Preparation method of moxifloxacin side chain key intermediate

Abstract

The invention provides a preparation method of a moxifloxacin side chain key intermediate, and belongs to the technical field of medical intermediate production, and the preparation method comprises the following steps: firstly salifying a compound 1 and L-(+) tartaric acid in proportion, dissociating the precipitated solid to obtain a compound 3, concentrating the filtrate, and simply refining to obtain a compound 2 with ee value of 100%, and the single resolution yield is 39%. In addition, the compound 3 is subjected to racemization to obtain a compound 1, and then the compound 1 is split again; and the yield can reach 85% or above after repeated cyclic resolution. L-(+) tartaric acid is used for resolution, a product with a high ee value is obtained in combination with a simple refining process, the resolution yield is improved to a certain extent, and the production cost is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate production, and in particular to a method for preparing a key intermediate of a moxifloxacin side chain. Background Art

[0002] Moxifloxacin hydrochloride is a fourth-generation quinolone broad-spectrum antibacterial drug developed by Bayer, Germany. It kills bacteria by inhibiting the synthesis of bacterial DNA. The antibacterial mechanism is to interfere with topoisomerase II and IV. Topoisomerase is a key enzyme in controlling DNA topology and DNA replication, repair and transcription. The drug has a broad-spectrum antibacterial activity and has a relatively good antibacterial effect on a variety of bacteria including Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, mycoplasma, chlamydia, and Legionella.

[0003] Moxifloxacin side chain is a key intermediate in the synthesis of moxifloxacin; there are many reports on the synthesis of moxifloxacin side chain, mainly focusing on the construction of chiral centers, such as chemical resolution, chiral center-induced asymmetric reduction, heavy metal-catalyzed asymmetric reduction or bioenzymatic reduction.

[0004] At present, domestic and foreign manufacturers still use the original traditional process, using pyridine dicarboxylic acid as the starting material; through amination, hydrogenation, reduction, splitting, debenzylation and other process flows to obtain the side chain of moxifloxacin. Since the original process is splitting after amide reduction, the theoretical yield of splitting does not exceed 50%; and the other part of the split material cannot be racemized and split again; resulting in poor overall yield and high production costs.

[0005] At present, the existing study "Synthesis Research of Key Intermediates of Antibacterial New Drug Moxifloxacin" reported the splitting method of compound 1. The splitting reagent is D-tartaric acid, and water and ethanol are used as solvents. This method takes a long time to crystallize, and the crystallization process requires fine control; the solvent used in the splitting and freeing process contains a large amount of water, and the product is easily hydrolyzed. Moreover, the split enantiomers are in the mother liquor, and the ethanol and water need to be separated first, and then racemized with sodium methoxide, and the racemization yield is also low. The overall yield is not high, and it is difficult to industrialize.

[0006] Patent WO2013053281 discloses a chiral center-induced asymmetric reduction method, which uses R-phenylethylamine chiral-induced asymmetric reduction hydrogenation to prepare the moxifloxacin side chain. However, the product prepared by this method has a low ee value and is difficult to purify later.

[0007] CN10862358.3 and CN10869001.7 disclose a method for preparing a moxifloxacin side chain intermediate catalyzed by iridium / rhodium, wherein compound 1 undergoes an asymmetric hydrogenation reaction under iridium / rhodium catalysis to prepare compound 2. The method has the advantages of high conversion rate and good enantiomeric selectivity, but the price of heavy metal iridium or rhodium and chiral ligand is relatively expensive, and the ee value of the obtained compound is not high. Further column chromatography is required to obtain compound 2 with a higher ee value, and the industrial value is low.

[0008] CN10426222.5 and CN10639941.8 disclose a method of using a 3-pyrrolidone analog as a starting material to construct a chiral center under the action of a transaminase, and then obtaining a moxifloxacin side chain through subsequent ring closure and deprotection. The method has a short route and high chiral selectivity. However, the starting material market is not common, and transaminase is currently difficult to achieve industrial application.

