Preparation method of high-purity fosfomycin intermediate compound

Abstract

The invention provides a preparation method of a high-purity fosfomycin intermediate cis-propenyl phosphoric acid (R)-(+)-alpha-phenylethylamine salt, which comprises the following steps: by taking propargyl bromide as an initial raw material, reacting propargyl bromide with trimethyl phosphite to obtain propadiene dimethyl phosphate, cracking into salt, and hydrogenating to obtain the key fosfomycin intermediate cis-propenyl phosphoric acid (R)-(+)-alpha-phenylethylamine salt. The cis-propenyl phosphoric acid (R)-(+)-alpha-phenylethylamine salt preparation method provided by the invention is simple in unit operation, better meets the environmental protection requirement of green synthesis, has higher purity, and is suitable for synthesis of fosfomycin drugs.

Description

Technical Field

[0001] The invention relates to a method for preparing a high-purity fosfomycin intermediate compound, and in particular to a method for preparing a fosfomycin intermediate cis-propylene phosphate (R)-(+)-α-phenylethylamine salt (abbreviated as cis-propylene phosphate phenylethylamine salt). Background Art

[0002] Fosfomycin is a broad-spectrum antibacterial drug, and there are related marketed drugs such as fosfomycin sodium, fosfomycin calcium and fosfomycin tromethamine. Fosfomycin has the effect of killing bacteria and inhibiting bacterial growth, and it shows excellent antibacterial effects on Staphylococci resistant to multiple antibiotics. It has strong antibacterial activity against Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Serratia, Shigella, Yersinia, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Vibrio and Aeromonas. In clinical practice, it is mainly used to treat respiratory tract infections, skin and soft tissue infections, intestinal infections, urinary tract infections, sepsis, peritonitis, meningitis, osteomyelitis, adnexitis, uterine infection, pelvic inflammatory disease and other diseases. It can also be used in combination with other antibiotics to treat severe infections caused by sensitive bacteria, and can also be used in combination with vancomycin to treat methicillin-resistant Staphylococcus aureus (MRSA) infections.

[0003] Compared with other antibiotics, fosfomycin has low toxicity, is not prone to allergies, is not prone to drug resistance, and can have synergistic effects with other antibiotics. Cis-propylene phosphate is an important intermediate in the Glamkowski method of chemically synthesizing fosfomycin antibiotics. In the prior art, the process of preparing this intermediate has problems such as low product purity (80-90%), low yield, and unstable samples.

[0004] The main synthetic routes of cis-propylene phosphoric acid are as follows:

[0005] Route 1: J. Org. Chem. Vol. 35, No. 10, 1970 discloses that tert-butyl alcohol reacts with phosphorus trichloride under low temperature conditions to generate di-tert-butyl chlorophosphate, which is then reacted with the raw material propargyl alcohol through substitution, rearrangement, selective hydrogenation, and acid hydrolysis to prepare cis-propylene phosphoric acid.

[0006]

[0007] In this route, propargyl alcohol is a highly regulated narcotic, and its purchase, use and transportation are strictly restricted. Phosphorus trichloride is highly corrosive, and a large amount of hydrochloric acid gas is released during the reaction, which puts great pressure on environmental protection and safety. At the same time, the use of benzene as a solvent does not meet the guidelines for avoiding the use of ICH Q3C Class I solvents for pharmaceutical intermediates. At the same time, the purity of the product cis-propylene phosphoric acid is only 87% (bromine titration), and impurities have not been studied and controlled.

[0008] Route 2: Antimicrob Agents Chemother, 2003, 47(7): 2242-2248. This discloses that di-tert-butyl phosphite and ethyl chloroformate are subjected to substitution, reduction and hydrolysis reaction with propargyl alcohol to prepare cis-propylene phosphoric acid after removing one molecule of hydrogen chloride.

[0009]

[0010] This route has relatively expensive raw material costs, relatively high toxicity of solvents and reagents, poor selective reduction of hydrazine hydrate, and low yield, and is therefore not suitable for industrial production.

