A production method of fosfomycin calcium raw material
By using ZSM-5 molecular sieve carrier and sodium tungstate and sodium molybdate in the production of fosfomycin calcium raw materials, the problems of difficulty in recycling catalysts and low yields in the existing processes are solved, and efficient fosfomycin The production of vegetarian calcium raw materials reduces the side effects of heavy metals and improves the safety and economicality of the process.
Patent Information
- Application Number
- CN202110545733.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2021-05-19
- Publication Date
- 2024-12-24
- Estimated Expiration
- 2041-05-19
AI Technical Summary
In the existing production process of fosfomycin calcium raw materials, the catalytic process of sodium tungstate or sodium molybdate has problems such as cumbersome separation of mixed rotary salts and difficulty in recycling catalysts, resulting in low yields and heavy metal toxic side effects.
ZSM-5 molecular sieve is used as a catalyst support, and the epoxidation product is formed by synergistic catalysis of sodium tungstate and sodium molybdate, combined with the dropping reaction of phenethylamine and hydrogen peroxide, and the use of modified ZSM-5 molecular sieve is maintained. The good crystal structure of the catalyst enables effective recycling and recycling of the catalyst.
The yield of fosfomycin (R)-1-phenyltamine salt was increased to 51.2%, reducing the use of tungsten, reducing the harm to the human body, and improving the safety and economical production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of raw material drug preparation and relates to a production method of fosfomycin calcium raw material drug. Background Art
[0002] Fosfomycin (FOM), whose chemical structure is L-cis-1,2-epoxypropyl phosphate, has a simple chemical structure, strong polarity, and a molecular weight of 138.02. It has a unique antibacterial mechanism due to its unique chemical structure. It blocks the synthesis of bacterial cell walls by preventing the synthesis of peptidoglycan to achieve antibacterial activity. It has a killing effect on both Gram-negative and Gram-positive bacteria. It is a new type of small molecule antibiotic. It is now mostly synthesized artificially. Because of its small molecular weight, good tissue permeability, wide distribution in body tissues, broad antibacterial spectrum, stable chemical properties, almost no degradation in the body, mostly excreted in urine in the original form, and relatively high safety, fosfomycin drugs are also widely used in clinical practice.
[0003] The original process adopts the Glamkowski synthesis method to perform chiral splitting to produce fosfomycin (R)-1-phenylethylamine salt, with a yield of 32.5%. The process has the problems of complicated operation, high energy consumption, difficult to master splitting technology, unstable yield, etc. in the mixed salt splitting process. Later, literatures successively reported the process of synthesizing fosfomycin (R)-1-phenylethylamine salt by epoxidation of cis-propylenephosphonic acid-(R)-(+)-α-phenylethylamine salt catalyzed by sodium tungstate or sodium molybdate, with a yield of 28%-30%. This type of process solves the problem of complicated mixed salt splitting, but the yield is not improved, and the catalyst used is difficult to recover, and there is a residue in fosfomycin, which causes the toxic side effects of heavy metals. Therefore, it is urgent to develop a production method of fosfomycin calcium raw material to solve the above problems. Summary of the invention
[0004] The object of the present invention is to provide a method for producing a fosfomycin calcium bulk drug.
[0005] The technical problems to be solved by the present invention are:
[0006] Literature has reported a process for synthesizing fosfomycin (R)-1-phenylethylamine salt by epoxidation of cis-propylenephosphonic acid-(R)-(+)-α-phenylethylamine salt catalyzed by sodium tungstate or sodium molybdate, with a yield of 28%-30%. This process solves the problem of cumbersome separation of mixed salts, but the yield is not improved, and the catalyst used is difficult to recover, and there is a residue in fosfomycin, which causes the toxic side effects of heavy metals.
[0007] The purpose of the present invention can be achieved through the following technical solutions:
[0008] A method for producing a fosfomycin calcium bulk drug comprises the following steps:
[0009] Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at a rate of 180-200 rpm, control the temperature at 35-38° C., drop (R)-(+)-α-phenylethylamine at a rate of 1-3 drops / second, after the addition is completed, heat to 40° C., react at constant temperature for 1.5-2 hours, then filter at 0° C., wash the filter cake with cyclohexane 2-3 times, transfer to a 50-55° C. vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1;
[0010] The reaction process is as follows:
[0011]
[0012] Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 200-210rpm and heat to 45°C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 1-2 drops / second. After the addition is completed, heat to 60°C, react at a constant temperature for 3-3.5 hours, filter while hot, freeze-dry the filtrate at -10°C for 10-12 hours, and then transfer to a 50°C vacuum drying oven and dry until there is no weight loss to obtain fosfomycin calcium raw material.
