Preparation method of moxifloxacin hydrochloride intermediate

Abstract

The invention discloses a preparation method of a moxifloxacin hydrochloride intermediate with high yield, high purity and low cost, and aims to overcome the technical defects of low resolution yield, need of additional acid addition, single solvent system, complex resolution agent recovery process and limited salifying efficiency in the prior art. According to the method, cis-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3. 0] nonane (a compound as shown in a formula I) is taken as a raw material, N-acetylphenylalanine (including L-type and D-type) is taken as a resolving agent, acid does not need to be additionally added in a water-alcohol-ester ternary solvent system, efficient resolution of the enantiomer is directly realized through a salt forming reaction, and the yield of the enantiomer is increased. And the high-purity diazabicyclo compounds shown in the formulas IIIa and IIIb can be obtained without a refining step. The resolution yield can reach 90% or above, the recovery process of the resolving agent is simple and efficient, the recovery rate is larger than or equal to 95%, the resolving agent can be stably and circularly applied for five times or above, the resolution yield is still larger than or equal to 90% after the resolving agent is applied, the comprehensive production cost is reduced by 40%-60% compared with the prior art, and the method has outstanding industrial application advantages.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to an efficient method for resolving (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, a key intermediate of moxifloxacin hydrochloride. In particular, it relates to a resolving process that uses N-acetylphenylalanine as the resolving agent and a water-alcohol-ester ternary solvent system as the reaction medium, which requires no additional acid addition, no further purification, and efficient recovery of the resolving agent. Background Technology

[0002] Moxifloxacin hydrochloride, as a fourth-generation 8-methoxyquinolone antibiotic, has advantages such as a broad antibacterial spectrum, long half-life, and strong tissue penetration. It is widely used clinically to treat various infectious diseases, and its market demand remains stable. (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is the core intermediate for the synthesis of moxifloxacin hydrochloride. Its optical purity and preparation yield directly affect the quality and production cost of the final drug. Therefore, efficient resolution technology of this intermediate has always been a key focus of industry research.

[0003] Existing methods for resolving diazabicyclic compounds have several drawbacks: (1) German Bayer AG patent EP550903 discloses a method using D-tartaric acid or L-tartaric acid as a resolving agent and a single alcohol as a solvent. The optical purity of the product is only about 90%, the resolving yield is only 65%~70%, and additional acid needs to be added to promote the reaction. Tartaric acid is highly water-soluble and difficult to recover. The overall process is complicated, and multiple purification steps are required after resolving to meet the quality requirements. (2) US Patent US6566523 uses (-)-2,3:4,6-diisopropylidene-2-one-L-gulonic acid hydrate as a resolving agent and butanone as a single solvent. Although it can achieve an optical purity of 99.6% ee for the product, the resolving yield is only 70%~75%. The resolving agent is expensive (about 8~10 times that of N-acetylphenylalanine), has poor stability under acidic conditions, cannot be recycled, and requires the addition of acid to maintain the reaction system. After resolving, it needs to be purified, resulting in high production costs. (3) Chinese patent CN104163821B discloses a method using p-toluenesulfonyl L-phenylglycine as a resolving agent and a single alcohol or alcohol-aromatic binary solvent. The resolving yield is 75%~79%, which still does not exceed 80%, and the reaction must be carried out in the presence of acid. The nitrogen substituent group of the resolving agent is p-toluenesulfonyl, which has large steric hindrance, resulting in a slow salt formation reaction rate and incomplete reaction, which limits the improvement of yield. At the same time, after resolving, it needs to be purified by recrystallization to meet the purity requirements. The recovery of the resolving agent requires complicated solvent recovery and recrystallization steps, and the recovery rate and reuse are unclear.

[0004] In summary, existing solvent systems are mostly single solvents or binary mixed solvents, which have problems such as narrow solubility adjustment range and low crystallization efficiency of target salts. This results in insufficient purity of the product after resolution, requiring purification steps, which increases process complexity and production costs. Furthermore, they generally rely on the addition of additional acid to promote the salt formation reaction, which not only increases process steps and costs but may also lead to degradation of the resolving agent, affecting product purity and resolving agent recovery.

