Levofloxacin reaction and post-treatment method

Abstract

The invention relates to the field of medicine synthesis, in particular to a synthetic method of levofloxacin, which comprises the following steps: (1) adding levofloxacin, N-methyl piperazine, a solvent and potassium fluoride into a reactor, heating to 70-90 DEG C, reacting for 3-6.5 hours, after the reaction is finished, controlling the internal temperature to be below 120 DEG C, recovering under reduced pressure until no distillate is produced, and then continuously recovering for 0.5 hour until the mixture is dry; and adding water into the filtrate, and carrying out reverse heating, cooling and suction filtration to obtain the levofloxacin. According to the synthetic method of levofloxacin provided by the invention, a solvent is added to filter out a byproduct of generated potassium bifluoride, and water is directly added into filtrate for crystallization. In the whole process before crystallization, no water is introduced, no hydrogen fluoride is dissociated, equipment corrosion is avoided, the pipette shrinkage reaction conditions are mild, the reaction time is short, no extraction operation is adopted, three wastes and energy consumption are reduced, the production efficiency is improved, and a crystallization solvent is the same as a reaction solvent and is convenient to recycle and reuse.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for synthesizing levofloxacin. Background Art

[0002] Levofloxacin is a kind of quinolone drug, has a broad-spectrum antibacterial effect, strong antibacterial effect, has strong antibacterial activity against most gram-negative bacteria, and also has antibacterial effect against gram-positive bacteria such as Staphylococcus aureus, Streptococcus pneumoniae and Mycoplasma pneumoniae. In the prior art, there are many literature reports as the method for synthesizing levofloxacin, such as patent CN101768167A discloses a levofloxacin piperazine synthesis method, using reactant N-methylpiperazine as raw material and solvent, and directly crystallizing after the reaction is completed and recovered and dried with different alkalis such as sodium hydroxide, sodium carbonate, potassium carbonate, ammonia water, etc. to adjust pH to neutrality, the finished product obtained by the invention will have more salt, which will eventually lead to unqualified content and residue, even if it is refined once more, it is difficult to pass, the mother liquor after alkali adjustment with ammonia water needs to be processed again, and ammonium fluoride recovery is easy to decompose and seriously corrodes the equipment. For example, in patent CN114478573A, levofloxacin is reacted with sodium hydroxide (this step of reaction has the risk of generating hydroxy impurities), sodium carboxylate is first generated, and then sodium carboxylate itself is used as an acid binding agent for piperization reaction. In this invention, more water is introduced into the piperization reaction (water will inhibit the occurrence of the reaction), so the reaction temperature needs to reach above 100°C and the time is close to 10h to complete the reaction. Due to the high reaction temperature and long time, the product appearance, impurities and production capacity have a certain impact, and the water introduced during the reaction is difficult to recycle. For example, patents CN101580514A, CN103113388A, CN103755722A, CN108892676A, etc. basically add water after the reaction is recovered, use chloroform and other solvents for repeated extraction, and then use another solvent (generally alcohols, such as ethanol, methanol, isopropanol, etc.) for crystallization after the organic phase is recovered. Since levofloxacin has a certain solubility in water, this step requires repeated extraction, otherwise the yield will be significantly reduced; the recovered material is levofloxacin hydrofluoride, and the water dissolution process causes serious corrosion to the equipment; the presence of a large amount of fluoride salts in the water layer after extraction greatly increases the cost of three wastes treatment, the cost of recovering the organic phase after extraction, and the cost of waste gas treatment, which is very uneconomical.

