Preparation method of Levcough Pine

Abstract

The invention provides a preparation method of levocough, and relates to the technical field of medicine synthesis. The invention provides a preparation method of levocough, which comprises the following steps: taking a compound SM-1 and a compound SM-2 as raw materials, and carrying out amidation reaction, cyclization-reduction reaction, chiral separation reaction and methylation reaction to obtain levocough. According to the method, cyclization and reduction are continuously carried out, so that the yield of the compound ZJT-2 is increased. The chiral separation reaction is carried out under the condition of one or more specific organic solvents of the alcohol solvent, the ester solvent, the nitrile solvent and the alkane solvent, and the obtained compound ZJT-3 is high in yield and high in chiral purity. The methylation reaction is carried out under the methylation reagent condition, so that the possibility of ester hydrolysis can be reduced, and the total yield of levocough is improved. The preparation method provided by the invention has the advantages of high total yield, high purity, simple steps, simplicity in operation, suitability for industrial production, low production cost and suitability for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for preparing lekeping. Background Art

[0002] Lekeping is a classic antitussive drug and can also be used to treat stroke and edema. The structure of Lekeping is as follows:

[0003]

[0004] The prior art discloses that 1,3-dihydro-5,7-dimethoxy-3-oxo-1-isobenzofurancarboxylic acid is chlorinated and then reacted with 4-bromo-7-methoxy-1,3-benzodione-5-ethylamine hydrochloride to form an amide, the amide is cyclized and then reduced at -78°C, the reduction product is methylated and then hydrogenated to remove the bromine to obtain (±)-α-lecoquin. The reaction route is shown in route 1. This synthesis method uses 4-bromo-7-methoxy-1,3-benzodione-5-ethylamine hydrochloride to avoid the generation of positional isomers, however, the total yield of lecoquin is only 28.5%.

[0005]

[0006] The prior art discloses that vanillin is used as a starting material, and compound 5 is obtained through bromination, hydroxylation, cyclization, Henry reaction and reduction. A large amount of lithium aluminum tetrahydride or highly toxic borane is used in the preparation of compound 5; 2,3-dimethoxybenzoic acid is subjected to cyclization, hydrolysis and chlorination to obtain compound 8; compound 5 is freed and added dropwise to compound 8 for amidation reaction, and then cyclization, splitting and methylation are performed to obtain levofloxacin. The reaction route is shown in route 2. However, this route has many reaction steps, the total yield of compound 5 is 22.5%, and the total yield of compound 8 is 43.4%. Dimer impurities are easily generated during the amidation reaction, resulting in a total yield of 9.4% for preparing levofloxacin by reacting compound 5 with compound 8, and the total yield of levofloxacin in the entire synthetic route is only 0.92%.

[0007] Summary of the invention

[0008] In view of this, the object of the present invention is to provide a preparation method of lecoping. The preparation method provided by the present invention has a high total yield of lecoping.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] The present invention provides a method for preparing Lekeping, comprising the following steps:

[0011] Compound SM-1 and compound SM-2 are subjected to an amidation reaction to obtain compound ZJT-1;

[0012] The compound ZJT-1 is subjected to a cyclization-reduction reaction to obtain a compound ZJT-2;

[0013] The compound ZJT-2 is subjected to a chiral separation reaction under an organic solvent condition to obtain a compound ZJT-3; the organic solvent comprises at least one of a solvent A and a solvent B; the solvent A comprises one or more of an alcohol solvent, an ester solvent and a nitrile solvent; the solvent B comprises an alkane solvent;

[0014] The compound ZJT-3 is subjected to a methylation reaction under methylating agent conditions to obtain Lecoping;

[0015]

[0016] Preferably, when the amidation reaction is carried out in the presence of an acid amine condensing agent:

[0017] The molar ratio of the compound SM-1 to the compound SM-2 is 1:0.7-2;

[0018] The organic solvent used in the amidation reaction includes one or more of an amide solvent, a sulfoxide solvent, a halogenated alkane solvent and an ether solvent;

[0019] The acid amine condensation agent includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, carbonyldiimidazole and 2-(1H-[7]benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, 4-N,N-dimethylpyridine, triethylamine, 1-hydroxybenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'- One or more of tetramethyluronium hexafluorophosphate, O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the molar ratio of the compound SM-1 to the acid amine condensing agent is 1:0.8-6;

[0020] The temperature of the amidation reaction is -10 to 80° C., and the time is 1 to 24 hours.

[0021] Preferably, when the amidation reaction is carried out in the absence of an acid amine condensing agent:

[0022] The molar ratio of the compound SM-1 to the compound SM-2 is 1:0.7-3;

[0023] The amidation reaction is carried out in an organic solvent or without a solvent, wherein the organic solvent comprises one or more of a benzene solvent, an alkane solvent and an ether solvent;

[0024] The temperature of the amidation reaction is 60 to 190° C., the pressure is -1 to 0 MPa, and the time is 0.5 to 12 hours.

[0025] Preferably, subjecting the compound ZJT-1 to a cyclization-reduction reaction comprises: subjecting the compound ZJT-1 to a cyclization reaction in the presence of a cyclization catalyst, and then subjecting the compound ZJT-1 to a reduction reaction in the presence of a reduction catalyst and a reducing agent.

[0026] Preferably, the cyclization catalyst includes one or more of phosphorus oxychloride, phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride and thionyl chloride; the mass ratio of the compound ZJT-1 to the cyclization catalyst is 1:0.5-20;

[0027] The temperature of the cyclization reaction is 5 to 150° C. and the time is 4 to 12 hours;

[0028] The cyclization reaction is carried out in an organic solvent or without a solvent, and the organic solvent includes one or more of a benzene solvent and a nitrile solvent.