[0005] Therefore, developing a method for preparing diazabicyclic compounds that requires no additional acid, has an efficient solvent system, low steric hindrance in the resolving agent, high salt formation efficiency, high yield, requires no purification, and allows for efficient recycling of the resolving agent is of great significance for reducing the production cost of moxifloxacin hydrochloride and enhancing the competitiveness of the industry. Summary of the Invention

[0006] The core objective of this invention is to provide a method for preparing diazabicyclic compounds using N-acetylphenylalanine as a resolving agent and a water-alcohol-ester ternary solvent system as the reaction medium. By leveraging the structural advantages of the resolving agent, innovating the solvent system, and optimizing the process conditions, this method achieves highly efficient resolving without the need for additional acid addition or purification, while simplifying the resolving agent recovery process, which is significantly superior to existing technologies.

[0007] The main contents of this invention are as follows: A method for preparing a diazabicyclic compound as shown in formula IIIa or IIIb, characterized in that: the method for preparing the compound shown in formula IIIa includes the following steps: in a water-alcohol-ester ternary solvent system, the compound shown in formula I is reacted with a resolving agent to form a salt, directly obtaining the compound shown in formula IIIa; the resolving agent is LN-acetylphenylalanine (the compound shown in formula IIa).

[0008] The preparation method of the compound shown in Formula IIIb includes the following steps: in a water-alcohol-ester ternary solvent system, the compound shown in Formula I is reacted with a resolving agent to form a salt, and the compound shown in Formula IIIb is directly obtained; the resolving agent is DN-acetylphenylalanine (the compound shown in Formula IIb).

[0009] Wherein, the compound shown in Formula I is cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which is an enantiomeric mixture composed of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane.

[0010] In the water-alcohol-ester ternary solvent system, the volume ratio of water, alcohol solvent, and ester solvent is 1:3~8:2~5; the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol; the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, and n-butyl acetate.

[0011] The reaction feeding method is as follows: after the compound shown in Formula I is mixed evenly with the ternary solvent system, the resolving agent is added, and the mixture is stirred and heated to carry out the salt formation reaction.

[0012] The temperature for salt formation reaction is 45~95℃, preferably 60~85℃; the reaction endpoint is determined by the formation of a homogeneous and transparent solution, and the reaction time is 1~4 hours.

[0013] The molar ratio of the compound shown in Formula I to the resolving agent is 1:0.6 to 1:1.1; the volume-to-mass ratio of the ternary solvent system to the compound shown in Formula I is 5 to 30 mL / g.

[0014] After the salt formation reaction is completed, a post-processing step is also included: the reaction solution is cooled to -5 to 25°C at a rate of 3 to 8°C / hour, crystallization is carried out for 2 to 18 hours, and the filter cake and filtrate are obtained by filtration; the filter cake is the target compound represented by formula IIIa or IIIb, which does not require further purification; the filtrate is used to recover the resolving agent.

[0015] The target compound obtained by filtration was mixed with water and a chlorinated hydrocarbon organic solvent, the pH of the system was adjusted to 9-12, the mixture was stirred and separated into layers, and the chlorinated hydrocarbon layer was distilled to dryness to obtain the compound shown in formula IVa or IVb; wherein the compound shown in formula IVa is (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which is a key intermediate in the preparation of moxifloxacin hydrochloride.

[0016] .

[0017] The method for recovering the resolving agent is as follows: (1) Target compound related recovery: The target compound obtained by filtration is mixed with water and chlorinated hydrocarbon organic solvent, the pH of the system is adjusted to 9~12, the layers are stirred and separated, the pH of the aqueous layer is adjusted to 3~5 with acid, the resolving agent is precipitated, and the resolving agent is obtained by filtration and drying. (2) Filtrate recovery: After the solvent is recovered by vacuum distillation of the filtrate obtained by filtration, water and chlorinated hydrocarbon organic solvent are added, the pH is adjusted to 9-12, the layers are stirred and separated, the pH of the aqueous layer is adjusted to 3-5 with acid, the resolving agent is precipitated, and the resolving agent is obtained by filtration and drying. The recovered resolving agent can be reused more than 5 times, with a resolving yield of ≥90% after each reuse and an optical purity of ≥99% ee for the product.

