Preparation method and application of 6-benzyl-1, 2, 3, 4-tetrahydro-6H-pyrrolo [3, 4-B] pyridine-5, 7-diketone

Abstract

The invention relates to a preparation method and application of 6-benzyl-1, 2, 3, 4-tetrahydro-6H-pyrrolo [3, 4-B] pyridine-5, 7-diketone, and the preparation method of the 6-benzyl-1, 2, 3, 4-tetrahydro-6H-pyrrolo [3, 4-B] pyridine-5, 7-diketone comprises the following steps: in an organic solvent, by taking (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 oxidizing agent, carrying out a reaction on (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4, 3, 0] nonane and ( The preparation method comprises the following steps: taking 2, 2, 3, 4-tetrahydro-6H-pyrrolo [3, 4-B] pyridine-5, 7-diketone as a raw material, and reacting under the irradiation of a blue light source to obtain 6-benzyl-1, 2, 3, 4-tetrahydro-6H-pyrrolo [3, 4-B The preparation method is mild in reaction condition, short in reaction time, simple to operate, environment-friendly, high in product conversion rate and good in selectivity, can be used for industrial large-scale production and can be better applied to synthesis of moxifloxacin, and the utilization rate of raw materials in synthesis of moxifloxacin is increased.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a preparation method and application of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. Background Art

[0002] Moxifloxacin, chemical name is 1-cyclopropyl-7-{(S,S)-2,8-diazo-bicyclo[4.3.0]non-8-yl}-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, molecular formula is C 21 H 24 FN3O4 is a fourth-generation quinolone antibacterial drug, which is mainly used clinically to treat acute bacterial sinusitis, acute exacerbation of chronic bronchitis, pneumonia, complicated intra-abdominal infection and skin infection.

[0003] The process route for the preparation of the moxifloxacin side chain is to use 2,3-dicarboxypyridine as a raw material, which first reacts with benzylamine to obtain imide (III); then the pyridine unit in the imide (III) is catalytically hydrogenated to obtain a racemate consisting of (II) and (IV). The racemate is subjected to imide reduction, chiral resolution, and catalytic hydrogenation debenzylation to obtain an optically pure moxifloxacin side chain (V).

[0004]

[0005] From the above synthesis process, it can be seen that the product obtained by catalytic hydrogenation of the pyridine ring contains 50% of the byproduct (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (II), which leads to high production cost and low atomic utilization. However, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane (II) has the skeleton required for the side chain of moxifloxacin. Therefore, how to use (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane has become an important problem that needs to be solved in the industry in the synthesis of the side chain of moxifloxacin.

[0006] In the prior art, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane is oxidatively dehydrogenated to eliminate chirality, and then hydrogenated to obtain a racemized product of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, thereby achieving the purpose of recycling. At present, some patents have reported methods for 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 of using MnO2 as an oxidant to perform an oxidative dehydrogenation reaction on (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (II) at 60-110°C to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. However, this method requires the use of excessive MnO2, which is not conducive to the control of "three wastes", is easy to pollute the environment, and may also cause heavy metal pollution to the product or subsequent products. For another 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 an ether or polar aprotic solvent at 10-40°C using iodine and oxygen as co-oxidants. However, in this method, iodine is easily sublimated and has certain toxicity and corrosiveness, which is not conducive to large-scale safe production. In addition, the above reactions are all intermittent reactions with low production efficiency, which is not conducive to large-scale industrial production. Summary of the invention

[0007] Based on this, it is necessary to provide a preparation method and application of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione for the above problems. The 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, can be used for industrial large-scale production, can be better applied to the synthesis of moxifloxacin, and improves 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 comprises the following steps: using (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane as a raw material in an organic solvent, reacting under the action of a photosensitizer and an oxidant under irradiation with a blue light source 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 the (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 the (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 the (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5-1:15.

[0012] In one embodiment, the photosensitizer is selected from at least one of terpyridyl ruthenium chloride hexahydrate, benzophenone, anthracene-9,10-dinitrile, 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-160 min.

