Preparation method of fosfomycin levo-phosphorus dextro-amine salt

Abstract

The invention provides a preparation method of fosfomycin levo-fosfomycin dextro-fosfomycin amine salt, and particularly relates to the field of medicines. The preparation method comprises the following steps: S1, dissolving 30-40g of crude fosfomycin levo-phosphorus dextro-amine salt in 100mL of trichloroethylene; s2, heating to 25-25 DEG C, adding 0.3-0.7 g of activated carbon, and carrying out heat preservation and decoloration for 25-35 minutes; s3, filtering, separating out the activated carbon, and freezing the clarified feed liquid at-8 to-12 DEG C for 0.5-1.5 h; s4, separating out crystals, filtering, and drying the obtained wet product to obtain the refined fosfomycin levo-fosfomycin dextro-fosfomycin amine salt; and S5, supplementing trichloroethylene to the obtained mother liquor until the volume is 100 mL, adding 25-35 g of the crude fosfomycin levo-phosphorus dextro-amine salt and 0.3-0.7 g of activated carbon, repeating the process, and applying the mother liquor for 5 times to obtain the refined fosfomycin levo-phosphorus dextro-amine salt. The production cost can be reduced, and the product yield can be improved.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a preparation method of levofosfomycin trometamol. Background Art

[0002] In the existing refining process of levofosfomycin trometamol, the crude levofosfomycin trometamol is generally refined by various solvents, but its effect still needs to be improved;

[0003] The invention with the publication number CN103113408A discloses a new method for preparing levofosfomycin trometamol. Using cis-propenyl phosphoric acid as a raw material, it is oxidized and cyclized under the action of a catalyst and an oxidant, and dynamically resolved under specific solvent conditions to precipitate levofosfomycin. Then, a certain proportion of dextrorotatory phenylethylamine is added, reacted, and refined to obtain levofosfomycin dextrorotatory phenylethylamine salt. Although this method has low reaction cost, few steps, few by-products, and little environmental pollution, it still needs to be further improved to reduce costs.

[0004] Therefore, a preparation method of levofosfomycin trometamol is needed, which can reduce production costs and improve product yield. Summary of the Invention

[0005] The purpose of the present invention is to provide a preparation method of levofosfomycin trometamol, which can reduce production costs and improve product yield.

[0006] The present invention provides the following technical solutions:

[0007] A preparation method of levofosfomycin trometamol, the steps are as follows:

[0008] S1. Dissolve 30 - 40 g of crude levofosfomycin trometamol in 100 mL of trichloroethylene;

[0009] S2. Heat to 25 - 25 °C, add 0.3 - 0.7 g of activated carbon, and keep warm for decolorization for 25 - 35 min;

[0010] S3. Filter, separate out the activated carbon, and freeze the clarified liquid at -8 to -12 °C for 0.5 - 1.5 h;

[0011] S4. Crystals precipitate, filter, and dry the obtained wet product to obtain the refined levofosfomycin trometamol;

[0012] S5. Supplement the obtained mother liquor with trichloroethylene to 100 mL, add 25 - 35 g of crude levofosfomycin trometamol and 0.3 - 0.7 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times to obtain the refined levofosfomycin trometamol.

[0013] Preferably, in step S1, dissolve 35 g of crude levofosfomycin trometamol in 100 mL of trichloroethylene;

[0014] Preferably, in step S2, heat to 30°C, add 0.5 g of activated carbon, and keep warm for decolorization for 30 min;

[0015] Preferably, in step S3, filter to separate out the activated carbon, and freeze the clarified liquid at -10°C for 1 h;

[0016] Preferably, in step S4, crystals precipitate, filter, and perform drying treatment on the obtained wet product to obtain the refined fosfomycin levofloxacin amide salt;

[0017] Preferably, in step S5, supplement the obtained mother liquor with trichloroethylene to 100 mL, add 30 g of crude fosfomycin levofloxacin amide salt and 0.5 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times.