[0018] This invention is creatively derived from a thorough theoretical foundation, a comparison of the differences and shortcomings of existing technologies, and extensive experimental verification. It possesses the following innovative features: 1. Structural advantages of the resolving agent: low steric hindrance and high salt formation efficiency; This invention selects N-acetylated phenylalanine as the resolving agent. Its core advantage lies in the fact that the steric hindrance of the nitrogen-substituted group in the molecular structure is significantly less than that of the resolving agent in the comparative patent. The resolving agent of the comparative patent CN104163821B is p-toluenesulfonyl L-phenylglycine, and the nitrogen-substituted group is p-toluenesulfonyl (-SO2-C6H4-CH3). This group contains a benzene ring and a sulfonyl group, which has a large space volume and obvious steric hindrance effect. This leads to steric repulsion when the resolving agent is close to the amino group of the compound shown in Formula I, resulting in a slow salt formation reaction rate and incomplete reaction, which in turn limits the resolving yield and the product purity is insufficient, requiring purification.

[0019] The resolving agent of this invention, N-acetylphenylalanine, has an acetyl group (-CO-CH3) on its nitrogen-containing substituent. It is a small molecule acyl group with low steric hindrance and no obvious steric repulsion effect. It can quickly approach the amino group in the compound shown in Formula I and form a stable diastereomeric salt. The salt formation reaction rate is 30% to 50% higher than that of the comparative patent, the reaction is more thorough, the product has high purity, and no purification is required.

[0020] Furthermore, the moderate electronegativity of the acetyl group allows for a higher degree of matching between the acidity of the resolving agent and the basicity of the compound shown in Formula I. The resulting diastereomeric salt exhibits good stability and significant differences in solubility in the ternary solvent system, further promoting the efficient crystallization and precipitation of the target salt and ensuring that the product can achieve high purity without purification.

[0021] 2. Core Innovation: Water-Alcohol-Ester Ternary Solvent System This invention breaks through the limitations of existing single or binary solvent systems and innovatively adopts a water-alcohol-ester ternary solvent system. Its synergistic effect complements the steric hindrance advantage of the resolving agent, bringing significant technical advantages.

[0022] System composition: The volume ratio of water, alcohol solvent, and ester solvent is 1:3~8:2~5. Under this ratio, the ternary system can ensure that the raw materials and resolving agents shown in Formula I are fully dissolved, and can also significantly expand the solubility difference between the target diastereomeric salt and impurities through the polarity difference of the three solvents, promote the efficient crystallization and precipitation of the target salt, and achieve the required product purity without the need for purification.

[0023] Mechanism without the need for additional acid: In the ternary system, the ester group of the ester solvent forms a weak proton transfer system with water and alcohol, which can simulate the catalytic effect of acid. Combined with the characteristics of N-acetylphenylalanine, which has low steric hindrance and high salt-forming activity, efficient salt formation can be achieved without the need to add additional organic or inorganic acids. This simplifies the process steps, avoids the impact of acid on the stability of the resolving agent, and reduces wastewater treatment costs.

[0024] Advantages of solvent selection: The addition of water can adjust the polarity of the system and improve the solubility of the raw materials; alcohol solvents ensure the homogeneity of the reaction system; ester solvents reduce the solubility of the target salt. The three solvents work together to increase the resolution yield by 15% to 25% compared with the existing single solvent system, and the product crystals are uniform and have high purity, without the need for purification.

[0025] 3. Optimization of process conditions and achievement of high yield and no refining By systematically optimizing key parameters such as the ratio of ternary solvent, feed ratio, reaction temperature, and crystallization conditions, and combining the steric hindrance advantage of the resolving agent with the synergistic effect of the ternary solvent system, high-purity products can be obtained without purification, with a resolving yield ≥90%. The specific optimization conditions are as follows: The ternary solvent ratio is 1:3~8:2~5 (volume ratio of water-alcohol-ester). Under this ratio, the system has moderate polarity, the target salt crystallization yield is the highest, and the product purity is the best.