[0009] Therefore, the above-mentioned chemical resolution, chiral center induced asymmetric reduction, heavy metal catalyzed asymmetric reduction and enzyme catalyzed asymmetric reduction methods all have the disadvantages of high production cost, low yield or difficult to obtain starting materials. Therefore, a preparation method with high single resolution yield, high product ee value, few by-products in the reaction process, high enantiomer recovery rate and high total yield of cyclic resolution is urgently needed to solve the above problems. Summary of the invention

[0010] In order to overcome the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing a key intermediate of the side chain of moxifloxacin, which uses L-(+) tartaric acid for splitting and combines with a simple refining process to obtain a product with a high ee value, and to a certain extent improves the splitting yield and reduces the production cost.

[0011] To achieve the above object, the present invention provides the following solutions:

[0012] A method for preparing a key intermediate of a moxifloxacin side chain, wherein the prepared key intermediate is (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine, and the reaction formula is as follows:

[0013]

[0014] The above reaction process comprises the following steps:

[0015] S1, adding compound 1 and L-(+) tartaric acid to a reaction kettle in proportion, then adding a reaction solvent to the reaction kettle, reacting at a specific reaction temperature, and finally filtering to obtain an initial filtrate and an initial filter cake, drying the initial filter cake, adding a free solvent, and adjusting the pH with an alkali to free the initial filter cake, washing with water, and concentrating the organic phase to obtain compound 3;

[0016] S2, adding hydrochloric acid to the initial filtrate obtained in step S1 for purification, filtering after precipitating solids to obtain an intermediate filtrate and an intermediate filter cake, drying the intermediate filter cake, adding a free solvent and adjusting the pH with alkali for freeing, washing with water, and concentrating the organic phase to obtain compound 1;

[0017] S3, evaporating the intermediate filtrate obtained in step S2 to dryness to obtain an oily substance, then adding a free solvent and adjusting the pH with a base to free it, washing with water, and concentrating the organic phase to obtain compound 2, i.e., the key intermediate (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine;

[0018] S4, adding compound 3 obtained in step S1, an organic solvent and a racemization agent into a high-pressure reactor, sealing the reactor and performing a racemization reaction at high temperature, cooling the reactor after the reaction is completed, adding concentrated hydrochloric acid, filtering the reactor to obtain a final filtrate and a final filter cake, drying the final filter cake, adding a free solvent, adjusting the pH with an alkali, washing the final filter cake with water, and concentrating the organic phase to obtain compound 1;

[0019] S5. After combining the compounds 1 obtained in step S2 and step S4, steps S1 to S4 are repeated again to cyclically prepare compound 2, i.e., the key intermediate (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine.

[0020] Preferably, in step S1, the molar ratio of compound 1 to L-(+) tartaric acid is 1:1 to 0.5.

[0021] Preferably, in step S1, the reaction solvent is one or more of tetrahydrofuran, ethanol and isopropanol.

[0022] Preferably, in step S1, compound 1 and L-(+) tartaric acid are added to a reaction kettle in proportion, and then a reaction solvent is added to the reaction kettle, and the reaction is carried out at a reaction temperature of 0 to 50° C. for 6 to 15 hours.

[0023] Preferably, in step S2, the weight ratio of compound 1 to concentrated hydrochloric acid is 1:0.2-1.

[0024] Preferably, in step S4, compound 3 obtained in step S1, an organic solvent and a racemization agent are added to a high-pressure reactor, which is sealed and subjected to a high-temperature racemization reaction at a reaction temperature of 80 to 140° C. for a reaction time of 1 to 6 h.

[0025] Preferably, in step S4, the organic solvent is one or more of toluene, xylene, methanol, ethanol, isopropanol, n-butanol, and tert-butanol.

[0026] Preferably, in step S4, the racemization reagent is one or more of phosphoric acid, sulfuric acid, and hydrochloric acid, and the weight volume ratio of the racemization reagent to compound 3 is 0.3 to 2:1.

[0027] Preferably, in steps S1 to S4, the free solvent is one or more of toluene, ethyl acetate, dichloromethane and chloroform.

[0028] Preferably, in steps S1 to S4, the free base used is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and triethylamine, and the adjusted pH is 7 to 10.