[0011] Route 3: Patent CN115677771A discloses the use of propargyl alcohol as a starting material, which undergoes an esterification reaction with phosphorus trichloride to generate allene phosphoryl chloride, which is hydrolyzed to obtain allene phosphoric acid, which is then selectively hydrogenated on palladium carbon to generate cis-propylene phosphoric acid.

[0012]

[0013] This route also uses the highly toxic propargyl alcohol as the raw material. A large amount of hydrochloric acid gas and acidic wastewater are produced during the reaction, and the purity of the intermediate cis-propylene phosphoric acid has not been improved.

[0014] Therefore, it is necessary to develop a method for preparing the fosfomycin intermediate cis-propylene phosphate which has simple process operation, high purity, environmental safety and is suitable for large-scale production for the synthesis of fosfomycin raw materials. Summary of the invention

[0015] The purpose of the present invention is to provide a method for preparing a high-purity fosfomycin intermediate compound (cis-propylene phosphate (R)-(+)-α-phenylethylamine) suitable for industrial production.

[0016] The method for preparing a high-purity fosfomycin intermediate compound of formula I described in the present invention, wherein the fosfomycin intermediate compound is cis-propylene phosphate (R)-(+)-α-phenylethylamine, comprises the following steps:

[0017] (1) mixing propargyl bromide (Formula II) and trimethyl phosphite (Formula III), heating and refluxing in a reaction solvent to obtain dimethyl propadienyl phosphate (Formula IV);

[0018] (2) in the presence of a cleavage agent, cleaving allenyl phosphate dimethyl ester (Formula IV) to obtain allenyl phosphate, and simultaneously reacting with (R)-(+)-α-phenylethylamine to form allenyl phosphate phenylethylamine salt (Formula V);

[0019] (3) In the presence of a catalyst, catalytic hydrogenation reduction of allene phosphate phenethylamine salt (Formula V) is performed to prepare cis-propylene phosphate phenethylamine salt (Formula I).

[0020] Its chemical synthesis route is as follows:

[0021]

[0022] The method for preparing the fosfomycin intermediate compound described above, in step (1), propargyl bromide and trimethyl phosphite react to prepare a compound (Formula IV), the molar ratio of propargyl bromide to trimethyl phosphite is 1: (1-2);

[0023] Propargyl bromide reacts with trimethyl phosphite to prepare compound IV, the reaction temperature is 100-120°C, preferably 100-110°C;

[0024] Propargyl bromide is reacted with trimethyl phosphite to prepare compound IV, the reaction solvent is toluene, and the amount of toluene is 1 to 5 times that of propargyl bromide (V / m, volume weight ratio).

[0025] In the above-mentioned method for preparing the fosfomycin intermediate compound, in step (2), the cleavage reagent is selected from trimethylsilyl bromide.

[0026] In the above-mentioned method for preparing the fosfomycin intermediate compound, in step (2), the reaction molar ratio of dimethyl propadienyl phosphate, trimethylsilyl bromide, and (R)-(+)-α-phenylethylamine is 1:(1.2-3):(1.2-3); preferably 1:(1.5-2.5):(1.5-2).

[0027] In the above-mentioned method for preparing the fosfomycin intermediate compound, in step (3), the catalyst is 5% palladium on carbon (Pd / C) or 5% Lindela catalyst, and the amount of the catalyst is 0.5% to 5% of the weight of the substrate allyl phosphate phenethylamine (Formula V).

[0028] In the above-mentioned method for preparing the fosfomycin intermediate compound, in step (3), the solvent for catalytic hydrogenation reduction is selected from methanol, ethanol, water or any combination thereof.

[0029] In the above-mentioned method for preparing the fosfomycin intermediate compound, in step (3), the reaction temperature for catalytic hydrogenation reduction of allyl phosphate phenethylamine (Formula V) to prepare compound I is 10 to 40°C, preferably 20 to 30°C; the reaction pressure of catalytic hydrogenation is 0.1 to 1 MPa, preferably 0.2 to 0.6 MPa.