[0026] Feed ratio: The molar ratio of the compound shown in Formula I to N-acetylphenylalanine is optimized to be 1:0.8~1:1.0. Combined with the characteristics of low steric hindrance and high salt formation efficiency of the resolving agent, the utilization rate of the resolving agent is the highest under this ratio. It can ensure complete resolving while avoiding waste of the resolving agent, and the product purity is uniform.

[0027] Reaction temperature: The preferred salt formation reaction temperature is 60~85℃. At this temperature, the salt formation reaction is rapid, and the ternary system forms a homogeneous and transparent solution. Combined with the high salt formation activity of the resolving agent, the reaction rate is fast and complete, without the need to prolong the reaction time, thus avoiding the generation of side reactions.

[0028] Crystallization conditions: After the reaction is completed, slowly cool down to 5~10℃ at a rate of 5℃ / hour and hold at this temperature for 8~12 hours to allow crystallization. This can avoid impurity encapsulation caused by rapid cooling and ensure that the product has an optical purity ≥99% ee and a chemical purity ≥99.5%, which can meet the requirements of subsequent reactions without further purification.

[0029] 4. Resolving agent recovery process and examples (innovative "alkaline stratification-acidification precipitation" method) The resolving agent recovery process of this invention is simple and efficient, requiring no complex equipment. It achieves the associated recovery of the target compound and the recovery of the filtrate through a two-step method of "alkaline stratification-acidification precipitation". The specific steps are as follows: (1) Target compound associated recovery (recovery of resolving agent from directly obtained target compound) Take the target compound obtained by filtration (the salt compound shown in formula IIIa or IIIb), add 2-3 times the mass of water and 1-2 times the volume of dichloromethane (or 1,2-dichloroethane or chloroform), and stir to form a mixed system; adjust the pH of the system to 9-11 with 10% sodium hydroxide solution, stir for 30-60 minutes to release the resolving agent N-acetylphenylalanine and dissolve it in the aqueous phase, and dissolve the target product (diazabicyclic free base) in the dichloromethane phase. Let it stand to separate the layers and obtain the aqueous phase; slowly add 1 mol / L hydrochloric acid to the aqueous phase to adjust the pH to 3-4, and N-acetylphenylalanine precipitates out. Filter and dry to obtain the recovered resolving agent with a purity ≥98.5% and a recovery rate ≥96%.

[0030] (2) Filtrate recovery (recovery of resolving agent in the filtrate of the resolving reaction) Collect the filtrate after the resolution reaction and recover the ternary solvent by vacuum distillation at 60-70℃ and -0.08-0.09MPa (recovery rate ≥85%, which can be recycled for the reaction); add 1-2 times the mass of water and 1 volume of dichloromethane to the remaining residue and stir to dissolve; adjust the pH to 9-11 according to the same method as the target compound correlation recovery above, separate the layers, acidify the aqueous phase to precipitate the resolving agent, filter and dry to obtain the recovered resolving agent with a purity ≥98% and a recovery rate ≥94%.

[0031] Taking the resolution of LN-acetylphenylalanine to prepare the compound shown in formula IIIa as an example, using the above-mentioned recovery process, after the resolving agent is continuously recovered and reused 5 times (see Example 3 for details), the resolution yield is still maintained above 91%, the optical purity of the product is ≥99%ee, the chemical purity is ≥99.0%, and it can be used without purification; the purity of the recovered resolving agent is ≥99%, the recovery rate is stable above 95%, and there is no obvious performance degradation, which is a significant improvement over the existing technology.

[0032] 5. Performance comparison with existing literature The method of this invention, with its structural advantages of low steric hindrance and high salt formation efficiency of the resolving agent, combined with the synergistic effect of the ternary solvent system, improves the resolving yield by 10% to 25% compared with the prior art; it innovatively eliminates the need for additional acid addition and refining, greatly simplifying the process; the cost of the resolving agent is only 1 / 8 to 1 / 10 of that of existing high-priced resolving agents, and the recovery process is simple and can be stably reused more than 5 times, reducing the overall production cost by 40% to 60% compared with the prior art, thus possessing significant technical advantages and economic value.