[0029] Preferably, the reduction catalyst comprises one or more of a palladium catalyst, a nickel catalyst, a cobalt catalyst, sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetylborohydride; the mass ratio of the compound ZJT-1 to the reduction catalyst is 1:0.01-1;

[0030] The reducing agent includes hydrogen and a solid reducing agent; the pressure of the hydrogen is 1 to 5 MPa; the solid reducing agent includes borohydride; the molar ratio of the compound ZJT-1 to the solid reducing agent is 1:0.5 to 6;

[0031] The reduction reaction temperature is 5 to 150° C. and the time is 8 to 80 hours;

[0032] The reduction reaction is carried out under the condition of an organic solvent, and the organic solvent includes an alcohol solvent.

[0033] Preferably, the chiral separation reaction is carried out with or without a resolving agent;

[0034] The resolving agent includes one or more of D-(+)-di-p-methylbenzoyl tartar, mandelic acid, glycine and malic acid;

[0035] The mass ratio of the compound ZJT-2 to the resolving agent is 1:0.2-3.

[0036] Preferably, the temperature of the chiral separation reaction is 80-85° C., and the time is 0.5-12 h.

[0037] Preferably, the methylating agent comprises one or more of methyl iodide, methyl chloride, methyl bromide, dimethyl sulfate and dimethyl carbonate;

[0038] The molar ratio of the compound ZJT-3 to the methylating agent is 1:0.5-2.

[0039] Preferably, the methylation reaction is carried out under alkaline reagent conditions, and the alkaline reagent includes at least one of carbonate and hydroxide; the molar ratio of the compound ZJT-3 to the alkaline reagent is 1:0.5-3;

[0040] The methylation reaction is carried out under solvent conditions, and the solvent includes one or more of an amide solvent, a ketone solvent, a nitrile solvent and water;

[0041] The temperature of the methylation reaction is 0-90° C. and the time is 0.5-6 hours.

[0042] The present invention provides a method for preparing levofloxacin, wherein compound SM-1 and compound SM-2 are used as initial raw materials, and levofloxacin can be prepared through amidation reaction, cyclization-reduction reaction, chiral separation reaction and methylation reaction. The present invention performs cyclization and reduction reactions continuously, simplifies the operation process, and improves the yield of compound ZJT-2. The present invention performs chiral separation reaction under the conditions of one or more specific organic solvents of alcohol solvents, ester solvents, nitrile solvents and alkane solvents, and the obtained compound ZJT-3 has high yield and high chiral purity. The present application performs methylation reaction under the conditions of methylating agent, which can reduce the possibility of ester hydrolysis and improve the total yield of levofloxacin. The preparation method provided by the present invention has high total yield and purity of levofloxacin, safe and non-toxic raw materials, simple steps, simple operation, suitable for industrial production, low production cost, and suitable for industrial production. As shown in the test results of the embodiment, the total yield of levofloxacin prepared by the present invention is 28.6-37.1%, and the purity is 99.801%.

[0043] Furthermore, compared with Route 1, the preparation method provided by the present invention does not require hydrogenation to remove bromine in the cyclization-reduction reaction, nor does it need to be carried out at -78°C, and has low equipment requirements, is suitable for industrial production, and has a higher total yield of Lekeping. In Route 2, the synthesis of compound 5 requires the use of a large amount of lithium aluminum tetrahydride or highly toxic borane; its compound (which is a hydrochloride) is directly split using tartaric acid or dibenzoyltartaric acid system. According to the principle of strong acid replacing weak acid, the splitting method cannot obtain the required target; the amount of three wastes generated is large, and it is not suitable for industrial production. Compared with Route 2, the preparation method provided by the present invention does not require the use of a large amount of lithium aluminum tetrahydride or highly toxic borane, the preparation raw materials are safe and non-toxic, the chiral separation reaction yield is high and the purity of the target is high, the preparation steps are simple, the three wastes generated are small, the cost is low, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The H NMR spectrum of the compound ZJT-2 prepared in Example 4;

[0045] Figure 2 This is the HPLC detection chart of compound ZJT-2 prepared in Example 4;

[0046] Figure 3 This is the chiral HPLC purity chart of compound ZJT-3 prepared in Example 8;

[0047] Figure 4 This is the H NMR spectrum of Lekeping prepared in Example 12;

[0048] Figure 5 This is the HPLC purity chart of Lecoping prepared in Example 12. DETAILED DESCRIPTION

[0049] The present invention provides a method for preparing Lekeping, comprising the following steps:

[0050] Compound SM-1 and compound SM-2 are subjected to an amidation reaction to obtain compound ZJT-1;

[0051] The compound ZJT-1 is subjected to a cyclization-reduction reaction to obtain a compound ZJT-2;

[0052] The compound ZJT-2 is subjected to a chiral separation reaction under an organic solvent condition to obtain a compound ZJT-3; the organic solvent comprises at least one of a solvent A and a solvent B; the solvent A comprises one or more of an alcohol solvent, an ester solvent and a nitrile solvent; the solvent B comprises an alkane solvent;

[0053] The compound ZJT-3 is subjected to a methylation reaction under methylating agent conditions to obtain Lecoping;

[0054]

[0055] In the present invention, the preparation route of the lecupine is as follows:

[0056]

[0057] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0058] In the present invention, compound SM-1 and compound SM-2 are subjected to amidation reaction to obtain compound ZJT-1.

[0059] In the present invention, the amidation reaction is carried out with or without an acid amine condensing agent.

[0060] The amidation reaction in the presence of an acid amine condensing agent is described below.

[0061] In the present invention, the molar ratio of compound SM-1 to compound SM-2 is preferably 1:0.7-2, and in specific embodiments it can be 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0062] In the present invention, the organic solvent used in the amidation reaction includes one or more of an amide solvent, a sulfoxide solvent, a halogenated alkane solvent and an ether solvent, and in a specific embodiment, it can be one or more of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dichloromethane, 1,2-dichloroethane, tetrahydrofuran and 1,4-dioxane; the mass ratio of the compound SM-1 to the organic solvent is preferably 1:0.5-30, and in a specific embodiment, it can be 1:0.5, 1:5, 1:10, 1:20 or 1:30.

