Synthesis method of fosfomycin sodium

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of fosfomycin sodium. Allylamine is used as a raw material and is subjected to an isomerization reaction, iodination, a Michaelis-Arbuzov reaction, phosphonyl chloride preparation, a hydrolysis reaction, a chlorine hydroxylation reaction, chiral resolution and an intramolecular nucleophilic substitution cyclization reaction in sequence, and finally the fosfomycin sodium is prepared. According to the invention, allylamine is taken as a starting raw material, and a new path which is different from a traditional Glamkowski method and is used for constructing a key intermediate propenyl phosphoric acid is provided. According to the route, a synthesis scheme starting from propargyl alcohol is avoided, the use of chemicals easy to explode is avoided from the source, and the initial safety of the process is improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing sodium fosfomycin. Background Technology

[0002] Fosfomycin sodium is a broad-spectrum antibiotic with a unique chemical structure and antibacterial mechanism. It exerts its bactericidal effect by irreversibly inhibiting a key enzyme in bacterial cell wall synthesis (UDP-N-acetylglucosamine enolpyruvyltransferase, MurA). Due to its unique mechanism of action and lack of cross-resistance with other antibiotics, it is becoming increasingly important in the treatment of multidrug-resistant bacterial infections.

[0003] Currently, the classic industrial method for producing sodium fosfomycin is the Glankowski synthesis. This traditional route typically uses propynyl alcohol (a potentially explosive chemical) as a starting material, and the catalytic hydrogenation step often requires high-pressure hydrogen conditions, placing stringent demands on production equipment and posing significant safety hazards. Furthermore, it generates a racemic chlorohydrin intermediate through chlorohydroxylation, and finally, chiral resolution is necessary to obtain a single enantiomer with pharmacological activity. To overcome these drawbacks, the industry has been exploring safer, more efficient, and more environmentally friendly new synthetic routes. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing fosfomycin sodium. This method offers a preliminary route for constructing a propenyl phosphate intermediate from inexpensive allylamine, avoiding the potentially explosive reagents such as propynyl alcohol involved in traditional Glankowski precursor synthesis. Although the embodiments of the present invention still employ the classic chlorohydroxylation-chiral resolution strategy for constructing the chiral center, its unique preliminary process route itself provides a new technical solution and option for the synthesis of fosfomycin sodium.

[0005] The objective of this invention is achieved through the following technical solution: A method for synthesizing fosfomycin sodium includes the following steps: (1) Allylamine was added to tetrahydrofuran, and tris(triphenylphosphine)carbonyl rhodium was added under an inert atmosphere at -78°C. The reaction was stirred to obtain intermediate 1-propen-1-amine. (2) Add intermediate 1-propen-1-amine to acetonitrile, add tetrabutylammonium iodide under an inert gas atmosphere at 20-25°C, stir to react, and obtain intermediate 1-iodo-1-propen; (3) Mix phosphorus trichloride and anhydrous aluminum chloride, heat at 60-70℃ for 30-40 min, then cool in an ice bath and add intermediate 1-iodo-1-propene. Stir for 1-1.5 h, then add potassium chloride and iron powder, continue stirring for 1-1.5 h, and distill to obtain intermediate 3. (4) Under ice bath conditions, intermediate 3 was added to thionyl chloride and reacted at 20-30°C. After the reaction was completed, thionyl chloride was removed by vacuum distillation to obtain intermediate 4. (5) Add intermediate 4 to water and reflux at 90-100℃ in an inert gas atmosphere to obtain intermediate 5; (6) Add intermediate 5 to water, add sodium hypochlorite at 0-5℃, stir and react to obtain 1-chloro-2-hydroxypropylphosphonic acid; then use (+)-α-phenylethylamine to resolve 1-chloro-2-hydroxypropylphosphonic acid to obtain intermediate 6; (7) Add intermediate 6 to an aqueous sodium hydroxide solution, stir to react, and purify to obtain the sodium fosfomycin.

[0006] This invention uses allylamine as a raw material and proceeds through isomerization, iodination, Michaelis-Arbuzov reaction, preparation of phosphonyl chloride, hydrolysis, chlorohydroxylation, chiral resolution, and intramolecular nucleophilic substitution cyclization reaction to finally obtain sodium fosfomycin.