[0030] Furthermore, the present invention also provides a method for refining cis-propylene phenethylamine phosphate salt. The preparation method of the above-mentioned fosfomycin intermediate compound, the cis-propylene phenethylamine phosphate salt prepared can be further purified by a recrystallization method to improve the purity. The recrystallization purification method is: dissolving the cis-propylene phenethylamine phosphate salt by heating with a solvent, optionally filtering the solution, then cooling and crystallizing, filtering and drying to obtain the purified cis-propylene phenethylamine phosphate salt.

[0031] The solvent of the above-mentioned purification method is selected from water, methanol, ethanol or any combination thereof; preferably 90% ethanol aqueous solution, and the volume dosage is 2 to 4 times the weight of cis-propylene phenylethylamine phosphate salt (V / m, i.e., volume to weight ratio, when cis-propylene phenylethylamine phosphate salt is 1g, the solvent dosage is 2 to 4ml) of the volume, and the preferred volume dosage is 3 times the weight of cis-propylene phenylethylamine phosphate salt.

[0032] Furthermore, the above-mentioned purification method is: heating the cis-acryl phenylethylamine phosphate salt with a 90% ethanol aqueous solution with a volume-to-weight ratio (V / m) of 3 times until it is completely dissolved, optionally filtering the solution, cooling the solution to precipitate a solid, filtering and drying the solid.

[0033] Furthermore, the purification method of the cis-propylene phosphate (R)-(+)-α-phenylethylamine salt shown in Formula I is: heating and dissolving the cis-propylene phosphate phenylethylamine salt with a 90% ethanol aqueous solution at a volume-to-weight ratio (V / m) of 3 times, and then filtering. After the filtrate is cooled and crystallized, the solid is filtered and dried to obtain the refined cis-propylene phosphate phenylethylamine salt.

[0034] The above-mentioned “optional” means that you can choose it or not.

[0035] The invention provides a method for preparing a high-purity fosfomycin intermediate cis-acryl phosphate phenethylamine salt. Compared with the existing process, the process operation is simple, green and environmentally friendly, the purity is high, and the storage and transportation are easy, and the method is more suitable as a pharmaceutical intermediate.

[0036] Specifically, the present invention has the following advantages:

[0037] (1) In the route and process of the present invention, the reaction process avoids the use of a large amount of phosphorus trichloride in the traditional process, reduces the treatment of strongly acidic wastewater, and is safer and more environmentally friendly.

[0038] (2) The reaction process does not require low temperature or deep cooling technology, the conditions are mild, the operation is simple, and it is easy to control.

[0039] (3) The cis-propylene phosphoric acid produced by the traditional process reported in the literature has a purity of only 80-90%, poor stability, easy degradation, many impurities, and an oily property, which is difficult to purify, store and transport. The present invention converts cis-propylene phosphoric acid into phenylethylamine salt, with a purity of not less than 98%, and the property is changed from the liquid cis-propylene phosphoric acid to the white solid cis-propylene phosphoric acid phenylethylamine salt, which has better stability and is easy to store; when the purity does not meet the requirements, it is more convenient to further purify it to improve its purity.

[0040] (4) The present invention provides a new fosfomycin intermediate and its preparation method and purification method. The post-treatment of each step is simple. The intermediate obtained is not a liquid or oily substance, but a solid with good physical properties, which is convenient for storage and quality control. It does not need to be distilled, recrystallized multiple times or purified by a preparative column. The intermediate obtained has high purity and yield, which is more conducive to the production of fosfomycin raw materials and the improvement of their quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 : HPLC chart of cis-propylene phosphate phenylethylamine salt of the present invention;

[0042] Figure 2 : HPLC positioning chromatogram of R-(+)-α-methylbenzylamine; DETAILED DESCRIPTION

