phosphate; the present invention uses an ethanol aqueous solution in S3, which can improve the dissolution rate of levornidazole disodium phosphate and achieve a desalting effect. The method comprises filtering out salt impurities such as sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate which are insoluble in the ethanol aqueous solution, thereby improving the purity and yield of the 1-ornidazole disodium phosphate and reducing the contents of chloride ions and impurities in the 1-ornidazole disodium phosphate; at a specific crystallization temperature, the alcohol solvent can completely precipitate the 1-ornidazole disodium phosphate in the filtrate, and through this refining step, not only the yield and purity of the 1-ornidazole disodium phosphate are greatly improved, but also the maximum single impurity in the 1-ornidazole disodium phosphate can be guaranteed to be ≤0.05%, and the chloride ion ≤0.01%, thereby greatly reducing the content of impurities.
[0011] Preferably, in S1, the inorganic phosphate salt is phosphorus oxychloride.
[0012] Preferably, in S1, the first organic solvent is at least one of ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform or toluene.
[0013] Preferably, in S1, the second organic solvent is at least one of ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform or toluene.
[0014] Preferably, in S1, the esterification reaction time is 2 h to 6 h.
[0015] Preferably, in S1, the hydrolysis reaction time is 2 h to 6 h.
[0016] Preferably, in S1, the mass ratio of the L-ornidazole to the inorganic phosphate salt is 1:(1-3).
[0017] Preferably, in S1, the mass volume ratio of the 1-ornidazole to the first organic solvent is 1 g: (3-8) mL.
[0018] Preferably, in S1, the volume ratio of the concentrate to the second organic solvent is 1:(1-3).
[0019] Preferably, in S1, the volume ratio of the concentrate to water is 1:(2-6).
[0020] Preferably, in S2, the third organic solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, acetone or tetrahydrofuran.
[0021] Preferably, in S2, the mass volume ratio of the levornidazole phosphate and the third organic solvent is 1 g: (2-6) mL.
[0022] Preferably, in S2, the pH adjusting agent for adjusting the pH is a sodium hydroxide aqueous solution with a mass percentage of 15% to 30%.
[0023] Preferably, in S3, the mass volume ratio of the crude levonidronate disodium phosphate and the ethanol aqueous solution is 1 g: (2-6) mL.
[0024] Preferably, in S3, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:(0.5-5).
[0025] By limiting the amount of ethanol water added and the concentration of the ethanol water solution, the levonidazole disodium phosphate in the crude levonidazole disodium phosphate can be dissolved to the maximum extent, and the dissolution of salt impurities such as sodium chloride, sodium dihydrogen phosphate and disodium hydrogen phosphate can be limited to achieve a desalting effect, thereby improving the yield and purity of the product and reducing the content of impurities and chloride ions.
[0026] Preferably, in S3, the volume ratio of the filtrate to the alcohol solvent is 1:(0.5-3).
[0027] Further preferably, in S3, the alcohol solvent is anhydrous ethanol.
[0028] The invention limits the addition amount of the alcohol solvent and the type of the alcohol solvent, and completely precipitates the levornidazole disodium phosphate through a refining method, thereby greatly improving the yield and purity of the product.
[0029] Preferably, in S3, the crystallization time is 1 h to 2 h.
[0030] The optimal crystallization time is beneficial to further improve the product yield.
[0031] Preferably, in S3, the drying condition is: vacuum drying the filter cake at 30° C. to 40° C. for 1 h to 5 h.
[0032] The preparation method of levornidazole disodium phosphate provided by the invention is easy to operate and easy to produce in a factory, reduces the discharge of three wastes, reduces the production cost, and further shortens the production cycle. DETAILED DESCRIPTION
[0033] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.