[0029] According to the specific embodiments provided by the present invention, the present invention discloses the following technical effects:

[0030] The invention provides a method for preparing a key intermediate of a side chain of moxifloxacin. L-(+) tartaric acid is used for reverse splitting to first split enantiomers, and then the mother liquor is subjected to simple post-treatment and purification to obtain a compound 2 with an ee value of 100%. The solvent used for splitting is an organic solvent, thereby avoiding a large amount of hydrolysis of the product in other splitting processes using water as a solvent or a mixed solvent with the participation of water, thereby improving the conversion rate. Meanwhile, dichloromethane is used as a solvent in the free process, and triethylamine is used as an organic base to adjust pH, thereby avoiding water residue in the pH adjustment process, thereby eliminating the risk of product hydrolysis. The racemization adopts a closed autoclave method, and compared with the prior art, the amount of phosphoric acid used is halved, thereby reducing the difficulty of post-treatment and improving the industrial value. Finally, the whole process of splitting-racemization-re-split is controlled, thereby reducing the probability of side reactions, improving the recovery efficiency of the product, and ensuring that the cyclic splitting yield can reach more than 85%. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0032] Figure 1 The present invention is a flow chart of a method for preparing a key intermediate of the side chain of moxifloxacin.

[0033] Figure 2 This is a diagram showing the chiral detection result of compound 2 prepared in Example 1;

[0034] Figure 3 This is a graph showing the purity test results of compound 2 prepared in step 1 of Example 1. DETAILED DESCRIPTION

[0035] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below with reference to the accompanying drawings and specific embodiments.

[0037] like Figure 1 As shown, the present invention provides a method for preparing a key intermediate of the side chain of moxifloxacin, and the prepared key intermediate is (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine, and the reaction formula is as follows:

[0038]

[0039] The above reaction process comprises the following steps:

[0040] S1, adding compound 1 and L-(+) tartaric acid to a reaction kettle in proportion, then adding a reaction solvent to the reaction kettle, reacting at a specific reaction temperature, and finally filtering to obtain an initial filtrate and an initial filter cake, drying the initial filter cake, adding a free solvent, and adjusting the pH with an alkali to free the initial filter cake, washing with water, and concentrating the organic phase to obtain compound 3;

[0041] S2, adding hydrochloric acid to the initial filtrate obtained in step S1 for purification, filtering after precipitating solids to obtain an intermediate filtrate and an intermediate filter cake, drying the intermediate filter cake, adding a free solvent and adjusting the pH with alkali for freeing, washing with water, and concentrating the organic phase to obtain compound 1;

[0042] S3, evaporating the intermediate filtrate obtained in step S2 to dryness to obtain an oily substance, then adding a free solvent and adjusting the pH with a base to dissociate it, washing with water, and concentrating the organic phase to obtain compound 2, that is, the key intermediate is (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine;

[0043] S4, adding compound 3 obtained in step S1, an organic solvent and a racemization agent into a high-pressure reactor, sealing the reactor and performing a racemization reaction at high temperature, cooling the reactor after the reaction is completed, adding concentrated hydrochloric acid, filtering the reactor to obtain a final filtrate and a final filter cake, drying the final filter cake, adding a free solvent, adjusting the pH with an alkali, washing the final filter cake with water, and concentrating the organic phase to obtain compound 1;

[0044] S5. After combining the compounds 1 obtained in step S2 and step S4, steps S1 to S4 are repeated again to cyclically prepare compound 2, that is, the key intermediate is (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine.

[0045] Wherein, in step S1, the molar ratio of compound 1 to L-(+) tartaric acid is 1:1 to 0.5. The reaction solvent is one or more of tetrahydrofuran, ethanol, and isopropanol. Compound 1 and L-(+) tartaric acid are added to a reaction kettle in proportion, and then the reaction solvent is added to the reaction kettle, and the reaction is carried out at a reaction temperature of 0 to 50° C. for 6 to 15 hours.

