Preparation method of fosfomycin tromethamine

Abstract

The invention discloses a preparation method of fosfomycin tromethamine, which comprises the following steps: in methanol, reacting fosfomycin levo-fosfomycin dextro-fosfomycin amine salt with tromethamine to generate fosfomycin tromethamine double salt; in methanol, fosfomycin levo-fosfomycin dextro-fosfomycin amine salt reacts with methanesulfonic acid to generate fosfomycin, and the fosfomycin reacts with the fosfomycin tromethamine double salt to obtain fosfomycin tromethamine. In the preparation process of the fosfomycin tromethamine, ring opening of the fosfomycin tromethamine is prevented by using a low-temperature reaction, and the pH is adjusted by using the fosfomycin tromethamine double salt, so that the pH of the fosfomycin tromethamine can be stably controlled, the content of impurities in the product can be effectively reduced, the product quality is improved, namely, the fosfomycin content is high, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a method for preparing fosfomycin tromethamine. Background Art

[0002] Fosfomycin trometamol is a mixture of fosfomycin and 2-amino-2-hydroxymethyl-1,3-propanediol salt in a ratio of 1:1, with fosfomycin as its active ingredient. Fosfomycin trometamol overcomes some of the defects of fosfomycin metal salts and has the advantages of mild efficacy, high oral absorption concentration, and long duration of action. It is a milder and more effective antibacterial drug. The molecular weight of fosfomycin trometamol is 259.19; its structural formula is shown in Formula I:

[0003]

[0004] Fosfomycin tromethamine is a white or off-white crystalline powder; odorless, salty taste; hygroscopic; easily soluble in water, soluble in methanol, very slightly soluble in ethanol, and insoluble in chloroform.

[0005] Fosfomycin tromethamine is used to treat acute simple lower urinary tract infections caused by sensitive bacteria (such as acute cystitis, acute exacerbation of chronic cystitis, acute urethral bladder syndrome, nonspecific urethritis, asymptomatic bacteriuria during pregnancy, and urinary tract infections after surgery) and to prevent urinary tract infections during surgery and infections caused by transurinary tract diagnostic procedures.

[0006] The molecular structure of fosfomycin is similar to that of phosphoenolpyruvate. It binds irreversibly to pyruvate-diphosphate uracil-acetylglucosamine transferase, interfering with the first step of bacterial cell wall mucopeptide synthesis and inhibiting subsequent reactions, thereby exerting a bactericidal effect. It only acts on the bacterial cell wall. Human cells do not have this target and are not affected. It can be used in pregnant women, children and elderly patients. In vitro tests have shown that fosfomycin has a long post-antibiotic effect (3.4 to 4.7 hours) on Escherichia coli and Proteus mirabilis. In vitro experiments have confirmed that fosfomycin has an inhibitory effect on the biofilm formation of Escherichia coli and Pseudomonas aeruginosa.

[0007] Chinese patent CN 109608497 B discloses a method for preparing fosfomycin tromethamine, wherein fosfomycin tromethamine salt and tromethamine are used as raw materials to generate fosfomycin tromethamine disalt under anhydrous ethanol conditions; then propionic anhydride or acetic anhydride is added dropwise to the disalt solution under methanol conditions, stirred for reaction, and then methanol is removed by reduced pressure distillation to obtain a crude product; then the crude product is refined and dried to obtain the finished product fosfomycin tromethamine. The inventors repeated the embodiment, wherein the yield of the disalt was 94%, the refined yield was 70%, and the actual yield was 65.8%, the yield was low, and the impurities were large.

[0008] In addition, the method disclosed in CN1264852C is: using fosfomycin sodium as a raw material, reacting with a hydrogen-type cation exchange resin in methanol at low temperature to obtain fosfomycin acid, adding tromethamine to the acid for neutralization reaction, and obtaining a fosfomycin monotromethamine salt product. The process for preparing fosfomycin tromethamine by resin technology has large differences in resin selection, poor resistance to organic solvents, slow reaction, and resin activation produces a large amount of wastewater, which is easy to cause environmental pollution, and has high cost and low yield.