[0007] Further, in step (1), the molar ratio of allylamine to rhodium tri(triphenylphosphine)carbonyl hydride is 1:(0.015-0.02); the stirring reaction time is 20-24 h.

[0008] Further, in step (2), the molar ratio of the intermediate 1-propen-1-amine and tetrabutylammonium iodide is 1:(2-2.5); the stirring reaction time is 2-4 h.

[0009] Further, in step (3), the molar ratio of phosphorus trichloride, anhydrous aluminum chloride, intermediate 1-iodo-1-propene, potassium chloride and iron powder is 1:(1.1-1.2):(1-1.1):(1.4-1.5):(1.07-1.25).

[0010] Further, in step (4), the molar ratio of intermediate 3 to thionyl chloride is 1:(1-1.1); the temperature is maintained at 10-15℃ during the addition of intermediate 3 to thionyl chloride; and the reaction time is 0.5-1 h.

[0011] Furthermore, in step (5), the ratio of intermediate 4 to water is 1 mmol: (5-6) mL; the reflux reaction time is 4-6 h.

[0012] Further, in step (6), the molar ratio of intermediate 5 and sodium hypochlorite is 1:(1.5-2); the stirring reaction time is 2-4 h; and the molar ratio of 1-chloro-2-hydroxypropylphosphonic acid and (+)-α-phenylethylamine is 1:(1.1-1.2).

[0013] Further, the separation process described in step (6) is as follows: 1-chloro-2-hydroxypropylphosphonic acid is added to an ethanol solution, (+)-α-phenylethylamine is added at 50-60 °C, the mixture is stirred for 0.5-1 h, and then cooled to 0-5 °C to grow crystals for 3-5 h to obtain the (+)-α-phenylethylamine salt of the target configuration. After recovering (+)-α-phenylethylamine and purifying, the solution is ready.

[0014] Further, in step (7), the ratio of intermediate 6 to sodium hydroxide aqueous solution is (90-100) mg: 1 mL; the concentration of sodium hydroxide aqueous solution is 10 mol / L; and the stirring reaction time is 5-6 h.

[0015] The present invention has the following advantages over the prior art: 1. This invention provides a novel route for constructing the key intermediate propenylphosphoric acid, using allylamine as a starting material, which differs from the traditional Glankowski process. This route avoids synthetic schemes starting from propynyl alcohol, thereby circumventing the use of potentially explosive chemicals at the source and improving the initial safety of the process.

[0016] 2. The overall synthetic route of this invention has a clear design logic, the reaction conditions of each step are relatively mild, no ultra-low temperature or ultra-high pressure are required, the operation is simple, the equipment requirements are not high, and it is easy to achieve safe and controllable large-scale industrial production. Detailed Implementation

[0017] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0018] Example 1 A method for synthesizing fosfomycin sodium includes the following steps: (1) Allylamine (10 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to −78 °C under nitrogen protection. The catalyst tris(triphenylphosphine)carbonyl rhodium hydride (CAS No.: 17185-29-4, 0.18 mmol) was added and the reaction was stirred at this temperature for 22 h. After the reaction was completed, the temperature was raised to room temperature and 50 mL of ethyl acetate was added to dilute the reaction solution. The catalyst was removed by diatomaceous earth filtration. The filtrate was collected and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.53 g of intermediate 1 (1-propen-1-amine, CAS: 77144-82-2), with a yield of about 92.1%. 1 HNMR(C3H7N, 400 MHz, DMSO): δ 6.81 (s, 2H), 5.77 (d, 1H), 4.51-4.47 (m, 1H), 2.05 (d, 3H); HRMS(ESI + ): [M+H] + The calculated value is 58.06, and the value is found to be 58.06.

[0019] (2) Intermediate 1 (10 mmol) was dissolved in 50 mL of anhydrous acetonitrile, and tetrabutylammonium iodide (22 mmol) was added at 25 °C under nitrogen protection and the mixture was stirred for 3 h. After the reaction was completed, 50 mL of 1 M Na2CO3 aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to obtain 1.36 g of intermediate 2 (1-iodo-1-propene, CAS: 7796-36-3), with a yield of about 80.8%. 1 H NMR(C3H5I, 400 MHz, DMSO): δ 6.60-5.56 (m, 1H), 6.11 (d, 1H), 2.05(d, 3H); HRMS(ESI + ): [M+H] + The calculation yields 168.94, and the result is 168.95.

