Method for synthesizing and purifying levofloxacin hydrochloride

Abstract

The invention relates to the field of medicinal chemistry, and particularly discloses a method for synthesizing and purifying levofloxacin hydrochloride. The method comprises the following steps: taking ethyl formate (I) as a raw material, reacting with ethyl acetate under the catalysis of NaH to obtain a compound as shown in a formula (II), then carrying out a series of reactions on the obtained compound as shown in the formula (II) to obtain a compound as shown in a formula (IX), and then salifying the compound as shown in the formula (IX) through ethyl acetate hydrochloride to obtain a levofloxacin hydrochloride crude product as shown in a formula (X). Adding water into the levofloxacin hydrochloride crude product as shown in the formula (X), heating, dissolving, decolorizing with activated carbon, filtering, crystallizing filtrate, filtering and drying to obtain purified levofloxacin hydrochloride. According to the synthesis route, the traditional process is simplified, the synthesis efficiency is improved, and the production cost is reduced. By optimizing reaction conditions and purification steps, generation of harmful by-products is effectively reduced, and environmental protection requirements are met. The obtained levofloxacin hydrochloride is high in purity, meets the medicinal standard and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and particularly to a method for synthesizing and purifying levofloxacin hydrochloride. Background Art

[0002] Levofloxacin hydrochloride is a fourth-generation fluoroquinolone broad-spectrum antibacterial drug, which is widely used in the treatment of various bacterial infections. Its antibacterial activity is twice that of ofloxacin, and it is clinically used for the treatment of respiratory tract, urinary tract and soft tissue infections, etc.

[0003] Its synthesis and purification processes have an important impact on product quality and production efficiency. Existing synthesis processes mostly use high-boiling organic solvents (such as dimethyl sulfoxide, DMF) as reaction media, which have problems such as difficult solvent recovery, large amounts of three wastes emissions, and high costs. In addition, the traditional process requires multi-step crystallization to separate intermediates, with a long process and easy introduction of impurities, resulting in insufficient purity of the final product. In existing synthesis methods, there are also often problems such as complex processes, large amounts of solvent used, and low purity. In addition, some purification methods use high-boiling solvents or halogenated hydrocarbons, which are not only costly but also environmentally unfriendly. Summary of the Invention

[0004] Object of the Invention: The object of the present invention is to provide a method for synthesizing levofloxacin hydrochloride; another object of the present invention is to provide a method for purifying levofloxacin hydrochloride. To solve the problems of complex existing synthesis and purification processes of levofloxacin hydrochloride and low purity, etc.

[0005] Technical Solution: A method for synthesizing levofloxacin hydrochloride, comprising the following steps:

[0006] S1. Using ethyl formate (I) as a raw material, reacting with ethyl acetate under the catalysis of NaH to obtain a compound of formula (II)

[0007]

[0008] S2. Reacting the compound of formula (II) with a compound of formula (III) in a diethylene glycol dimethyl ether system to obtain a compound of formula (IV);

[0009] S3. Reacting the compound of formula (IV) obtained in step S2 with aminopropanol to obtain a compound of formula (V);

[0010] S4. Reacting the compound of formula (V) obtained in step S3 under the catalysis of KF to obtain a compound of formula (VI);

[0011] S5. Reacting the compound of formula (VI) obtained in step S4 with anhydrous piperazine under the catalysis of a base to obtain a compound of formula (VII);

[0012] S6. React the compound of formula (VII) obtained in step S5 with dimethyl sulfate to obtain the compound of formula (VIII);

[0013] S7. Hydrolyze the compound of formula (VIII) to obtain the compound of formula (IX);

[0014]

[0015] S8. Salt out the compound of formula (IX) with hydrochloric acid ethyl acetate to obtain the crude product of levofloxacin hydrochloride of formula (X);

[0016]

[0017] By using the hydrochloric acid ethyl acetate system for salting out, impurities can be effectively removed to improve the purity. For subsequent purification, only water is needed, reducing the use of organic solvents.

[0018] The reaction solvent systems in steps S2, S3, S4 and S5 are all diethylene glycol dimethyl ether, reducing the types of solvent residues in the finished product. At the same time, in steps S2 and S3, no post-treatment is required, and the reaction solution can be directly used for the next step reaction, reducing costs while reducing waste liquid treatment and operation time.

[0019] In order to further improve the synthesis efficiency of the present invention, preferably,

[0020] The reaction conditions in step S8 are: the reaction solvent is ethyl acetate, the volume dosage is 3 times the weight of the compound of formula (IX), the molar ratio of hydrochloric acid in 2M hydrochloric acid ethyl acetate to the compound of formula (IX) is 1.05:1 - 1.1:1, the reaction temperature is 5 - 10 °C, and the reaction time is 1 - 2 h.

[0021] After the reaction of the present invention is completed, the reaction product can be treated by common treatment methods in the art, such as concentration and organic solvent extraction; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product;

[0022] In order to further improve the purity of the reaction product of the present invention, it is preferably salted out in an ethyl acetate system and then washed with ethyl acetate and dried to obtain.