[0013] The reaction process is as follows:
[0014]
[0015] Furthermore, the usage ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine in step A1 is 0.23-0.31 mol:80-90 mL:0.24-0.33 mol, and the volume fraction of the ethanol solution is 76%.
[0016] Furthermore, the dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 130-140 mL: 3-4 g: 0.3-0.4 g: 25-30 mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
[0017] Further, the catalyst is prepared by the following steps:
[0018] Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 400-450°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water for 2-3 times, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve;
[0019] Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at a speed of 230-250 rpm and heat to 60-65° C., react for 7-10 hours, then cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 55-60° C. for 3-4 hours to obtain a catalyst.
[0020] Furthermore, the dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 2-3 g: 140-150 mL, and the concentration of the NaOH solution is 0.5 mol / L.
[0021] Furthermore, the usage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 40-50g: 5-10g: 500-600mL: 15-20mL: 20-30g, and the mass fraction of phosphoric acid solution is 80%.
[0022] The beneficial effects of the present invention are as follows: the present invention adds a resolution agent phenylethylamine to the reaction solution of cis-propylene phosphonic acid to form a racemate, and then adds an oxidizing agent to form epoxy propylene phosphonic acid. The epoxidation of cis-propylene phosphonic acid to produce a racemic mixture is a key step of the entire synthesis reaction. The addition of the catalyst can enable cis-propylene phosphonic acid to be epoxidized at a relatively low temperature. The addition of the ZSM-5 molecular sieve serves as a catalyst carrier, which enables the catalyst to maintain a good crystal structure. Sodium tungstate and sodium molybdate are well dispersed in the pores of the ZSM-5 molecular sieve, which not only avoids the mixing of the catalyst and the product to affect the purity of the product, but also effectively recovers the catalyst, which is repeatedly recycled and used, and is more environmentally friendly and economical. In addition, the synergistic catalysis of sodium molybdate and sodium tungstate also increases the yield of fosfomycin (R)-1-phenylethylamine salt to 51.2%, reduces the amount of tungsten added, and also reduces harm to the human body, making it safer. DETAILED DESCRIPTION
[0023] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0024] Example 1
[0025] A production method of fosfomycin calcium raw material drug, comprising the following steps:
[0026] Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at 180 rpm, control the temperature at 35°C, and drip (R)-(+)-α-phenylethylamine at 1 drop / second. After the addition is completed, raise the temperature to 40°C, react at this temperature for 1.5 hours, and then filter at 0°C. Wash the filter cake twice with cyclohexane, transfer to a 50°C vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1;
[0027] Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 200 rpm and heat to 45 ° C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 1 drop / second. After the addition is completed, the temperature is raised to 60 ° C, and the reaction is carried out at a constant temperature for 3 hours. The filtrate is filtered while hot, and the filtrate is freeze-dried at -10 ° C for 10 hours, and then transferred to a 50 ° C vacuum drying oven and dried until there is no weight loss to obtain the fosfomycin calcium raw material.
[0028] Wherein, the usage ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine in step A1 is 0.23 mol:80 mL:0.24 mol, and the volume fraction of ethanol solution is 76%.
[0029] Wherein, the dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 130mL:3g:0.3g:25mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
[0030] The catalyst is prepared by the following steps:
[0031] Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 400°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water twice, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve;
[0032] Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at 230 rpm and heat to 60°C, react for 7 hours, cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 55°C for 3 hours to obtain a catalyst.
[0033] Wherein, the dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 2 g:140 mL, and the concentration of the NaOH solution is 0.5 mol / L.
[0034] Wherein, the usage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 40g:5g:500mL:15mL:20g, and the mass fraction of phosphoric acid solution is 80%.
[0035] Example 2
[0036] A method for producing a fosfomycin calcium bulk drug comprises the following steps:
[0037] Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at 200 rpm, control the temperature at 36° C., add (R)-(+)-α-phenylethylamine at 2 drops / second, after the addition is completed, heat to 40° C., react at constant temperature for 2 hours, then filter at 0° C., wash the filter cake with cyclohexane 3 times, transfer to a 52° C. vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1;
[0038] Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 200 rpm and heat to 45 ° C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 1 drop / second. After the addition is completed, the temperature is raised to 60 ° C, and the reaction is carried out at a constant temperature for 3.5 hours. The filtrate is filtered while hot, and the filtrate is freeze-dried at -10 ° C for 11 hours, and then transferred to a 50 ° C vacuum drying oven and dried until there is no weight loss to obtain the fosfomycin calcium raw material.
[0039] Wherein, the amount ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine described in step A1 is 0.26 mol:85 mL:0.28 mol, and the volume fraction of ethanol solution is 76%.