[0020] (3) Phosphorus trichloride (1 mmol) and anhydrous aluminum chloride (1.15 mmol) were added to a flask. The mixture was heated at 65 °C for 30 min, cooled in an ice bath, and intermediate 2 (1.05 mmol) was added dropwise over 0.5 h with continuous stirring. After the addition was complete, stirring was continued for 1.2 h. Then, dry potassium chloride (1.45 mmol) and iron powder (1.15 mmol) were added to the reaction system, and stirring was continued for 1 h. A distillation condenser was added, and the mixture was distilled. The fraction collected at 78–165 °C was collected. The fraction was then fractionated three times to obtain 0.11 g of intermediate 3, which was a colorless liquid with a yield of 74.9%. 1 H NMR (C3H5Cl2P, 400 MHz, DMSO): δ 7.20-7.13 (m, 2H), 2.05 (d, 3H); HRMS (ESI + [M] Calculation yields 141.95, and the value is found to be 141.95.

[0021] (4) Add 105 mmol of thionyl chloride to a 100 mL four-necked flask equipped with a thermometer and a rubber stopper, place it in an ice-water bath, and seal the reaction with a condenser. Then, weigh 100 mmol of intermediate 3 using a 50 mL constant-pressure dropping funnel and quickly transfer it to the four-necked flask; connect the top of the condenser to a drying bottle containing concentrated sulfuric acid (indirectly connected via a buffer device) and start stirring; when the temperature inside the flask is 0 °C, add intermediate 3 dropwise, maintaining the reaction temperature at 12 °C during the dropwise addition process, and the dropwise addition time is 18 min; then keep the reaction system at 25 °C for 0.5 h, remove thionyl chloride by vacuum distillation, and obtain 15.27 g of intermediate 4, with a yield of 96.7%; 1 H NMR(C3H5Cl2OP, 400 MHz, DMSO): δ 5.80-5.76(m, 1H), 4.97(d, 1H), 2.05 (d, 3H); HRMS(ESI + [M] Calculation yields 157.95, and the value is found to be 157.95.

[0022] (5) Intermediate 4 (10 mmol) was dissolved in 55 mL of deionized water and heated to 95 °C under nitrogen protection. The mixture was then stirred and hydrolyzed under reflux for 5 h. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to neutral, and the byproducts were removed by extraction. The aqueous phase was concentrated under reduced pressure to obtain 1.11 g of intermediate 5, with a yield of 90.6%. 1H NMR(C3H7O3P, 400 MHz, DMSO): δ 5.82-5.78(m, 1H), 5.01(d, 1H), 4.80(s, 2H), 2.05 (d, 3H); HRMS(ESI + ): [M+H] + The result is 123.01, and the value is 123.02.