[0023] Preferably,

[0024] The reaction conditions in step S2 are: the reaction solvent is diethylene glycol dimethyl ether, the volume dosage is 12.5 times the weight of the compound of formula (II), the molar ratio of the compound of formula (III) to the compound of formula (II) is 1:1.01 - 1:1.02, the reaction temperature is 20 - 30 °C, and the reaction time is 6 - 8 h;

[0025] According to the method described above, whether the reaction in step S2 is complete can be judged according to the conventional methods in the art, such as TLC technology;

[0026] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration, organic solvent extraction; those skilled in the art can know the appropriate treatment method according to the properties of the reaction solvent and the product;

[0027] In order to reduce costs and at the same time reduce waste liquid treatment and operation time, the present invention preferably does not perform post-treatment after the reaction is completed, and the reaction solution is directly used for the next step of the reaction.

[0028] The reaction conditions for step S3 are as follows: the reaction solvent is from step S2, the volume used is 12.5 times the weight of the compound of formula (II), the molar ratio of aminopropanol to the compound of formula (III) is 1.2:1 - 1.3:1, the reaction temperature is 90 - 100 °C, and the reaction time is 6 - 8 h;

[0029] According to the method described above, whether the reaction in step S3 is complete can be judged according to the conventional methods in the art, such as TLC technology;

[0030] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration, organic solvent extraction; those skilled in the art can know the appropriate treatment method according to the properties of the reaction solvent and the product;

[0031] In order to reduce costs and at the same time reduce waste liquid treatment and operation time, the present invention preferably does not perform post-treatment after the reaction is completed, and the reaction solution is directly used for the next step of the reaction.

[0032] The reaction conditions for step S4 are as follows: the reaction solvent is from step S3, the volume used is 12.5 times the weight of the compound of formula (II), the catalyst is potassium fluoride, the mass ratio of the catalyst to the compound of formula (V) is 1:1.5, and the reaction temperature is 120 °C;

[0033] According to the method described above, whether the reaction in step S4 is complete can be judged according to the conventional methods in the art, such as TLC technology;

[0034] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration, organic solvent extraction; those skilled in the art can know the appropriate treatment method according to the properties of the reaction solvent and the product;

[0035] In order to further improve the purity of the reaction product, the present invention preferably distills off the solvent under reduced pressure after the reaction is completed, adds water to the residue for pulping while stirring rapidly while it is hot, filters, adds the filter cake to water for pulping again, filters, and dries it under vacuum to obtain the product;

[0036] Among them, the volume of water added while stirring the residue quickly while it is hot is 0.48 times the volume of diglyme in the reaction system, the pulping time is 30 min, the volume of the filter cake added to water for pulping again is 0.48 times the volume of diglyme in the reaction system, the pulping time is 30 min, the vacuum drying temperature is 60 °C, and the drying time is 12 h.

[0037] The reaction conditions in step S5 are as follows: the reaction solvent is diglyme, the volume used is 4 times the weight of the compound of formula (VI), the catalyst is triethylamine, the amount used is 0.35 times the weight of the compound of formula (VI), the molar ratio of anhydrous piperazine to the compound of formula (VI) is 1.2:1, and the reaction temperature is 130 °C;

[0038] According to the method described above, whether the reaction in step S5 is complete can be judged by the conventional methods in the art according to the prior art, such as TLC technology;

[0039] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration and organic solvent extraction; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product;

[0040] In order to further improve the purity of the reaction product of the present invention, it is preferably obtained by distilling off the solvent under reduced pressure after the reaction is completed.

[0041] The reaction conditions in step S6 are as follows: the reaction solvent is dioxane, the volume used is 7 times the weight of the compound of formula (VII), the catalyst is potassium hydroxide, the amount used is 0.3 times the weight of the compound of formula (VII), the molar ratio of dimethyl sulfate to the compound of formula (VII) is 1.2:1, and the reaction temperature is 80 °C;

[0042] According to the method described above, whether the reaction in step S6 is complete can be judged by the conventional methods in the art according to the prior art, such as TLC technology;

[0043] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration and organic solvent extraction; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product;

[0044] In order to further improve the purity of the reaction product of the present invention, it is preferably obtained by distilling off the solvent under reduced pressure after the reaction is completed.

[0045] The reaction conditions of step S7 are as follows: the reaction solvent is purified water, and the volume used is 2 times the weight of the compound of formula (VIII); the amount of sodium hydroxide used is 13-15% of the weight of the compound of formula (VIII); the reaction temperature is 60-80 °C; the reaction time is 1-2 h, and the percentage is calculated based on the weight of the compound of formula (VIII) being 100%;

[0046] According to the method described above, for the reaction in step S7, whether the reaction is complete can be determined by the conventional methods in the art according to the prior art, such as TLC technology;

[0047] After the reaction of the present invention is completed, the reaction product can be treated by the commonly used treatment methods in the art, such as concentration and extraction with organic solvents; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product;

[0048] In order to further improve the purity of the reaction product, the present invention preferably adjusts the pH with 2M hydrochloric acid after the reaction is completed, extracts with dichloromethane, then dries the dichloromethane layer with anhydrous magnesium sulfate, and concentrates to dryness to obtain the product;

[0049] Among them, it can be further preferably extracted three times, and the volume of dichloromethane used each time is 3.57 times the weight of the compound of formula (VIII);

[0050] Among them, it can be even more preferably that the drying is carried out for 2-3 h;

[0051] Among them, it can also be preferably that the weight of anhydrous magnesium sulfate used is 2 times the weight of the compound of formula (VIII).

