Green synthesis method of moxifloxacin hydrochloride

Abstract

The invention discloses a green synthesis method of moxifloxacin hydrochloride, which comprises the following steps: under a heating condition, reacting moxifloxacin cyclization ester with moxifloxacin ((S, S)-2, 8-diazabicyclo [4, 3, 0] nonane) in a solvent, alkali and catalyst system to obtain moxifloxacin ester, and then carrying out hydrolysis one-pot method in an acidic system to obtain the moxifloxacin hydrochloride. The moxifloxacin hydrochloride is directly prepared. The invention provides a green synthesis method of moxifloxacin hydrochloride. According to the green synthesis method, moxifloxacin is obtained through direct reaction of moxixane cyclization ester and moxixane. According to the method, the moxifloxacin serving as a target product is synthesized by taking the moxixane cyclization ester as a raw material without forming a chelate compound with boric acid ester and directly reacting with the moxixane through a one-pot method, no three wastes are generated in the preparation process, and the method has the advantages of short reaction steps, mild conditions, high yield and the like.

Description

Technical Field

[0001] This invention relates to a green synthesis method for preparing moxifloxacin hydrochloride in the pharmaceutical field, specifically, to a green synthesis method for moxifloxacin hydrochloride. Background Technology

[0002] Moxifloxacin hydrochloride was developed by Bayer and is currently marketed in more than 90 countries and regions, including the United States, Germany, and other EU countries, under the brand name Avell. Moxifloxacin hydrochloride sodium oxide injection was launched in the United States in 2001 and in China in 2004, with a dosage of 400mg (moxifloxacin) / 250ml. To date, it has been marketed in more than 40 countries and regions, including the United States, Germany, and other EU countries.

[0003] As a fourth-generation, broad-spectrum quinolone anti-infective drug, it is used to treat adults with upper and lower respiratory tract infections, such as acute sinusitis, acute exacerbations of chronic bronchitis, community-acquired pneumonia, and skin and soft tissue infections.

[0004] As of the end of 2022, the global market size for moxifloxacin hydrochloride reached approximately US$4.5 billion, and is projected to grow to around US$5.2 billion by 2027, at a compound annual growth rate (CAGR) of approximately 3%. In 2022, national sales reached 50 million units, a year-on-year increase of 8.7%, with a market size of approximately RMB 1.5 billion. It is projected that by 2027, the market size will exceed RMB 6 billion, with a CAGR of approximately 5.2% during this period.

[0005] Currently, there are two main synthetic methods for moxifloxacin reported in the literature. One method is the chelation method, which involves reacting the moxifloxacin core with a chelating agent to form a chelate. The resulting chelate introduces an electron-withdrawing group, causing electron cloud transfer and improving the selectivity of the reaction. Specifically, the moxifloxacin ester core forms a chelate, increasing the reactivity of the fluorine at the 7-position of the benzene ring, thereby allowing it to add to the side-chain moxifloxacin ring to generate the moxifloxacin derivative. This method has good reaction selectivity, is easy to scale up, and has stable processes, making it the mainstream reaction preparation process. The chelation method process route is as follows: .

[0006] The disadvantages of this synthesis method are that the process is relatively long, generates a large amount of waste, and has a low yield, which puts great pressure on environmental protection.

[0007] Another preparation method is the non-chelation method. This method does not form chelates and directly reacts with the side chain to prepare moxifloxacin hydrochloride. The non-chelation method process route is as follows: .

[0008] In the non-chelation synthetic route, the 7-position fluorine on the benzene ring of the moxifloxacin ester is not activated and cannot preferentially participate in the reaction. The 6- and 7-position fluorine produced in the reaction process react with the moxifloxacin side chain ring to generate the moxifloxacin isomer. The reaction yield is low and the product quality cannot meet the requirements of pharmaceutical quality.

[0009] Examples of specific preparation routes for moxifloxacin reported in existing literature are as follows.

[0010] Example 1. Bayer disclosed a synthetic route in its original patents EP1998007237 and EP0550903, using quinoline carboxylic acid as the starting material and reacting it directly with moxicillin. The preparation route is as follows: .

[0011] Synthesized via this route, the overall yield is only 42%-46% (based on quinoline carboxylic acid). The process uses relatively reactive potassium tert-butoxide reagent, the reaction conditions are harsh and the steps are cumbersome, there are many side reactions, and purification is difficult. From the perspective of yield and quality, this route is not competitive enough.