[0043] The technical scheme of the present invention is now further described in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention rather than to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0044] Example 1: Synthesis of dimethyl propadienyl phosphate (IV)

[0045] Propargyl bromide (44.5 g, 0.37 mol) and trimethyl phosphite (47.2 g, 0.38 mol) were added with 50 ml of toluene, heated to 100°C, and stirred for 5 hours. The unreacted propargyl bromide and trimethyl phosphite with low boiling point were distilled under reduced pressure, and the 50-70°C / 0.5 mmHg fraction was collected and distilled again for purification (BP 69-71°C / 1 mm Hg) to obtain dimethyl propadienyl phosphate with a yield of 85% and a purity of 95% (GC).

[0046] Example 2: Synthesis of dimethyl propadienyl phosphate (IV)

[0047] Propargyl bromide (44.5 g, 0.37 mol) and trimethyl phosphite (74.5 g, 0.6 mol) were added with 90 ml of toluene, heated to 105°C, and stirred for 6 hours. The unreacted propargyl bromide and trimethyl phosphite with low boiling point were distilled under reduced pressure, and the 50-70°C / 0.5 mmHg fraction was collected and distilled again for purification (BP 69-71°C / 1 mm Hg) to obtain dimethyl propadienyl phosphate with a yield of 88% and a purity of 96% (GC).

[0048] Example 3: Synthesis of dimethyl propadienyl phosphate (IV)

[0049] Propargyl bromide (44.5 g, 0.37 mol) and trimethyl phosphite (74.5 g, 0.6 mol) were added with 220 ml of toluene, heated to 110°C, and stirred for 5 hours. The unreacted propargyl bromide and trimethyl phosphite with low boiling point were distilled under reduced pressure, and the 50-70°C / 0.5 mmHg fraction was collected and purified again by distillation (BP 69-71°C / 1 mm Hg) to obtain dimethyl propadienyl phosphate with a yield of 83% and a purity of 98% (GC).

[0050] Example 4: Synthesis of allylphosphophenylethylamine salt (V)

[0051] Trimethylsilyl bromide (71g, 0.46mol) was added to dichloromethane (180ml), and dimethyl propadienyl phosphate (30g, 0.20mol) was slowly added under nitrogen protection, and the mixture was stirred at 20-30°C for 3h. 240ml of methanol was added dropwise to quench the reaction, and (R)-(+)-α-phenylethylamine (48.5g, 0.40mol) was added, and the solid was precipitated by stirring, filtered, washed with methanol, and dried in vacuo to obtain phenylethylamine propadienyl phosphate salt (V) (38.8g, purity 98.2%, yield 79.4%).

[0052] Example 5: Synthesis of allyl phosphate phenylethylamine salt (V)

[0053] Trimethylsilyl bromide (53.3 g, 0.3 mol) was added to dichloromethane (150 ml), and dimethyl propadienyl phosphate (30 g, 0.2 mol) was slowly added under nitrogen protection, and the reaction was stirred at 20-30°C for 5 h. 200 ml of methanol was added dropwise to quench the reaction, and (R)-(+)-α-phenylethylamine (36.5 g, 0.4 mol) was added, and the solid was precipitated by stirring, filtered, washed with methanol, and vacuum dried to obtain phenylethylamine propadienyl phosphate salt (V) (39.9 g, content or purity 98.5%, yield 82.7%).

[0054] Example 6: Synthesis of cis-acrylphosphophenylethylamine (I)

[0055] Propylene phosphophenethylamine (V) (30 g) was dissolved in 150 ml of ethanol and 15 ml of water, added to a hydrogenation reactor, and 0.9 g of a 5% palladium carbon catalyst was added. The air was replaced by nitrogen three times, and the nitrogen was replaced by hydrogen three times. The reaction was carried out at 20-25°C and the pressure was maintained at 0.2-0.4 MPa for 10 h to complete the reaction. The catalyst was filtered and concentrated under reduced pressure until solid precipitated, and then cooled and crystallized. After filtration and drying, cis-propene phosphophenethylamine (I) (25.9 g, purity 98.81%, yield 85.6%) was obtained.