[0052] The obtained product can be directly used in the next step of the reaction until levofloxacin hydrochloride is obtained, which does not prevent the achievement of the purpose of the present invention;

[0053] In order to further improve the purity of the product, the present invention can also preferably recrystallize the crude product of the compound of formula (IX) obtained;

[0054] For the recrystallization mentioned above, those skilled in the art can know the appropriate solvent according to the properties of the product. In order to better improve the purity of the product, the present invention can further preferably recrystallize with ethanol;

[0055] The amount of ethanol used can be determined by those skilled in the art according to the conventional recrystallization method. The preferred volume of ethanol used in the present invention is 3.57 times the weight of the compound of formula (VIII);

[0056] The recrystallization operation of the present invention can further preferably be: adding the product into ethanol, heating to dissolve it completely, adding activated carbon with a weight 0.071 times that of the compound of formula (VIII), refluxing for decolorization for 30 min, filtering while it is hot, slowly cooling the filtrate to 0 - 5°C for crystallization for 6 h, and then filtering and drying in vacuum at 45°C to obtain the pure product.

[0057] Preferably, the reaction conditions for the reaction of the compound of formula (II) are: the solvent is tetrahydrofuran, and the volume used is 3 times the weight of the compound of formula (I). The sodium hydride is washed with ether for defatting before use. The molar ratio of ethyl acetate to the compound of formula (I) is 1:1.5. The temperature when adding the compound of formula (I) is 0 - 10°C, and after addition, the reaction is carried out at room temperature.

[0058] After the reaction of the present invention is completed, the reaction product can be treated by common treatment methods in the art, such as concentration and extraction with an organic solvent; those skilled in the art can know the appropriate treatment methods according to the properties of the reaction solvent and the product.

[0059] In order to further improve the purity of the reaction product, the present invention preferably evaporates the solvent under reduced pressure at 40°C after the reaction is completed. The residue is added with cyclohexane and slurried at room temperature for 1 h, filtered, and dried in vacuum at 40°C for 5 h to obtain.

[0060] A method for purifying levofloxacin hydrochloride, comprising: adding water to the crude product of levofloxacin hydrochloride of formula (X) obtained in step S8, heating to dissolve it completely, decolorizing with activated carbon, filtering, crystallizing the filtrate, filtering, and drying to obtain.

[0061] Preferably, the purification conditions are: the solvent is purified water, and the volume used is 4 times the weight of the compound of formula (X). The temperature for heating to dissolve completely is 60 - 70°C. The amount of activated carbon used is 10 - 15%. The crystallization temperature is 0 - 5°C. The drying is carried out by blowing air for drying, and the drying temperature is 65 ± 5°C. The percentage is calculated based on the weight of the compound of formula (X) being 100%.

[0062] Beneficial effects:

[0063] (1). The synthetic route of the present invention simplifies the traditional process, improves the synthesis efficiency, and reduces the production cost.

[0064] (2). By optimizing the reaction conditions and purification steps, the generation of harmful by-products is effectively reduced, meeting the environmental protection requirements.

[0065] (3). The obtained levofloxacin hydrochloride has high purity, meets the pharmaceutical standards, and is suitable for large-scale industrial production.

[0066] (4). This method is simple to operate, easy to control, and suitable for application in laboratories and production lines of different scales. Description of the Drawings

[0067] Figure 1 It is the chemical structure diagram of levofloxacin hydrochloride.

[0068] Figure 2 It is the nuclear magnetic resonance spectrum of the compound (VI) of the present invention.

[0069] Figure 3 It is the nuclear magnetic resonance spectrum of levofloxacin of the present invention.

[0070] Figure 4 It is the HPLC spectrum of levofloxacin hydrochloride of the present invention.

