Preparation method of (1R, 2S)-1, 2-epoxypropylphosphonic acid calcium salt

Abstract

The invention discloses a preparation method of (1R, 2S)-1, 2-epoxypropyl calcium phosphonate, and belongs to the technical field of chemical pharmacy. Comprising the following steps: (1) adding coarse fosfomycin disodium powder into absolute ethyl alcohol, pulping, filtering and separating to obtain wet fosfomycin disodium powder; (2) dissolving the wet powder into deionized water, carrying out inert gas replacement, and adding activated carbon for decoloration in an inert gas atmosphere; (3) under the condition of heat preservation, adding calcium chloride, carrying out staged heating reaction, cooling and filtering to obtain wet powder of calcium (1R, 2S)-1, 2-epoxypropyl phosphonate; and (4) washing with deionized water and ethanol, and drying to obtain the (1R, 2S)-1, 2-epoxypropyl calcium phosphonate monohydrate. The raw material fosfomycin disodium coarse powder is subjected to ethanol pulping under the protection of inert gas to remove soluble cyclopropane ring-opening impurities, and then a high-purity target product is obtained through a calcification reaction under the protection of the inert gas, so that the method has the characteristics of high yield and high purity.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmacy, and particularly relates to the preparation of calcium (1R,2S)-1,2-epoxypropylphosphonate. Background Art

[0002] Fosfomycin is a broad-spectrum antibiotic drug. It mainly inhibits the synthesis of bacterial cell walls by interfering with the early stage of bacterial cell wall synthesis, thereby causing bacterial death. Clinically, it is used to treat various systemic bacterial infections, and has the advantages of good curative effect, low toxicity, no adverse interaction with other antibiotics, no cross-drug resistance and synergistic effect. Fosfomycin is a free acid molecule with strong hygroscopicity. It is insoluble in organic solvents such as ethanol, acetone, and ether. There are mainly three varieties of fosfomycin sodium salt, calcium salt, and tromethamine salt in the products. Among them, fosfomycin sodium salt is mainly used for injection and has good curative effect on respiratory tract infections, skin and soft tissue infections, and intestinal infections caused by sensitive bacteria. Calcium salt and tromethamine salt are mainly used for oral administration. After the calcium salt is absorbed from the intestine, it is used for bacterial enteritis, gynecology, respiratory tract infections, intestinal infections, etc. Tromethamine is a water-soluble salt of fosfomycin and is the first choice drug for urinary tract infections, used for the treatment of acute simple cystitis or the prevention of urinary tract infections. Although the antibacterial active ingredients are the same, the differences in dosage forms lead to obvious differences in their clinical applications. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a preparation method of calcium (1R,2S)-1,2-epoxypropylphosphonate. After removing soluble cyclopropane ring-opening impurities from the raw materials, under the protection of an inert gas, high-purity water-insoluble calcium (1R,2S)-1,2-epoxypropylphosphonate monohydrate is obtained through a calcification reaction, which has the characteristics of high yield and high purity.

[0004] To achieve the above-mentioned invention object, the technical solution of the present invention is as follows: The preparation method of calcium (1R,2S)-1,2-epoxypropylphosphonate comprises the following steps: (1) Under the protection of an inert gas, add the crude powder of disodium fosfomycin to absolute ethanol for pulping, and then filter and separate to obtain the wet powder of disodium fosfomycin; (2) Dissolve the wet powder in deionized water, then perform inert gas replacement. Under the inert gas atmosphere, add 0.5-2% of the weight of the crude powder of activated carbon and perform decolorization at 20-45 °C; (3) Under the condition of keeping warm, slowly add calcium chloride, raise the temperature in stages for reaction. After the reaction is complete, cool down and filter to obtain the wet powder of calcium (1R,2S)-1,2-epoxypropylphosphonate; (4) Wash with deionized water, then wash with ethanol twice, and vacuum dry at 45-55 °C until the water content ≤ 12.0% to obtain white powdery calcium (1R,2S)-1,2-epoxypropylphosphonate monohydrate.