[0056] Example 7: Synthesis of cis-acrylphosphophenylethylamine (I)

[0057] Propylene phosphophenethylamine (V) (30 g) was dissolved in 180 ml of methanol and added to a hydrogenation reactor. 1.5 g of 5% Lindela catalyst was added. The air was replaced by nitrogen three times and the nitrogen was replaced by hydrogen three times. The reaction was carried out at 25-30°C and the pressure was maintained at 0.4-0.6 MPa for 12 h to complete the reaction. The catalyst was filtered, the methanol was concentrated under reduced pressure and then cooled for crystallization to obtain cis-propene phosphophenethylamine (I) (25.5 g, purity 98.62%, yield 84.3%).

[0058] Example 8: Synthesis of cis-acrylphosphophenylethylamine (I)

[0059] Propylene phosphophenylethylamine (V) (30 g) was dissolved in 150 ml of ethanol and 15 ml of water, added to a hydrogenation reactor, and 1.5 g of a 5% palladium carbon catalyst was added. The air was replaced by nitrogen three times, and the nitrogen was replaced by hydrogen three times. The reaction was catalytically hydrogenated at 25-30 ° C, and the pressure was maintained at 0.1-0.2 MPa for 20 h to complete the reaction. The catalyst was filtered, and the mixture was concentrated under reduced pressure until solids precipitated, cooled and crystallized, and filtered and dried to obtain cis-propene phosphophenylethylamine (I) (25.0 g, purity 97.5%, yield 82.6%).

[0060] Example 9: Synthesis of cis-acrylphosphophenylethylamine (I)

[0061] Propylene phosphophenylethylamine (V) (30 g) was dissolved in 150 ml of ethanol and 15 ml of water, added to a hydrogenation reactor, and 0.3 g of a 5% palladium carbon catalyst was added. The air was replaced by nitrogen three times, and the nitrogen was replaced by hydrogen three times. The reaction was carried out at 20-25°C and the pressure was maintained at 0.8-1 MPa for 8 h to complete the reaction. The catalyst was filtered, and the solvent was concentrated under reduced pressure until solids precipitated, and then cooled and crystallized. The cis-propene phosphophenylethylamine (I) (25.1 g, purity 97.3%, yield 83.0%) was obtained.

[0062] Example 10: Purification of cis-acrylphosphophenylethylamine (I)

[0063] The propylene phosphate phenethylamine (V) (10 g) obtained in Example 6 was heated and stirred with 90% ethanol / water (30 ml) until it was completely dissolved and then filtered. The filtrate was stirred and cooled to 0-5°C for crystallization for 2 hours, and filtered and dried to obtain 8.6 g (purity 99.8%) of cis-propylene phosphate phenethylamine.

[0064] Example 11: Purification of cis-acrylphosphophenylethylamine (I)

[0065] The propylene phosphate phenethylamine (V) (10 g) obtained in Example 9 was heated and stirred with 90% ethanol / water (10 ml) until it was completely dissolved and then filtered. The filtrate was stirred and cooled to 0-5°C for crystallization for 2 hours, and filtered and dried to obtain 8.6 g (purity 99.7%) of cis-propylene phosphate phenethylamine.

[0066] Example 12: Purification of cis-acrylphosphophenylethylamine (I)

[0067] The propylene phenethylamine phosphate (V) (5 g) obtained in Example 9 was heated and stirred with 90% ethanol / water (12 ml) until it was completely dissolved. The solution was then stirred and cooled to 0-5°C for crystallization for 2 hours, and filtered and dried to obtain 4.3 g (purity 99.4%) of cis-propylene phenethylamine phosphate.

[0068] Example 13: Preparation of Fosfomycin Levophosphoamylamine Salt by Cis-Propylene Phosphate ...