[0071] Figure 5 It is the X-ray spectrum of levofloxacin hydrochloride of the present invention. Detailed implementation manners

[0072] To make the technical solution of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0073] Example 1 (1)

[0075]

[0076] Weigh 10.56 g of sodium hydride and add it to a reaction flask under argon protection. Add an appropriate amount of diethyl ether and wash it 3 times. Then add 17.62 g of ethyl acetate to the reaction flask, add 66.6 ml of THF, cool down to 5 ± 5 °C, and add 22.2 g of ethyl formate dropwise while controlling the temperature below 30 °C. After the addition is complete, react at room temperature for 2 h. Evaporate THF under reduced pressure at 40 °C. Add cyclohexane to the residue and stir at room temperature for 1 h. Filter, wash the filter cake with cyclohexane 2 times, and dry it under vacuum at 40 °C for 5 h to obtain 25.13 g of ethyl formylacetate sodium salt, and the product yield is 91%. (2)

[0078]

[0079] Weigh 20 g of ethyl formylacetate sodium salt into the reaction flask, add 250 ml of diethylene glycol dimethyl ether, cool down to 15 °C, and add 30.47 g of 2,3,4,5-tetrafluorobenzoyl chloride dropwise while controlling the temperature below 30 °C. After the addition is complete, react at 25 ± 5 °C for 6 h. Detect by TLC and if there is no spot of 2,3,4,5-tetrafluorobenzoyl chloride, ethyl 2-formyl-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate is obtained, and the reaction solution is directly used for the next step of the reaction. (3)

[0081]

[0082] After the previous step reaction is completed, add 12.92 g of aminopropanol to the reaction system of the previous step, heat the temperature to 90 °C and react for 8 h. When there is no ethyl 2-formyl-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate detected by TLC, ethyl 3-(1-hydroxypropan-2-ylamino)-2-oxo-2-(2,3,4,5-tetrafluorophenyl)acrylate is obtained, and the reaction solution is directly used for the next step reaction. (4)

[0084]

[0085] After the previous step reaction is completed, add 33.38 g of potassium fluoride to the reaction system of the previous step. Heat the system to 120 °C and react for 8 h. After the reaction is completed, evaporate the solvent under reduced pressure. While the residue is hot, add 120 ml of water and stir rapidly for 30 min, then filter. The filter cake is added to 120 ml of water again and stirred for 30 min, then filtered. Dry at 60 °C under vacuum for 12 h to obtain 26.96 g of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, and the combined yield is 60.8%. Molecular formula of the product: C 15 H 13 F 2 NO 4 , molecular weight: 309.26. HPLC purity analysis > 99%, LC-MS: 309.08, elemental analysis: C 58.25%, H 4.24%, F 12.29%, N 4.53%, O 20.69%. (5)

[0087]

[0088] Add 100 ml of diethylene glycol dimethyl ether, 8.75 g of triethylamine, 8.36 g of anhydrous piperazine and 25 g of the product ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate obtained from the previous step into the reaction flask in sequence. After adding, heat to 130 °C and react for 6 h. When there is no spot of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate detected by TLC, evaporate the solvent under reduced pressure, and the residue is the target product. 29.13 g of ethyl (S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate is obtained, and the yield is 96%. Molecular formula of the product: C 19 H 22 FN3 O 4 , molecular weight: 375.39. HPLC purity analysis > 97%, LC-MS: 375.16, elemental analysis: C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.0%. (6)

[0090]

[0091] 28 g of the target product (S)-ethyl 9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate obtained in the previous step was added to the reaction flask, 196 ml of dioxane and 8.4 g of KOH were added, the mixture was stirred and heated to 35 °C, 11.29 g of dimethyl sulfate was slowly added dropwise, the dropping time was controlled at 20 - 30 min, after the addition was completed, the temperature was slowly raised to 80 °C and the reaction was carried out for 5 h. TLC detection showed no spot of (S)-ethyl 9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate. After the reaction was completed, it was evaporated to dryness under reduced pressure to obtain the product (S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino [2,3,4-ij]quinoline-6-carboxylate 28.46 g, yield 98%. Product molecular formula: C 20 H 24 FN 3 O 4 , molecular weight: 389.42. HPLC purity analysis > 97%, LC-MS: 389.18, elemental analysis: C 61.68%, H 6.21%, F 4.88%, N 10.79%, O 16.43%. (7)

[0093]

[0094] 28 g of the product obtained from the previous step reaction was added to the reactor, 56 g of water and 3.64 g of NaOH were added, heated to 60 °C and reacted for 2 h. After the reaction was completed, the pH was adjusted to 6 - 7 with 2 M hydrochloric acid aqueous solution, extracted three times with 100 ml of DCM each time, the DCM phases were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure. The residue was dissolved in 100 g of ethanol by heating, 2 g of activated carbon was added and refluxed for 30 min, filtered while hot, slowly cooled to 0 - 5 °C for crystallization for 6 h, filtered, washed with a small amount of ethanol, and dried to constant weight at 45 °C under vacuum to obtain 19.49 g of levofloxacin product, yield 75%. Product molecular formula: C 18 H 20 FN3 O 4 , Molecular weight: 361.37. HPLC purity analysis > 99%, LC-MS: 361.14, elemental analysis: C 59.83%, H 5.58%, F 5.26%, N 11.63%, O 17.71%. (8)

[0096]