[0023] (6) Dissolve intermediate 5 (10 mmol) in 50 mL of water, cool to 0 °C, and add sodium hypochlorite aqueous solution (18 mmol, 20 mL) dropwise. After the addition is complete, raise the temperature to room temperature and continue stirring for 3 h. After the reaction is complete, adjust the pH to 1 with concentrated hydrochloric acid, concentrate under reduced pressure to 1 / 4 of the original volume, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry, and concentrate to obtain 1.48 g of 1-chloro-2-hydroxypropylphosphonic acid, with a yield of 85.0%. Subsequently, according to the molar ratio of 1-chloro-2-hydroxypropylphosphonic acid to (+)-α-phenylethylamine 1:1.1, dissolve 1-chloro-2-hydroxypropylphosphonic acid in 50 mL of 90% ethanol solution, heat to 50 °C, add (+)-α-phenylethylamine (CAS: 223-423-4) dropwise, and continue stirring for 0.5 h after the addition is complete. Then cool naturally to room temperature, and then cool to 0 °C to grow crystals. h, filter, wash the filter cake with a small amount of ice-cold 95% ethanol solution, and vacuum dry to obtain the (+)-α-phenylethylamine salt of the target configuration; suspend the (+)-α-phenylethylamine salt in water, add 30% sodium hydroxide solution to adjust the pH to 12.5, stir thoroughly, and extract with methyl tert-butyl ether to recover (+)-α-phenylethylamine; adjust the pH of the aqueous phase to 1.0 with concentrated hydrochloric acid, concentrate under reduced pressure, add anhydrous ethanol to precipitate sodium chloride, filter, concentrate the filtrate to dryness under reduced pressure, dissolve the residue in water, precisely adjust the pH to 7.8 with 50% sodium hydroxide solution, cool to crystallize, filter, wash with water, and vacuum dry to obtain enantiomeric excess chlorohydrin intermediate 6. HPLC analysis showed an ee value >99%, a resolution efficiency of 85%, a melting point of 107.5-108.5℃, and an optical rotation [α]. 405 =+19.03° (c= 3.415, solvent is water); 1 H NMR(C3H8ClO4P, 400 MHz, DMSO): δ 6.20(s, 1H), 4.80(s, 2H), 4.02-3.98(m, 1H), 3.4 (d, 1H), 1.28(d, 3H); HRMS(ESI + [M] Calculation yields 173.98, and the value is found to be 173.98.

[0024] (7) Intermediate 6 (95 mg) was added to 1 mL of 10 M sodium hydroxide aqueous solution and stirred for 5 h. The pH of the solution was adjusted to 9.5 with hydrochloric acid aqueous solution. The mixture was concentrated under reduced pressure. 5 mL of methanol was added to the residue, the mixture was stirred and filtered, and the solvent was removed under reduced pressure to obtain 73.3 mg of fosfomycin sodium, with a yield of 73.8%. 1 H NMR(C3H5Na2O4P, 400 MHz, DMSO): δ 3.02-2.98(m, 1H), 2.59 (dd, 1H), 1.36(d, 3H); HRMS(ESI + [M] Calculation yields 181.97, and the value is found to be 181.97.

[0025] Example 2 A method for synthesizing fosfomycin sodium includes the following steps: (1) Allylamine (10 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to −78 °C under nitrogen protection. The catalyst tris(triphenylphosphine)carbonyl rhodium hydride (0.15 mmol) was added and the reaction was stirred at this temperature for 20 h. After the reaction was completed, the temperature was raised to room temperature and 50 mL of ethyl acetate was added to dilute the reaction solution. The catalyst was removed by diatomaceous earth filtration. The filtrate was collected and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.52 g of intermediate 1, with a yield of about 91.5%.

[0026] (2) Intermediate 1 (10 mmol) was dissolved in 50 mL of anhydrous acetonitrile, and tetrabutylammonium iodide (20 mmol) was added at 20 °C under nitrogen protection and the mixture was stirred for 4 h. After the reaction was completed, 50 mL of 1 M Na2CO3 aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to obtain 1.35 g of intermediate 2, with a yield of about 80.1%.

[0027] (3) Phosphorus trichloride (1 mmol) and anhydrous aluminum chloride (1.1 mmol) were added to a flask. The mixture was heated at 60-70 °C for 40 min, cooled in an ice bath, and intermediate 2 (1 mmol) was added dropwise over 0.5 h with continuous stirring. After the addition was complete, stirring was continued for 1 h. Then, dry potassium chloride (1.4 mmol) and iron powder (1.07 mmol) were added to the reaction system, and stirring was continued for 1 h. A distillation condenser was added, and the mixture was distilled. The fraction at 78-165 °C was collected. The fraction was then fractionated three times to obtain 0.104 g of intermediate 3, which was a colorless liquid with a yield of 73.2%.

[0028] (4) Add 100 mmol of thionyl chloride to a 100 mL four-necked flask equipped with a thermometer and a rubber stopper, place it in an ice-water bath, and connect a condenser to seal the reaction. Then, weigh 100 mmol of intermediate 3 using a 50 mL constant pressure dropping funnel and quickly transfer it to the four-necked flask; connect the top of the condenser to a drying bottle containing concentrated sulfuric acid (indirectly connected via a buffer device) and turn on the stirrer; when the temperature inside the flask is 0 °C, add intermediate 3 dropwise, maintaining the reaction temperature at 10 °C during the dropwise addition process, and the dropwise addition time is 20 min; then keep the reaction system at 20 °C for 1 h, remove the thionyl chloride by vacuum distillation, and obtain 15.0 g of intermediate 4, with a yield of 95.0%.