[0040] Wherein, the dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 135mL:3.5g:0.35g:28mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
[0041] The catalyst is prepared by the following steps:
[0042] Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 450°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water for 3 times, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve;
[0043] Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at 240 rpm and heat to 62°C, react for 8 hours, cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 58°C for 4 hours to obtain a catalyst.
[0044] Wherein, the dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 2.5 g:145 mL, and the concentration of the NaOH solution is 0.5 mol / L.
[0045] Wherein, the usage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 45g:8g:550mL:17mL:25g, and the mass fraction of phosphoric acid solution is 80%.
[0046] Example 3
[0047] A method for producing a fosfomycin calcium bulk drug comprises the following steps:
[0048] Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at 180 rpm, control the temperature at 35°C, and drip (R)-(+)-α-phenylethylamine at 1 drop / second. After the addition is completed, raise the temperature to 40°C, react at this temperature for 1.5 hours, and then filter at 0°C. Wash the filter cake twice with cyclohexane, transfer to a 50°C vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1;
[0049] Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 200 rpm and heat to 45 ° C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 1 drop / second. After the addition is completed, the temperature is raised to 60 ° C, and the reaction is carried out at a constant temperature for 3 hours. The filtrate is filtered while hot, and the filtrate is freeze-dried at -10 ° C for 12 hours, and then transferred to a 50 ° C vacuum drying oven and dried until there is no weight loss to obtain the fosfomycin calcium raw material.
[0050] Wherein, the usage ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine in step A1 is 0.29 mol:88 mL:0.30 mol, and the volume fraction of ethanol solution is 76%.
[0051] Wherein, the dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 138 mL: 3.8 g: 0.38 g: 29 mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
[0052] The catalyst is prepared by the following steps:
[0053] Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 450°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water for 3 times, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve;
[0054] Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at 240 rpm and heat to 62°C, react for 8 hours, cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 58°C for 3 hours to obtain a catalyst.
[0055] Wherein, the dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 2.8 g:148 mL, and the concentration of the NaOH solution is 0.5 mol / L.
[0056] Wherein, the dosage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 49g:9g:585mL:18.5mL:28g, and the mass fraction of phosphoric acid solution is 80%.
[0057] Example 4
[0058] A method for producing a fosfomycin calcium bulk drug comprises the following steps:
[0059] Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at 200 rpm, control the temperature at 38° C., add (R)-(+)-α-phenylethylamine at 2 drops / second, after the addition is completed, heat to 40° C., react at constant temperature for 2 hours, then filter at 0° C., wash the filter cake with cyclohexane 3 times, transfer to a 55° C. vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1;
[0060] Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 205 rpm and heat to 45 ° C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 2 drops / second. After the addition is completed, the temperature is raised to 60 ° C, and the reaction is carried out at a constant temperature for 3.5 hours. The filtrate is filtered while hot, and the filtrate is freeze-dried at -10 ° C for 12 hours, and then transferred to a 50 ° C vacuum drying oven and dried until there is no weight loss, to obtain the fosfomycin calcium raw material.
[0061] Wherein, the usage ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine in step A1 is 0.31 mol:90 mL:0.33 mol, and the volume fraction of ethanol solution is 76%.
[0062] Wherein, the dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 140mL:4g:0.4g:30mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
[0063] The catalyst is prepared by the following steps:
[0064] Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 450°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water for 3 times, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve;
[0065] Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at 250 rpm and heat to 65°C, react for 10 hours, then cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 60°C for 4 hours to obtain a catalyst.
[0066] Wherein, the dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 3 g:150 mL, and the concentration of the NaOH solution is 0.5 mol / L.
[0067] Wherein, the usage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 50g:10g:600mL:20mL:30g, and the mass fraction of phosphoric acid solution is 80%.
[0068] Comparative Example 1
[0069] This comparative example is a production method of fosfomycin calcium raw material on the market, and the specific steps are as follows:
[0070] Step S1, dissolving 10 g of cis-propylenephosphonic acid in 30 mL of deionized water, adding (R)-(+)-α-phenylethylamine dropwise at 25° C., and after the addition is complete, adding 0.4 g of sodium molybdate, stirring for 10 minutes, to obtain a mixed solution;
[0071] Step S2, add 3.5 mL of 30% hydrogen peroxide to the mixed solution prepared in step S1, the addition is completed in 0.5 hours, and then react at 60° C. for 1.5 hours, remove 70% of the water in vacuo, add 30 mL of 95% ethanol solution by volume, stir evenly, place in a -5° C. refrigerator for 12 hours, filter with suction, rinse the filter cake with anhydrous ethanol, and then dry at 50° C. for 2 hours to obtain fosfomycin calcium raw material.