[0034] Example 1
[0035] This embodiment provides a method for preparing levornidazole disodium phosphate, comprising the following steps:
[0036] S1. Adding L-ornidazole and phosphorus oxychloride to ethyl acetate, reacting at 80° C. for 2 h, and concentrating under reduced pressure to obtain a concentrate; adding water and acetonitrile to the concentrate, reacting at 40° C. for 6 h, and concentrating under reduced pressure to obtain L-ornidazole phosphate; wherein the mass ratio of L-ornidazole to phosphorus oxychloride is 1:1, the mass volume ratio of L-ornidazole to ethyl acetate is 1 g:3 mL, the volume ratio of the concentrate to water is 1:2, and the volume ratio of the concentrate to acetonitrile is 1:3;
[0037] S2, adding the left ornidazole phosphate to methanol, and then adjusting the pH to 5 with a 5% by mass sodium hydroxide aqueous solution, filtering, adjusting the pH of the filtrate to 8 with a 30% by mass sodium hydroxide aqueous solution, precipitating a solid, filtering, and obtaining a crude product of left ornidazole disodium phosphate; wherein the mass volume ratio of left ornidazole phosphate to methanol is 1g:6mL;
[0038] S3. Dissolve the crude product of levonidazole disodium phosphate in an ethanol aqueous solution, filter, add anhydrous ethanol to the filtrate, crystallize at 25°C for 1h, filter, and vacuum dry the filter cake at 40°C for 5h to obtain levonidazole disodium phosphate; wherein the mass volume ratio of the crude product of levonidazole disodium phosphate and the ethanol aqueous solution is 1g:6mL, the volume ratio of water and anhydrous ethanol in the ethanol aqueous solution is 1:0.5, and the volume ratio of the filtrate to ethanol is 1:3.
[0039] Example 2
[0040] This embodiment provides a method for preparing levornidazole disodium phosphate, comprising the following steps:
[0041] S1. Adding L-ornidazole and phosphorus oxychloride to tetrahydrofuran, reacting at 40° C. for 6 hours, and concentrating under reduced pressure to obtain a concentrate; adding water and dichloromethane to the concentrate, reacting at 80° C. for 2 hours, and concentrating under reduced pressure to obtain L-ornidazole phosphate; wherein the mass ratio of L-ornidazole to phosphorus oxychloride is 1:3, the mass volume ratio of L-ornidazole to tetrahydrofuran is 1 g:8 mL, the volume ratio of the concentrate to water is 1:6, and the volume ratio of the concentrate to dichloromethane is 1:1;
[0042] S2, adding the left ornidazole phosphate to isopropanol, then adjusting the pH to 4 with a 10% by mass sodium hydroxide aqueous solution, filtering, adjusting the pH of the filtrate to 10 with a 30% by mass sodium hydroxide aqueous solution, precipitating a solid, filtering, and obtaining a crude product of left ornidazole disodium phosphate; wherein the mass volume ratio of left ornidazole phosphate to isopropanol is 1g:2mL;
[0043] S3. Dissolve the crude product of levornidazole disodium phosphate in an ethanol aqueous solution, filter, add ethanol to the filtrate, crystallize at 0°C for 2h, filter, and vacuum dry the filter cake at 30°C for 4h to obtain levornidazole disodium phosphate; wherein the mass volume ratio of the crude product of levornidazole disodium phosphate and the ethanol aqueous solution is 1g:2mL, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:5, and the volume ratio of the filtrate to anhydrous ethanol is 1:0.5.