[0097] Add 18 g of the product obtained from the previous step to the reaction flask, add 90 ml of ethyl acetate and stir to dissolve. After dissolution is clear, cool down to 5 °C, control the temperature below 10 °C and dropwise add 2 M hydrochloric acid ethyl acetate solution until the pH is 2 - 3. Control the temperature at 7.5 ± 2.5 °C and stir for crystallization for 2 h, filter, wash with ethyl acetate, and dry in vacuum at 50 °C to obtain 17.44 g of crude levofloxacin hydrochloride, with a yield of 88%. Product molecular formula: C 18 H 21 ClFN 3 O 4 , Molecular weight: 397.83. HPLC purity analysis > 98%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%. (9)

[0099]

[0100] Add 16 g of the product obtained from the previous step to the reaction flask, then add 46 ml of purified water, heat to 60 °C until dissolution is clear, add 1.6 g of activated carbon and stir for 30 min, filter while it is hot, cool the filtrate to 5 °C for crystallization for 2 h, filter, wash the filter cake with a small amount of purified water at 5 °C, suction filter until no liquid drips, and dry in a blast at 65 ± 5 °C to constant weight to obtain 15.36 g of the product, with a yield of 96%. Product molecular formula: C 18 H 21 ClFN 3 O 4 , Molecular weight: 397.83. HPLC purity analysis > 99.9%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%.

[0101] Example 2 (1)

[0103]

[0104] Weigh 31.68 g of sodium hydride and add it to a reaction flask under argon protection. Add an appropriate amount of diethyl ether and wash it 3 times. Then add 52.86 g of ethyl acetate to the reaction flask, add 200 ml of THF, cool down to 5 ± 5 °C, and add 66.6 g of ethyl formate dropwise while controlling the temperature below 30 °C. After the addition is complete, react at room temperature for 2 h. Evaporate THF under reduced pressure at 40 °C. Add cyclohexane to the residue and stir at room temperature for 1 h. Filter, wash the filter cake with cyclohexane 2 times, and dry it under vacuum at 40 °C for 5 h to obtain 64.45 g of sodium formylacetate ethyl ester, with a product yield of 90.8%. (2)

[0106]

[0107] Weigh 60 g of sodium formylacetate ethyl ester into a reaction flask, add 750 ml of diethylene glycol dimethyl ether, cool down to 15 °C, and add 91.41 g of 2,3,4,5 - tetrafluorobenzoyl chloride dropwise while controlling the temperature below 30 °C. After the addition is complete, react at 25 ± 5 °C for 7 h. When TLC detection shows no spot of 2,3,4,5 - tetrafluorobenzoyl chloride, ethyl 2 - formyl - 3 - oxo - 3 - (2,3,4,5 - tetrafluorophenyl) propionate is obtained, and the reaction solution is directly used for the next step of the reaction. (3)

[0109]

[0110] After the above - step reaction is completed, add 41.99 g of 2 - aminopropanol to the above - step reaction system, heat the temperature to 100 °C and react for 6 h. When TLC detection shows no ethyl 2 - formyl - 3 - oxo - 3 - (2,3,4,5 - tetrafluorophenyl) propionate, ethyl 3 - (1 - hydroxypropan - 2 - amino) - 2 - oxo - 2 - (2,3,4,5 - tetrafluorophenyl) acrylate is obtained, and the reaction solution is directly used for the next step of the reaction. (4)

[0112]

[0113] After the above - step reaction is completed, add 100.14 g of potassium fluoride to the above - step reaction system, heat the system to 120 °C and react for 8 h. After the reaction is completed, evaporate the solvent under reduced pressure. Add 360 ml of water to the residue and stir it into a slurry at high speed while it is still hot for 30 min. Filter, add the filter cake to 360 ml of water again and stir it into a slurry for 30 min. Filter, and dry it under vacuum at 60 °C for 12 h to obtain 81.28 g of ethyl (S) - (-) - 9,10 - difluoro - 2,3 - dihydro - 3 - methyl - 7 - oxo - 7H - pyrido[1,2,3 - de][1,4]benzoxazine - 6 - carboxylate, with an overall yield of 61.1%. Product molecular formula: C 15 H 13 F 2 NO 4, Molecular weight: 309.26. HPLC purity analysis > 99%, LC-MS: 309.08, elemental analysis: C 58.25%, H 4.24%, F 12.29%, N 4.53%, O 20.69%. (5)

[0115]

[0116] Add 300 ml of diethylene glycol dimethyl ether, 26.25 g of triethylamine, 25.08 g of anhydrous piperazine and 75 g of the product ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate obtained from the previous step into the reaction flask in sequence. After addition, heat to 130 °C and react for 6 h. TLC detection shows no spot of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. Distill off the solvent under reduced pressure. The residue is the target product, and 87.12 g of the target product ethyl (S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate is obtained, with a yield of 95.7%. The molecular formula of the product is C 19 H 22 FN 3 O 4 , Molecular weight: 375.39. HPLC purity analysis > 97%, LC-MS: 375.16, elemental analysis: C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.0%. (6)

[0118]

