Preparation methods and applications of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione

Abstract

This invention relates to a method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione and its application. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione involves reacting (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane in an organic solvent under blue light irradiation with the aid of a photosensitizer and an oxidizing agent to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. This preparation method not only has mild reaction conditions, short reaction time, simple operation, and environmental friendliness, but also has high product conversion rate and good selectivity. It can be used for large-scale industrial production and can be better applied to the synthesis of moxifloxacin, thereby improving the utilization rate of raw materials in the synthesis of moxifloxacin.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione and its application. Background Technology

[0002] Moxifloxacin, chemically named 1-cyclopropyl-7-{(S,S)-2,8-diazo-bicyclo[4.3.0]nonyl-8-yl}-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, has the molecular formula C2. 21 H 24 FN3O4 is a fourth-generation quinolone antibiotic, mainly used clinically to treat acute bacterial sinusitis, acute exacerbations of chronic bronchitis, pneumonia, complicated intra-abdominal infections, and skin infections.

[0003] The process route for moxifloxacin side chain preparation uses 2,3-dicarboxypyridine as a starting material, which is first reacted with benzylamine to obtain imide (III); then, the pyridine unit in imide (III) is catalytically hydrogenated to obtain a racemic mixture composed of (II) and (IV). This racemic mixture is then subjected to imide reduction, chiral resolution, and catalytic hydrogenation to remove the benzyl group, yielding optically pure moxifloxacin side chain (V).

[0004]

[0005] As can be seen from the above synthesis process, the product obtained by catalytic hydrogenation of pyridine contains 50% of the byproduct (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane(II), resulting in high production costs and low atom utilization. However, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane(II) has the backbone required for the moxifloxacin side chain. Therefore, how to utilize (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane has become an important problem that urgently needs to be solved industrially in the synthesis of moxifloxacin side chain.

[0006] In existing technologies, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane is oxidized and dehydrogenated to eliminate chirality, and then hydrogenated to obtain the racemic product of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, achieving the purpose of recycling. Currently, some patents have reported methods for the oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane. For example, Chinese patent CN101429199A discloses a method for oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane(II) to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione using MnO2 as an oxidant at 60-110℃. However, this method requires the use of excessive MnO2, which is not conducive to the control of "three wastes" (waste gas, wastewater, and solid waste) and is likely to cause environmental pollution. It may also cause heavy metal pollution to the product or subsequent products. For example, Chinese patent CN103788090A discloses a method for oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0] in ethers or polar aprotic solvents at 10-40°C using elemental iodine and oxygen as co-oxidants. However, elemental iodine in this method is prone to sublimation and has certain toxicity and corrosiveness, which is not conducive to large-scale safe production. In addition, the above reactions are all batch reactions with low production efficiency, which is not conducive to large-scale industrial production. Summary of the Invention

[0007] Therefore, it is necessary to provide a method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione and its application, addressing the aforementioned problems. This method not only features mild reaction conditions, short reaction time, simple operation, and environmental friendliness, but also high product conversion rate and good selectivity, making it suitable for large-scale industrial production. It can be better applied to the synthesis of moxifloxacin, improving the utilization rate of raw materials in the synthesis of moxifloxacin.

[0008] A method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione involves reacting (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane in an organic solvent under blue light irradiation with the aid of a photosensitizer and an oxidizing agent to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0009] In one embodiment, the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the photosensitizer is 1:0.01-1:0.05;

[0010] And / or, the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxidant is 1:40-1:200;

[0011] And / or, the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5 to 1:15.

[0012] In one embodiment, the photosensitizer is selected from at least one of terpyridine ruthenium chloride hexahydrate, benzophenone, anthracene-9,10-dianitron, and 9-fluorenone;

[0013] And / or, the oxidant is selected from at least one of air, oxygen, and hydrogen peroxide solution.

[0014] In one embodiment, the wavelength of the blue light source is 430nm-460nm.

[0015] In one embodiment, the organic solvent is selected from at least one of toluene, dimethyl sulfoxide, acetonitrile, and ethanol.

[0016] In one embodiment, the reaction time is 80 min to 160 min.

[0017] In one embodiment, the preparation method includes:

[0018] The (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer, and the organic solvent were mixed to obtain a mixture.