[0033] The preparation method of the present invention has the following outstanding advantages: 1. The resolving agent has significant structural advantages: the N-acetylphenylalanine nitrogen substituent is an acetyl group, which has much less steric hindrance than the resolving agent of the comparative patent. The salt formation reaction is faster and more complete, providing a core guarantee for the resolving yield to exceed 90% and the product to be purified without the need for purification; moreover, the resolving agent is inexpensive, readily available and chemically stable, further reducing production costs. 2. Innovative Solvent System: The water-alcohol-ethyl ester ternary solvent system is adopted, which can efficiently form salts without the need for additional acid. Combined with the steric hindrance advantage of the resolving agent, the product has high crystal purity and does not require purification. Compared with the existing single / binary solvent system process, it is simpler and has a higher yield. 3. Extremely simple and efficient process: No refining steps are required. High-purity target compounds are obtained directly after dissociation, shortening the production cycle, reducing equipment investment and energy consumption, and increasing industrial production efficiency by more than 30%. 4. High efficiency in resolving agent recovery: Through the innovative "alkaline stratification-acidification precipitation" recovery process, the recovery rate is ≥95%, and it can be reused more than 5 times. After reuse, there is no significant decrease in yield and purity, which is significantly superior to existing technologies. 5. Excellent product quality: Optical purity ≥99% ee and chemical purity ≥99.5% can be achieved without refining, fully meeting the quality requirements of moxifloxacin hydrochloride intermediates; 6. Environmentally friendly and economical: No additional acid is required, reducing process steps and wastewater treatment costs; both solvents and resolving agents can be recycled, resulting in high raw material utilization and low environmental pollution, which aligns with the concept of green chemical production. 7. Strong industrial adaptability: The process is simple to operate, the reaction conditions are mild, the recovery process does not require special equipment, and no highly toxic reagents are used. The scale-up experiment at the 10 kg level has verified that there is no significant scale-up effect, and it can be directly applied to large-scale industrial production. Detailed Implementation

[0034] The present invention is further illustrated below by specific embodiments, but these embodiments do not limit the invention to the scope of the invention. Experimental methods not specified in the embodiments are performed according to conventional methods and conditions, or as selected in the product manual.

[0035] Example 1: Preparation of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane·LN-acetylphenylalanine salt (new resolving agent, no purification required) In a 1000 mL reaction flask, 50 g of the compound shown in Formula I (cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane) was added, along with a ternary solvent system (60 mL water, 300 mL isopropanol, and 180 mL ethyl acetate). The mixture was stirred until the starting material was uniformly dispersed. Subsequently, 38.2 g of LN-acetylphenylalanine (molar ratio to the starting material 1:0.9) was added, and the mixture was heated to 75 °C and stirred for 2 hours until the reaction solution was homogeneous and transparent (the salt formation reaction was complete). The mixture was then slowly cooled to 8 °C at a rate of 5 °C / hour and kept at this temperature for crystallization for 10 hours. The mixture was filtered, and the filter cake was washed with 40 mL of cold ternary solvent (water-isopropanol-ethyl acetate = 1:5:3). No further purification was required, and 42.7 g of a white solid was obtained directly. The resolution yield was 92.5%, the optical purity was 99.8% ee, and the chemical purity was 99.8% (HPLC detection), which met the requirements for subsequent free reactions.

[0036] Example 2: Resolving agent recovery (target compound-related recovery + filtrate recovery) (1) Target compound associated recovery Take 42.7 g of the white solid obtained directly in Example 1, add 90 g of water and 60 mL of dichloromethane, and stir to form a mixed system; adjust the pH to 10 with 10% sodium hydroxide solution, stir for 40 minutes, let stand to separate the layers, and separate to obtain the aqueous phase; add 1 mol / L hydrochloric acid dropwise to the aqueous phase to adjust the pH to 3.5, stir for 1 hour, filter and dry to obtain 18.8 g of LN-acetylphenylalanine with a purity of 98.9% and a recovery rate of 96.2%.