[0029] (5) Intermediate 4 (10 mmol) was dissolved in 50 mL of deionized water and heated to 90 °C under nitrogen protection. The mixture was then stirred and hydrolyzed under reflux for 6 h. After the reaction was complete, the mixture was cooled to room temperature, the pH was adjusted to neutral, and byproducts were extracted. The aqueous phase was concentrated under reduced pressure to obtain 1.08 g of intermediate 5, with a yield of 88.7%. 1 H NMR and HRMS were consistent with those in Example 1.

[0030] (6) Dissolve intermediate 5 (10 mmol) in 50 mL of water, cool to 5 °C, and add sodium hypochlorite aqueous solution (15 mmol, 20 mL) dropwise. After the addition is complete, raise the temperature to room temperature and continue stirring for 2 h. After the reaction is complete, adjust the pH to 1.5 with concentrated hydrochloric acid, concentrate under reduced pressure to 1 / 4 of the original volume, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry, and concentrate to obtain 1.47 g of 1-chloro-2-hydroxypropylphosphonic acid, with a yield of 84.2%. Subsequently, according to the molar ratio of 1-chloro-2-hydroxypropylphosphonic acid to (+)-α-phenylethylamine 1:1.2, dissolve 1-chloro-2-hydroxypropylphosphonic acid in 50 mL of 90% ethanol solution, heat to 60 °C, add (+)-α-phenylethylamine (CAS: 223-423-4) dropwise, and continue stirring for 1 h after the addition is complete. Then cool naturally to room temperature, and then cool to 5 °C to grow crystals. h, filter, wash the filter cake with a small amount of ice-cold 95% ethanol solution, and vacuum dry to obtain the (+)-α-phenylethylamine salt of the target configuration; suspend the (+)-α-phenylethylamine salt in water, add 30% sodium hydroxide solution to adjust the pH to 13.0, stir thoroughly, extract and recover (+)-α-phenylethylamine with methyl tert-butyl ether, adjust the pH of the aqueous phase to 1.5 with concentrated hydrochloric acid, concentrate under reduced pressure, add anhydrous ethanol to precipitate sodium chloride, filter, concentrate the filtrate to dryness under reduced pressure, dissolve the residue in water, precisely adjust the pH to 8.0 with 50% sodium hydroxide solution, cool to crystallize, filter, wash with water, and vacuum dry to obtain enantiomeric excess chlorohydrin intermediate 6, HPLC analysis shows ee value > 99%, resolution efficiency is 85%.

[0031] (7) Add intermediate 6 (90 mg) to 1 mL of 10 M sodium hydroxide aqueous solution, stir and react for 5 h, adjust the pH of the solution to 9 with hydrochloric acid aqueous solution, concentrate the mixture under reduced pressure, add 5 mL of methanol to the residue, stir the mixture and filter, remove the solvent under reduced pressure to obtain 67.88 mg of fosfomycin sodium, with a yield of 72.1%.

[0032] Example 3 A method for synthesizing fosfomycin sodium includes the following steps: (1) Allylamine (10 mmol) was dissolved in 15 mL of tetrahydrofuran and cooled to −78 °C under nitrogen protection. The catalyst tris(triphenylphosphine)carbonyl rhodium hydride (0.2 mmol) was added and the reaction was stirred at this temperature for 24 h. After the reaction was completed, the temperature was raised to room temperature and 50 mL of ethyl acetate was added to dilute the reaction solution. The catalyst was removed by diatomaceous earth filtration. The filtrate was collected and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1, v / v) to obtain 0.516 g of intermediate 1, with a yield of about 90.4%.

[0033] (2) Intermediate 1 (10 mmol) was dissolved in 50 mL of anhydrous acetonitrile, and tetrabutylammonium iodide (25 mmol) was added at 25 °C under nitrogen protection and the mixture was stirred for 2 h. After the reaction was completed, 50 mL of 1 M Na2CO3 aqueous solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation and the mixture was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1, v / v) to obtain 1.32 g of intermediate 2 (1-iodo-1-propene, CAS: 7796-36-3), with a yield of about 78.5%.