[0009] Therefore, from the existing process conditions for preparing fosfomycin tromethamine, there are the following problems: (1) the yield is low and the impurities are large; (2) the resin selection is difficult and the cost is high; (3) there is a large amount of wastewater, which is difficult to treat and easily causes environmental pollution. Summary of the invention

[0010] Technical issues

[0011] Therefore, the present invention has been made in view of the above problems. The object of the present invention is to provide a method for preparing fosfomycin tromethamine, which has good product quality (high content), high yield, good stability, and is easy to operate and environmentally friendly.

[0012] Technical Solution

[0013] According to the present invention, the preparation method of fosfomycin tromethamine provided by the present invention comprises the following steps:

[0014] Preparation of Fosfomycin Tromethamine Disalt

[0015] At 30-60° C., in methanol, react fosfomycin tromethamine salt with tromethamine for 6-12 hours; after the reaction, cool to 0-5° C., grow crystals, and filter to obtain fosfomycin tromethamine disalt;

[0016] Preparation of Fosfomycin Tromethamine

[0017] At 5-15°C, fosfomycin tromethamine salt is added to methanol to obtain fosfomycin tromethamine salt solution, methanesulfonic acid is added dropwise thereto, and the reaction is stirred for 1-4 hours; then the fosfomycin tromethamine disalt obtained above is added thereto so that the pH of the system is 3-6; then, the reaction solution is decolorized with activated carbon, concentrated under reduced pressure, and a crystallization solvent ethanol or aqueous ethanol is added to the concentrate to obtain fosfomycin tromethamine monosalt.

[0018] Beneficial Effects

[0019] The technical advantages of the present invention are:

[0020] In the preparation process of fosfomycin tromethamine, a low temperature reaction is used to prevent the ring opening of fosfomycin tromethamine, and fosfomycin tromethamine disalt is used to adjust the pH, so that the pH of fosfomycin tromethamine can be stably controlled, the content of impurities in the product can be effectively reduced, and the product quality is improved, that is, the fosfomycin content is high and the yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the HPLC high performance liquid chromatography analysis spectrum of the standard reference substance of fosfomycin tromethamine monosalt;

[0022] Figure 2 It is the HPLC high performance liquid chromatography analysis spectrum of fosfomycin tromethamine prepared in Example 1. DETAILED DESCRIPTION

[0023] Hereinafter, the preparation method of fosfomycin tromethamine of the present invention will be described in detail to promote understanding of the present invention. However, various different forms of changes can be carried out to embodiments of the present invention, and the scope of the present invention is not limited to the embodiments to be described below. Embodiments of the present invention are provided to make this disclosure clear and complete, to fully illustrate the present invention to those of ordinary skill in the art.

[0024] According to the present invention, the preparation method of fosfomycin tromethamine provided by the present invention comprises the preparation of fosfomycin tromethamine disalt and the preparation of fosfomycin tromethamine, and the reaction principle is as follows:

[0025]

[0026] First, fosfomycin tromethamine salt reacts with tromethamine in methanol to form fosfomycin tromethamine disalt;

[0027] In the second step:

[0028]

[0029] That is, fosfomycin fosfoximine salt reacts with methanesulfonic acid in methanol to produce fosfomycin, and the fosfomycin reacts with the above-mentioned fosfomycin tromethamine disalt to obtain fosfomycin tromethamine.

[0030] The key to this reaction is the reaction of fosfomycin tromethamine salt with methanesulfonic acid, the phenethylamine in fosfomycin tromethamine salt is reacted with methanesulfonic acid to generate phenethylamine methanesulfonate soluble in organic solvents, and fosfomycin is released, and fosfomycin is adjusted by fosfomycin tromethamine disalt, fosfomycin tromethamine disalt is decomposed into fosfomycin tromethamine monosalt and tromethamine, and excess tromethamine reacts with fosfomycin to prepare the finished fosfomycin tromethamine monosalt. The reaction temperature is low during this reaction process, which prevents fosfomycin from opening the ring to form impurities during the reaction with the organic solvent and removes the influence of phenethylamine on the finished product.

[0031] Specifically, in the preparation of the fosfomycin tromethamine disalt, fosfomycin tromethamine salt and tromethamine are reacted in methanol at 30-60° C. for 6-12 hours; after the reaction, the temperature is lowered to 0-5° C., crystals are grown, and fosfomycin tromethamine disalt is obtained by filtration.