[0003] It can be seen that there are the following three problems in the prior art. First, the material contains hydrogen fluoride after the piperidine recovery, and there will be serious equipment corrosion problems in the process of adding water to dissolve and then extracting. Second, the post-processing extraction will inevitably lead to high cost of three wastes, reduced production capacity, and increased energy consumption of recovering and extracting organic phases. If the extraction operation is not performed, direct alkali adjustment crystallization will lead to unqualified content and residue, and refining may not be qualified. Third, the crystallization solvent is mainly a mixed solvent of alcohol and water (reaction, extraction and refining need to use three different kinds of solvents, which is cumbersome and costly), and the product loss in the mother liquor is large. Summary of the invention

[0004] In order to solve the problems of complicated operation, three wastes treatment, namely energy consumption cost, large crystal loss, equipment corrosion and the like, the present invention provides a levofloxacin synthesis method. Potassium fluoride is added in a certain solvent system. In the recovery process after the reaction, hydrogen fluoride is bound by potassium fluoride to generate potassium hydrogen fluoride insoluble in polar aprotic solvent. After the solvent is added, the mixture is filtered in an anhydrous system. Water is added to the filtrate to prepare an aqueous solution of the solvent in a certain proportion (levofloxacin will precipitate in a large amount during the water addition process). The mixture is heated to reflux and then kept warm. The mixture is cooled, crystallized and dried to obtain a finished product.

[0005] In order to achieve the above object, the technical solution of the present invention is: a method for synthesizing levofloxacin, comprising the following steps:

[0006] (1) adding levofloxacin, N-methylpiperazine, solvent and potassium fluoride to a reactor, heating to 70°C to 90°C for reaction for 3 to 6.5 hours, controlling the internal temperature below 120°C, recovering under reduced pressure until no distillation occurs, and then continuing to recover for 0.5 hours until dryness;

[0007] (2) adding a solvent, heating and filtering to obtain a filtrate, adding water to the filtrate, heating it up, cooling it down, and filtering it with suction to obtain levofloxacin; the solvent in step (1) and step (2) is the same, and the solvent is selected from DMSO, DMF, N-methylpyrrolidone, acetonitrile, and isopropanol.

[0008] Preferably, the heating temperature in step (1) is 70°C to 90°C, and the reaction time is 3 to 6.5 hours, preferably 80°C for 7 hours.

[0009] Preferably, the reduced pressure recovery temperature in step (1) is an internal temperature below 120°C, preferably, the internal temperature is 100-120°C, and the vacuum degree is ≤-0.09MPa.

[0010] Preferably, the solvent in step (1) and step (2) is the same, and the solvent is selected from DMSO, DMF, and N-methylpyrrolidone, preferably DMSO.

[0011] Preferably, the heating and hot filtering temperature in step (2) is 110-115°C.

[0012] Preferably, in step (2), the filtrate temperature is controlled at 110-115°C.

[0013] Preferably, in step (2), the reverse heating temperature is 110-120°C, and the cooling temperature is controlled at 25-35°C.

[0014] Preferably, the solvent is selected from DMSO, and the ratio of the amount of levofloxacin, N-methylpiperazine, DMSO, and potassium fluoride in step (1) is 1:1.25-3:2.5-7:0.6-1.5. The preferred equivalent is 1:1.5:5:0.95.

[0015] Preferably, in step (2), the weight ratio of levofloxacin, DMSO, and water is 1:2.0-3:1-2.5, and the preferred ratio is 1:2.5:1.6.

[0016] Preferably, the reverse heating and heat preservation time is 20 to 30 minutes, and the cooling and heat preservation time is 20 minutes to 1.5 hours.

[0017] The above-mentioned preferred conditions can be combined arbitrarily based on the principles of the art.

[0018] The reagents and raw materials used in the invention are commercially available.

[0019] The beneficial effects of the present invention are:

[0020] 1. In the prior art, after the piperazine shrinking reaction is completed and recovered to dryness, water needs to be added to dissolve and then extracted with chloroform. The recovered material is levofloxacin hydrofluoride, which has serious corrosion to commonly used stainless steel and glass-lined materials. The present invention does not require extraction, reduces the three wastes and energy consumption and improves production efficiency. After the recovery, free levofloxacin is obtained (potassium fluoride is used to take away the hydrofluoric acid on N-methylpiperazine during the recovery process, so that the levofloxacin shrinking is in a free form after the recovery), no water is introduced and no hydrogen fluoride is free, thereby avoiding corrosion of equipment.