[0069]

[0070] To cis-acryl phosphate phenylethylamine salt (100 g, prepared according to the method of Example 6), add anhydrous ethanol (270 ml), water (30 ml), stir, add 64.08 g of D-(-)α-phenylethylamine, add 3 g of sodium tungstate, 0.5 g of EDTA, add 60.5 g of 30% hydrogen peroxide at 40°C, after the addition is complete, control the temperature at 40°C to react for 1 h, cool to 0-5°C after the reaction is completed, stir and crystallize at the same temperature for 2 h, filter, add the solid to 300 ml of anhydrous ethanol, stir and wash for 1 h, crystallize at 0-5°C for 2 h, filter, and dry the solid for 12 h to obtain 40.4 g of an off-white solid, which is fosfomycin left phosphoamylamine salt, with a yield of 38%.

[0071] Example 14: Preparation of Fosfomycin Sodium from Fosfomycin Levofosfosamine Salt

[0072]

[0073] Add 200 ml of anhydrous ethanol to the reaction bottle, add 6.48 g of sodium hydroxide and stir to dissolve, add 20 g of fosfomycin left-phosphamide salt, control the temperature to 30±5℃ and react for 12 hours, cool to 20±5℃ and stir for 2 hours, filter, rinse the solid with 40 ml of anhydrous ethanol, and dry under reduced pressure at 50℃ for 12 hours to obtain 15.41 g of white solid fosfomycin sodium.

[0074] Comparative Example 1: Preparation of cis-propylene phosphoric acid (reference CN202211326227.6)

[0075] Under magnetic stirring, add 3.5L of anhydrous ethanol and 334.5g of allenoic acid to the reaction bottle, replace with nitrogen three times, add 12g of palladium carbon (5%), replace with hydrogen three times, and react at room temperature and normal pressure for 30h until allenoic acid is gone, filter and obtain an ethanol solution of cis-propylene phosphoric acid.

[0076] Comparative Example 2: Preparation of Fosfomycin Left-phosphoamyl Right-amine Salt from Cis-propylene Phosphoric Acid

[0077] Add ethanol solution of cis-propylene phosphoric acid to the reaction bottle under stirring, and add 300.2g of R(+)-alpha-methylbenzylamine to the system at a temperature below 35°C to make the pH of the system 5.8-5.9. Dissolve 12.24g of sodium tungstate and 2.47g of disodium ethylenediaminetetraacetate in 31.5mL of purified water by heating, and then add them dropwise to the system. The system changes from clear to yellow turbid. Slowly add 427g of hydrogen peroxide at 40-55°C. After the addition is complete, keep the temperature at 50-55°C for 2h. When the system is slowly cooled to 10°C, a white solid is precipitated. Then, cool the system to -5°C and keep the temperature for 2h, filter, rinse the filter cake with ethanol, drain it, and dry it at 45°C under reduced pressure for 5h to obtain 208g of white powder, with a yield of 30%.

[0078] Table 1 Comparison of the quality of cis-propylene phosphate phenylethylamine salt of the present invention and cis-propylene phosphate solution of comparative example 1

[0079]

[0080] The experimental results show that the cis-propylene phosphoric acid of the present invention is convenient for storage and use after being salted, and has higher purity, less impurities and better stability.

[0081] Table 2 Comparison of the quality of the left phosphorus right amine salt prepared by the intermediate of the present invention and the left phosphorus right amine salt of comparative example 2

[0082]

[0083]

[0084] The experimental results show that the cis-propylene phosphate phenethylamine salt prepared by the present invention is used to synthesize fosfomycin phosphotoxin amine salt, which is significantly better than comparative example 2 in terms of impurity control, chiral purity control and effective content, and is more suitable for directly preparing raw materials such as fosfomycin sodium, fosfomycin calcium and fosfomycin tromethamine.