[0034] (3) Phosphorus trichloride (1 mmol) and anhydrous aluminum chloride (1.2 mmol) were added to a flask. The mixture was heated at 70 °C for 30 min, cooled in an ice bath, and intermediate 2 (1.1 mmol) was added dropwise over 0.5 h with continuous stirring. After the addition was complete, stirring was continued for 1.5 h. Then, dry potassium chloride (1.5 mmol) and iron powder (1.25 mmol) were added to the reaction system, and stirring was continued for 1 h. A distillation condenser was added, and the mixture was distilled. The fraction at 78–165 °C was collected. The fraction was then fractionated three times to obtain 0.102 g of intermediate 3, with a yield of 72.0%.

[0035] (4) Add 110 mmol of thionyl chloride to a 100 mL four-necked flask equipped with a thermometer and a rubber stopper, place it in an ice-water bath, and connect a condenser to seal the reaction. Then, weigh 100 mmol of intermediate 3 using a 50 mL constant pressure dropping funnel and quickly transfer it to the four-necked flask; connect the top of the condenser to a drying bottle containing concentrated sulfuric acid (indirectly connected via a buffer device) and start stirring; when the temperature inside the flask is 0 °C, add intermediate 3 dropwise, maintaining the reaction temperature at 15 °C during the dropwise addition process, and the dropwise addition time is 15 min; then keep the reaction system at 30 °C for 0.5 h, remove thionyl chloride by vacuum distillation, and obtain 14.90 g of intermediate 4, with a yield of 94.3%.

[0036] (5) Dissolve intermediate 4 (10 mmol) in 60 mL of deionized water, heat to 100 °C under nitrogen protection, and stir and hydrolyze for 4 h under reflux. After the reaction is completed, cool to room temperature, adjust pH to neutral, extract to remove byproducts, and concentrate the aqueous phase under reduced pressure to obtain 1.065 g of intermediate 5, with a yield of 87.3%.

[0037] (6) Dissolve intermediate 5 (10 mmol) in 50 mL of water, cool to 0 °C, and add sodium hypochlorite aqueous solution (20 mmol, 20 mL) dropwise. After the addition is complete, raise the temperature to room temperature and continue stirring for 4 h. After the reaction is complete, adjust the pH to 1.5 with concentrated hydrochloric acid, concentrate under reduced pressure to 1 / 4 of the original volume, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry, and concentrate to obtain 1.46 g of 1-chloro-2-hydroxypropylphosphonic acid, with a yield of 83.7%. Subsequently, according to the molar ratio of 1-chloro-2-hydroxypropylphosphonic acid to (+)-α-phenylethylamine 1:1.2, dissolve the crude 1-chloro-2-hydroxypropylphosphonic acid in 50 mL of 90% ethanol solution, heat to 50 °C, add (+)-α-phenylethylamine dropwise, and continue stirring for 1 h after the addition is complete. Then cool naturally to room temperature, and then cool to 5 °C to grow crystals 5. h. Filter, wash the filter cake with a small amount of ice-cold 95% ethanol solution, and vacuum dry to obtain the (+)-α-phenylethylamine salt of the target configuration; suspend the (+)-α-phenylethylamine salt in water, add 30% sodium hydroxide solution to adjust the pH to 12.5, stir thoroughly, and extract with methyl tert-butyl ether to recover (+)-α-phenylethylamine. Adjust the pH of the aqueous phase to 1.5 with concentrated hydrochloric acid, concentrate under reduced pressure, add anhydrous ethanol to precipitate sodium chloride, filter, concentrate the filtrate to dryness under reduced pressure, dissolve the residue in water, precisely adjust the pH to 8.0 with 50% sodium hydroxide solution, cool to crystallize, filter, wash with water, and vacuum dry to obtain enantiomeric excess chlorohydrin intermediate 6. HPLC analysis showed an ee value >99% and a resolution efficiency of 80%.