[0021] 2. The prior art extraction process generates a large amount of fluorine-containing wastewater and the recovery of the extraction organic solvent and the treatment of waste gas occupy a high cost. The present invention adds a solvent after the recovery of the piperazine to directly filter out the by-product potassium bifluoride (the by-product can be sold, with positive income), without wastewater and recovery, solves the above problems and reduces the cost of the three wastes.

[0022] 3. Reaction, extraction and purification require the use of three different solvents, which is cumbersome and costly. The present invention directly adds water to the solvent used for the reaction and then heats up for crystallization. The crystallization solvent is the same as the reaction solvent, and only one solvent is used, which is more convenient for recycling. DETAILED DESCRIPTION

[0023] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0024] Example 1

[0025] 50g of levofloxacin, 27g of N-methylpiperazine, 50g of DMSO and 9.3g of potassium fluoride were put into a 500ml three-necked reaction bottle, heated to 85°C with stirring and kept warm for 8h. After the reaction, the external temperature was set to 100°C and the water pump was used to reduce the pressure to -0.09MPa to recover DMSO and N-methylpiperazine. When the water pump recovered until there was basically no distillation, it was replaced with an oil pump to continue the reduced pressure recovery for 2h.

[0026] After recovery, 150g DMSO was added and heated to 110°C for hot filtration, and rinsed with 50g hot DMSO. The filtrate was stirred and heated to 110°C, at which time the filtrate was in a clear state, 107g of water was added, and a large amount of precipitation was precipitated, and then the temperature was raised to 120°C and kept warm for 20min, and then the temperature was lowered to 30°C and kept warm for 30min, and then filtered by suction, and the filter cake was rinsed with 50g DMSO, and the filter cake was dried under reduced pressure to obtain a total of 59.86g of product solids. According to the United States Pharmacopoeia quality standard, the product purity was 99.72%, and the molar yield was 90.9% (based on the molecular weight of carboxylic acid 281.21 and the molecular weight of levofluorohemihydrate 370.37).

[0027] Example 2

[0028] 50g of levofloxacin, 35.7g of N-methylpiperazine, 40g of DMSO and 8.3g of potassium fluoride were put into a 500ml three-necked reaction bottle, stirred and heated to 85°C for 7h. After the reaction, the external temperature was set to 100°C and the water pump was reduced to vacuum -0.09MPa to recover DMSO and N-methylpiperazine. When the water pump recovered until there was basically no distillation, it was replaced with an oil pump to continue the reduced pressure recovery for 2h.

[0029] After recovery, add 125g DMSO and heat to 110°C for hot filtration (reducing the amount of solvent), rinse with 25g hot DMSO (do not reduce pressure during rinsing, the rinsing liquid slowly penetrates, playing a slow rinsing effect, and vacuum is pulled after the liquid surface is invisible). The filtrate is stirred and heated to 110°C, at which time the filtrate is in a clear state, add 81g of water, and after a large amount of precipitation, heat it up to 120°C and keep it warm for 20min, cool it to 30°C and keep it warm for 30min, filter it with suction, rinse the filter cake with 50g DMSO, and dry the filter cake under reduced pressure to obtain a total of 60.4g of product solids. According to the quality standard of the United States Pharmacopoeia, the product purity is 99.65%, and the molar yield is 91.7% (based on the molecular weight of carboxylic acid 281.21 and the molecular weight of levofluorohemihydrate 370.37).

[0030] Example 3

[0031] 50g of levofloxacin, 53.6g of N-methylpiperazine, 50g of DMSO and 10.3g of potassium fluoride were put into a 500ml three-necked reaction bottle, stirred and heated to 80℃ for 7h. After the reaction, the external temperature was set to 100℃ and the water pump was used for decompression recovery. When the water pump recovered until there was basically no distillation, it was replaced with an oil pump to continue decompression recovery for 2h.