[0119] 84 g of the target product (S)-ethyl 9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate obtained in the previous step was added to the reaction flask, 590 ml of dioxane and 25.2 g of KOH were added, the mixture was stirred and heated to 35 °C, 33.87 g of dimethyl sulfate was slowly added dropwise, the dropping time was controlled for 20 - 30 min, after the addition was completed, the temperature was slowly raised to 80 °C and reacted for 5 h. TLC detection showed no spot of (S)-ethyl 9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate. After the reaction was completed, it was evaporated to dryness under reduced pressure to obtain the product (S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxa [2,3,4-ij]quinoline-6-carboxylate 85.47 g, yield 98.1%. The molecular formula of the product: C 20 H 24 FN 3 O 4 , molecular weight: 389.42. HPLC purity analysis > 97%, LC-MS: 389.18, elemental analysis: C 61.68%, H 6.21%, F 4.88%, N 10.79%, O 16.43%. (7)

[0121]

[0122] 84 g of the product obtained from the previous step reaction was added to the reactor, 168 g of water and 11.76 g of NaOH were added, heated to 70 °C and reacted for 2 h. After the reaction was completed, the pH was adjusted to 6 - 7 with 2 M hydrochloric acid aqueous solution, extracted three times with 100 ml of DCM each time, the DCM phases were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure. The residue was dissolved by heating with 300 g of ethanol, 6 g of activated carbon was added and refluxed for 30 min, filtered while hot, slowly cooled to 0 - 5 °C and crystallized for 6 h, filtered, washed with a small amount of ethanol, and dried to constant weight at 45 °C under vacuum to obtain 58.86 g of levofloxacin product, yield 75.5%. The molecular formula of the product: C 18 H 20 FN 3 O 4 , molecular weight: 361.37. HPLC purity analysis > 99%, LC-MS: 361.14, elemental analysis: C 59.83%, H 5.58%, F 5.26%, N 11.63%, O 17.71%. (8)

[0124]

[0125] Add 54 g of the product obtained from the previous step to a reaction flask, add 270 ml of ethyl acetate and stir to dissolve. After dissolution is clear, cool the temperature to 5 °C, control the temperature below 10 °C and dropwise add 2 M hydrochloric acid ethyl acetate solution until the pH is 2 - 3. Control the temperature at 7.5 ± 2.5 °C and stir to crystallize for 2 h. Filter, wash with ethyl acetate, and dry in vacuo at 50 °C to obtain 52.44 g of crude levofloxacin hydrochloride, with a yield of 88.2%. Molecular formula of the product: C 18 H 21 ClFN 3 O 4 , molecular weight: 397.83. HPLC purity analysis > 98%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%. (9)

[0127]

[0128] Add 48 g of the product obtained from the previous step to a reaction flask, then add 138 ml of purified water, heat to 65 °C until dissolution is clear, add 6.24 g of activated carbon and stir for 30 min. Filter while hot, cool the filtrate to 0 °C and crystallize for 2 h. Filter, wash the filter cake with a small amount of purified water at 0 °C, suction filter until no liquid drips, and dry in a blast at 65 ± 5 °C to constant weight to obtain 46.37 g of the product, with a yield of 96.6%. Molecular formula of the product: C 18 H 21 ClFN 3 O 4 , molecular weight: 397.83. HPLC purity analysis > 99.9%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%.

[0129] Example 3 (1)

[0131]

[0132] Weigh 105.6 g of sodium hydride and add it to a reaction flask under argon protection. Add an appropriate amount of ether and wash 3 times. Then add 176.2 g of ethyl acetate to the reaction flask, add 666 ml of THF, cool the temperature to 5 ± 5 °C, control the temperature below 30 °C and dropwise add 222 g of ethyl formate. After the addition is complete, react at room temperature for 2 h. Distill off THF under reduced pressure at 40 °C. Add cyclohexane to the residue and stir at room temperature for 1 h. Filter, wash the filter cake with cyclohexane 2 times, and dry in vacuo at 40 °C for 5 h to obtain 252.13 g of sodium formylacetate ethyl ester, with a product yield of 91.3%. (2)

[0134]

[0135] Weigh 218.2 g of sodium formylacetate into the reaction flask, add 2500 ml of diethylene glycol dimethyl ether, cool down to 15°C, and control the temperature below 30°C to dropwise add 304.7 g of 2,3,4,5-tetrafluorobenzoyl chloride. After the addition is complete, control the temperature at 25±5°C and react for 6 h. When no 2,3,4,5-tetrafluorobenzoyl chloride spots are detected by TLC, ethyl 2-formyl-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate is obtained, and the reaction solution is directly used for the next step of the reaction. (3)

[0137]

[0138] After the previous step of the reaction is completed, add 139.97 g of 3-aminopropanol to the reaction system of the previous step, heat the temperature to 100°C and react for 7 h. When no ethyl 2-formyl-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate is detected by TLC, ethyl 3-(1-hydroxypropan-2-ylamino)-2-oxo-2-(2,3,4,5-tetrafluorophenyl)acrylate is obtained, and the reaction solution is directly used for the next step of the reaction. (4)

[0140]