[0038] (7) Add intermediate 6 (100 mg) to 1 mL of 10 M sodium hydroxide aqueous solution, stir and react for 6 h, adjust the pH of the solution to 10 with hydrochloric acid aqueous solution, concentrate the mixture under reduced pressure, add 5 mL of methanol to the residue, stir the mixture and filter, remove the solvent under reduced pressure to obtain 74.79 mg of fosfomycin sodium, with a yield of 71.5%.

[0039] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.

Claims

1. A method for synthesizing sodium fosfomycin, characterized in that, Includes the following steps: (1) Allylamine was added to tetrahydrofuran, and tris(triphenylphosphine)carbonyl rhodium was added under an inert atmosphere at -78°C. The reaction was stirred to obtain intermediate 1-propen-1-amine. (2) Add intermediate 1-propen-1-amine to acetonitrile, add tetrabutylammonium iodide under an inert gas atmosphere at 20-25°C, stir to react, and obtain intermediate 1-iodo-1-propen; (3) Mix phosphorus trichloride and anhydrous aluminum chloride, heat at 60-70℃ for 30-40 min, then cool in an ice bath and add intermediate 1-iodo-1-propene. Stir for 1-1.5 h, then add potassium chloride and iron powder, continue stirring for 1-1.5 h, and distill to obtain intermediate 3. (4) Under ice bath conditions, intermediate 3 was added to thionyl chloride and reacted at 20-30°C. After the reaction was completed, thionyl chloride was removed by vacuum distillation to obtain intermediate 4. (5) Add intermediate 4 to water and reflux at 90-100℃ in an inert gas atmosphere to obtain intermediate 5; (6) Add intermediate 5 to water, add sodium hypochlorite at 0-5℃, stir and react to obtain 1-chloro-2-hydroxypropylphosphonic acid; then use (+)-α-phenylethylamine to resolve 1-chloro-2-hydroxypropylphosphonic acid to obtain intermediate 6; (7) Add intermediate 6 to an aqueous sodium hydroxide solution, stir to react, and purify to obtain the sodium fosfomycin.

2. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, The molar ratio of allylamine and tris(triphenylphosphine)carbonyl rhodium hydride in step (1) is 1:(0.015-0.02); the stirring reaction time is 20-24 h.

3. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, The molar ratio of the intermediate 1-propen-1-amine and tetrabutylammonium iodide in step (2) is 1:(2-2.5); the stirring reaction time is 2-4 h.

4. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, The molar ratio of phosphorus trichloride, anhydrous aluminum chloride, intermediate 1-iodo-1-propene, potassium chloride and iron powder in step (3) is 1:(1.1-1.2):(1-1.1):(1.4-1.5):(1.07-1.25).

5. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, In step (4), the molar ratio of intermediate 3 to thionyl chloride is 1:(1-1.1); the temperature is maintained at 10-15℃ during the addition of intermediate 3 to thionyl chloride; and the reaction time is 0.5-1 h.

6. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, In step (5), the ratio of intermediate 4 to water is 1 mmol: (5-6) mL; the reflux reaction time is 4-6 h.

7. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, In step (6), the molar ratio of intermediate 5 and sodium hypochlorite is 1:(1.5-2); the stirring reaction time is 2-4 h; and the molar ratio of 1-chloro-2-hydroxypropylphosphonic acid and (+)-α-phenylethylamine is 1:(1.1-1.2).

8. The method for synthesizing sodium fosfomycin according to claim 7, characterized in that, The separation process described in step (6) is as follows: 1-chloro-2-hydroxypropylphosphonic acid is added to an ethanol solution, and (+)-α-phenylethylamine is added at 50-60 °C. The mixture is stirred for 0.5-1 h and then cooled to 0-5 °C to grow crystals for 3-5 h to obtain the (+)-α-phenylethylamine salt of the target configuration. After (+)-α-phenylethylamine is recovered and purified, the solution is ready.

9. The method for synthesizing sodium fosfomycin according to claim 1, characterized in that, In step (7), the ratio of intermediate 6 to sodium hydroxide aqueous solution is (90-100) mg: 1 mL; the concentration of sodium hydroxide aqueous solution is 10 mol / L; and the stirring reaction time is 5-6 h.

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