[0019] The mixture and the oxidant are continuously fed together and then continuously reacted under the irradiation of the blue light source to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0020] In one embodiment, after the reaction is irradiated by a blue light source, a gas-liquid separation process is further included to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0021] A method for preparing a moxifloxacin side chain, the method further comprising:

[0022] Using the preparation method of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione described above, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane was oxidatively dehydrogenated to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione;

[0023] Then, the 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione was subjected to catalytic hydrogenation and chiral resolution to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane.

[0024] A method for preparing moxifloxacin includes the method for preparing moxifloxacin side chains as described above.

[0025] In the preparation method of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione of the present invention, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane can be oxidized and dehydrogenated at room temperature under the combined action of a photosensitizer and an oxidant, and under blue light irradiation, to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. This preparation method is not only mild in reaction conditions, short in reaction time, simple in operation, and environmentally friendly, but also has high product conversion rate and good selectivity, and can be used for large-scale industrial production. Therefore, it can be better applied to the synthesis of moxifloxacin and improve the utilization rate of raw materials in the synthesis of moxifloxacin. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 This is a schematic diagram of the production system for 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to one embodiment of the present invention.

[0028] Reference numerals: 1. Feed bottle; 2. Oxygen cylinder; 3. Liquid flow pump; 4. Gas flow meter; 5. First preheater; 6. Second preheater; 7. First temperature display; 8. Second temperature display; 9. Mixer; 10. Blue light source; 11. Reactor; 12. Gas-liquid separator; 13. Discharge bottle. Detailed Implementation

[0029] To facilitate understanding of the present invention, it will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. Rather, these embodiments or examples are provided to make the disclosure of the present invention more thorough and complete.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments or examples only and is not intended to limit the invention. The optional scope of the term "and / or" as used herein includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items, including any two related listed items, any more related listed items, or a combination of all related listed items.

[0031] The present invention provides a method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. In an organic solvent, using (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane as a raw material, the reaction is carried out under blue light irradiation in the presence of a photosensitizer and an oxidizing agent to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0032] Specifically, the synthetic route for 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is as follows:

[0033]

[0034] As can be seen from the above synthetic route, in the preparation method of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione of the present invention, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, under the combined action of photosensitizer and oxidant and under blue light irradiation, can complete the oxidative dehydrogenation to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione in only one step. Moreover, the reaction can be completed at room temperature, and the conversion rate of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione can reach up to 99%, and the yield can reach up to 95%. Therefore, this preparation method not only has mild reaction conditions, short reaction time, simple operation, and environmental friendliness, but also has high product conversion rate and good selectivity, and can be used for large-scale industrial production. Thus, it can be better applied to the synthesis of moxifloxacin side chains and improve the utilization rate of raw materials in the synthesis of moxifloxacin side chains.

[0035] Optionally, the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the photosensitizer is 1:0.01-1:0.05, preferably 1:0.01-1:0.03. It is understood that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the photosensitizer can be 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.035, 1:0.04, 1:0.045, or 1:0.05, or any ratio within the range of 1:0.01-1:0.05. This setup can further improve the photocatalytic efficiency of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and further shorten the reaction time.

[0036] Furthermore, the photosensitizer is selected from at least one of terpyridine ruthenium chloride hexahydrate (Ru(bpy)3Cl2·6H2O), benzophenone, anthracene-9,10-dionitrile, and 9-fluorenone, preferably terpyridine ruthenium chloride hexahydrate.

[0037] Optionally, the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxidant is 1:40-1:200. It is understood that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxidant can be 1:40, 1:80, 1:120, 1:160, 1:200, or any ratio within the range of 1:40-1:200. This setting can further improve the photocatalytic oxidation efficiency of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, that is, improve the efficiency of oxidative dehydrogenation and shorten the reaction time.

[0038] Furthermore, the oxidant is selected from at least one of air, oxygen (O2), and hydrogen peroxide solution, wherein the mass fraction of hydrogen peroxide in the hydrogen peroxide solution is 15%-27%, preferably oxygen. This configuration reduces the need for additional raw materials and reagents, and minimizes post-processing.

[0039] Optionally, the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5 to 1:15. It is understood that the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent can be 1:5, 1:10, 1:15, or any ratio within the range of 1:15 to 1:15.