[0141] After the previous step of the reaction is completed, add 333.8 g of potassium fluoride to the reaction system of the previous step, heat the system to 120°C and react for 8 h. After the reaction is completed, evaporate the solvent under reduced pressure. While the residue is hot, quickly stir and add 1200 ml of water to make a slurry for 30 min, filter, add the filter cake to 1200 ml of water again to make a slurry for 30 min, filter, and dry at 60°C under vacuum for 12 h to obtain 270.9 g of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, and the combined yield is 61.1%. Molecular formula of the product: C 15 H 13 F 2 NO 4 , molecular weight: 309.26. HPLC purity analysis > 99%, LC-MS: 309.08, elemental analysis: C 58.25%, H 4.24%, F 12.29%, N 4.53%, O 20.69%. (5)

[0143]

[0144] 1000 ml of diethylene glycol dimethyl ether, 87.5 g of triethylamine, 83.6 g of anhydrous piperazine and 250 g of the product ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate obtained from the previous step were successively added to a reaction flask. After the addition, the mixture was heated to 130 °C and reacted for 6 h. TLC detection showed no spot of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. The solvent was removed by distillation under reduced pressure, and the residue was the target product. 291.6 g of the target product ethyl (S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate was obtained, with a yield of 96.1%. The molecular formula of the product is C 19 H 22 FN 3 O 4 , and the molecular weight is 375.39. The HPLC purity analysis is >97%, LC-MS: 375.16, and the elemental analysis shows C 60.79%, H 5.91%, F 5.06%, N 11.19%, O 17.0%. (6)

[0146]

[0147] 280 g of the target product ethyl (S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate obtained in the previous step was added to a reaction flask. 1960 ml of dioxane and 84 g of KOH were added, and the mixture was stirred and heated to 35 °C. 112.9 g of dimethyl sulfate was slowly added dropwise, controlling the dropping time to 20 - 30 min. After the addition, the temperature was slowly raised to 80 °C and reacted for 5 h. TLC detection showed no spot of ethyl (S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure to obtain 284.0 g of the product ethyl (S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino [2,3,4-ij]quinoline-6-carboxylate, with a yield of 97.8%. The molecular formula of the product is C 20 H 24 FN 3 O 4, Molecular weight: 389.42. HPLC purity analysis > 97%, LC-MS: 389.18, elemental analysis: C 61.68%, H 6.21%, F 4.88%, N 10.79%, O 16.43%. (7)

[0149]

[0150] Add 280 g of the product obtained from the previous step to the reactor, add 560 g of water and 42 g of NaOH, heat to 80 °C and react for 1 h. After the reaction, adjust the pH to 6 - 7 with 2 M hydrochloric acid aqueous solution, extract three times with 1000 ml of DCM each time, combine the DCM phases, dry over anhydrous magnesium sulfate, filter, evaporate to dryness under reduced pressure. Add 1000 g of ethanol to the residue and heat to dissolve clearly. Add 20 g of activated carbon and reflux for 30 min, filter while hot, slowly cool to 0 - 5 °C and crystallize for 6 h, filter, wash with a small amount of ethanol, and dry at 45 °C under vacuum to constant weight to obtain 197.75 g of levofloxacin product, with a yield of 76.1%. Product molecular formula: C 18 H 20 FN 3 O 4 , Molecular weight: 361.37. HPLC purity analysis > 99%, LC-MS: 361.14, elemental analysis: C 59.83%, H 5.58%, F 5.26%, N 11.63%, O 17.71%. (8)

[0152]

[0153] Add 180 g of the product obtained from the previous step to the reaction flask, add 900 ml of ethyl acetate and stir to dissolve. After dissolving clearly, cool to 5 °C, control the temperature below 10 °C and dropwise add 2 M hydrochloric acid ethyl acetate solution until the pH is 2 - 3. Control the temperature at 7.5 ± 2.5 °C and stir to crystallize for 2 h, filter, wash with ethyl acetate, and dry at 50 °C under vacuum to obtain 175.59 g of crude levofloxacin hydrochloride, with a yield of 88.6%. Product molecular formula: C 18 H 21 ClFN 3 O 4 , Molecular weight: 397.83. HPLC purity analysis > 98%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%. (9)

[0155]

[0156] Add 160 g of the product obtained from the previous step to the reaction flask, then add 460 ml of purified water, heat to 70 °C until dissolved clearly, add 24 g of activated carbon and stir for 30 min, filter while it is hot, cool the filtrate to 0 °C to crystallize for 2 h, filter, wash the filter cake with a small amount of purified water at 0 °C, suction filter until no liquid drips, dry at 65 ± 5 °C by blowing air until constant weight, and obtain 153.44 g of the product with a yield of 95.9%. The molecular formula of the product: C 18 H 21 ClFN 3 O 4 , molecular weight: 397.83. The HPLC purity analysis > 99.9%, LC-MS: 397.12, elemental analysis: C 54.34%, H 5.32%, Cl 8.91%, F 4.78%, N 10.56%, O 16.09%.