[0005] The obtained calcium (1R,2S)-1,2-epoxypropylphosphonate monohydrate is pulverized by a jet mill to control the particle size of calcium (1R,2S)-1,2-epoxypropylphosphonate to 0.5 - 25 μm, which is convenient for further tabletting, granulation or encapsulation.

[0006] The washing ethanol is 75 - 95% ethanol for washing.

[0007] The crude powder of fosfomycin disodium can be prepared by a chemical method or obtained by a biological method.

[0008] Calcium chloride can be anhydrous calcium chloride solid, calcium chloride monohydrate solid, calcium chloride aqueous solution or suspension, preferably calcium chloride aqueous solution with a concentration of 15 - 25%.

[0009] In step (1), the mass ratio of the wet powder to deionized water is 1:2 - 4.

[0010] In step (2), the staged temperature rise is as follows: after adding calcium chloride, the reaction is carried out at 20 - 45 °C for 2 hours, then the temperature is raised to 60 - 70 °C for 0.5 hour, and after the reaction is completed, the temperature is slowly lowered to 0 - 10 °C and filtered to obtain the wet powder of calcium (1R,2S)-1,2-epoxypropylphosphonate.

[0011] In step (3), the molar ratio of fosfomycin disodium to calcium chloride is 1:0.97 - 1.02.

[0012] The beneficial effects produced by adopting the above technical scheme are as follows: The crude powder of fosfomycin disodium as a raw material, under the protection of an inert gas, is slurried with ethanol to remove soluble cyclopropane ring-opening impurities, and then under the protection of an inert gas, high-purity water-insoluble calcium (1R,2S)-1,2-epoxypropylphosphonate monohydrate is obtained through a calcification reaction, which has the characteristics of high yield and high purity. The present invention adopts staged temperature rise. The reaction substrate fosfomycin disodium is sensitive to temperature. The purpose of the staged temperature rise reaction is to shorten the high-temperature stage time and ensure the stability of the material. The calcium (1R,2S)-1,2-epoxypropylphosphonate after jet milling has the characteristic of uniform particle size, which is convenient for sub-packaging, granulation and tabletting. Description of the Drawings

[0013] Figure 1 It is the liquid chromatogram of the crude powder of fosfomycin disodium containing impurities before washing. Detailed Embodiments

[0014] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. Example 1

[0015] Under nitrogen protection, 18.76 g of crude fosfomycin disodium with a content of 97% was added to 56.28 g of absolute ethanol for pulping, and then filtered and separated. After removing the impurities in the crude powder, wet fosfomycin disodium powder was obtained, which was added to 37.52 g of deionized water and stirred for dissolution. Then nitrogen replacement was carried out. Under a nitrogen atmosphere, 0.1 g of activated carbon was added for decolorization at 45 °C. Under the condition of keeping warm, 74 g of calcium chloride aqueous solution with a content of 15% was slowly added, and the reaction was carried out at 45 °C for 2 h. Then the temperature was raised to 70 °C and the reaction was carried out for 0.5 h. The temperature was slowly lowered to 10 °C, and after filtration, wet powder of (1R,2S)-1,2-epoxypropylphosphonic acid calcium was obtained. After washing with deionized water, it was washed twice with 18.76 g of ethanol with a content of 95%. It was vacuum dried at 55 °C until the water content ≤ 12.0%, and 17.28 g of white powdery (1R,2S)-1,2-epoxypropylphosphonic acid calcium monohydrate was obtained, with a weight yield of 92.1%.