[0044] Example 3
[0045] This embodiment provides a method for preparing levornidazole disodium phosphate, comprising the following steps:
[0046] S1. Add L-ornidazole and phosphorus oxychloride to acetone, react at 50° C. for 3 hours, and concentrate under reduced pressure to obtain a concentrate; add water and acetonitrile to the concentrate, react at 60° C. for 4 hours, and concentrate under reduced pressure to obtain L-ornidazole phosphate; wherein the mass ratio of L-ornidazole to phosphorus oxychloride is 1:2, the mass volume ratio of L-ornidazole to acetone is 1 g:4 mL, the volume ratio of the concentrate to water is 1:4, and the volume ratio of the concentrate to acetonitrile is 1:2;
[0047] S2, adding the left ornidazole phosphate to ethanol, then adjusting the pH to 5 with a 15% by mass sodium hydroxide aqueous solution, filtering, adjusting the pH of the filtrate to 9 with a 30% by mass sodium hydroxide aqueous solution, precipitating a solid, filtering, and obtaining a crude product of left ornidazole disodium phosphate; wherein the mass volume ratio of left ornidazole phosphate to ethanol is 1g:5mL;
[0048] S3. Dissolve the crude product of levornidazole disodium phosphate in an ethanol aqueous solution, filter, add ethanol to the filtrate, crystallize at 15°C for 1.5 hours, filter, and vacuum dry the filter cake at 30°C for 4 hours to obtain levornidazole disodium phosphate; wherein the mass volume ratio of the crude product of levornidazole disodium phosphate and the ethanol aqueous solution is 1 g:5 mL, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:4, and the volume ratio of the filtrate to anhydrous ethanol is 1:2.
[0049] Example 4
[0050] This embodiment provides a method for preparing levornidazole disodium phosphate, which is different from Example 1 in that:
[0051] In S3, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:7.
[0052] The other steps are the same as those in Example 1.
[0053] Comparative Example 1
[0054] This comparative example provides a method for preparing levornidazole disodium phosphate, which differs from Example 1 in that the ethanol aqueous solution is replaced with an equal amount of methanol aqueous solution, and the specific operation is as follows:
[0055] S3. Dissolve the crude product of levornidazole disodium phosphate in aqueous methanol solution, filter, add ethanol to the filtrate, crystallize at 25°C for 1h, filter, and vacuum dry the filter cake at 40°C for 5h to obtain levornidazole disodium phosphate; wherein the mass volume ratio of the crude product of levornidazole disodium phosphate and aqueous methanol solution is 1g:6mL, the volume ratio of water to methanol in the aqueous methanol solution is 1:0.5, and the volume ratio of the filtrate to anhydrous ethanol is 1:3
[0056] The other steps are the same as those in Example 1.
[0057] Comparative Example 2
[0058] This comparative example provides a method for preparing levornidazole disodium phosphate, which is different from Example 1 in that the pH value of the first adjustment is reduced, and the specific operation is as follows:
[0059] S2, adding the left ornidazole phosphate to methanol, and then adjusting the pH to 3 with a 5% by mass sodium hydroxide aqueous solution, filtering, adjusting the pH of the filtrate to 8 with a 30% by mass sodium hydroxide aqueous solution, precipitating a solid, filtering, and obtaining a crude product of left ornidazole disodium phosphate; wherein the mass volume ratio of left ornidazole phosphate to methanol is 1g:6mL;
[0060] The other steps are the same as those in Example 1.
[0061] Comparative Example 3
[0062] This comparative example provides a method for preparing levornidazole disodium phosphate, which is different from Example 1 in that the pH value of the first adjustment is increased, and the specific operation is as follows:
[0063] S2, adding the left ornidazole phosphate to methanol, and then adjusting the pH to 5 with a 5% by mass sodium hydroxide aqueous solution, filtering, adjusting the pH of the filtrate to 12 with a 30% by mass sodium hydroxide aqueous solution, precipitating a solid, filtering, and obtaining a crude product of left ornidazole disodium phosphate; wherein the mass volume ratio of left ornidazole phosphate to methanol is 1g:6mL;
[0064] The other steps are the same as those in Example 1.
[0065] Comparative Example 4
[0066] This comparative example provides a method for preparing levornidazole disodium phosphate, which is different from Example 1 in that the crystallization temperature is increased, and the specific operation is as follows:
[0067] S3. Dissolve the crude product of levornidazole disodium phosphate in an ethanol aqueous solution, filter, add ethanol to the filtrate, crystallize at 30°C for 1h, filter, and vacuum dry the filter cake at 40°C for 5h to obtain levornidazole disodium phosphate; wherein the mass volume ratio of the crude product of levornidazole disodium phosphate and the ethanol aqueous solution is 1g:6mL, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:0.5, and the volume ratio of the filtrate to anhydrous ethanol is 1:3
[0068] The other steps are the same as those in Example 1.