[0046] In addition, in step S2, the weight ratio of compound 1 to concentrated hydrochloric acid is 1:0.2-1. The synthetic routes of compound 2 and compound 3 are:

[0047]

[0048] In step S4, compound 3, an organic solvent and a racemization agent obtained in step S1 are added to a high-pressure reactor, which is sealed and subjected to a high-temperature racemization reaction. The reaction temperature is 80 to 140° C. and the reaction time is 1 to 6 hours. The organic solvent is one or more of toluene, xylene, methanol, ethanol, isopropanol, n-butanol and tert-butanol. The racemization agent is one or more of phosphoric acid, sulfuric acid and hydrochloric acid, and the weight-to-volume ratio of the racemization agent to compound 3 is 0.3 to 2:1. In the above steps, the free solvent is one or more of toluene, ethyl acetate, dichloromethane and chloroform. The free base used is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and triethylamine, and the adjusted pH is 7 to 10.

[0049] The features and performance of the present invention are further described in detail below with reference to specific embodiments. The process condition values ​​taken in the following embodiments are all exemplary, and the possible value ranges are as shown in the above content.

[0050] Example 1

[0051] Compound 1 (100 g, 40.93 mmol) was added to a 2L three-necked flask, and 1500 mL of a 95 / 5 tetrahydrofuran / ethanol mixed solvent was added. After stirring evenly at 25-30°C, L-(+) tartaric acid (30.71 g, 20.47 mmol) was added, and then the mixture was kept warm for 6 hours at 25-30°C. After the reaction, a white solid was precipitated, which was filtered and rinsed with ethanol. The filter cake was dried to obtain an off-white solid. Subsequently, 325 ml of dichloromethane was added to the white solid, and the mixture was stirred at room temperature to be evenly dispersed. Triethylamine was added dropwise to adjust the system pH to 7-8, and the reaction was stirred for 30 minutes after the pH stabilized. Wash with water (100 ml*3) and separate the liquids, collect the organic phase, and dry it with anhydrous sodium sulfate to obtain compound 3.

[0052] Add 60g of concentrated hydrochloric acid to the separated filtrate and react at 60-65℃ for 2h. Then cool to 25-30℃ and keep warm for 1h to crystallize. Filter and dry the filter cake to obtain an off-white solid. Add 145ml of dichloromethane to the off-white solid and stir at room temperature to disperse evenly. Add triethylamine dropwise to adjust the system pH to 7-8. Stir and react for 30min after the pH stabilizes. Wash with water (45ml*3) and separate the liquids. Collect the organic phase and dry it over anhydrous sodium sulfate to obtain compound 1.

[0053] The filtrate obtained by filtration in the above step was concentrated to obtain a viscous liquid, 325 ml of dichloromethane was added, and the mixture was stirred at room temperature to make it uniformly dispersed. Triethylamine was added dropwise to adjust the system pH to 7-8, and the reaction was stirred for 30 minutes after the pH stabilized. Wash with water (100 ml*3) and separate the liquids, collect the organic phase, dry it with anhydrous sodium sulfate, and evaporate it to obtain compound 2, with a yield of 38.56% and an ee value of 100%. The chiral detection results are as follows: Figure 2 As shown; the purity is 99.34%, the purity test results are as follows Figure 3 shown.

[0054] Example 2

[0055] Compound 1 (100 g, 40.93 mmol) was added to a 2L three-necked flask, followed by 1500 mL of a 90 / 10 tetrahydrofuran / ethanol mixed solvent. After stirring evenly at 25-30°C, L-(+) tartaric acid (30.71 g, 20.47 mmol) was added, and then the mixture was kept warm at 25-30°C for 6 h. After the reaction, a white solid was precipitated, filtered, rinsed with ethanol, and the filter cake was dried to obtain an off-white solid. 325 ml of dichloromethane was added to the white solid, stirred at room temperature to disperse evenly, triethylamine was added dropwise to adjust the system pH to 7-8, and the reaction was stirred for 30 min after the pH stabilized. Wash with water (100 ml*3) and separate the liquids, collect the organic phase, and dry it over anhydrous sodium sulfate to obtain compound 3.