[0012] Example 2. Chinese Patent CN104230924A discloses a preparation route for moxifloxacin hydrochloride, which uses quinoline carboxylic acid and a small-ring side-chain compound of moxifloxacin as raw materials. First, quinoline carboxylic acid is chelated and then condensed in acetonitrile, followed by deprotection to obtain moxifloxacin hydrochloride. The preparation route is as follows: .

[0013] However, this route has low reaction selectivity (generating a larger number of 6-position substituted isomers), and purification by column chromatography is required after the reaction, which is too costly and inefficient. Therefore, this route is not very meaningful for industrial scale-up.

[0014] Example 3. Patent WO2008059521 reports the use of quinolinonitrile as a raw material, which undergoes a condensation reaction with a small ring of moxifloxacin (or a small ring derivative protected at the 8-position). After hydrolysis and salt formation, moxifloxacin hydrochloride is obtained. The main reaction route involved is as follows: .

[0015] The starting material quinoline nitrile in this process route is rare and expensive, making it much more costly and unsuitable for industrialization. The subsequent hydrolysis is not easy to complete, posing a risk of impurities and presenting significant challenges for industrialization.

[0016] Example 4. Zhejiang Guobang's patent CN111777632 reports the synthesis of moxifloxacin hydrochloride chelate by reacting moxifloxacin cyclase with trimethyl borate in an acetic acid system under heating. Following an addition reaction, the moxifloxacin compound is obtained by deboronization. The reaction route is as follows: .

[0017] In the subsequent acid hydrolysis process of this synthesis method, the borate chelate exhibits incomplete deesterification, which significantly affects the quality of the product.

[0018] Example 5. Patent CN110194767A describes a process that uses Lewis acids to enhance the activity of the fluorine at the 7-position of moxicyclo ester, thereby improving selectivity and conversion. The content of the R isomer in the process is approximately 3%-5%. The process involves purifying the intermediate into tartrate crystals to reduce the content of the 6-position substituted isomer impurity. The synthetic route is as follows: .

[0019] Although this process reduces the number of components, the quenching treatment using Lewis acids such as aluminum trichloride generates a large amount of waste residue and wastewater. Furthermore, the separation and purification of intermediates are achieved through repeated neutralization with ammonia to adjust the solution pH. In addition, the excessively high content of the 6-position byproduct in the process severely impacts the quality of moxifloxacin.

[0020] In conclusion, developing a green method for preparing moxifloxacin with low energy consumption, low waste, and high yield is of great significance. Summary of the Invention

[0021] The purpose of this invention is to provide a green method for preparing moxifloxacin hydrochloride. In view of the shortcomings of the prior art, this method has the advantages of short process route, simple operation, low cost, green and environmentally friendly, mild conditions, and good yield. It can be used to solve the technical problems of industrial waste, excessively long process route and high cost in the preparation of moxifloxacin in the prior art.

[0022] To achieve the above objectives, the present invention provides a green synthesis method for moxifloxacin hydrochloride. In this method, under heating conditions, moxifloxacin cyclase and moxifloxacin ring are reacted in a solvent, alkali and catalyst system to obtain moxifloxacin ester, and then moxifloxacin hydrochloride is directly prepared by a one-pot hydrolysis method under acidic conditions.

[0023] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses moxifloxacin cyclase as ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate or methyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate; and moxifloxacin small ring is (S,S)-2,8-diazabicyclo[4,3,0]nonane.

[0024] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses a molar ratio of moxifloxacin cyclic ester to moxifloxacin ring of 1.0 to 3.0.

[0025] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses a molar ratio of 1.0 to 1.5 for moxifloxacin cyclic ester and moxifloxacin small ring.

[0026] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses a polar aprotic solvent as the solvent, which includes any one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, dichloroethane, dimethyl sulfoxide, acetonitrile, and chloroform.

[0027] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses an organic amine as the base, including any one or more combinations of triethylamine, diisopropylethylamine, and n-propylamine.

[0028] The above-mentioned green synthesis method for moxifloxacin hydrochloride uses a catalyst comprising any one or more combinations of lithium chloride, lithium bromide, lithium fluoride, lithium carbonate, potassium fluoride, and sodium fluoride.

[0029] The above-mentioned green synthesis method for moxifloxacin hydrochloride, wherein the heating conditions in the method are in the temperature range of 30~120℃.

[0030] The above-mentioned green synthesis method for moxifloxacin hydrochloride involves directly adding hydrochloric acid to an acidic system to prepare moxifloxacin hydrochloride in a one-pot process.