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

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

[0019] The mixed solution and the oxidant are continuously fed and mixed, and then reacted continuously 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 under the irradiation of 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 preparation 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 as described above, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane is subjected to oxidative dehydrogenation 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 is 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 comprises the method for preparing the moxifloxacin side chain 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 complete oxidative dehydrogenation at room temperature under the joint action of a photosensitizer and an oxidant and under the irradiation of a blue light source to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. The preparation method has mild reaction conditions, short reaction time, simple operation and environmental friendliness, and high product conversion rate and good selectivity, and can be used for large-scale industrial production, so that it can be better applied to the synthesis of moxifloxacin and improve the utilization rate of raw materials in the synthesis of moxifloxacin. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] 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 or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1 The figure is a schematic structural diagram of a system for producing 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] Figure 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 DESCRIPTION

[0029] For ease of understanding of the present invention, the present invention 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. On the contrary, the purpose of providing these embodiments or examples is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific implementation methods or embodiments, and are not intended to limit the present invention. The optional scope of the term "and / or" used herein includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the combinations include any two related listed items, any more related listed items, or all related listed items.

[0031] The invention provides a method for preparing 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. The method comprises the following steps: using (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane as a raw material in an organic solvent, reacting under the action of a photosensitizer and an oxidant and irradiating with a blue light source to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

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

[0033]

[0034] It can be seen from the above synthesis route that 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 complete oxidative dehydrogenation to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione in only one step under the combined action of a photosensitizer and an oxidant and under the irradiation of a blue light source. 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, the preparation method has mild reaction conditions, short reaction time, simple operation and environmental friendliness, and high product conversion rate and good selectivity, and can be used for large-scale industrial production, so that it can be better applied to the synthesis of the moxifloxacin side chain and improve the utilization rate of raw materials in the synthesis of the moxifloxacin side chain.

[0035] Optionally, the molar ratio of the (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 can be understood that the molar ratio of the (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, 1:0.05, or any ratio within the range of 1:0.01-1:0.05. Such an arrangement 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 terpyridyl ruthenium chloride hexahydrate (Ru(bpy)3Cl2·6H2O), benzophenone, anthracene-9,10-dinitrile, and 9-fluorenone, preferably terpyridyl ruthenium chloride hexahydrate.

[0037] Optionally, the molar ratio of the (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 the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxidant may be 1:40, 1:80, 1:120, 1:160, 1:200, or any ratio within the range of 1:40-1:200. Such an arrangement 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 arrangement can reduce the addition of raw material reagents and reduce post-processing.

[0039] Optionally, the mass ratio of the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5-1:15. 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 1:15-1:15.

[0040] In one embodiment, when the photosensitizer in the present invention is terpyridine ruthenium chloride hexahydrate and the oxidant is oxygen, the synthesis route of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione is as follows:

[0041]

[0042] In this way, a photocatalytic oxidation system composed of Ru(bpy)3Cl2·6H2O and O2 is used to react at room temperature, which can further improve the product conversion rate and yield. In addition, the reaction conditions are mild, the reaction time is short, the operation is simple, and it is environmentally friendly. There is no need to use iodine compounds, and oxygen is used directly as an oxidant. The reaction is easier to control, there is no need to remove iodide, and the post-processing process is reduced.

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

[0044] Further, 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. The use of a blue light source within this wavelength range is conducive to 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 / cm 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-160 min, preferably 120 min.

[0048] Optionally, after the reaction under the irradiation of 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. Such an arrangement is conducive to 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 the gas-liquid separation treatment, the temperature is further lowered to -5°C to -10°C at a cooling rate of 4°C / h-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 the present invention, the feeding method of the organic solvent, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer and the oxidant can be carried out in the following two ways:

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

[0052] The second method: the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer and the organic solvent are mixed to obtain a mixed solution; the mixed solution and the oxidant are continuously fed and mixed, 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. It can be understood that in this method, the mixed solution and the oxidant are fed in a continuous manner, that is, the feeding method is a method of reacting while feeding, so as to carry out a continuous reaction. Compared with intermittent reactions, the production efficiency is high and it is conducive to large-scale industrial production.