[0056] Add 60g of concentrated hydrochloric acid to the separated filtrate and react at 60-65℃ for 2h. Then cool to 25-30℃ and keep warm for 1h to crystallize. Filter and dry the filter cake to obtain an off-white solid. Add 145ml of dichloromethane to the off-white solid and stir at room temperature to disperse evenly. Add triethylamine dropwise to adjust the system pH to 7-8. Stir and react for 30min after the pH stabilizes. Wash with water (45ml*3) and separate the liquids. Collect the organic phase and dry it over anhydrous sodium sulfate to obtain compound 1.

[0057] The filtrate obtained by filtration in the above step was concentrated to obtain a viscous liquid, 325 ml of dichloromethane was added, and the mixture was stirred at room temperature to be uniformly dispersed. Triethylamine was added dropwise to adjust the system pH to 7-8, and the reaction was stirred for 30 minutes after the pH stabilized. The mixture was washed with water (100 ml*3) and separated, and the organic phase was collected and dried over anhydrous sodium sulfate to obtain compound 2, with a yield of 35.32%, an ee value of 100%, and a purity of 99.31%.

[0058] Example 3

[0059] Take compound 1 (100g, 40.93mmol) and add it to a 2L three-necked flask, then add 1500mL of tetrahydrofuran. After stirring at 25-30°C, add L-(+) tartaric acid (30.71g, 20.47mmol), and then keep warm at 25-30°C for 6h. After the reaction is completed, a white solid is precipitated, which is filtered and rinsed with ethanol, and the filter cake is dried to obtain an off-white solid. Add 325ml of dichloromethane to the white solid, stir at room temperature to make it evenly dispersed, add triethylamine dropwise to adjust the system pH to 7-8, and stir the reaction for 30min after the pH stabilizes. Wash with water (100ml*3) and separate the liquids, collect the organic phase, and evaporate it to dryness over anhydrous sodium sulfate to obtain compound 3.

[0060] Add 60g of concentrated hydrochloric acid to the separated filtrate and react at 60-65℃ for 2h. Then cool to 25-30℃ and keep warm for 1h to crystallize. Filter and dry the filter cake to obtain an off-white solid. Add 145ml of dichloromethane to the off-white solid and stir at room temperature to disperse evenly. Add triethylamine dropwise to adjust the system pH to 7-8. Stir and react for 30min after the pH stabilizes. Wash with water (45ml*3) and separate the liquids. Collect the organic phase and dry it over anhydrous sodium sulfate to obtain compound 1.

[0061] The filtrate obtained by the above step was concentrated to obtain a viscous liquid, 325 ml of dichloromethane was added, and the mixture was stirred at room temperature to make it uniformly dispersed. Triethylamine was added dropwise to adjust the pH of the system to 7-8, and the reaction was stirred for 30 minutes after the pH stabilized. The mixture was washed with water (100 ml*3) and separated, and the organic phase was collected and dried over anhydrous sodium sulfate to obtain compound 2, with a yield of 39.05%, an ee value of 100%, and a purity of 97.32%.

[0062] Example 4

[0063] Compound 1 (100 g, 40.93 mmol) was added to a 2L three-necked flask, followed by 1500 mL of a 1 / 1 tetrahydrofuran / isopropanol mixed solvent. After stirring at 25-30°C, L-(+) tartaric acid (30.71 g, 20.47 mmol) was added, and then the mixture was kept warm at 25-30°C for 6 h. After the reaction, a white solid was precipitated, filtered, rinsed with ethanol, and the filter cake was dried to obtain an off-white solid. 325 ml of dichloromethane was added to the white solid, stirred at room temperature to disperse evenly, triethylamine was added dropwise to adjust the system pH to 7-8, and the reaction was stirred for 30 min after the pH stabilized. Wash with water (100 ml*3) and separate the liquids, collect the organic phase, and dry it over anhydrous sodium sulfate to obtain compound 3.

[0064] Add 60g of concentrated hydrochloric acid to the separated filtrate and react at 60-65℃ for 2h. Then cool to 25-30℃ and keep warm for 1h to crystallize. Filter and dry the filter cake to obtain an off-white solid. Add 145ml of dichloromethane to the off-white solid and stir at room temperature to disperse evenly. Add triethylamine dropwise to adjust the system pH to 7-8. Stir and react for 30min after the pH stabilizes. Wash with water (45ml*3) and separate the liquids. Collect the organic phase and dry it over anhydrous sodium sulfate to obtain compound 1.