[0032] After recovery, add 100g DMSO, heat to 125℃, filter hot, rinse with 25g hot DMSO (do not reduce pressure during rinsing, slowly infiltrate the rinsing liquid, and pull vacuum after the liquid surface is invisible). The filtrate is stirred and heated to 110℃, at which time the filtrate is slightly turbid, add 53.8g water, and after a large amount of precipitation, heat it back to 120℃ and keep it warm for 20min, cool it to 30℃ and keep it warm for 30min, filter with suction, rinse the filter cake with 25g DMSO, and dry the filter cake under reduced pressure to obtain a total of 60.7g of product solids. According to the quality standard of the United States Pharmacopoeia, the product purity is 99.72%, and the molar yield is 92.2% (based on the molecular weight of carboxylic acid 281.21 and the molecular weight of levofluorohemihydrate 370.37).

[0033] Example 4

[0034] 50g of levofloxacin, 44.6g of N-methylpiperazine, 50g of DMSO and 10.3g of potassium fluoride were put into a 500ml three-necked reaction bottle, heated to 80°C with stirring and kept for reaction for 7h. After the reaction, the oil pump was used to continue to reduce the pressure and recover until dryness, and then continue to recover for 1.5h.

[0035] After recovery, add 100g DMSO, heat to 125℃, filter hot, rinse with 25g hot DMSO (do not reduce pressure during rinsing, slowly infiltrate the rinse liquid, and pull vacuum after the liquid surface is invisible). The filtrate is stirred and heated to 115℃, at which time the filtrate is in a clear state, add 53.8g water, and after a large amount of precipitation, heat it back to 120℃ and keep it warm for 20min, cool it to 30℃ and keep it warm for 30min, filter with suction, rinse the filter cake with 25g DMSO, and dry the filter cake under reduced pressure to obtain a total of 60.84g of product solids. According to the quality standard of the United States Pharmacopoeia, the product purity is 99.74%, and the molar yield is 92.38% (based on the molecular weight of carboxylic acid 281.21 and the molecular weight of levofluorohemihydrate 370.37).

[0036] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for synthesizing levofloxacin, characterized in that: The steps include: (1) adding levofloxacin, N-methylpiperazine, solvent and potassium fluoride to a reactor, heating to 70°C to 90°C for reaction for 3 to 6.5 hours, controlling the internal temperature below 120°C, recovering under reduced pressure until no distillation occurs, and then continuing to recover for 0.5 hours until dryness; (2) adding a solvent, heating and filtering to obtain a filtrate, adding water to the filtrate, heating it up, cooling it down, and filtering it with suction to obtain levofloxacin; the solvent in step (1) and step (2) is the same, and the solvent is selected from DMSO, DMF, N-methylpyrrolidone, acetonitrile, and isopropanol.

2. The synthesis method according to claim 1, characterized in that In step (1), the heating temperature is 70° C. to 90° C., and the reaction time is 3 to 6.5 hours.

3. The synthesis method according to claim 1, characterized in that The reduced pressure recovery temperature in step (1) is 100-120° C., and the vacuum degree is ≤-0.09 MPa.

4. The synthesis method according to claim 1, characterized in that The solvent in step (1) and step (2) is the same, and the solvent is selected from DMSO, DMF, and N-methylpyrrolidone.

5. The synthesis method according to claim 1, characterized in that The heating and hot filtering temperature in step (2) is 110-125°C.

6. The synthesis method according to claim 1, characterized in that In step (2), the filtrate temperature is controlled to be 110-115°C.

7. The synthesis method according to claim 1, characterized in that In step (2), the reverse heating temperature is 110-120°C, and the cooling temperature is controlled at 25-35°C.

8. The synthesis method according to claim 1, characterized in that The solvent is selected from DMSO, and the ratio of the amount of levofloxacin, N-methylpiperazine, DMSO and potassium fluoride in step (1) is 1:1.25-3:2.5-7:0.6-1.

5.

9. The synthesis method according to claim 8, characterized in that In step (2), the weight ratio of levofloxacin, DMSO and water is 1:2.0 to 3:1 to 2.

5.

10. The synthesis method according to claim 1, characterized in that The reverse heating and heat preservation time is 20 to 30 minutes, and the cooling and heat preservation time is 20 minutes to 1.5 hours.