[0031] The above-mentioned green synthesis method for moxifloxacin hydrochloride, wherein the reaction formula for preparing moxifloxacin hydrochloride in the method is as follows: .

[0032] The present invention also provides the use of the above-mentioned green synthesis method of moxifloxacin hydrochloride in the preparation of quinolone drugs.

[0033] The green synthesis method for moxifloxacin hydrochloride provided by this invention has the following advantages: This invention directly uses simple and inexpensive moxifloxacin ester as a raw material, eliminating the need for reaction with boron chelating agents to form chelates. Moxifloxacin hydrochloride is synthesized in a one-pot process with moxifloxacin small rings. This method overcomes the shortcomings of traditional processes. It addresses the issues of existing technologies requiring a 5-10 times acetic acid system for boron reagent preparation, quenching and washing the chelate with 20-30 times more water after chelate formation, and the need for drying before the next coupling reaction. Furthermore, the subsequent acid hydrolysis process often results in incomplete deesterification of the boron ester chelate, affecting product quality.

[0034] This invention enables the one-step synthesis of moxifloxacin hydrochloride, which has advantages over existing industrial synthesis methods, including being environmentally friendly, having a short reaction time, mild conditions, and high yield. Attached Figure Description

[0035] Figure 1 This is an HPLC detection result of the coupling reaction solution during the preparation of the green synthesis method of moxifloxacin hydrochloride of the present invention.

[0036] Figure 2 The HPLC detection results of the reaction for preparing moxifloxacin hydrochloride using the green synthesis method of moxifloxacin hydrochloride of the present invention are shown in the figure. Detailed Implementation

[0037] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings. These drawings are only for illustrating the embodiments of the present disclosure and are not intended to limit the scope of the disclosure.

[0038] The present invention provides a green synthesis method for moxifloxacin hydrochloride. The method involves reacting moxifloxacin cyclase and moxifloxacin ring under heating conditions in a solvent, alkali and catalyst system to obtain moxifloxacin ester, and then directly preparing moxifloxacin hydrochloride by a one-pot hydrolysis method under acidic conditions.

[0039] Preferably, the moxicycloester used in this method is ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate or methyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate; and the moxi small ring is (S,S)-2,8-diazabicyclo[4,3,0]nonane.

[0040] More preferably, the molar ratio of moxicyclo ester to moxicyclotinus ring used in this method is 1.0 to 3.0.

[0041] More preferably, the molar ratio of moxicyclopentadiene and moxicyclopentadiene is 1.0 to 1.5.

[0042] In this method, the solvent used is a polar aprotic reagent, including any one or more combinations of solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, dichloroethane, dimethyl sulfoxide (DMSO), acetonitrile, and chloroform (trichloromethane).

[0043] Further preferred are any one or a combination of solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and DMSO.

[0044] In this method, the base used is an organic amine, including any one or a combination of triethylamine, N,N-diisopropylethylamine (DIPEA), n-propylamine, etc.

[0045] The catalyst used in this method includes any one or more combinations of lithium chloride, lithium bromide, lithium fluoride, lithium carbonate, potassium fluoride, and sodium fluoride.

[0046] Further preferred are any one or a combination of lithium salts such as lithium chloride, lithium bromide, and lithium fluoride.

[0047] In this method, the temperature range for heating conditions is 30~120℃.

[0048] More preferably, the heating temperature is 60~120℃.

[0049] In this method, hydrochloric acid is directly added to an acidic system to prepare moxifloxacin hydrochloride in a one-pot process.

[0050] One-pot synthesis is an organic synthesis method. The multi-step reaction in one-pot synthesis can start from relatively simple and readily available raw materials, and directly obtain structurally complex molecules without the separation of intermediates. It is more advantageous in terms of economy and environmental friendliness.

[0051] In this method, moxifloxacin hydrochloride is prepared by heating moxifloxacin cyclase and moxifloxacin ring under catalytic and alkaline conditions, followed by one-pot acidification. The specific reaction equation is shown below: .

[0052] This invention directly synthesizes moxifloxacin hydrochloride from simple and inexpensive moxifloxacin ester and moxifloxacin ring as raw materials, and obtains the target product by adding hydrochloric acid to the reaction system for hydrolysis.

[0053] This invention also provides the use of the green synthesis method of moxifloxacin hydrochloride in the preparation of quinolone drugs.

[0054] To make the inventive objectives, technical solutions, and beneficial effects of this application clearer, the green synthesis method of moxifloxacin hydrochloride provided by this invention will be further described below with reference to embodiments.