[0040] In one embodiment, the photosensitizer in this invention is ruthenium tripyridine chloride hexahydrate, and the oxidant is oxygen. The synthetic route for 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is as follows:

[0041]

[0042] This setup, using a photocatalytic oxidation system composed of Ru(bpy)3Cl2·6H2O and O2, allows for a reaction at room temperature, which can further improve the product conversion rate and yield. Moreover, the reaction conditions are mild, the reaction time is short, the operation is simple, and it is environmentally friendly. It does not require the use of iodine compounds, and oxygen is used directly as the oxidant, making the reaction easier to control. It also eliminates the need to remove iodides and reduces post-processing.

[0043] It should be noted that blue light refers to visible light with wavelengths in the range of 400nm-500nm. It can be understood that in this invention, the wavelength of the blue light source is 400nm-500nm.

[0044] Furthermore, the wavelength of the blue light source is 430nm-460nm, preferably 450nm. It is understood that the wavelength of the blue light source includes, but is not limited to, 430nm, 440nm, and 460nm. Using a blue light source within this wavelength range is beneficial for improving the conversion rate and yield of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0045] In one embodiment, the light intensity of the blue light source is 0.08 W / cm². 2 -0.2W / cm 2 .

[0046] Optionally, the organic solvent is selected from at least one of toluene, dimethyl sulfoxide, acetonitrile, and ethanol, preferably acetonitrile.

[0047] Optionally, the reaction time is 80 min to 160 min, preferably 120 min.

[0048] Optionally, after the reaction under blue light irradiation, a gas-liquid separation process is further included to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. This setup is beneficial for improving the purity of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0049] In one embodiment, after gas-liquid separation, the mixture is further cooled to -5°C to -10°C at a cooling rate of 4°C / h to 6°C / h for crystallization, filtration, and drying to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0050] In this invention, the feeding methods for the organic solvent, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, photosensitizer, and oxidant can be carried out in the following two ways;

[0051] The first method involves mixing an organic solvent, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, a photosensitizer, and an oxidant, and then reacting them under blue light irradiation to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0052] The second method involves mixing (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer, and the organic solvent to obtain a mixture. This mixture and the oxidant are then continuously fed together and subjected to continuous reaction under blue light irradiation to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. It can be understood that in this method, the mixture and oxidant are fed continuously, meaning the reaction is carried out while the oxidant is being fed, thus enabling a continuous reaction. Compared to batch reactions, this method offers higher production efficiency and is beneficial for large-scale industrial production.

[0053] Therefore, the second method is preferred in this invention.

[0054] In one embodiment, when the organic solvent, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, photosensitizer, and oxidant are added in the second manner, and the oxidant is oxygen, the production system for 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione of the present invention can be used as follows: Figure 1 As shown, the production system includes a feeding device, an oxygen supply device, a mixer 9, a reactor 11, and a blue light source 10. The feeding device and the oxygen supply device are connected to the mixer 9, the reactor 11 is connected to the mixer 9, and the blue light source 10 is located above the reactor 11.

[0055] The reactor 11 can be a transparent flexible tube, and further, the transparent flexible tube has a length of 40m-50m, an outer diameter of 5mm-7mm, and an inner diameter of 3mm-5mm.

[0056] In one embodiment, the blue light source 10 is vertically irradiated onto the reactor 11, and the blue light source 10 can be a blue LED lamp.

[0057] Furthermore, the feeding device includes a feed bottle 1, a liquid flow pump 3, a first preheater 5, a first temperature display 7, and a first shut-off valve connected in sequence, wherein the first shut-off valve is connected to the mixer 9. With this configuration, the raw materials, photosensitizer, and organic solvent are mixed in the feed bottle 1 to obtain a mixture, and the feed bottle 1 is connected to the mixer 9 via the liquid flow pump 3, the first preheater 5, the first temperature display 7, and the first shut-off valve to control the flow rate of the mixture entering the reactor 11.

[0058] The oxygen supply equipment includes an oxygen cylinder 2, a pressure reducing valve, a gas flow meter 4, a second preheater 6, a second temperature display 8, and a second shut-off valve connected in sequence. The second shut-off valve is connected to the mixer 9. In this configuration, the oxygen cylinder 2 is connected to the mixer 9 via the pressure reducing valve, the gas flow meter 4, the second preheater 6, the second temperature display 8, and the second shut-off valve, thereby controlling the oxygen flow rate.

[0059] Furthermore, the production system also includes a gas-liquid separator 12 and a discharge bottle 13 connected to the gas-liquid separator 12, wherein the gas-liquid separator 12 is connected to the reactor 11.