[0063] In the present invention, the acid amine condensing agent preferably includes 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 4-N,N-dimethylpyridine (DMAP), triethylamine (TEA), 1-hydroxybenzotriazole (HOBT), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(6-chloro-1H-benzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU), O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (TBTU), O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) (TSTU) and O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (TNTU), in a specific embodiment, it can be a mixture of DECI and HOBT or a mixture of CDI and DMPA. In the present invention, the molar ratio of the compound SM-1 to the acid amine condensing agent is preferably 1:0.8-6, and in specific embodiments can be 1:0.8, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5 or 1:6. The present invention performs the amidation reaction under the condition of the acid amine condensing agent, which can simplify the post-processing steps.

[0064] In the present invention, the temperature of the amidation reaction is preferably -10 to 80°C, and in specific embodiments it can be -10°C, 0°C, 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C or 80°C; the time of the amidation reaction is preferably 1 to 24h, and in specific embodiments it can be 1h, 5h, 10h, 15h, 20h or 24h.

[0065] In the present invention, the amidation reaction preferably comprises: adding compound SM-1, an organic solvent (or no solvent), and compound SM-2, cooling, adding an acid amine condensing agent under stirring, and performing an amidation reaction. In the present invention, the temperature after cooling is preferably -10 to 30°C, and in specific embodiments can be -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C.

[0066] After completing the amidation reaction, the present invention preferably further comprises: mixing the reaction system obtained by the amidation reaction with ice water, separating the solid and the liquid, washing the obtained solid component with water and then drying it to obtain compound ZJT-1. In the present invention, the mass ratio of the compound SM-1 and ice water is preferably 1:1 to 50, and in specific embodiments it can be 1:1, 1:10, 1:20, 1:30, 1:40 or 1:50. In the present invention, the solid-liquid separation preferably includes suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30 to 100°C, and in specific embodiments it can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time, and the solvent can be completely removed.

[0067] The amidation reaction in the absence of an acid amine condensing agent is described below.

[0068] In the present invention, the molar ratio of compound SM-1 to compound SM-2 is preferably 1:0.7-3, and in specific embodiments can be 1:0.7, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:3.

[0069] In the present invention, the amidation reaction is preferably carried out in an organic solvent or without a solvent; the organic solvent preferably includes one or more of a benzene solvent, an alkane solvent and an ether solvent, and in a specific embodiment, it can be one or more of benzene and toluene. In the present invention, the mass ratio of the compound SM-1 to the organic solvent is preferably 1:0 to 50, and in a specific embodiment, it can be 1:0, 1:10, 1:20, 1:30, 1:40 or 1:50.

[0070] In the present invention, the temperature of the amidation reaction is preferably 60-190°C, and in specific embodiments it can be 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C or 190°C; the pressure of the amidation reaction is preferably -1-0MPa, and in specific embodiments it can be -1MPa, -0.8MPa, -0.6MPa, -0.5MPa, -0.3MPa, -0.2MPa, -0.1MPa or 0MPa; the time of the amidation reaction is preferably 0.5-12h, and in specific embodiments it can be 0.5h, 1h, 2h, 3h, 5h, 8h, 10h or 12h.

[0071] After completing the amidation reaction, the present invention preferably further comprises: first cooling the reaction system obtained by the amidation reaction, adding non-polar solvent n-hexane, second cooling under stirring, heat preservation and crystallization, solid-liquid separation, and drying the obtained solid component to obtain compound ZJT-1. In the present invention, the temperature after the first cooling is preferably 50 to 80°C, and in a specific embodiment it can be 50°C, 60°C, 70°C or 80°C. In the present invention, the non-polar solvent preferably includes one or more of n-hexane, cyclohexane, n-heptane and petroleum ether. In the present invention, the mass ratio of the compound SM-1 and the non-polar solvent is preferably 1:0.5 to 10, and in a specific embodiment it can be 1:0.5, 1:1, 1:2, 1:3, 1:5, 1:7, 1:9 or 1:10. In the present invention, the temperature after the second cooling (i.e., the temperature of the heat preservation crystallization) is preferably 0 to 30°C, and in specific embodiments, it can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C or 30°C. In the present invention, the heat preservation crystallization time is preferably 0.5 to 5h, and in specific embodiments, it can be 0.5h, 1h, 2h, 3h, 4h or 5h. In the present invention, the solid-liquid separation preferably includes suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30 to 100°C, and in specific embodiments, it can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time, and the solvent can be completely removed.

[0072] After obtaining compound ZJT-1, the present invention performs a cyclization-reduction reaction on compound ZJT-1 to obtain compound ZJT-2.

[0073] In the present invention, the subjecting the compound ZJT-1 to a cyclization-reduction reaction preferably comprises: subjecting the compound ZJT-1 to a cyclization reaction in the presence of a cyclization catalyst, and then subjecting the compound ZJT-1 to a reduction reaction in the presence of a reduction catalyst and a reducing agent.

[0074] In the present invention, the cyclization catalyst preferably includes one or more of phosphorus oxychloride, phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride and thionyl chloride. In the present invention, the mass ratio of the compound ZJT-1 to the cyclization catalyst is preferably 1:0.5-20.

[0075] In the present invention, the temperature of the cyclization reaction is preferably 5 to 150°C, and in specific embodiments it can be 5°C, 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 85°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C or 150°C; the time of the cyclization reaction is preferably 4 to 12h, and in specific embodiments it can be 4h, 6h, 8h, 10h or 12h.

[0076] In the present invention, the cyclization reaction is preferably carried out in an organic solvent or without solvent, and the organic solvent includes one or more of a benzene solvent and a nitrile solvent, and in a specific embodiment, it can be toluene and / or acetonitrile. In the present invention, the mass ratio of the compound ZJT-1 to the organic solvent is preferably 1:0 to 20, and in a specific embodiment, it can be 1:0, 1:5, 1:10, 1:15 or 1:20.