[0053] For this reason, the second method is preferred in the present 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 of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione of the present invention can be 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, wherein the feeding device and the oxygen supply device are respectively connected to the mixer 9, the reactor 11 is connected to the mixer 9, and the blue light source 10 is arranged above the reactor 11.

[0055] The reactor 11 may be a transparent hose. Furthermore, the transparent hose 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 irradiates the reactor 11 vertically, and the blue light source 10 may be a blue light LED lamp.

[0057] Further, the feeding device comprises a feeding bottle 1, a liquid flow pump 3, a first preheater 5, a first temperature display 7 and a first stop valve connected in sequence, wherein the first stop valve is connected to the mixer 9. In this arrangement, the raw material, the photosensitizer and the organic solvent are mixed in the feeding bottle 1 to obtain a mixed liquid, and the feeding bottle 1 is connected to the mixer 9 through the liquid flow pump 3, the first preheater 5, the first temperature display 7 and the first stop valve to control the flow of the mixed liquid entering the reactor 11.

[0058] The oxygen supply device comprises 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 stop valve which are connected in sequence, and the second stop valve is connected to the mixer 9. In this arrangement, the oxygen cylinder 2 is connected to the mixer 9 through the pressure reducing valve, the gas flow meter 4, the second preheater 6, the second temperature display 8 and the second stop valve to control the flow of oxygen.

[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] At the same time, the present invention also provides a method for preparing a moxifloxacin side chain, the preparation 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 as described above, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane is subjected to oxidative dehydrogenation to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione;

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

[0063] Specifically, the oxidative dehydrogenation method of the present invention is used to oxidatively dehydrogenate the byproduct (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane produced in the process of synthesizing the side chain of moxifloxacin to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione, and then hydrogenate to obtain the racemization product of 8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, and then the racemization product is chirally resolved by the existing technology to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione. The (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane required for the synthesis of the moxifloxacin side chain is converted into optically pure (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, and 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 the present invention, thereby achieving the purpose of recycling, and further better applied to the synthesis of the moxifloxacin side chain, thereby improving the utilization rate of raw materials in the synthesis of the moxifloxacin side chain.

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

[0065] Hereinafter, 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 described by the following specific examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If no specific conditions are specified in the examples, the conventional conditions or the conditions recommended by the manufacturer are followed. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially.

[0066] Example 1

[0067] (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) were mixed to obtain a mixed solution, and then the mixed solution was continuously fed into a reactor, and oxygen (6 mol) was continuously introduced into the reactor at a wavelength of 450 nm and a light intensity of 0.1 W / cm 2The reaction mixture was irradiated with a blue light source and reacted at room temperature for 120 minutes to obtain a reaction solution, 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 1:0.015, and the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and the The molar ratio of oxygen is 1:120, the mass ratio of the (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the acetonitrile is 1:10, the reaction liquid is subjected to gas-liquid separation, then gradually cooled to -10°C for crystallization, filtered, and dried to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0068] Example 2

[0069] (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) were mixed to obtain a mixed solution, and then the mixed solution was continuously fed into a reactor, and oxygen (2 mol) was continuously introduced into the reactor at a wavelength of 400 nm and a light intensity of 0.2 W / cm 2 The mixture was irradiated with a blue light source and reacted at room temperature for 80 minutes to obtain a reaction solution, wherein the molar ratio of the (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 (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and 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 and acetonitrile is 1:5; the reaction liquid is subjected to gas-liquid separation, and then the temperature is gradually reduced to -10°C 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 mixed solution, and then the mixed solution was continuously fed into a reactor, and oxygen (10 mol) was continuously introduced into the reactor at a wavelength of 500 nm and a light intensity of 0.1 W / cm 2 The reaction mixture was irradiated with a blue light source and reacted at room temperature for 160 minutes to obtain a reaction solution, wherein the molar ratio of the (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 (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and the The molar ratio of the oxygen is 1:200, and the mass ratio of the (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane and acetonitrile is 1:15; the reaction liquid is subjected to gas-liquid separation, and then the temperature is gradually reduced to -10°C 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] Compared with Example 1, Example 4 differs only in that the molar ratio of (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to terpyridine ruthenium chloride hexahydrate is 1:0.005, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0074] Example 5