[0055] It should be understood that the embodiments described are for illustrative purposes only and are not intended to limit the scope of the application. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and those skilled in the art can easily understand other advantages and effects of this application from the content disclosed in this description.

[0056] Example 1 Moxifloxacin was obtained by reacting moxifloxacin cyclohexyl ester (1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester) with moxifloxacin small ring ((S,S)-2,8-diazabicyclo[4,3,0]nonane) by heating and then directly acidifying and hydrolyzing.

[0057] The specific process is as follows: Under a nitrogen atmosphere, moxifloxacin ethyl ester (32.3 g, 0.1 mol) and moxifloxacin ring (12.7 g, 0.1 mol) were added to a reaction flask containing 325 mL of dichloromethane. Then, triethylamine (10.2 g, 0.1 mol) and lithium bromide (8.65 g, 0.1 mol) were added sequentially. The reaction solution was heated to reflux, preferably at 80-90 °C. After reacting for 4 hours, the coupling reaction solution was detected by HPLC to confirm that the reaction was complete. Then, 30 mL (0.36 mL) of concentrated hydrochloric acid was added dropwise to the reaction system. The reaction temperature was preferably at 60-80 °C. After refluxing for another 4 hours, the reaction was stopped and cooled to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was collected to obtain the crude product, moxifloxacin hydrochloride, which was then analyzed by HPLC.

[0058] The reaction equation is shown below: .

[0059] The molar yield of moxifloxacin hydrochloride was 85.5%, and the purity was 99.63%.

[0060] For the automated scale chromatogram of the coupling reaction solution obtained by HPLC (High Performance Liquid Chromatography), please refer to [link to relevant documentation]. Figure 1 The peak results data in the figure are shown in Table 1 below.

[0061] Table 1. HPLC peak detection results of the coupling reaction solution.

[0062] The automated scale chromatogram for the HPLC detection of moxifloxacin hydrochloride is shown below. Figure 2 The peak results data in the figure are shown in Table 2 below.

[0063] Table 2. HPLC peak detection results of moxifloxacin hydrochloride reaction.

[0064] Example 2 Under a nitrogen atmosphere, 32.3 g (0.1 mol) of moxifloxacin ethyl ester and 12.7 g (0.1 mol) of moxifloxacin ring were added to a reaction flask containing 325 ml of tetrahydrofuran. Then, triethylamine (10.2 g, 0.1 mol) and lithium chloride (4.25 g, 0.1 mol) were added sequentially. The reaction solution was heated to reflux, preferably at 80-100 °C. After reacting for 4 hours, the reaction was checked to be complete. Then, 30 ml (0.36 ml) of concentrated hydrochloric acid was added dropwise to the reaction system. The reaction temperature was preferably at 50-70 °C. After continuing to reflux for 4 hours, the reaction was stopped and cooled to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was collected to obtain crude moxifloxacin hydrochloride.

[0065] The molar yield of the obtained moxifloxacin hydrochloride was 80.5%, and the purity was 99.1%.

[0066] Example 3 Under a nitrogen atmosphere, moxifloxacin methyl ester (32.3 g, 0.1 mol) and moxifloxacin ring (12.7 g, 0.1 mol) were added to a reaction flask containing 325 ml of chloroform. Then, diisopropylethylamine (12.9 g, 0.1 mol) and lithium fluoride (2.59 g, 0.1 mol) were added sequentially. The reaction solution was heated to reflux, preferably at 90-120 °C. After reacting for 4 hours, the reaction was checked to be complete. Then, 30 ml (0.36 ml) of concentrated hydrochloric acid was added dropwise to the reaction system. The reaction temperature was preferably at 80-90 °C. After continuing to reflux for 4 hours, the reaction was stopped and cooled to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was collected to obtain crude moxifloxacin hydrochloride.

[0067] The molar yield of the obtained moxifloxacin hydrochloride was 82.5%, and the purity was 99.2%.

[0068] Example 4 Under a nitrogen atmosphere, 30.9 g (0.1 mol) of moxifloxacin ethyl ester and 12.7 g (0.1 mol) of moxifloxacin ring were added to a reaction flask containing 325 ml of N,N-dimethylformamide. Then, triethylamine (10.2 g, 0.1 mol) and potassium fluoride (5.85 g, 0.1 mol) were added sequentially. The reaction solution was heated to 70-90 °C and reacted for 4 hours. After the reaction was confirmed to be complete, 30 ml (0.36 ml) of concentrated hydrochloric acid was added dropwise to the reaction system. The reaction was continued to be refluxed at 60-80 °C for 4 hours. The reaction was then stopped and cooled to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was collected to obtain crude moxifloxacin hydrochloride.