[0077] In the present invention, when the cyclization reaction is carried out under the condition of an organic solvent, the cyclization reaction preferably further comprises: removing the solvent by reduced pressure distillation from the reaction system obtained by the cyclization reaction, and then adding an alcohol solvent to remove the solvent by reduced pressure distillation to obtain a cyclization reaction product. In the present invention, the alcohol solvent preferably includes one or more of methanol, ethanol and isopropanol.

[0078] In the present invention, the reduction catalyst preferably includes one or more of a palladium catalyst, a nickel catalyst, a cobalt catalyst, sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetylborohydride; the palladium catalyst preferably includes one or more of 10wt% palladium carbon, 5wt% palladium carbon, palladium acetate, palladium chloride and palladium hydroxide; the nickel catalyst preferably includes Raney nickel; the cobalt catalyst preferably includes Raney cobalt. In the present invention, the mass ratio of the compound ZJT-1 and the reduction catalyst is preferably 1:0.01 to 1, and in specific embodiments it can be 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1.

[0079] In the present invention, the reducing agent preferably includes hydrogen and a solid reducing agent. In the present invention, the pressure of the hydrogen is preferably 1 to 5 MPa, and in a specific embodiment, it can be 1 MPa, 2 MPa, 3 MPa, 4 MPa or 5 MPa. In the present invention, the solid reducing agent preferably includes borohydride, and more preferably includes one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetylborohydride; the solid reducing agent is preferably added in batches; before adding the solid reducing agent, the present invention preferably first reduces the temperature of the system to -50 to 10 ° C, and in a specific embodiment, it can be -50 ° C, -40 ° C, -30 ° C, -20 ° C, -10 ° C, -5 ° C, 0 ° C, 5 ° C or 10 ° C. In the present invention, the molar ratio of the compound ZJT-1 and the solid reducing agent is preferably 1:0.5 to 6, and in a specific embodiment, it can be 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6.

[0080] In the present invention, the reduction reaction is preferably carried out in an organic solvent or without a solvent, and the organic solvent includes an alcohol solvent, and in a specific embodiment, it can be methanol. In the present invention, the mass ratio of the compound ZJT-1 to the organic solvent is preferably 1:2 to 30, and in a specific embodiment, it can be 1:2, 1:5, 1:10, 1:20 or 1:30.

[0081] In the present invention, the mass ratio of the organic solvent to the compound ZJT-2 is preferably ≤100, and in specific embodiments may be 0, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90 or 100.

[0082] In the present invention, the temperature of the reduction reaction is preferably 5-150°C, and in specific embodiments it can be 5°C, 10°C, 20°C, 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 85°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C or 150°C; the time of the reduction reaction is preferably 8-80h, and in specific embodiments it can be 8h, 15h, 20h, 24h, 30h, 40h, 50h, 60h, 70h or 80h.

[0083] In the present invention, when the reducing agent is hydrogen, the reduction reaction preferably further comprises: separating the reaction system obtained by the reduction reaction into solid and liquid, concentrating the obtained liquid component under reduced pressure to dryness, mixing the obtained concentrate with water, adjusting the pH value to alkaline, separating the solid and liquid, washing the obtained solid component with water and drying it to obtain compound ZJT-2. In the present invention, the mass ratio of the compound ZJT-1 to water is preferably 1:3 to 15, and in specific embodiments it can be 1:3, 1:5, 1:7.5, 1:10, 1:12.5 or 1:15. In the present invention, the alkaline pH value is preferably 7 to 12, and in specific embodiments it can be 7, 8, 9, 10, 11 or 12. In the present invention, the alkali used to adjust the pH value preferably includes one or more of ammonia water, hydroxide, carbonate and bicarbonate, and more preferably includes one or more of ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the present invention has no special restrictions on the concentration and dosage of the alkali, and the pH value of the system can be adjusted to the above pH range. In the present invention, the two solid-liquid separations independently preferably include suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30 to 100°C, and in specific embodiments it can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special restrictions on the drying time, and the solvent can be completely removed.

[0084] In the present invention, when the reducing agent is a solid reducing agent, the reduction reaction preferably further comprises: cooling the reaction system obtained by the reduction reaction to -50 to 10°C (in a specific embodiment, it can be -50°C, -40°C, -30°C, -20°C, -10°C, -5°C, 0°C, 5°C or 10°C), dropping acetic acid for heat preservation reaction, solid-liquid separation, mixing the obtained solid component with water, adjusting the pH value to alkaline, solid-liquid separation, washing the obtained solid component with water and drying, and obtaining compound ZJT-2. In the present invention, the mass ratio of the compound ZJT-1 to acetic acid is preferably 1:0.05 to 2, and in a specific embodiment, it can be 1:0.05, 1:0.1, 1:0.5, 1:1, 1:1.5 or 1:2. In the present invention, the heat preservation reaction time is preferably 0.5 to 5h, and in a specific embodiment, it can be 0.5h, 1h, 2h, 3h, 4h or 5h. In the present invention, the mass ratio of the compound ZJT-1 to water is preferably 1:3-15, and in specific embodiments, it can be 1:3, 1:5, 1:7.5, 1:10, 1:12.5 or 1:15. In the present invention, the alkaline pH value is preferably 7-12, and in specific embodiments, it can be 7, 8, 9, 10, 11 or 12. In the present invention, the base used to adjust the pH value preferably includes one or more of ammonia water, hydroxides, carbonates and bicarbonates, and more preferably includes one or more of ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the present invention has no special restrictions on the concentration and dosage of the base, and the pH value of the system can be adjusted to the above pH range. In the present invention, the two solid-liquid separations independently preferably include suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30-100°C, and in specific embodiments can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time, as long as the solvent is completely removed.