[0075] Compared with Example 1, Example 5 differs only in 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 the 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] Compared with Example 1, Example 6 differs only in that the molar ratio of the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxygen is 1:20, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0078] Example 7

[0079] Compared with Example 1, Example 7 differs only in that the molar ratio of the (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the oxygen is 1:240, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0080] Example 8

[0081] The only difference between Example 8 and Example 1 is that benzophenone is used instead of terpyridine ruthenium chloride hexahydrate, and the 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] The only difference between Example 9 and Example 1 is that air is used instead of oxygen, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0084] Example 10

[0085] The only difference between Example 10 and Example 1 is that toluene is used instead of acetonitrile, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0086] Embodiment 11

[0087] The only difference between Example 11 and Example 1 is that ethanol is used instead of acetonitrile, and the 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] The only difference between Example 12 and Example 1 is that a blue light source with a wavelength of 400 nm is used for irradiation, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0090] Embodiment 13

[0091] The only difference between Example 13 and Example 1 is that a blue light source with a wavelength of 420 nm is used for irradiation, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0092] Embodiment 14

[0093] The only difference between Example 14 and Example 1 is that a blue light source with a wavelength of 470 nm is used for irradiation, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0094] Embodiment 15

[0095] The only difference between Example 15 and Example 1 is that after reacting at room temperature for 70 minutes, the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0096] Comparative Example 1

[0097] The difference between Comparative Example 1 and Example 1 is that the step of not containing terpyridine ruthenium chloride hexahydrate and using a blue light source for irradiation is omitted, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0098] Comparative Example 2

[0099] The difference between Comparative Example 2 and Example 1 is that the step of introducing oxygen is not included, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0100] Comparative Example 3

[0101] The only difference between Comparative Example 3 and Example 1 is that a light source with a wavelength of 510 nm is used for irradiation, and the other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

[0102] Comparative Example 4

[0103] The only difference between Comparative Example 4 and Example 1 is that a light source with a wavelength of 350 nm is used for irradiation, and other conditions are the same to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

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

[0105] Among them, the conversion rate of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione = (amount of reacted raw materials / initial raw materials) × 100%; the yield of 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione = (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 Embodiment 11 89 80 Example 12 93 85 Embodiment 13 95 88 Embodiment 14 96 85 Embodiment 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-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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 above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached 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, (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane is used as a raw material, and reacts under the action of a photosensitizer and an oxidant under irradiation with a blue light source to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

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 the (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 the (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 the (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane to the organic solvent is 1:5-1:

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 photosensitizer is selected from at least one of terpyridyl ruthenium chloride hexahydrate, benzophenone, anthracene-9,10-dinitrile, and 9-fluorenone; And / or, the oxidant is selected from at least one of air, oxygen and hydrogen peroxide solution.

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 wavelength of the blue light source is 430nm-460nm.

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 organic solvent is selected from at least one of toluene, dimethyl sulfoxide, acetonitrile and ethanol.

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 reaction time is 80min-160min.

7. 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 comprises: Mixing the (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4,3,0]nonane, the photosensitizer and the organic solvent to obtain a mixed solution; The mixed solution and the oxidant are continuously fed and mixed, and then reacted continuously 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.

8. 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 to 7, characterized in that: After reacting under the irradiation of a blue light source, the method further includes gas-liquid separation treatment to obtain 6-benzyl-1,2,3,4-tetrahydro-6H-pyrrolo[3,4-B]pyridine-5,7-dione.

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

10. A method for preparing moxifloxacin, characterized in that: The invention comprises the method for preparing the moxifloxacin side chain as claimed in claim 9.

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