[0060] Meanwhile, the present invention also provides a method for preparing moxifloxacin side chains, the method further comprising:

[0061] Using the preparation method of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione described above, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane was oxidatively dehydrogenated to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione;

[0062] The 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione was then subjected to catalytic hydrogenation and chiral resolution to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane. The (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (IV) was recycled for the synthesis of the moxifloxacin side chain.

[0063] Specifically, the oxidative dehydrogenation method of this invention is used to oxidatively dehydrogenate (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, a byproduct generated in the process of synthesizing the moxifloxacin side chain, to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. Then, hydrogenation is added to obtain a racemic product of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane. This racemic product is then subjected to chiral resolution using existing techniques. The optically pure (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane required for the synthesis of moxifloxacin side chains is obtained. The (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane obtained by chiral resolution can be reused by oxidative dehydrogenation and subsequent catalytic hydrogenation using the oxidative dehydrogenation method of this invention, thereby achieving the purpose of recycling and better applying it to the synthesis of moxifloxacin side chains, thus improving the utilization rate of raw materials in the synthesis of moxifloxacin side chains.

[0064] Furthermore, the present invention also provides a method for preparing moxifloxacin, including the method for preparing moxifloxacin side chains as described above.

[0065] The preparation method and application of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione will be further illustrated below through specific examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples were performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products.

[0066] Example 1

[0067] A mixture of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (12.21 g, 0.05 mol), terpyridine ruthenium chloride hexahydrate (0.56 g, 0.00075 mol), and acetonitrile (122.15 g) was prepared. This mixture was then continuously fed into a reactor, while simultaneously introducing 6 mol of oxygen. A light source with a wavelength of 450 nm and an intensity of 0.1 W / cm² was used. 2After irradiation with a blue light source and reaction at room temperature for 120 min, a reaction solution was obtained, wherein the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and terpyridine ruthenium chloride hexahydrate was 1:0.015, and the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and the... The molar ratio of oxygen is 1:120, and the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to acetonitrile is 1:10. The reaction solution is subjected to gas-liquid separation, and then the temperature is gradually reduced to -10℃ for crystallization, filtration, and drying to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0068] Example 2

[0069] A mixture of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (12.21 g, 0.05 mol), terpyridine ruthenium chloride hexahydrate (0.37 g, 0.0005 mol), and acetonitrile (61.05 g) was prepared. This mixture was then continuously fed into a reactor, while simultaneously introducing 2 mol of oxygen. A light source with a wavelength of 400 nm and an intensity of 0.2 W / cm² was used. 2 After irradiation with a blue light source and reaction at room temperature for 80 min, a reaction solution was obtained, wherein the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to terpyridine ruthenium chloride hexahydrate was 1:0.01, and the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to terpyridine ruthenium chloride hexahydrate was 1:0.01. The molar ratio of oxygen is 1:40, and the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to acetonitrile is 1:5. The reaction solution is subjected to gas-liquid separation, followed by gradient cooling to -10℃ for crystallization, filtration, and drying to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0070] Example 3

[0071] (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (12.21 g, 0.05 mol), terpyridine ruthenium chloride hexahydrate (1.87 g, 0.0025 mol), and acetonitrile (183.15 g) were mixed to obtain a mixture. This mixture was then continuously fed into a reactor, while simultaneously introducing 10 mol of oxygen. A light source with a wavelength of 500 nm and an intensity of 0.1 W / cm² was used. 2 After irradiation with a blue light source and reaction at room temperature for 160 min, a reaction solution was obtained, wherein the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to terpyridine ruthenium chloride hexahydrate was 1:0.05, and the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to terpyridine ruthenium chloride hexahydrate was 1:0.05. The molar ratio of oxygen is 1:200, and the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to acetonitrile is 1:15. The reaction solution is subjected to gas-liquid separation, and then the temperature is gradually reduced to -10℃ for crystallization, filtration, and drying to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0072] Example 4

[0073] The only difference between Example 4 and Example 1 is that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and terpyridine ruthenium chloride hexahydrate is 1:0.005, and all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0074] Example 5

[0075] The only difference between Example 5 and Example 1 is that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and terpyridine ruthenium chloride hexahydrate is 1:0.06, and all other conditions are the same, to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0076] Example 6

[0077] The only difference between Example 6 and Example 1 is that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and oxygen is 1:20, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0078] Example 7

[0079] The only difference between Example 7 and Example 1 is that the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and oxygen is 1:240, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0080] Example 8