[0085] After obtaining compound ZJT-2, the present invention performs a chiral separation reaction on compound ZJT-2 under organic solvent conditions to obtain compound ZJT-3; the organic solvent includes at least one of solvent A and solvent B; the solvent A includes one or more of alcohol solvents, ester solvents and nitrile solvents; the solvent B includes an alkane solvent.

[0086] In the present invention, the chiral separation reaction is preferably carried out with or without a resolving agent. In the present invention, the resolving agent preferably includes one or more of D-(+)-di-p-methylbenzoyltartar, mandelic acid, glycine and malic acid; the resolving agent is preferably used in the form of a resolving agent solution, and the mass ratio of the resolving agent to the solvent in the resolving agent solution is preferably 0.3 to 0.6:1, and in specific embodiments, it can be 0.3:1, 0.4:1, 0.5:1 or 0.6:1; the solvent in the resolving agent solution preferably includes one or more of methanol, ethanol and isopropanol. In the present invention, the mass ratio of the compound ZJT-2 and the resolving agent is preferably 1:0.2 to 3, and in specific embodiments, it can be 1:0.2, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0087] In the present invention, the organic solvent includes at least one of solvent A and solvent B; the solvent A includes one or more of alcohol solvents, ester solvents and nitrile solvents, and in a specific embodiment, it can be at least one of isopropanol, n-butanol, sec-butanol, ethyl acetate, isopropyl acetate and acetonitrile; the solvent B includes an alkane solvent, and in a specific embodiment, it can be one or more of n-hexane, n-heptane and cyclohexane; the mass ratio of the solvent A to the solvent B is preferably 0-50:0-50 (and not 0 at the same time), and in a specific embodiment, it can be 1:0.5.

[0088] In the present invention, the mass ratio of the compound ZJT-2 to the organic solvent is preferably 1:5 to 50, and in specific embodiments may be 1:5, 1:10, 1:15, 1:20, 1:30, 1:40 or 1:50.

[0089] In the present invention, the temperature of the chiral separation reaction is preferably 80-85°C, and in specific embodiments it can also be 80°C or 85°C; the time of the chiral separation reaction is preferably 0.5-12h, and in specific embodiments it can be 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h.

[0090] In the present invention, when the chiral separation reaction is carried out without a resolving agent, the chiral separation reaction preferably further comprises: cooling the reaction system obtained by the chiral separation reaction and then heat-keeping and crystallizing, solid-liquid separation, and drying the obtained solid component to obtain compound ZJT-3. In the present invention, the temperature after cooling is preferably 0 to 50°C, and in specific embodiments, it can be 0°C, 10°C, 20°C, 25°C, 30°C, 40°C or 50°C; the heat-keeping and crystallization time is preferably 0.5 to 5h, and in specific embodiments, it can be 0.5h, 1h, 2h, 3h, 4h or 5h; the heat-keeping and crystallization is preferably carried out under stirring conditions. In the present invention, the solid-liquid separation preferably includes suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30 to 100°C, and in specific embodiments, it can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time, and the solvent can be completely removed.

[0091] In the present invention, when a chiral separation reaction is carried out under the condition of a resolving agent, the chiral separation reaction preferably further comprises: cooling the reaction system obtained by the chiral separation reaction, heat preservation and crystallization, solid-liquid separation, mixing the obtained solid component with water, adjusting the pH value to alkaline, stirring, solid-liquid separation, and drying the obtained solid component to obtain compound ZJT-3. In the present invention, the temperature after cooling is preferably 0 to 50°C, and in specific embodiments, it can be 0°C, 10°C, 20°C, 25°C, 30°C, 40°C or 50°C; the heat preservation and crystallization time is preferably 0.5 to 5h, and in specific embodiments, it can be 0.5h, 1h, 2h, 3h, 4h or 5h; the heat preservation and crystallization is preferably carried out under stirring conditions. In the present invention, the two solid-liquid separations independently preferably include suction filtration, filtration or centrifugal separation. In the present invention, the mass ratio of the compound ZJT-2 and water is preferably 1:1-30, and in specific embodiments, it can be 1:1, 1:5, 1:10, 1:20 or 1:30. In the present invention, the alkaline pH value is preferably 7-12, and in specific embodiments, it can be 7, 8, 9, 10, 11 or 12. In the present invention, the base used to adjust the pH value preferably includes one or more of ammonia water, hydroxides, carbonates and bicarbonates, and more preferably includes one or more of ammonia water, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the present invention has no special restrictions on the concentration and dosage of the base, and the pH value of the system can be adjusted to the above pH range. In the present invention, the two solid-liquid separations independently preferably include suction filtration, filtration or centrifugal separation. In the present invention, the stirring time after adjusting the pH value to alkalinity is preferably 0.5-5h, and in specific embodiments, it can be 0.5h, 1h, 2h, 3h, 4h or 5h. In the present invention, the drying temperature is preferably 30-100°C, and in specific embodiments can be 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C; the present invention has no special limitation on the drying time, as long as the solvent is completely removed.

[0092] In the present invention, before the first solid component is mixed with water, the present invention preferably further comprises: mixing the obtained solid component with a resolving salt refining solvent, heating and then keeping warm and stirring, cooling and then keeping warm and stirring, solid-liquid separation, and then mixing the obtained solid component with water. In the present invention, the mass ratio of the compound ZJT-2 to the resolving salt refining solvent is preferably 1:10-100, and in specific embodiments, it can be 1:10, 1:20, 1:30, 1:40, 1:50, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100; the resolving salt refining solvent preferably includes one or more of water, alcohol solvents, acetonitrile, acetone, tetrahydrofuran and 1,4-dioxane, and in specific embodiments, it can be an alcohol aqueous solution; the alcohol solvent preferably includes one or more of isopropanol, methanol and ethanol; the concentration of the alcohol aqueous solution is preferably 40-90wt%, and in specific embodiments, it can be 40wt%, 50wt%, 60wt%, 70wt%, 80wt% or 90wt%. In the present invention, the heat preservation and stirring after heating is preferably heated to 50-95°C (in a specific embodiment, it can be 50°C, 60°C, 70°C, 80°C, 88°C or 95°C) and then heat preservation and stirring for 0.5-5h (in a specific embodiment, it can be 0.5h, 1h, 2h, 3h, 4h or 5h). In the present invention, the heat preservation and stirring after cooling is preferably cooled to 0-50°C (in a specific embodiment, it can be 0°C, 10°C, 20°C, 25°C, 30°C, 40°C or 50°C) and then heat preservation and stirring for 0-5h (in a specific embodiment, it can be 0.5h, 1h, 2h, 3h, 4h or 5h). In the present invention, the solid-liquid separation preferably includes suction filtration, filtration or centrifugal separation.