[0085] The outstanding contribution of the present invention is firstly to provide a new synthesis route of a key intermediate and a preparation method thereof, on which the scheme can be further optimized to achieve the purpose of being more economical and environmentally friendly. The above is only an explanation of a typical embodiment of the present invention. On the basis of the disclosure of the present invention, a person of ordinary skill in the art can make various modifications and changes to the reaction conditions and post-treatment of each step, such as changing the feed ratio of the reaction raw materials, changing the reaction temperature, using similar alternative reagents, etc., all of which belong to the protection scope of the present invention.

Claims

1. A method for preparing a fosfomycin intermediate compound of formula I, wherein the fosfomycin intermediate compound is cis-propylene phosphate (R)-(+)-α-phenylethylamine salt, characterized in that: The following steps are involved: (1) mixing propargyl bromide (Formula II) and trimethyl phosphite (Formula III), heating and reacting in a reaction solvent to obtain dimethyl propadienyl phosphate (Formula IV); (2) in the presence of a cleavage agent, cleaving dimethyl allyl phosphate (Formula IV) to obtain allyl phosphate, and simultaneously reacting with (R)-(+)-α-phenylethylamine to form allyl phosphate phenylethylamine salt (Formula V); (3) In the presence of a catalyst, catalytic hydrogenation reduction of allene phosphate phenethylamine salt (Formula V) is performed to prepare cis-propylene phosphate phenethylamine salt (Formula I).

2. The method for preparing a fosfomycin intermediate compound according to claim 1, characterized in that: In step (1), the molar ratio of propargyl bromide to trimethyl phosphite is 1:(1-2); the reaction temperature is 100-120°C; preferably 100-110°C; the reaction solvent is toluene, and the amount of toluene is 1-5 times (V / m) of the propargyl bromide.

3. The method for preparing a fosfomycin intermediate compound according to claim 1, characterized in that: In step (2), the cleavage reagent is selected from trimethylsilyl bromide.

4. The method for preparing a fosfomycin intermediate compound according to claim 3, characterized in that: In step (2), the reaction molar ratio of dimethyl propadienyl phosphate, trimethylsilyl bromide, and (R)-(+)-α-phenylethylamine is 1:(1.2-3):(1.2-3); preferably 1:(1.5-2.5):(1.5-2).

5. The method for preparing a fosfomycin intermediate compound according to claim 1, characterized in that: In step (3), the catalyst is selected from palladium carbon or Lindella catalyst, and the amount used is 0.5% to 5% of the weight of propylene phosphate phenethylamine.

6. The method for preparing a fosfomycin intermediate compound according to claim 5, characterized in that: In step (3), the solvent for the catalytic hydrogenation reduction reaction is selected from methanol, ethanol, water or any combination thereof.

7. The method for preparing a fosfomycin intermediate compound according to any one of claims 5 to 6, characterized in that: In step (3), the reaction temperature of the catalytic hydrogenation reduction is 10 to 40°C.

8. The method for preparing a fosfomycin intermediate compound according to any one of claims 5 to 7, characterized in that: In step (3), the reaction pressure of catalytic hydrogenation is 0.2 to 1 MPa, preferably 0.2 to 0.6 MPa.

9. The method for preparing a fosfomycin intermediate compound according to any one of claims 1 to 8, characterized in that: The preparation method may further include a recrystallization refining step to further improve the purity; the recrystallization method is: heating and dissolving the cis-propylene phenethylamine phosphate salt with a solvent, then cooling and crystallizing, filtering and drying to obtain the refined cis-propylene phenethylamine phosphate salt; the refined solvent is selected from water, methanol, ethanol or any combination thereof; preferably 90% ethanol aqueous solution, and the volume usage is 2 to 4 times the weight of the cis-propylene phenethylamine phosphate salt, preferably 3 times.

10. A method for refining cis-propylene phosphoric acid (R)-(+)-α-phenylethylamine salt, characterized in that: Cis-propylene phenylethylamine phosphate salt is dissolved by heating with 90% ethanol aqueous solution in a volume-to-weight ratio of 3 times, and then filtered. After the filtrate is cooled and crystallized, the solid is filtered and dried to obtain the refined cis-propylene phenylethylamine phosphate salt.

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