[0032] In the reaction of fosfomycin fosfoximine salt and tromethamine, the molar ratio of fosfomycin fosfoximine salt to tromethamine can be between 1:2.0 and 2.5.

[0033] The amount of the solvent methanol is not limited as long as the reaction proceeds smoothly. Specifically, the amount of methanol is 7 to 20 ml, preferably 7 to 15 ml, per gram of tromethamine. At 30 to 60° C., in methanol, fosfomycin phosphocyanamide salt reacts with tromethamine for 6 to 12 hours. Then, the mixture is stirred and cooled to 0 to 5° C., filtered, and the material is washed with methanol to obtain fosfomycin tromethamine disalt.

[0034] According to the present invention, in the preparation of fosfomycin tromethamine, fosfomycin tromethamine salt is added to methanol at 5 to 15° C. to obtain a fosfomycin tromethamine salt solution, methanesulfonic acid is added dropwise thereto, and the solution is stirred for reaction for 1 to 4 hours; then the fosfomycin tromethamine disalt obtained above is added thereto so that the pH value of the system is 3 to 6; then, the reaction solution is decolorized by activated carbon, concentrated under reduced pressure, and a crystallization solvent ethanol or aqueous ethanol is added to the concentrate to obtain fosfomycin tromethamine monosalt.

[0035] At 5 to 15° C., in methanol, fosfomycin phosphoamyl salt reacts with methanesulfonic acid to generate fosfomycin, wherein the molar ratio of fosfomycin phosphoamyl salt to methanesulfonic acid may be between 1:0.8 and 1.5. The amount of the solvent methanol is not limited as long as the reaction proceeds smoothly. Specifically, the amount of methanol may be 1 to 10 ml, preferably 5 to 10 ml, per g of fosfomycin phosphoamyl salt; and the reaction time may be 1 to 4 hours.

[0036] Then, the above-obtained fosfomycin tromethamine disalt is added thereto to make the pH of the system be 3-6; then, the reaction solution is decolorized by activated carbon, concentrated under reduced pressure, and a crystallization solvent ethanol or aqueous ethanol is added to the concentrate to obtain fosfomycin tromethamine.

[0037] The dosage of fosfomycin tromethamine disalt is such that the pH of the system is 3 to 6, preferably 3 to 5, and the molar ratio of methanesulfonic acid to fosfomycin tromethamine disalt can be 1:1.00 to 1.10.

[0038] Then, the reaction solution is decolorized by activated carbon, concentrated under reduced pressure, and then a crystallization solvent ethanol or aqueous ethanol is added to the concentrate to obtain fosfomycin tromethamine, wherein the water content in the aqueous ethanol is less than or equal to 5% by volume. Specifically, the reaction solution is decolorized by activated carbon, concentrated under reduced pressure, and the concentration multiple is 2 to 10 times, preferably 5 to 10 times; then after reduced pressure concentration, a crystallization solvent is added to the concentrate, and the amount of the crystallization solvent is 20 to 50 ml, preferably 20 to 45 ml, per g of fosfomycin left phosphorus right amine salt; and the temperature is cooled to 0 to 5° C. by stirring, crystallization is grown for 1 to 4 hours, filtered, the material is washed with a crystallization solvent, and the material is discharged to obtain the finished product fosfomycin tromethamine.

[0039] The preparation method of fosfomycin tromethamine of the present invention is further described in detail below by way of examples, and the protection scope of the present invention is not limited to the following examples, which are listed only for illustrative purposes and are not intended to limit the present invention in any way.

[0040] Example 1

[0041] Preparation of Fosfomycin Tromethamine Disalt

[0042] In a reaction bottle, add 2300 ml of methanol, stir and heat to 40°C, add tromethamine 251.8 g (2.08 mol), after tromethamine is dissolved, add fosfomycin left phosphocyanate 270 g (1.04 mol), at this temperature, stir and react for 6 hours, then stir and cool to 0-5°C, filter, wash the material with methanol, and obtain fosfomycin tromethamine disalt 488 g wet material with a drying loss of 19.1%.