[0093] After obtaining the compound ZJT-3, the present invention performs a methylation reaction on the compound ZJT-3 under the condition of a methylating agent to obtain levofloxacin.

[0094] In the present invention, the methylating agent preferably includes one or more of methyl iodide, methyl chloride, methyl bromide, dimethyl sulfate and dimethyl carbonate;

[0095] The molar ratio of the compound ZJT-3 and the methylating agent is preferably 1:0.5-2, and in specific embodiments it can be 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8 or 1:2; the methylating agent is preferably added dropwise, and the dropping time is preferably 0.5-24h, and in specific embodiments it can be 0.5h, 2h, 5h, 10h, 15h, 20h or 24h; the temperature of the system during the dropwise addition is preferably the same as the temperature of the methylation reaction.

[0096] In the present invention, the methylation reaction is carried out under the condition of an alkaline reagent, and the alkaline reagent includes at least one of a carbonate and a hydroxide, and in a specific embodiment, it can be one or more of potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. In the present invention, the molar ratio of the compound ZJT-3 and the alkaline reagent is preferably 1:0.5-3, and in a specific embodiment, it can be 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0097] In the present invention, the methylation reaction is preferably carried out under solvent conditions, and the solvent preferably includes one or more of an amide solvent, a ketone solvent, a nitrile solvent and water, and in a specific embodiment, it can be one or more of DMF, acetone, acetonitrile and water. In the present invention, the mass ratio of the compound ZJT-3 to the solvent is preferably 1:5 to 50, and in a specific embodiment, it can be 1:5, 1:10, 1:15, 1:20, 1:30, 1:40 or 1:50.

[0098] In the present invention, the temperature of the methylation reaction is preferably 0-90°C, and in specific embodiments it can be 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C or 90°C; the time of the methylation reaction is preferably 0.5-5h, and in specific embodiments it can be 0.5h, 1h, 2h, 3h, 4h or 5h; the time of the methylation reaction starts when the methylation reagent is added.

[0099] After the methylation reaction, the present invention preferably further comprises: mixing the reaction system obtained by the methylation reaction with ice water, separating the solid and the liquid, and drying the obtained solid component to obtain levofloxacin. In the present invention, the mass ratio of the compound ZJT-3 and ice water is preferably 1:10 to 60, and in specific embodiments it can be 1:10, 1:20, 1:30, 1:40, 1:50 or 1:60. In the present invention, the solid-liquid separation independently preferably includes suction filtration, filtration or centrifugal separation. In the present invention, the drying temperature is preferably 30 to 80°C, and in specific embodiments it can be 30°C, 40°C, 50°C, 60°C, 70°C or 80°C; the present invention has no special limitation on the drying time, and the solvent can be completely removed.

[0100] In order to further illustrate the present invention, the preparation method of Lekeping provided by the present invention is described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0101] Example 1

[0102] Synthesis of 4,5-dimethoxy-N-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)-3-oxo-1,3-dihydroisobenzofuran-1-carboxamide (ZJT-1)

[0103] Add 30 g of compound SM-1, 300 g of DMF, and 24.6 g of compound SM-2, cool to 0°C, add 30 g of DECI and 20 g of HOBT under stirring, raise the temperature to 25°C after the addition, and keep the reaction for 24 hours. Pour the reaction system into 900 g of ice water, filter with suction, wash the filter cake with water, and dry at 60°C until the solvent is completely removed to obtain compound ZJT-1 as an off-white solid, 50.8 g, with a yield of 97.1%.

[0104] Example 2

[0105] Synthesis of 4,5-dimethoxy-N-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)-3-oxo-1,3-dihydroisobenzofuran-1-carboxamide (ZJT-1)

[0106] Add 30 g of compound SM-1 and 300 g of DMF, cool to 0°C, add 26.6 g of CDI and 3.1 g of DMPA with stirring, and react for 3 hours after the addition. Add 24.6 g of compound SM-2, raise the temperature to 25°C after the addition, and react for 24 hours. Pour the reaction system into 900 g of ice water, filter with suction, wash the filtrate with water, and heat at 60°C until the solvent is completely removed to obtain compound ZJT-1 as an off-white solid, 48.9 g, with a yield of 93.5%.

[0107] Example 3

[0108] Synthesis of 4,5-dimethoxy-N-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)-3-oxo-1,3-dihydroisobenzofuran-1-carboxamide (ZJT-1)

[0109] Add 50g SM-1 and 50g compound SM-2 to a 250ml reaction bottle, heat to 150°C, maintain the reaction system in vacuum at -0.1MPa, keep the temperature and pressure for 2h, cool to 60°C, add 100g n-hexane, stir and cool to 20°C, keep the temperature and crystallize for 1h, filter with suction, and dry the filter cake at 60°C until the solvent is completely removed to obtain compound ZJT-1 as an off-white solid, 82.8g, with a yield of 95.0%.