[0018] Advantages of the present invention:

[0019] The present invention abandons p-toluenesulfonic acid, simplifies the reaction steps, can reduce the material cost, and thus reduces the production cost; the product yield is improved through the synergistic effect of acetic acid and acetic anhydride. Specific embodiments

[0020] Example 1:

[0021] A method for preparing fosfomycin levofloxacin amide salt, the steps are as follows:

[0022] S1. Dissolve 30 g of crude fosfomycin levofloxacin amide salt in 100 mL of trichloroethylene;

[0023] S2. Heat to 25°C, add 0.3 g of activated carbon, and keep warm for decolorization for 25 min;

[0024] S3. Filter to separate out the activated carbon, and freeze the clarified liquid at -8°C for 1.5 h;

[0025] S4. Crystals precipitate, filter, and perform drying treatment on the obtained wet product to obtain the refined fosfomycin levofloxacin amide salt;

[0026] S5. Supplement the obtained mother liquor with trichloroethylene to 100 mL, add 25 g of crude fosfomycin levofloxacin amide salt and 0.3 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times to obtain 105.1 g of refined fosfomycin levofloxacin amide salt.

[0027] Example 2:

[0028] A method for preparing fosfomycin levofloxacin amide salt, the steps are as follows:

[0029] S1. Dissolve 35 g of crude fosfomycin levofloxacin amide salt in 100 mL of trichloroethylene;

[0030] S2. Heat to 30°C, add 0.5 g of activated carbon, and keep warm for decolorization for 30 min;

[0031] S3. Filter to separate out the activated carbon, and freeze the clarified liquid at -10°C for 1 h;

[0032] S4. Crystals precipitate, filter, and dry the obtained wet product to obtain the refined fosfomycin levofloxacin amide salt;

[0033] S5. Supplement the obtained mother liquor with trichloroethylene to 100 mL, add 30 g of crude fosfomycin levofloxacin amide salt and 0.5 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times to obtain 131.3 g of the refined fosfomycin levofloxacin amide salt in total.

[0034] Example 3:

[0035] A method for preparing fosfomycin levofloxacin amide salt comprises the following steps:

[0036] S1. Dissolve 40 g of crude fosfomycin levofloxacin amide salt in 100 mL of trichloroethylene;

[0037] S2. Heat to 25°C, add 0.7 g of activated carbon, and keep warm for decolorization for 35 min;

[0038] S3. Filter to separate out the activated carbon, and freeze the clarified liquid at -12°C for 0.5 h;

[0039] S4. Crystals precipitate, filter, and dry the obtained wet product to obtain the refined fosfomycin levofloxacin amide salt;

[0040] S5. Supplement the obtained mother liquor with trichloroethylene to 100 mL, add 35 g of crude fosfomycin levofloxacin amide salt and 0.7 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times to obtain 150.3 g of the refined fosfomycin levofloxacin amide salt.

[0041] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent substitution on some of the technical features. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing levofloxacin fosfomycin salt, characterized in that, The steps are as follows: S1. Dissolve 30 - 40 g of crude fosfomycin levofloxacin in 100 mL of trichloroethylene. S2. Heat to 25 - 25 °C, add 0.3 - 0.7 g of activated carbon, and keep the temperature for decolorization for 25 - 35 min. S3. Filter to separate the activated carbon, and freeze the clarified liquid at -8 to -12 °C for 0.5 - 1.5 h. S4. Crystals precipitate out, filter, and dry the obtained wet product to obtain the refined fosfomycin levofloxacin. S5. Make up the obtained mother liquor to 100 mL with trichloroethylene, add 25 - 35 g of crude fosfomycin levofloxacin and 0.3 - 0.7 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times to obtain the refined fosfomycin levofloxacin.

2. The preparation method of fosfomycin levofloxacin and dextroamphetamine salt according to claim 1, characterized in that: In step S1, dissolve 35 g of crude fosfomycin levofloxacin in 100 mL of trichloroethylene.

3. A preparation method of fosfomycin levofloxacin and dextrorotatory aminosalt according to claim 1, characterized in that: In step S2, heat to 30 °C, add 0.5 g of activated carbon, and keep the temperature for decolorization for 30 min.

4. A preparation method of fosfomycin levofloxacin salt according to claim 1, characterized in that: In step S3, filter to separate the activated carbon, and freeze the clarified liquid at -10 °C for 1 h.

5. A preparation method of fosfomycin levofloxacin and dextrorotatory amine salt according to claim 1, characterized in that: In step S4, crystals precipitate out, filter, and dry the obtained wet product to obtain the refined fosfomycin levofloxacin.

6. A preparation method of fosfomycin levofloxacin and dextrorotatory aminosalt according to any one of claims 1, characterized in that: In step S5, make up the obtained mother liquor to 100 mL with trichloroethylene, add 30 g of crude fosfomycin levofloxacin and 0.5 g of activated carbon, repeat the above process, and recycle the mother liquor 5 times.