[0081] Compared with Example 1, Example 8 differs only in that benzophenone is used instead of terpyridine ruthenium chloride hexahydrate, while all other conditions are the same, to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0082] Example 9

[0083] Example 9 differs from Example 1 only in that air is used instead of oxygen, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0084] Example 10

[0085] Example 10 differs from Example 1 only in that toluene is used instead of acetonitrile, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0086] Example 11

[0087] Example 11 differs from Example 1 only in that ethanol is used instead of acetonitrile, while all other conditions are the same, to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0088] Example 12

[0089] Example 12 differs from Example 1 only in that it is irradiated with a blue light source with a wavelength of 400 nm, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0090] Example 13

[0091] Example 13 differs from Example 1 only in that it is irradiated with a blue light source with a wavelength of 420 nm, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0092] Example 14

[0093] Example 14 differs from Example 1 only in that it is irradiated with a blue light source with a wavelength of 470 nm, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0094] Example 15

[0095] Example 15 differs from Example 1 only in that the reaction was carried out at room temperature for 70 min, while all other conditions remained the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0096] Comparative Example 1

[0097] Comparative Example 1 differs from Example 1 only in that it does not contain terpyridine ruthenium chloride hexahydrate and does not use blue light irradiation. All other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0098] Comparative Example 2

[0099] Comparative Example 2 differs from Example 1 only in that it does not contain the step of introducing oxygen, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0100] Comparative Example 3

[0101] Comparative Example 3 differs from Example 1 only in that it is irradiated with a light source with a wavelength of 510 nm, while all other conditions are the same, yielding 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0102] Comparative Example 4

[0103] Comparative Example 4 differs from Example 1 only in that it is irradiated with a light source with a wavelength of 350 nm, while all other conditions are the same, resulting in 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0104] The conversion and yield of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione prepared in Examples 1-15 and Comparative Examples 1-4 were calculated, and the results are shown in Table 1.

[0105] The conversion rate of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is calculated as (amount of reacted raw material / initial amount of raw material) × 100%; the yield of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is calculated as (actual amount of target product produced / theoretical amount of target product produced) × 100%.

[0106] Table 1

[0107] Raw material conversion rate / % Product yield / % Example 1 99 95 Example 2 98 93 Example 3 98 94 Example 4 92 87 Example 5 98 90 Example 6 95 85 Example 7 98 89 Example 8 85 80 Example 9 92 90 Example 10 86 81 Example 11 89 80 Example 12 93 85 Example 13 95 88 Example 14 96 85 Example 15 83 79 Comparative Example 1 0 0 Comparative Example 2 0 0 Comparative Example 3 73 62 Comparative Example 4 71 63

[0108] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0109] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione, characterized in that, In an organic solvent, using (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane as a raw material, under the action of a photosensitizer and an oxidant, and irradiated by a blue light source, 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is obtained. The photosensitizer is selected from at least one of terpyridine ruthenium chloride hexahydrate and benzophenone, and the oxidant is selected from at least one of air, oxygen, and hydrogen peroxide solution.

2. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to claim 1, characterized in that, The molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the photosensitizer is 1:0.01-1:0.05; And / or, the molar ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxidant is 1:40-1:200; And / or, the mass ratio of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5 to 1:

15.

3. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to claim 1, characterized in that, The wavelength of the blue light source is 430nm-460nm.

4. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to claim 1, characterized in that, The organic solvent is selected from at least one of toluene, dimethyl sulfoxide, acetonitrile, and ethanol.

5. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to claim 1, characterized in that, The reaction time is 80 min-160 min.

6. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to claim 1, characterized in that, The preparation method includes: The (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer, and the organic solvent were mixed to obtain a mixture. The mixture and the oxidant are continuously fed together and then continuously reacted under the irradiation of the blue light source to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

7. The method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione according to any one of claims 1-6, characterized in that, After the reaction is carried out under blue light irradiation, the gas-liquid separation process is also included to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

8. A method for preparing a moxifloxacin side chain, characterized in that, The preparation method further includes: The preparation method of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione as described in any one of claims 1-7 involves oxidative dehydrogenation of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. Then, the 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione was subjected to catalytic hydrogenation and chiral resolution to obtain (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane.

9. A method for preparing moxifloxacin, characterized in that, This includes the method for preparing the moxifloxacin side chain as described in claim 8.

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