[0069] The reaction equation is shown below: .

[0070] The molar yield of the obtained moxifloxacin hydrochloride was 85.5%, and the purity was 99.5%.

[0071] Example 5 Under a nitrogen atmosphere, moxifloxacin methyl ester (30.9 g, 0.1 mol) and moxifloxacin ring (12.7 g, 0.1 mol) were added to a reaction flask containing 325 ml of N,N-dimethylacetamide. Then, n-propylamine (5.91 g, 0.1 mol) and sodium fluoride (4.2 g, 0.1 mol) were added sequentially. The reaction solution was heated to 30-80 °C and reacted for 4 hours. After the reaction was confirmed to be complete, 30 ml (0.36 ml) of concentrated hydrochloric acid was added dropwise to the reaction system. The reaction was continued to be refluxed at 40-60 °C for 4 hours. The reaction was then stopped and cooled to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. The filter cake was collected to obtain crude moxifloxacin hydrochloride.

[0072] The molar yield of the obtained moxifloxacin hydrochloride was 81.5%, and the purity was 99.4%.

[0073] The green synthesis method of moxifloxacin hydrochloride provided by this invention is a green synthesis method of moxifloxacin hydrochloride that the inventors discovered through extensive exploration and research, and completed this application based on this method.

[0074] This invention involves reacting moxifloxacin cyclohexyl ester (ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate or methyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate) with moxifloxacin ring ((S,S)-2,8-diazabicyclo[4,3,0]nonane) under catalytic and alkaline conditions, followed by direct acidification and hydrolysis to obtain moxifloxacin. In other words, moxifloxacin hydrochloride is obtained through a one-pot acidification process. This method uses moxifloxacin cyclohexyl ester directly as a raw material, eliminating the need for chelation with borate esters, and directly reacting with the moxifloxacin ring to obtain the target product in a one-pot manner. This invention synthesizes moxifloxacin in a one-pot process, generating no waste, and has advantages such as a short process route, simple operation, low cost, environmental friendliness, mild conditions, and good yield. It can be used to solve problems in existing technologies.

[0075] Although the present invention has been described in detail through the preferred embodiments above, it should be understood that the above description should not be considered as a limitation of the present invention. Various modifications and substitutions to the present invention will be apparent to those skilled in the art after reading the above description. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A green process for the synthesis of moxifloxacin hydrochloride, characterized in that, The method is to react the moxifloxacin cyclic ester and the moxifloxacin small ring in a solvent, a base and a catalyst system under heating conditions to obtain the moxifloxacin ester, and then directly prepare the moxifloxacin hydrochloride by hydrolysis one-pot method under an acid system.

2. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 1 wherein, The method adopts the moxifloxacin cyclic ester as 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester or 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl ester, and the moxifloxacin small ring as (S,S)-2,8-diazabicyclo[4,3,0]nonane.

3. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 2 wherein, The method adopts the moxifloxacin cyclic ester and the moxifloxacin small ring in a molar ratio of 1.0-3.

0.

4. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 3 wherein, The method adopts the moxifloxacin cyclic ester and the moxifloxacin small ring in a molar ratio of 1.0-1.

5.

5. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 1 wherein, The method adopts the solvent as a polar aprotic solvent, which comprises any one or a combination of multiple of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, methyl tetrahydrofuran, dichloromethane, dichloroethane, dimethyl sulfoxide, acetonitrile, chloroform solvent. ​ 6. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 1 wherein, The method adopts the base as an organic amine, which comprises any one or a combination of multiple of triethylamine, diisopropylethylamine, n-propylamine.

7. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 1 wherein, The method adopts the catalyst comprising any one or a combination of multiple of lithium chloride, lithium bromide, lithium fluoride, lithium carbonate, potassium fluoride, sodium fluoride.

8. The process for green synthesis of moxifloxacin hydrochloride as claimed in claim 1 wherein, In the method, the temperature range of the heating condition is 30-120 DEG C.

9. The process for green synthesis of moxifloxacin hydrochloride as claimed in any one of the claims 1 to 8 wherein, In the method, the acid system is directly added with hydrochloric acid to prepare the moxifloxacin hydrochloride by one-pot method.

10. The green synthesis method of moxifloxacin hydrochloride as described in claim 9, characterized in that, In the method, the reaction formula for preparing the moxifloxacin hydrochloride is shown as follows: 。

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