Synthesis process of fosfomycin tromethamine

Abstract

The invention provides a fosfomycin trometamol synthesis process, and particularly relates to the field of medicines. The preparation method comprises the following steps: S1, mixing and dissolving 18-20 parts by mass of absolute ethyl alcohol and 1-2 parts by mass of tromethamine, then adding 1-2 parts by mass of levofossylate and dextromethamine salt, heating to 30-40 DEG C, and keeping the temperature for 1 hour; s2, then cooling to 7-9 DEG C, filtering the precipitate, finally washing with 1-2 parts by mass of ethanol, and carrying out ultrasonic drying to obtain fosfomycin bis-tromethamine; s3, stirring and mixing 35-40 parts by mass of absolute methanol and 7-9 parts by mass of fosfomycin bis-tromethamine salt for 20 minutes, cooling to 13-17 DEG C, adjusting the pH to 5-6 by using acetic acid, and performing suction filtration to obtain filtrate; s4, adding 40-45 parts by mass of acetic anhydride into the filtrate, crystallizing, cooling to 8-12 DEG C, stirring for 1 hour, and performing suction filtration to obtain a solid; and S5, washing the solid with 0.5-0.7 part by mass of acetic anhydride, and carrying out low-pressure concentration and evaporation to dryness to obtain a target product. The method can improve the product yield and reduce the production cost.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a synthetic process of fosfomycin trometamol. Background Art

[0002] Fosfomycin trometamol is used for the treatment of acute simple lower urinary tract infections caused by sensitive bacteria; the existing technologies for preparing fosfomycin trometamol generally adopt the ion exchange method and the double decomposition method. In the ion exchange method, an H-type cation exchange resin is replaced, and then the product is obtained through steps such as addition; in the double decomposition method, an organic acid and trometamol are combined and then undergo a double decomposition reaction with the raw material sodium fosfomycin to obtain the product; however, the existing process technologies still have problems such as low yield and high production cost.

[0003] The patent with the application number CN201410348128.7 discloses a preparation method of fosfomycin trometamol. p-Toluenesulfonic acid monohydrate reacts with trometamol in an anhydrous alcohol solution A, and then after separation and drying, the anhydrous p-toluenesulfonic acid trometamol salt is obtained; the p-toluenesulfonic acid trometamol salt reacts with levofosfomycin dibenzylamine salt monohydrate in an anhydrous alcohol solution B to obtain the crude product of fosfomycin trometamol, and then the product is refined. The use of p-toluenesulfonic acid in this patent not only has a high cost but also a complex process, and still needs to be further improved. Summary of the Invention

[0004] The purpose of the present invention is to provide a synthetic process of fosfomycin trometamol, which can improve the product yield and reduce the production cost.

[0005] The present invention provides the following technical solutions:

[0006] A synthetic process of fosfomycin trometamol, the steps are as follows:

[0007] S1. Mix and dissolve 18 - 20 parts of absolute ethanol and 1 - 2 parts of trometamol, then add 1 - 2 parts of levofosfomycin dibenzylamine salt, and heat to 30 - 40 °C and keep warm for 1 hour;

[0008] S2. Subsequently, cool to 7 - 9 °C, filter the precipitate, and finally wash with 1 - 2 parts of ethanol, and obtain fosfomycin ditrometamol through ultrasonic drying;

[0009] S3. Stir and mix 35 - 40 parts of absolute methanol and 7 - 9 parts of fosfomycin ditrometamol salt for 20 minutes, cool to 13 - 17 °C, adjust the pH to 5 - 6 with acetic acid, and filter to obtain the filtrate;

[0010] S4. Add 40 - 45 parts of acetic anhydride to the filtrate, after crystallization, cool to 8 - 12 °C, stir for 1 hour, and then filter to obtain the solid;

[0011] S5. Wash the solid with 0.5 - 0.7 parts of acetic anhydride, perform low-pressure concentration and evaporation to dryness to obtain the target product.

[0012] Advantages of the present invention:

[0013] 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

[0014] Example 1:

[0015] A synthesis process of fosfomycin trometamol is as follows:

[0016] S1. Mix and dissolve 180 g of absolute ethanol and 10 g of trometamol, then add 10 g of left-phosphorus right-ammonia salt, and heat to 30 - 40 °C for insulation for 1 hour;

[0017] S2. Subsequently, cool to 7 °C, filter the precipitate, and finally wash with 1 g of ethanol, and obtain 19.3 g of fosfomycin di-trometamol through ultrasonic drying

[0018] S3. Stir and mix 350 g of absolute methanol and 70 g of fosfomycin di-trometamol salt for 20 minutes, cool to 13 °C, adjust the pH to 5 with acetic acid, and filter to obtain the filtrate;

[0019] S4. Add 400 g of acetic anhydride to the filtrate, cool to 8 °C after crystallization, stir for 1 hour, and then filter to obtain a solid;

[0020] S5. Wash the solid with 5 g of acetic anhydride, perform low-pressure concentration and evaporation to dryness to obtain 18.6 g of fosfomycin mono-trometamol, with a yield of 96.2% and an HPLC of 99.1%.