[0043] Preparation of Fosfomycin Tromethamine

[0044] In the reaction bottle, add 900ml methanol, stir and cool to 10-12°C, add 135g (0.52mol) of fosfomycin tromethamine salt, stir and dissolve, add 50.1g (0.52mol) of methanesulfonic acid dropwise, control the temperature during the addition process to 10-12°C, react for 2.5h, after the reaction, detect the pH of the feed solution to be 0.96; add the above-obtained fosfomycin tromethamine disalt to the reaction bottle until it is completely dissolved, adjust the pH to 3.5, use a total of 244.3g (about 0.52mol) of the above-mentioned undried fosfomycin tromethamine disalt, wait for it to stabilize, add activated carbon for decolorization for 30min, filter and obtain the filtrate below 20°C for reduced pressure concentration, concentrate 5 times, stop concentrating, add 3000ml Crystallize with 95% ethanol, cool to 0-5°C with stirring, grow crystals for 2 hours, filter, wash the material with 95% ethanol, and discharge to obtain 240 g of finished product fosfomycin tromethamine, with a molar yield of 89.0%.

[0045] According to the measurement method of specific rotation and pH of fosfomycin tromethamine specified in the 2020 edition of the Pharmacopoeia of the People's Republic of China, the specific rotation of fosfomycin tromethamine prepared in this embodiment is -3.23°, and the pH value is 4.88. The 2020 edition of the Pharmacopoeia of the People's Republic of China stipulates that the specific rotation of fosfomycin tromethamine monosalt should be between -2.0° and -4.0°, and its pH should be in the range of 3.5 to 5.5. The specific rotation and pH of fosfomycin tromethamine prepared in this embodiment meet the requirements of the Pharmacopoeia.

[0046] According to the HPLC high performance liquid chromatography detection method specified in European Pharmacopoeia 7.0, chromatographic analysis was performed on the fosfomycin tromethamine monosalt standard reference substance and the fosfomycin tromethamine prepared in Example 1, and the chromatographic analysis patterns were respectively: Figure 1 and Figure 2 .Depend on Figure 1 It can be seen that the main peak position of the fosfomycin tromethamine monosalt standard reference substance in the chromatographic detection is approximately at 9.8 min. Figure 2 It shows that the fosfomycin tromethamine prepared in Example 1 has a characteristic peak at 9.8 min.

[0047] Example 2

[0048] Preparation of Fosfomycin Tromethamine Disalt

[0049] In a reaction flask, add 2300 ml of methanol, stir and heat to 48°C, add 251.8 g (2.08 mol) of tromethamine, and after tromethamine is dissolved, add 270 g (1.04 mol) of fosfomycin tromethamine salt, stir and react at this temperature for 8 hours, then stir and cool to 0-5°C, filter, and wash the material with methanol to obtain 453 g of fosfomycin tromethamine disalt wet material. The drying loss is 12.9%.

[0050] Preparation of Fosfomycin Tromethamine

[0051] In the reaction bottle, add 900ml methanol, stir and cool to 10-12°C, add fosfomycin left phosphoamyl salt 135g (0.52mol), stir and dissolve, add methanesulfonic acid 44.9g (0.468mol), control the temperature during the addition process to 10-11°C, after the addition is complete, the reaction process is 3.5h, and the pH of the reaction solution is detected to be 1.23; add the above-obtained fosfomycin tromethamine disalt to the reaction bottle, wait for it to be completely dissolved, use a total of fosfomycin tromethamine disalt 204.2g (about 0.468mol) to adjust the pH to 4.5, wait for it to stabilize, add activated carbon for decolorization for 30min, filter the filtrate to be below 20°C and concentrate under reduced pressure, concentrate 6 times, stop concentrating, add 3000ml Crystallize with 95% ethanol, cool to 0-5°C with stirring, grow crystals for 2 hours, filter, wash the material with 95% ethanol, and discharge to obtain 214.9 g of finished fosfomycin tromethamine with a molar yield of 83.9%.

[0052] According to the measurement method of specific rotation and pH of fosfomycin tromethamine specified in the Pharmacopoeia of the People's Republic of China 2020 edition, the specific rotation of fosfomycin tromethamine prepared in this embodiment is -3.13° and the pH value is 4.85.