[0069] The total yield, purity, chloride ion content and maximum single impurity content of the levonidazole disodium phosphate prepared in Examples 1 to 4 and Comparative Examples 1 to 4 were tested, and the results are shown in Table 1:
[0070] Table 1
[0071]
[0072]
[0073] The levonidazole disodium phosphate prepared by the preparation method of levonidazole disodium phosphate provided by the embodiment of the present invention has high yield and high purity, and the preparation method is easy to operate and easy to be mass-produced in factories, thereby reducing the discharge of three wastes, reducing production costs, and further shortening the production cycle.
[0074] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing levonidazole disodium phosphate, characterized in that: The steps include: S1, adding L-ornidazole and an inorganic phosphate salt to a first organic solvent, performing an esterification reaction at 40° C. to 80° C., and concentrating under reduced pressure to obtain a concentrate; adding water and a second organic solvent to the concentrate, performing a hydrolysis reaction at 40° C. to 80° C., and concentrating under reduced pressure to obtain L-ornidazole phosphate; S2, adding the levornidazole phosphate to the third organic solvent, then adjusting the pH to 4-5, filtering, adjusting the pH of the filtrate to 8-10, filtering, and obtaining a crude product of levornidazole disodium phosphate; S3. Add the crude product of levornidazole disodium phosphate to an ethanol aqueous solution, filter, add an alcohol solvent to the filtrate, crystallize at 0° C. to 25° C., filter, and dry to obtain levornidazole disodium phosphate.
2. The method for preparing levornidazole disodium phosphate as claimed in claim 1, characterized in that: In S1, the inorganic phosphate salt is phosphorus oxychloride; and / or In S1, the first organic solvent is at least one of ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform or toluene; and / or In S1, the second organic solvent is at least one of ethyl acetate, acetonitrile, tetrahydrofuran, acetone, dichloromethane, chloroform or toluene.
3. The method for preparing levornidazole disodium phosphate as claimed in claim 1, characterized in that: In S1, the esterification reaction time is 2h to 6h; and / or In S1, the hydrolysis reaction time is 2h to 6h.
4. The method for preparing levornidazole disodium phosphate according to claim 1, wherein In S1, the mass ratio of the 1-ornidazole to the inorganic phosphate salt is 1:(1-3); and / or In S1, the mass volume ratio of the L-ornidazole to the first organic solvent is 1 g: (3-8) mL.
5. The method for preparing levornidazole disodium phosphate as claimed in claim 1, characterized in that, In S1, the volume ratio of the concentrate to the second organic solvent is 1:(1-3); and / or In S1, the volume ratio of the concentrate to water is 1:(2-6).
6. The method for preparing levornidazole disodium phosphate according to claim 1, characterized in that: In S2, the third organic solvent is at least one of methanol, ethanol, isopropanol, acetonitrile, acetone or tetrahydrofuran; and / or In S2, the mass volume ratio of the levornidazole phosphate and the third organic solvent is 1 g: (2-6) mL.
7. The method for preparing levornidazole disodium phosphate according to claim 1, characterized in that: In S3, the mass volume ratio of the crude levonidin disodium phosphate to the ethanol aqueous solution is 1 g: (2-6) mL; and / or In S3, the volume ratio of water to anhydrous ethanol in the ethanol aqueous solution is 1:(0.5-5).
8. The method for preparing levornidazole disodium phosphate according to claim 1, wherein: In S3, the volume ratio of the filtrate to the alcohol solvent is 1:(0.5-3).
9. The method for preparing levornidazole disodium phosphate according to claim 1, characterized in that: In S3, the alcohol solvent is anhydrous ethanol.
10. The method for preparing levornidazole disodium phosphate according to claim 1, characterized in that: In S3, the crystallization time is 1 h to 2 h.