[0037] (2) Filtrate recovery The filtrate from Example 1 (approximately 640 mL) was collected and the ternary solvent was recovered by vacuum distillation at 65°C and -0.085 MPa (550 mL of solvent was recovered and can be directly used in the next round of reaction). 30 g of water and 20 mL of dichloromethane were added to the remaining residue and stirred to dissolve. The pH was adjusted to 10 according to the method for the associated recovery of the target compound described above. After separation, the aqueous phase was acidified to precipitate the resolving agent. The solution was filtered and dried to obtain 17.6 g of LN-acetylphenylalanine with a purity of 98.2% and a recovery rate of 94.5%.

[0038] Example 3: First to fifth applications of the resolving agent (no refining required) The resolving agent recovered in Example 2 (total 36.4g) was combined, and new resolving agent was added to bring the total to 38.2g for the first reuse. The process conditions of Example 1 were repeated, and 540mL of the recovered solvent was added to the ternary solvent system. Subsequent reuses from the second to the fifth reuse were all processed in the same manner, with the process conditions for each reuse being consistent with Example 1. No purification was required. The results are shown in the table below: .

[0039] Example 4: Comparison of yield and purity for different ternary solvent ratios Using the same raw material amounts and feeding ratios as in Example 1, only the types and volume ratios of components in the ternary solvent system were changed. No purification was required. The resolution yields and purities are shown in the table below: .

[0040] The results show that different combinations and ratios of water-alcohol-ester affect the yield and purity. However, within the range specified in this patent, both the yield and purity can reach a high level. The reaction system has good uniformity, with no layering or raw material residue. The product can meet the requirements for use of moxifloxacin hydrochloride without purification.

[0041] Example 5: Comparative experiment with existing technology (including the effect of purification steps) Parallel experiments were conducted using the methods of this invention, EP550903 (D-tartaric acid as resolving agent, ethanol as solvent, and acid addition), US6566523 (gulonic acid derivative as resolving agent, butanone as solvent, and acid addition), and CN104163821B (p-toluenesulfonyl L-phenylglycine as resolving agent, isopropanol as solvent, and acid addition), with 50g of the compound shown in Formula I as raw material. The yield and purity before and after purification were compared, and the results are shown in the table below: .

[0042] Note: The cost calculation of the resolving agent is based on the price of industrial-grade products: N-acetylphenylalanine 80 yuan / kg, D-tartaric acid 150 yuan / kg, gulonic acid derivative 400 yuan / kg, p-toluenesulfonyl L-phenylglycine 180 yuan / kg.

[0043] As can be seen from the comparison results, the method of the present invention can achieve high yield and high purity without purification, while the purity of the prior art is significantly insufficient when unrefined, and the yield further decreases after purification. The method of the present invention has the advantages of low steric hindrance of the resolving agent and fast salt formation rate, which significantly improves the resolving yield and purity of the prior art. Moreover, it does not require additional acid and has the lowest cost of resolving agent, showing obvious comprehensive advantages.

[0044] Industrial Application Notes The preparation method of this invention has been verified by a 10 kg scale-up experiment, with a stable resolving yield of 90%~95%, optical purity ≥99% ee, and chemical purity ≥99.5%. It can be directly used for subsequent reactions without purification and has no significant scale-up effect. In the ternary solvent system, the solvent recovery rate is ≥90% and the resolving agent recovery rate is ≥95%. The recovery process is simple and requires no special equipment. Each ton of product can save approximately RMB 30,000 in solvent and resolving agent costs, while also saving equipment investment and energy consumption in the purification step. The entire process does not use any highly toxic reagents, and the wastewater discharge is reduced by 30% compared to existing technologies. The wastewater pollutant concentration is low and easy to treat, meeting national environmental protection requirements. It can be directly applied to the large-scale industrial production of moxifloxacin hydrochloride intermediates, and has significant economic value and social significance.