[0053] Example 3

[0054] Preparation of Fosfomycin Tromethamine Disalt

[0055] In a reaction flask, add 2300 ml of methanol, stir and heat to 60°C, add 251.8 g (2.08 mol) of tromethamine, and after tromethamine is dissolved, add 270 g (1.04 mol) of fosfomycin tromethamine salt, stir and react for 12 hours at this temperature, then stir and cool to 0-5°C, filter, and wash the material with methanol to obtain 454 g of fosfomycin tromethamine disalt wet material. The drying loss is 13.1%.

[0056] Preparation of Fosfomycin Tromethamine

[0057] In the reaction bottle, add 900ml of methanol, stir and cool to 10-12°C, add 135g (0.52mol) of fosfomycin tromethamine salt, stir and dissolve, add 75g (0.78mol) of methanesulfonic acid dropwise, and control the temperature during the dropwise addition process to 10-11°C. After the dropwise addition is completed, react at this temperature for 1.5h, and measure the pH of the reaction solution to be 0.46; add the above-obtained fosfomycin tromethamine disalt to the reaction bottle, wait for it to be completely dissolved, and adjust the pH to 4.0. A total of 341.1g (about 0.78mol) of fosfomycin tromethamine disalt is used. After it stabilizes, add activated carbon for decolorization for 30min, filter and obtain a filtrate below 20°C for reduced pressure concentration, and after concentrating 7 times, stop concentrating, and add 3000ml Crystallize with 95% ethanol, cool to 0-5°C with stirring, grow crystals for 2 hours, filter, wash the material with 95% ethanol, and discharge to obtain 282.2 g of finished fosfomycin tromethamine with a molar yield of 83.7%.

[0058] According to the measurement method of specific rotation and pH of fosfomycin tromethamine specified in the 2020 edition of the Pharmacopoeia of the People's Republic of China, the specific rotation of fosfomycin tromethamine prepared in this embodiment is -3.20° and the pH value is 4.89.

[0059] Comparative Example 1

[0060] According to patent Example 1 of Chinese patent CN109608497B of KEDA Huacai (Wuhan) Biotechnology Co., Ltd., 46 g of tromethamine and 566 g of anhydrous ethanol were stirred and dissolved, 48 g of fosfomycin tromethamine salt was added, the temperature was raised and refluxed for 1 hour, and the mixture was cooled and crystallized to obtain 58 g of fosfomycin tromethamine.

[0061] Take fosfomycin tromethamine (18.0 g 0.0473 mol) and 90 g of methanol, stir at room temperature for 15 min, slowly add acetic anhydride (4.93 0.0483 mol), stir for reaction, remove methanol, use anhydrous ethanol for crystallization, and dry to obtain 7.9 g of solid fosfomycin tromethamine, with a molar yield of 65%.

[0062] According to the measurement method of specific rotation and pH of fosfomycin tromethamine specified in the 2020 edition of the Pharmacopoeia of the People's Republic of China, the specific rotation of fosfomycin tromethamine prepared in Comparative Example 1 is -3.18° and the pH (pH value) is 5.13.

[0063] The fosfomycin tromethamine of the embodiment and the comparative example was tested according to the detection method of fosfomycin tromethamine in the EP2.0 pharmacopoeia, and the data are as follows:

[0064]

[0065] Data analysis: It can be clearly seen from the above table that according to Examples 1-3 of the present invention, the yield is significantly increased, the content is more stable, the EP impurities are lower, and the product quality is better.

[0066] According to the preliminary accelerated stability experiment, the stability test of fosfomycin tromethamine prepared in the examples and comparative examples was carried out under the conditions of 40°C ± 2°C and 75% RH. Samples were taken for testing at 0, 1, 3, and 6 months, and the data are as follows:

[0067]

[0068]

[0069] Data analysis: The stability of fosfomycin tromethamine was placed for 6 months, and it can be clearly seen that the stability of fosfomycin tromethamine prepared in Examples 1-3 according to the embodiments of the present invention is significantly improved, providing a better raw material for the subsequent preparation of fosfomycin tromethamine powder.

[0070] Those skilled in the art should understand that various changes and modifications can be made to the method for preparing fosfomycin tromethamine provided by the present invention without departing from the spirit and scope of the present invention, and it should be understood that these changes and modifications are within the scope of the attached claims, and the scope of protection of the present invention should be determined by the contents of the attached claims.