[0065] The filtrate obtained by the above step was concentrated to obtain a viscous liquid, 325 ml of dichloromethane was added, and the mixture was stirred at room temperature to be evenly dispersed. Triethylamine was added dropwise to adjust the pH of the system to 7-8, and the reaction was stirred for 30 minutes after the pH stabilized. The mixture was washed with water (100 ml*3) and separated, and the organic phase was collected and dried over anhydrous sodium sulfate to obtain compound 2, with a yield of 36.95%, an ee value of 100%, and a purity of 95.94%.

[0066] The synthetic route for preparing compound 1 by racemization of compound 3 is as follows:

[0067]

[0068] Example 5

[0069] Add 1000mL of isopropanol and compound 3 (100g, 40.93mmol) to a 2L autoclave and stir to dissolve. Then add 50mL of phosphoric acid, stir and heat the reaction system to 130±5℃ in a closed environment, and stir and react for 3h. Then cool to 70±5℃, add concentrated hydrochloric acid (60g), and continue to stir and heat at 70±5℃ for 1h. Then cool to 0-5℃ and keep warm for crystallization for 1h, filter, rinse with isopropanol (100mL*3), and then dry in a blast drying oven at 45±5℃ to obtain an off-white solid.

[0070] Add 500mL of chloroform and off-white solid into a 1000mL reaction bottle, stir and disperse evenly, then adjust the pH to 7-8 with triethylamine, and stir and react at room temperature for 30 minutes after the pH stabilizes. Wash with water (200ml*3) and separate the liquids, collect the organic phase, and dry it with anhydrous sodium sulfate to obtain compound 1. The yield is 85.84% and the purity is 99.44%. The sample is continuously split in a cycle, and the comprehensive yield after 4 cycles of splitting is about 82%.

[0071] Example 6

[0072] Add 1000mL of tert-butyl alcohol and compound 3 (100g, 40.93mmol) to a 2L autoclave and stir to dissolve. Then add 50mL of phosphoric acid, stir in a closed environment, and heat the reaction system to 130±5℃, keep stirring and react for 3h. Then cool to 70±5℃, add concentrated hydrochloric acid (60g), and continue to keep stirring at 70±5℃ for 1h. Then cool to 0-5℃ and keep crystallizing for 1h, filter, rinse with isopropanol (100mL*3), and dry in a blast drying oven at 45±5℃ to obtain an off-white solid.

[0073] Add 500mL of chloroform and off-white solid into a 1000mL reaction bottle, stir and disperse evenly, then adjust the pH to 7-8 with triethylamine, and stir and react at room temperature for 30 minutes after the pH stabilizes. Wash with water (200ml*3) and separate the liquids, collect the organic phase, and dry it with anhydrous sodium sulfate to obtain compound 1. The yield is 90.95% and the purity is 98.99%. The sample is continuously split in a cycle, and the comprehensive yield after 4 cycles of splitting is about 85%.

[0074] Example 7

[0075] Add 1000mL of tert-butyl alcohol and compound 3 (100g, 40.93mmol) to a 2L autoclave and stir to dissolve. Then add 50mL of phosphoric acid, stir in a closed environment, and heat the reaction system to 120±5℃, keep stirring and react for 3h. Then cool to 70±5℃, add concentrated hydrochloric acid (60g), and continue to keep stirring at 70±5℃ for 1h. Then cool to 0-5℃ and keep crystallizing for 1h, filter, rinse with isopropanol (100mL*3), and dry in a blast drying oven at 45±5℃ to obtain an off-white solid.

[0076] Add 500mL of chloroform and off-white solid into a 1000mL reaction bottle, stir and disperse evenly, then adjust the pH to 7-8 with triethylamine, and stir and react at room temperature for 30 minutes after the pH stabilizes. Wash with water (200ml*3) and separate the liquids, collect the organic phase, and dry it with anhydrous sodium sulfate to obtain compound 1. The yield is 88.56% and the purity is 98.35%. The sample is continuously split in a cycle, and the comprehensive yield after 4 cycles of splitting is about 84%.