[0157] The above embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A method for synthesizing levofloxacin hydrochloride, characterized in that: The steps include: S1. Using ethyl formate (I) as a raw material, reacting with ethyl acetate under the catalysis of NaH to obtain a compound of formula (II) S2, reacting the compound of formula (II) with the compound of formula (III) in a diethylene glycol dimethyl ether system to obtain a compound of formula (IV); S3, reacting the compound of formula (IV) obtained in step S2 with aminopropanol to obtain a compound of formula (V); S4, reacting the compound of formula (V) obtained in step S3 under KF catalysis to obtain a compound of formula (VI); S5, reacting the compound of formula (VI) obtained in step S4 with anhydrous piperazine under base catalysis to obtain a compound of formula (VII); S6, reacting the compound of formula (VII) obtained in step S5 with dimethyl sulfate to obtain a compound of formula (VIII); S7, hydrolyzing the compound of formula (VIII) to obtain the compound of formula (IX); S8. The compound of formula (IX) is salified with ethyl acetate hydrochloride to obtain a crude product of levofloxacin hydrochloride of formula (X) 2. The synthetic method of levofloxacin hydrochloride according to claim 1, characterized in that, The reaction conditions of step S8 are as follows: the reaction solvent is ethyl acetate, the volume used is 3 times the weight of the compound of formula (IX), the molar ratio of hydrochloric acid to the compound of formula (IX) in 2M hydrochloric acid ethyl acetate is 1.05:1-1.1:1, the reaction temperature is 5-10°C, and the reaction time is 1-2h.

3. The synthetic method of levofloxacin hydrochloride according to claim 1 or 2, characterized in that, The reaction conditions of step S2 are as follows: the reaction solvent is diethylene glycol dimethyl ether, the volume dosage is 12.5 times the weight of the compound of formula (II), the molar ratio of the compound of formula (III) to the compound of formula (II) is 1:1.01-1:1.02, the reaction temperature is 20-30° C., and the reaction time is 6-8 h; The reaction conditions of step S3 are as follows: the reaction solvent is from step S2, the volume amount is 12.5 times the weight of the compound of formula (II), the molar ratio of aminopropanol to the compound of formula (III) is 1.2:1-1.3:1, the reaction temperature is 90-100° C., and the reaction time is 6-8 h; The reaction conditions of step S4 are as follows: the reaction solvent is from step S3, the volume used is 12.5 times the weight of the compound of formula (II), the catalyst is potassium fluoride, the mass ratio of the catalyst to the compound of formula (V) is 1:1.5, and the reaction temperature is 120°C; The reaction conditions of step S5 are as follows: the reaction solvent is diethylene glycol dimethyl ether, the volume amount is 4 times the weight of the compound of formula (VI), the catalyst is triethylamine, the amount is 0.35 times the weight of the compound of formula (VI), the molar ratio of anhydrous piperazine to the compound of formula (VI) is 1.2:1, and the reaction temperature is 130° C.; The reaction conditions of step S6 are as follows: the reaction solvent is dioxane, the volume amount is 7 times the weight of the compound of formula (VII), the catalyst is potassium hydroxide, the amount is 0.3 times the weight of the compound of formula (VII), the molar ratio of dimethyl sulfate to the compound of formula (VII) is 1.2:1, and the reaction temperature is 80°C; The reaction conditions of step S7 are: the reaction solvent is purified water, the volume used is 2 times the weight of the compound of formula (VIII), the amount of sodium hydroxide used is 13-15% of the weight of the compound of formula (VIII), the reaction temperature is 60-80° C., and the reaction time is 1-2 h. The percentages are based on the weight of the compound of formula (VIII) as 100%.

4. The synthetic method of levofloxacin hydrochloride according to claim 3, characterized in that, In step S1, the reaction conditions are as follows: the solvent is tetrahydrofuran, the volume amount is 3 times the weight of the compound of formula (I), the sodium hydride is deoiled and washed with ether before use, the molar ratio of ethyl acetate to the compound of formula (I) is 1:1.5, the temperature is 0-10°C when the compound of formula (I) is added, and the reaction is carried out at room temperature after the addition is completed.

5. A method for purifying levofloxacin hydrochloride synthesized by the levofloxacin hydrochloride synthesis method according to any one of claims 1 to 4, characterized in that: The method comprises: adding water to the crude levofloxacin hydrochloride of formula (X) obtained in step S8, heating to dissolve, decolorizing with activated carbon, filtering, crystallizing the filtrate, filtering, and drying to obtain the product.

6. The method for purifying levofloxacin hydrochloride according to claim 5, characterized in that: The purification conditions are as follows: the solvent is purified water, the volume dosage is 4 times the weight of the compound of formula (X), the heating dissolution temperature is 60-70°C, the amount of activated carbon is 10-15%, the crystallization temperature is 0-5°C, the drying is forced air drying, the drying temperature is 65±5°C, and the percentages are based on the weight of the compound of formula (X) as 100%.

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