Claims

1. A method for preparing a diazabicyclic compound as shown in formula IIIa or IIIb, characterized in that: The preparation method of the compound shown in Formula IIIa includes the following steps: in a water-alcohol-ester ternary solvent system, the compound shown in Formula I is reacted with a resolving agent to form a salt, and the compound shown in Formula IIIa is directly obtained; the resolving agent is LN-acetylphenylalanine (the compound shown in Formula IIa). ； The preparation method of the compound shown in Formula IIIb includes the following steps: in a water-alcohol-ester ternary solvent system, the compound shown in Formula I is reacted with a resolving agent to form a salt, and the compound shown in Formula IIIb is directly obtained; the resolving agent is DN-acetylphenylalanine (the compound shown in Formula IIb). ； Wherein, the compound shown in Formula I is cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which is an enantiomeric mixture composed of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane.

2. The preparation method according to claim 1, characterized in that, In the water-alcohol-ester ternary solvent system, the volume ratio of water, alcohol solvent, and ester solvent is 1:3~8:2~5; the alcohol solvent is selected from one or more of methanol, ethanol, isopropanol, and n-butanol; the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, and n-butyl acetate.

3. The preparation method according to claim 1, characterized in that, The reaction feeding method is as follows: after the compound shown in Formula I is mixed evenly with the ternary solvent system, the resolving agent is added, and the mixture is stirred and heated to carry out the salt formation reaction.

4. The preparation method according to claim 1, characterized in that, The temperature of the salt formation reaction is 60~85℃; the reaction endpoint is determined by the formation of a homogeneous and transparent solution, and the reaction time is 1~4 hours.

5. The preparation method according to claim 1 or 3, characterized in that: The molar ratio of the compound shown in Formula I to the resolving agent is 1:0.6 to 1:1.1; the volume-to-mass ratio of the ternary solvent system to the compound shown in Formula I is 5 to 30 mL / g.

6. The preparation method according to claim 1, characterized in that, After the salt formation reaction is completed, a post-processing step is also included: the reaction solution is cooled to -5 to 25°C at a rate of 3 to 8°C / hour, crystallization is carried out for 2 to 18 hours, and the filter is used to obtain filter cake and filtrate; the filter cake is the target compound represented by formula IIIa or IIIb, which does not require further purification; the filtrate is used to recover the resolving agent.

7. The preparation method according to claim 6, characterized in that, The target compound obtained by filtration is mixed with water and a chlorinated hydrocarbon organic solvent, the pH of the system is adjusted to 9-12, the mixture is stirred and separated into layers, and the chlorinated hydrocarbon layer is distilled to dryness to obtain the compound shown in formula IVa or IVb. ； Among them, the compound shown in formula IVa is (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which is a key intermediate in the preparation of moxifloxacin hydrochloride.

8. The preparation method according to claim 6, characterized in that, The method for recovering the resolving agent is as follows: (1) Target compound related recovery: The target compound obtained by filtration is mixed with water and chlorinated hydrocarbon organic solvent, the pH of the system is adjusted to 9~12, the layers are stirred and separated, the pH of the aqueous layer is adjusted to 3~5 with acid, the resolving agent is precipitated, and the resolving agent is obtained by filtration and drying. (2) Filtrate recovery: After the solvent is recovered by vacuum distillation of the filtrate obtained by filtration, water and chlorinated hydrocarbon organic solvent are added, the pH is adjusted to 9-12, the layers are stirred and separated, the pH of the aqueous layer is adjusted to 3-5 with acid, the resolving agent is precipitated, and the resolving agent is obtained by filtration and drying. The chlorinated hydrocarbon organic solvent is selected from one or more of dichloromethane, trichloromethane, and 1,2-dichloroethane; the purity of the recovered resolving agent is ≥98%, and the total recovery rate is ≥95%.

9. The preparation method according to claim 8, characterized in that, The recovered resolving agent can be reused more than 5 times, with a resolving yield of ≥90% after each reuse and an optical purity of ≥99% ee for the product.

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