[0072] The yield of the method for preparing fosfomycin calcium bulk drug in Examples 1-3 and Comparative Example 1 was tested, and the test results are shown in Table 1 below:
[0073] Example 1 Example 2 Example 3 Comparative Example 1 Yield 51.2％ 49.6％ 50.2％ 33.5％
[0074] It can be seen from Table 1 above that the yield of fosfomycin calcium raw material prepared by the method for preparing fosfomycin calcium raw material in Examples 1-3 is 49.6-51.2%, while the yield of fosfomycin calcium raw material prepared by the method for preparing fosfomycin calcium raw material in Comparative Example 1 is 33.5%, indicating that the yield of fosfomycin calcium raw material prepared by the method of the present invention is much higher than that of Comparative Example 1, and the raw material price used in the method is relatively low, and the catalyst can be recycled, which greatly reduces the production cost of fosfomycin calcium raw material.
[0075] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.
Claims
1. A method for producing a fosfomycin calcium bulk drug, characterized in that: The following steps are involved: Step A1, add cis-propylenephosphonic acid into a three-necked flask, add ethanol solution, stir at a rate of 180-200 rpm, control the temperature at 35-38° C., drop (R)-(+)-α-phenylethylamine at a rate of 1-3 drops / second, after the addition is completed, heat to 40° C., react at constant temperature for 1.5-2 hours, then filter at 0° C., wash the filter cake with cyclohexane 2-3 times, transfer to a 50-55° C. vacuum drying oven and dry until there is no weight loss, to obtain intermediate 1; The reaction process is as follows: Step A2, add the intermediate 1 prepared in step A1 and the ethanol solution to a three-necked flask, stir at a rate of 200-210rpm and heat to 45°C until the intermediate 1 is dissolved, add a catalyst and sodium monohydrogen phosphate, and then use a constant pressure dropping funnel to drip hydrogen peroxide at 1-2 drops / second. After the addition is completed, heat to 60°C, react at a constant temperature for 3-3.5 hours, filter while hot, freeze-dry the filtrate at -10°C for 10-12 hours, and then transfer to a 50°C vacuum drying oven and dry until there is no weight loss, to obtain fosfomycin calcium raw material; The reaction process is as follows: The catalyst is prepared by the following steps: Step S1, taking a ZSM-5 molecular sieve, placing it in a muffle furnace at 400-450°C, calcining it for 4 hours, adding a NaOH solution and heating it to 70°C, reacting it for 1 hour, taking it out and placing it in an ice bath to cool it for 15 minutes, and then filtering it, washing the filter cake with deionized water for 2-3 times, and then drying it at 70°C to obtain a modified ZSM-5 molecular sieve; Step S2, add sodium molybdate and sodium tungstate into a flask, add deionized water and stir until dissolved, add phosphoric acid solution dropwise, and then add the modified ZSM-5 molecular sieve prepared in step S2, stir at a speed of 230-250 rpm and heat to 60-65° C., react for 7-10 hours, then cool to room temperature, filter under reduced pressure, wash the filter cake with deionized water until neutral, and dry at 55-60° C. for 3-4 hours to obtain a catalyst.
2. The method for producing a fosfomycin calcium bulk drug according to claim 1, wherein: The usage ratio of cis-acrylphosphonic acid, ethanol solution and (R)-(+)-α-phenylethylamine in step A1 is 0.23-0.31 mol:80-90 mL:0.24-0.33 mol, and the volume fraction of the ethanol solution is 76%.
3. The method for producing a fosfomycin calcium bulk drug according to claim 1, characterized in that: The dosage ratio of the ethanol solution, catalyst, sodium monohydrogen phosphate and hydrogen peroxide described in step A2 is 130-140 mL: 3-4 g: 0.3-0.4 g: 25-30 mL, the mass fraction of hydrogen peroxide is 35%, and the volume fraction of the ethanol solution is 65%.
4. The method for producing a fosfomycin calcium bulk drug according to claim 1, characterized in that: The dosage ratio of the ZSM-5 molecular sieve and the NaOH solution in step S1 is 2-3 g: 140-150 mL, and the concentration of the NaOH solution is 0.5 mol / L.
5. The method for producing a fosfomycin calcium bulk drug according to claim 1, characterized in that: The dosage ratio of sodium molybdate, sodium tungstate, deionized water, phosphoric acid solution and modified ZSM-5 molecular sieve described in step S2 is 40-50g: 5-10g: 500-600mL: 15-20mL: 20-30g, and the mass fraction of phosphoric acid solution is 80%.