Preparation method of levofloxacin-N-oxide

Abstract

The invention discloses a preparation method of levofloxacin-N-oxide. In the existing preparation method, a large number of reaction impurities exist, purification cannot be carried out easily, the consumption of hydrogen peroxide in reaction is large, and the subsequent treatment is troublesome. The preparation method comprises the following steps of: mixing levofloxacin and a solvent glacial acetic acid, and stirring the mixture at 60-70 DEG C until dissolution; adding catalyst which can be phosphotungstic acid, phosphomolybdic acid or sodium tungstate; adding hydrogen peroxide solution with the mass concentration of 25-35 percent in batches, and making the mixture react for 2-4 hours after each batch is added, and adding the hydrogen peroxide solution until the reaction is fully completed; carrying out vacuum distillation on reaction solution prepared via the reaction until the volume of the solution is one third of the original volume, adding an appropriate amount of water, then carrying out vacuum distillation on reaction solution again until the volume of the solution is one third of the original volume, repeating the vacuum distillation twice to three times, and drying via evaporation; and carrying out vacuum distillation on the prepared residues, adding a recrystallization solvent for recrystallization to obtain the levofloxacin-N-oxide. The invention has the advantages of fewer side actions, higher product purity, low consumption of the hydrogen peroxide, and convenient subsequent treatment.

Description

technical field

[0001] The invention relates to the field of medicine levofloxacin, in particular to a preparation method of levofloxacin-N-oxide. Background technique

[0002] Fluoroquinolones have achieved great success in clinical anti-infection treatment due to their high-efficiency, broad-spectrum, and low-toxic antibacterial properties. Ofloxacin and levofloxacin developed by Japan's Daiichi Pharmaceutical Company are excellent varieties among them. Among them, levofloxacin was launched in Japan in 1993 as raw materials and tablets, and is now on the market in Britain, the United States and other countries. Levofloxacin is the S enantiomer of racemic ofloxacin, and the antibacterial activity of ofloxacin is mainly attributed to the S enantiomer.

[0003] At present, the quality standards of levofloxacin are recorded in national standards and import standards, neither of which controls known impurities. According to literature reports, M.Lalitha Devi et al. (J Pharma B...

Examples

Embodiment 1

[0020] Add 5 grams of levofloxacin and 50 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of sodium tungstate, 5mL of hydrogen peroxide (30%), keep warm at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue to keep warm for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of ethanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.5 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

Embodiment 2

[0022] Add 5 grams of levofloxacin and 70 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of phosphotungstic acid, 5mL of hydrogen peroxide (30%), keep the reaction at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue the reaction for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of methanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.4 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

Embodiment 3

[0024] Add 5 grams of levofloxacin and 70 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of phosphomolybdic acid, 5mL of hydrogen peroxide (30%), keep the reaction at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue the reaction for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of ethanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.3 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

technical field

[0001] The invention relates to the field of medicine levofloxacin, in particular to a preparation method of levofloxacin-N-oxide. Background technique

[0002] Fluoroquinolones have achieved great success in clinical anti-infection treatment due to their high-efficiency, broad-spectrum, and low-toxic antibacterial properties. Ofloxacin and levofloxacin developed by Japan's Daiichi Pharmaceutical Company are excellent varieties among them. Among them, levofloxacin was launched in Japan in 1993 as raw materials and tablets, and is now on the market in Britain, the United States and other countries. Levofloxacin is the S enantiomer of racemic ofloxacin, and the antibacterial activity of ofloxacin is mainly attributed to the S enantiomer.

[0003] At present, the quality standards of levofloxacin are recorded in national standards and import standards, neither of which controls known impurities. According to literature reports, M.Lalitha Devi et al. (J Pharma B...

Examples

Embodiment 1

[0020] Add 5 grams of levofloxacin and 50 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of sodium tungstate, 5mL of hydrogen peroxide (30%), keep warm at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue to keep warm for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of ethanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.5 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

Embodiment 2

[0022] Add 5 grams of levofloxacin and 70 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of phosphotungstic acid, 5mL of hydrogen peroxide (30%), keep the reaction at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue the reaction for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of methanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.4 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

Embodiment 3

[0024] Add 5 grams of levofloxacin and 70 mL of glacial acetic acid into a 100 mL three-necked flask, and raise the temperature to 60-70 °C to completely dissolve the levofloxacin. Add 0.3g of phosphomolybdic acid, 5mL of hydrogen peroxide (30%), keep the reaction at 60-70°C for 2 hours, then add 5mL of hydrogen peroxide (30%) and continue the reaction for 3 hours, and the reaction is completed by TLC. Evaporate under reduced pressure until about one-third of the volume of the solution remains, then add some water, continue to evaporate under reduced pressure until about one-third of the remaining volume, repeat this step 3 times, and then evaporate to dryness. The residue was dissolved by adding 55 mL of ethanol (90%) and heated under reflux, then filtered, and the filtrate was cooled and crystallized in the refrigerator, and filtered and dried the next day to obtain 3.3 g of levofloxacin-N-oxide. m / z: 378.1461 (m+H).

Images