[0110] Example 4

[0111] Synthesis of 6,7-dimethoxy-3-(4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-2)

[0112] Under nitrogen protection, 100 g of acetonitrile and 20 g of compound ZJT-1 were added, and 25 g of phosphorus oxychloride was added dropwise with stirring. The temperature was raised to 85°C, and the mixture was stirred and reacted for 6 h. The solvent was removed under reduced pressure, and 100 g of methanol was added. After the solvent was removed under reduced pressure, 200 g of methanol was added, and 2 g of 10 wt% palladium carbon was added. Under a hydrogen atmosphere, the mixture was stirred and reacted at 25°C for 24 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. 150 g of water was added, and the pH was adjusted to 10 with aqueous ammonia. The filter cake was washed with water and dried at 60°C until the solvent was completely removed to obtain compound ZJT-2 as an off-white solid, 17.1 g, with a yield of 89.1%.

[0113] The H NMR spectrum of the compound ZJT-2 prepared in Example 4 is as follows: Figure 1 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:7.23(1H,d),6.45(1H,s),6.09(1H,d),6.02(2H,t),5.72( 1H,d),4.59(1H,d),3.99(3H,s),3.88(6H,d),2.54(1H,m),2.39(1H,m),2.16(2H,m).

[0114] Example 5

[0115] Synthesis of 6,7-dimethoxy-3-(4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-2)

[0116] Under nitrogen protection, 100 g of toluene and 20 g of compound ZJT-1 were added, 3.5 g of phosphorus pentoxide was added under stirring, 15 g of phosphorus oxychloride was added dropwise, the temperature was raised to 90°C, the mixture was stirred and reacted for 4 h, the solvent was removed under reduced pressure, 100 g of methanol was added, and after the solvent was removed under reduced pressure, 200 g of methanol was added, and 2 g of 10 wt% palladium carbon was added. Under a hydrogen atmosphere, the mixture was stirred and reacted at 25°C for 24 h, and the mixture was filtered off. The filtrate was concentrated to dryness under reduced pressure, 150 g of water was added, the pH was adjusted to 10 with aqueous ammonia, and the filter cake was washed with water and dried at 60°C until the solvent was completely removed to obtain compound ZJT-2 as an off-white solid, 15.6 g, with a yield of 81.2%.

[0117] Example 6

[0118] Synthesis of 6,7-dimethoxy-3-(4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-2)

[0119] Under nitrogen protection, 100 g of acetonitrile and 20 g of compound ZJT-1 were added, and 46 g of thionyl chloride was added dropwise with stirring. The temperature was raised to 80°C, and the mixture was stirred and reacted for 12 h. The solvent was removed under reduced pressure, and 100 g of methanol was added. After the solvent was removed under reduced pressure, 200 g of methanol was added, and 2 g of palladium carbon with a content of 10% was added. Under a hydrogen atmosphere, the mixture was stirred and reacted at 25°C for 24 h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. 150 g of water was added, and the pH was adjusted to 10 with aqueous ammonia. The mixture was filtered and washed with water. The filter cake was dried at 60°C until the solvent was completely removed to obtain compound ZJT-2 as an off-white solid, 16.4 g, with a yield of 85.4%.

[0120] Example 7

[0121] Synthesis of 6,7-dimethoxy-3-(4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-2)

[0122] Under nitrogen protection, 100 g of acetonitrile and 20 g of compound ZJT-1 were added, and 25 g of phosphorus oxychloride was added dropwise while stirring. The temperature was raised to 85°C, and the mixture was stirred and reacted for 6 h. The solvent was removed under reduced pressure, and 100 g of methanol was added. After the solvent was removed under reduced pressure, 200 g of methanol was added, the temperature was lowered to -5°C, and 7 g of sodium borohydride was added in batches. After the addition, the temperature was raised to 25°C, and the mixture was stirred and reacted for 8 h. The temperature was lowered to 0°C, and 10 g of acetic acid was added dropwise. After the addition, the mixture was stirred and reacted for 2 h. The mixture was filtered, 150 g of water was added to the filter cake, and the pH was adjusted to 10 with aqueous ammonia, filtered, the filter cake was washed with water, and dried at 60°C until the solvent was completely removed to obtain compound ZJT-2 as an off-white solid, 15.4 g, with a yield of 80.2%.

[0123] Example 8

[0124] Synthesis of (R)-6,7-dimethoxy-3-((S)-4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-3)

[0125] Add 10 g of compound ZJT-2 and 500 g of isopropanol to a 1000 ml reaction bottle, heat to 83 ° C, keep warm and stir for 1 hour, cool the resulting chiral reaction system to 30 ° C, keep warm and stir for 30 minutes, filter, and dry the filter cake at 60 ° C until the solvent is completely removed to obtain compound ZJT-3, 4.5 g of white solid, with a yield of 45%.

[0126] The HPLC test chart of the compound ZJT-2 prepared in Example 4 (the purity of the compound ZJT-2 is 100%) is shown in Figure 2 Compound ZJT-2 has two chiral centers. Four peaks will appear during chiral HPLC detection, one of which is the target and the other three are isomers.

[0127] The chiral HPLC purity of compound ZJT-3 is shown in Figure 3 It can be seen that the chiral purity of compound ZJT-3 is 99.93%.

[0128] Example 9

[0129] Synthesis of (R)-6,7-dimethoxy-3-((S)-4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-3)

[0130] In a 1000 ml reaction bottle, add 10 g of compound ZJT-2 and 100 g of isopropyl acetate, heat to 85 ° C, add 50 g of n-heptane dropwise, keep warm and stir for 1 hour after the addition, cool to 40 ° C, keep warm and stir for 30 minutes, filter with suction, and dry the filter cake at 60 ° C until the solvent is completely removed to obtain compound ZJT-3, a white solid, 4.1 g, with a yield of 41%.

[0131] Example 10

[0132] Synthesis of (R)-6,7-dimethoxy-3-((S)-4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-3)

[0133] Add 10g of compound ZJT-2, add 100g of acetonitrile, heat to 80°C, add dropwise 4.9g of D-(+)-di-p-methylbenzoyltartaric acid in 10g of methanol solution, keep warm for 1h after the addition, cool to 25°C, keep warm and stir for 30min, filter with suction, add the filter cake to 50g of water, adjust the pH to 8 with ammonia water, stir for 30min, filter with suction, and dry the filter cake at 60°C until the solvent is completely removed to obtain compound ZJT-3 as a white solid, 4.5g, with a yield of 45%.