[0077] Therefore, a method for preparing a key intermediate of the side chain of moxifloxacin is adopted, L-(+) tartaric acid is used for splitting, and a product with a high ee value is obtained in combination with a simple refining process, and the splitting yield is improved to a certain extent, and the production cost is reduced.

[0078] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0079] The principles and implementation methods of the present invention are described in this article using specific examples. The description of the above embodiments is only used to help understand the method and core idea of ​​the present invention. At the same time, for those skilled in the art, according to the idea of ​​the present invention, there will be changes in the specific implementation methods and application scope. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A method for preparing a key intermediate of the side chain of moxifloxacin, characterized in that: The key intermediate prepared is (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine, and the reaction formula is as follows: The above reaction process comprises the following steps: S1, adding compound 1 and L-(+) tartaric acid to a reaction kettle in proportion, then adding a reaction solvent to the reaction kettle, reacting at a specific reaction temperature, and finally filtering to obtain an initial filtrate and an initial filter cake, drying the initial filter cake, adding a free solvent, and adjusting the pH with an alkali to free the initial filter cake, washing with water, and concentrating the organic phase to obtain compound 3; S2, adding hydrochloric acid to the initial filtrate obtained in step S1 for purification, filtering after precipitating solids to obtain an intermediate filtrate and an intermediate filter cake, drying the intermediate filter cake, adding a free solvent and adjusting the pH with alkali for freeing, washing with water, and concentrating the organic phase to obtain compound 1; S3, evaporating the intermediate filtrate obtained in step S2 to dryness to obtain an oily substance, then adding a free solvent and adjusting the pH with a base to free it, washing with water, and concentrating the organic phase to obtain compound 2, i.e., the key intermediate (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine; S4, adding compound 3 obtained in step S1, an organic solvent and a racemization agent into a high-pressure reactor, sealing the reactor and performing a racemization reaction at high temperature, cooling the reactor after the reaction is completed, adding concentrated hydrochloric acid, filtering the reactor to obtain a final filtrate and a final filter cake, drying the final filter cake, adding a free solvent, adjusting the pH with an alkali, washing the final filter cake with water, and concentrating the organic phase to obtain compound 1; S5. After combining the compounds 1 obtained in step S2 and step S4, steps S1 to S4 are repeated again to cyclically prepare compound 2, i.e., the key intermediate (R, S) 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine.

2. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 1, characterized in that: In step S1, the molar ratio of compound 1 to L-(+) tartaric acid is 1:1 to 0.

5.

3. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 2, characterized in that: In step S1, the reaction solvent is one or more of tetrahydrofuran, ethanol, and isopropanol.

4. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 3, characterized in that: In step S1, compound 1 and L-(+) tartaric acid are added to a reaction kettle in proportion, and then a reaction solvent is added to the reaction kettle, and the reaction is carried out at a reaction temperature of 0 to 50° C. for 6 to 15 hours.

5. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 1, characterized in that: In step S2, the weight ratio of compound 1 to concentrated hydrochloric acid is 1:0.2-1.

6. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 1, characterized in that: In step S4, compound 3 obtained in step S1, an organic solvent and a racemization reagent are added to a high-pressure reactor, which is sealed and subjected to a high-temperature racemization reaction at a reaction temperature of 80 to 140° C. for a reaction time of 1 to 6 hours.

7. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 6, characterized in that: In step S4, the organic solvent is one or more of toluene, xylene, methanol, ethanol, isopropanol, n-butanol, and tert-butanol.

8. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 7, characterized in that: In step S4, the racemization reagent is one or more of phosphoric acid, sulfuric acid, and hydrochloric acid, and the weight volume ratio of the racemization reagent to compound 3 is 0.3 to 2:

1.

9. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 1, characterized in that: In steps S1 to S4, the free solvent is one or more of toluene, ethyl acetate, dichloromethane, and chloroform.

10. The method for preparing a key intermediate of the side chain of moxifloxacin according to claim 9, characterized in that: In steps S1 to S4, the free base used is one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and triethylamine, and the adjusted pH is 7 to 10.

Images