[0016] The crystallized (1R,2S)-1,2-epoxypropylphosphonic acid calcium monohydrate was crushed by a jet mill, and the particle size of (1R,2S)-1,2-epoxypropylphosphonic acid calcium was controlled to be below 25 μm, and then further pressed into tablets. Example 2

[0017] Under helium protection, 18.76 g of crude fosfomycin disodium with a content of 97% was added to 56.28 g of absolute ethanol for pulping, and then filtered and separated to obtain wet fosfomycin disodium powder, which was added to 75.04 g of deionized water and stirred for dissolution. Then helium replacement was carried out. Under a helium atmosphere, 0.37 g of activated carbon was added for decolorization at 45 °C. Under the condition of keeping warm, 11.32 g of calcium chloride was slowly added, and the reaction was carried out at 45 °C for 2 h. Then the temperature was raised to 70 °C and the reaction was carried out for 0.5 h. The temperature was slowly lowered to 10 °C, and after filtration, wet powder of (1R,2S)-1,2-epoxypropylphosphonic acid calcium was obtained. After washing with deionized water, it was washed twice with 18.76 g of ethanol with a content of 95%. It was vacuum dried at 55 °C until the water content ≤ 12.0%, and 16.05 g of white powdery (1R,2S)-1,2-epoxypropylphosphonic acid calcium monohydrate was obtained, with a weight yield of 85.6%. Example 3

[0018] Under the condition of argon protection, 18.76 g of crude phosphomycin disodium with a content of 97% was added to 56.28 g of absolute ethanol for pulping, and then the wet phosphomycin disodium powder was obtained by filtration and separation. It was dissolved with deionized water in a ratio of 1:2.5 (the amount of added water was 46.9 g). After that, argon replacement was carried out. Under the argon atmosphere, 0.19 g of activated carbon based on the weight of the crude powder was added for decolorization at 45 °C. Under the condition of heat preservation, 10.76 g of calcium chloride was slowly added and reacted at 45 °C for 2 h. Then the temperature was raised to 65 °C and reacted for 0.5 h. The temperature was slowly lowered to 5 °C. After filtration, the wet powder of (1R,2S)-1,2-epoxypropylphosphonic acid calcium was obtained. After washing with deionized water, it was washed twice with 95% ethanol and vacuum dried at 50 °C until the water content ≤ 12.0% to obtain 16.43 g of white powdery (1R,2S)-1,2-epoxypropylphosphonic acid calcium monohydrate, and the weight yield was 87.6%.

[0019] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principle and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Preparation method of calcium (1R,2S)-1,2-epoxypropylphosphonate, characterized in that, It includes the following steps: (1) Under the protection of inert gas, add the crude powder of fosfomycin disodium into absolute ethanol for pulping, and then filter and separate to obtain the wet powder of fosfomycin disodium; (2) Dissolve the wet powder in deionized water, then conduct inert gas replacement. Under the inert gas atmosphere, add activated carbon accounting for 0.5 - 2% of the weight of the crude powder and conduct decolorization at 20 - 45 °C; (3) Under the heat preservation condition, slowly add calcium chloride and carry out stepwise temperature rise reaction. After the reaction is complete, cool down and filter to obtain the wet powder of (1R,2S)-1,2-epoxypropylphosphonic acid calcium; (4) Wash with deionized water, then wash twice with ethanol, and conduct vacuum drying at 45 - 55 °C until the water content ≤ 12.0% to obtain white powdery (1R,2S)-1,2-epoxypropylphosphonic acid calcium monohydrate.

2. The preparation method of calcium (1R,2S)-1,2-epoxypropylphosphonate according to claim 1, characterized in that, In step (1), the mass ratio of the wet powder to deionized water is 1:2 - 4.

3. The preparation method of the calcium salt of (1R,2S)-1,2-epoxypropylphosphonic acid according to claim 1, characterized in that, In step (1), the inert gas is nitrogen, argon or helium.

4. The preparation method of the calcium salt of (1R,2S)-1,2-epoxypropylphosphonic acid according to claim 1, characterized in that, In step (3), the stepwise temperature rise is as follows: After adding calcium chloride, react at 20 - 45 °C for 2 hours, then raise the temperature to 60 - 70 °C and react for 0.5 hour. After the reaction is complete, slowly cool down to 0 - 10 °C and filter to obtain the wet powder of (1R,2S)-1,2-epoxypropylphosphonic acid calcium.

5. The preparation method of calcium (1R,2S)-1,2-epoxypropylphosphonate according to claim 1, characterized in that, In step (3), the molar ratio of fosfomycin disodium to calcium chloride is 1:0.97 - 1.02.

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