[0021] Example 2:

[0022] A synthesis process of fosfomycin trometamol is as follows:

[0023] S1. Mix and dissolve 190 g of absolute ethanol and 15.00 g of trometamol, then add 16.00 g of left-phosphorus right-ammonia salt, and heat to 35 °C for insulation for 1 hour;

[0024] S2. Subsequently, cool to 8 °C, filter the precipitate, and finally wash with 15 g of ethanol, and obtain 22.5 g of fosfomycin di-trometamol through ultrasonic drying;

[0025] S3. Stir and mix 380 g of absolute methanol and 79 g of fosfomycin di-trometamol salt for 20 minutes, cool to 15 °C, adjust the pH to 5.5 with acetic acid, and filter to obtain the filtrate;

[0026] S4. Add 420 g of acetic anhydride to the filtrate, cool to 10 °C after crystallization, stir for 1 hour, and then filter to obtain a solid;

[0027] S5. Wash the solid with 6 g of acetic anhydride, concentrate it under reduced pressure until dry by evaporation, obtaining 20.8 g of fosfomycin trometamol, with a yield of 97.1% and an HPLC purity of 99.9%.

[0028] Example 3:

[0029] A synthetic process for fosfomycin trometamol is as follows:

[0030] S1. Mix and dissolve 200 g of absolute ethanol and 20 g of trometamol, then add 20 g of levofloxacin fosfomycin salt and heat to 40 °C for 1 hour of insulation.

[0031] S2. Subsequently, cool to 9 °C, filter the precipitate, and finally wash it with 20 g of ethanol, and obtain 28.2 g of fosfomycin ditrometamol through ultrasonic drying.

[0032] S3. Stir and mix 400 g of absolute methanol and 90 g of fosfomycin ditrometamol salt for 20 minutes, keep the temperature at 17 °C, adjust the pH to 6 with acetic acid, and filter to obtain the filtrate.

[0033] S4. Add 450 g of acetic anhydride to the filtrate, cool to 12 °C after crystallization, stir for 1 hour and then filter to obtain the solid.

[0034] S5. Wash the solid with 7 g of acetic anhydride, concentrate it under reduced pressure until dry by evaporation, obtaining 25.3 g of fosfomycin trometamol, with a yield of 96.3% and an HPLC purity of 99.6%.

[0035] 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, for those skilled in the art, they can still modify the technical solutions described 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 fosfomycin trometamol synthesis process, characterized in that, The steps are as follows: S1. Mix and dissolve 18 - 20 parts by mass of absolute ethanol and 1 - 2 parts by mass of tromethamine, then add 1 - 2 parts by mass of levofloxacin ammonia salt, and heat to 30 - 40 °C for insulation for 1 hour; S2. Subsequently, cool to 7 - 9 °C, filter the precipitate, and finally wash with 1 - 2 parts by mass of ethanol, and obtain fosfomycin tromethamine through ultrasonic drying; S3. Stir and mix 35 - 40 parts by mass of anhydrous methanol and 7 - 9 parts by mass of fosfomycin tromethamine salt for 20 minutes, cool to 13 - 17 °C, adjust the pH to 5 - 6 with acetic acid, and filter to obtain the filtrate; S4. Add 40 - 45 parts by mass of acetic anhydride to the filtrate, cool to 8 - 12 °C after crystallization, stir for 1 hour, and then filter to obtain the solid; S5. Wash the solid with 0.5 - 0.7 parts by mass of acetic anhydride, carry out low-pressure concentration and evaporation to dryness to obtain the target product.

2. The fosfomycin trometamol synthesis process according to claim 1, characterized in that: In step S1, S1. Mix and dissolve 19 parts by mass of absolute ethanol and 1.5 parts by mass of tromethamine, then add 1.5 parts by mass of levofloxacin ammonia salt, and heat to 35 °C for insulation for 1 hour.

3. The synthesis process of fosfomycin trometamol according to claim 1, wherein: In step S2, S2. Subsequently, cool to 8 °C, filter the precipitate, and finally wash with 1.5 parts by mass of ethanol, and obtain fosfomycin tromethamine through ultrasonic drying.

4. The fosfomycin trometamol synthesis process according to claim 1, characterized in that: In step S3, stir and mix 38 parts by mass of anhydrous methanol and 8 parts by mass of fosfomycin tromethamine salt for 20 minutes, cool to 15 °C, adjust the pH to 5.5 with acetic acid, and filter to obtain the filtrate.

5. A fosfomycin trometamol synthesis process according to claim 1, characterized in that: In step S4, add 42 parts by mass of acetic anhydride to the filtrate, cool to 10 °C after crystallization, stir for 1 hour, and then filter to obtain the solid.

6. A fosfomycin trometamol synthesis process according to any one of claims 1, characterized in that: Wash the solid with 0.6 parts by mass of acetic anhydride, carry out low-pressure concentration and evaporation to dryness to obtain the target product.