Claims

1. A method for preparing fosfomycin tromethamine, comprising the steps of: Preparation of Fosfomycin Tromethamine Disalt At 30-60° C., in methanol, react fosfomycin tromethamine salt with tromethamine for 6-12 hours; after the reaction, cool to 0-5° C., grow crystals, and filter to obtain fosfomycin tromethamine disalt; Preparation of Fosfomycin Tromethamine At 5-15°C, fosfomycin tromethamine salt is added to methanol to obtain fosfomycin tromethamine salt solution, methanesulfonic acid is added dropwise thereto, and the reaction is stirred for 1-4 hours; then the fosfomycin tromethamine disalt obtained above is added thereto so that the pH of the system is 3-6; then, the reaction solution is decolorized with activated carbon, concentrated under reduced pressure, and a crystallization solvent ethanol or aqueous ethanol is added to the concentrate to obtain fosfomycin tromethamine monosalt.

2. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of the fosfomycin tromethamine disalt, the molar ratio of fosfomycin tromethamine salt to tromethamine is between 1:2.0 and 2.

5.

3. The preparation method of fosfomycin tromethamine according to claim 1, characterized in that In the preparation of the fosfomycin tromethamine disalt, the amount of methanol used is 7 to 20 ml per gram of tromethamine.

4. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of fosfomycin tromethamine, fosfomycin tromethamine salt reacts with methanesulfonic acid in methanol at 5-15° C. to generate fosfomycin, wherein the molar ratio of fosfomycin tromethamine salt to methanesulfonic acid is 1:0.8-1.

5.

5. The method for preparing fosfomycin tromethamine according to claim 1, characterized in that: In the preparation of fosfomycin tromethamine, the amount of methanol used is 1 to 10 ml per gram of fosfomycin tromethamine salt.

6. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of fosfomycin tromethamine, the amount of fosfomycin tromethamine disalt is such that the pH value of the system is 3 to 6, and the molar ratio of methanesulfonic acid to fosfomycin tromethamine disalt is 1:1.00 to 1.

10.

7. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of fosfomycin tromethamine, the reaction solution is decolorized by activated carbon, concentrated under reduced pressure, and then a crystallization solvent ethanol or hydrous ethanol is added to the concentrate to obtain fosfomycin tromethamine, wherein the water content in the hydrous ethanol is less than or equal to 5% by volume.

8. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of fosfomycin tromethamine, the reaction solution is decolorized by activated carbon, and concentrated under reduced pressure, and the concentration multiple is 2 to 10 times; then after the reduced pressure concentration, a crystallization solvent is added to the concentrate, and the amount of the crystallization solvent is 20 to 50 ml per gram of fosfomycin tromethamine salt; and the reaction solution is stirred and cooled to 0 to 5°C, and the crystals are grown for 1 to 4 hours, filtered, and the material is washed with the crystallization solvent, and the material is discharged to obtain the finished product fosfomycin tromethamine.

9. The method for preparing fosfomycin tromethamine according to claim 1, wherein In the preparation of the fosfomycin tromethamine disalt, the molar ratio of fosfomycin tromethamine salt to tromethamine is 1:2.0-2.5, and the amount of methanol used is 7-20 ml per gram of tromethamine; In the preparation of fosfomycin tromethamine, fosfomycin levophosphamide salt reacts with methanesulfonic acid in methanol at 5-15°C to generate fosfomycin, wherein the molar ratio of fosfomycin levophosphamide salt to methanesulfonic acid is 1:0.8-1.5; the amount of fosfomycin tromethamine disalt is such that the pH value of the system is 3-6, and the molar ratio of methanesulfonic acid to fosfomycin tromethamine disalt is 1:1.00-1.10; the reaction solution is decolorized by activated carbon, and concentrated under reduced pressure by 2-10 times; and then after reduced pressure concentration, a crystallization solvent is added to the concentrate, and the amount of the crystallization solvent is 20-50 ml per gram of fosfomycin levophosphamide salt; and the temperature is cooled to 0-5°C with stirring, and crystals are grown for 1-4 hours, filtered, and the material is washed with a crystallization solvent, and the material is discharged to obtain a finished product of fosfomycin tromethamine.

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