[0134] Embodiment 11

[0135] Synthesis of (R)-6,7-dimethoxy-3-((S)-4-methoxy-5,6,7,8-tetrahydro-[1,3]dioxo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one (ZJT-3)

[0136] Add 10g of compound ZJT-2, add 100g of methanol, heat to 80°C, add dropwise a mixed solution of 4.9g of D-(+)-di-p-methylbenzoyltartaric acid and 10g of methanol, keep warm for 1h after the addition, cool to 25°C, keep warm and stir for 30min, filter with suction, add the filter cake to 500g of 60% isopropanol aqueous solution, heat to 88°C, keep warm and stir for 30min, cool to 25°C, keep warm and stir for 30min, filter with suction, add the filter cake to 50g of water, adjust the pH to 8 with ammonia water, stir for 30min, filter with suction, and dry the filter cake at 60°C until the solvent is completely removed to obtain compound ZJT-3 as a white solid, 4.0g, with a yield of 40%.

[0137] Example 12

[0138] Synthesis of Lecoping

[0139] 20 g of compound ZJT-3, 200 g of DMF and 3.5 g of potassium carbonate were added to 500 ml. The temperature was controlled at 20°C and the dropping speed was controlled for 5 h to complete the dropping of 7.1 g of methyl iodide. After the addition was completed, the reaction was kept warm for 1 h. The reaction system was poured into 600 g of ice water and filtered. The filter cake was dried at 60°C until the solvent was completely removed to obtain levofloxacin as a white solid, 19.7 g, with a yield of 95.2%.

[0140] The NMR spectrum of Lekeping is as follows Figure 4 As shown, the NMR data are as follows: 1 H-NMR(400MHz,DMSO-d6)δ:7.27(1H,d),6.46(1H,s),6.17(1H,d),6.00(2H,d),5.53(1H,d) ,4.24(1H,d),3.95(3H,s),3.95(6H,d),2.57(1H,m),2.46(4H,m),2.31(1H,m),1.91(1H,m).

[0141] The HPLC purity chart of Lekeping is shown in Figure 5 It can be seen that the purity of Lekeping is 99.801%.

[0142] Comparative Example 1

[0143] Synthesis of Lecoping

[0144] Add 4 g of compound ZJT-3, 48.8 mL of formic acid, and 10 mL of 37 wt% formaldehyde aqueous solution, heat to reflux for 30 min, cool, concentrate, add 200 mL of 10 wt% hydrochloric acid aqueous solution, adjust the pH to 8 with concentrated ammonia water under ice-water bath, filter, and dry the filter cake at 60 ° C until the solvent is completely removed to obtain levofloxacin as a gray solid, 2.1 g, with a yield of 50.7%.

[0145] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing Lekeping, comprising the following steps: Compound SM-1 and compound SM-2 are subjected to an amidation reaction to obtain compound ZJT-1; The compound ZJT-1 is subjected to a cyclization-reduction reaction to obtain a compound ZJT-2; The compound ZJT-2 is subjected to a chiral separation reaction under an organic solvent condition to obtain a compound ZJT-3; the organic solvent comprises at least one of a solvent A and a solvent B; the solvent A comprises one or more of an alcohol solvent, an ester solvent and a nitrile solvent; the solvent B comprises an alkane solvent; The compound ZJT-3 is subjected to a methylation reaction under methylating agent conditions to obtain Lecoping; 2. The preparation method according to claim 1, characterized in that: When the amidation reaction is carried out in the presence of an acid amine condensing agent: The molar ratio of the compound SM-1 to the compound SM-2 is 1:0.7-2; The organic solvent used in the amidation reaction includes one or more of an amide solvent, a sulfoxide solvent, a halogenated alkane solvent and an ether solvent; The acid amine condensation agent includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, dicyclohexylcarbodiimide, diisopropylcarbodiimide, carbonyldiimidazole and 2-(1H-[7]benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate, 4-N,N-dimethylpyridine, triethylamine, 1-hydroxybenzotriazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, O-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'- One or more of tetramethyluronium hexafluorophosphate, O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and O-(tetrahydro-1H-pyrazolo[3,4-b]pyridin-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the molar ratio of the compound SM-1 to the acid amine condensing agent is 1:0.8-6; The temperature of the amidation reaction is -10 to 80° C., and the time is 1 to 24 hours.

3. The preparation method according to claim 1, characterized in that: When the amidation reaction is carried out without an acid amine condensing agent: The molar ratio of the compound SM-1 to the compound SM-2 is 1:0.7-3; The amidation reaction is carried out in an organic solvent or without a solvent, wherein the organic solvent comprises one or more of a benzene solvent, an alkane solvent and an ether solvent; The temperature of the amidation reaction is 60 to 190° C., the pressure is -1 to 0 MPa, and the time is 0.5 to 12 hours.

4. The preparation method according to claim 1, characterized in that: The subjecting the compound ZJT-1 to a cyclization-reduction reaction comprises: subjecting the compound ZJT-1 to a cyclization reaction in the presence of a cyclization catalyst, and then subjecting the compound ZJT-1 to a reduction reaction in the presence of a reduction catalyst and a reducing agent.

5. The preparation method according to claim 4, characterized in that: The cyclization catalyst includes one or more of phosphorus oxychloride, phosphorus pentoxide, phosphorus trichloride, phosphorus pentachloride and thionyl chloride; the mass ratio of the compound ZJT-1 to the cyclization catalyst is 1:0.5-20; The temperature of the cyclization reaction is 5 to 150° C. and the time is 4 to 12 hours; The cyclization reaction is carried out in an organic solvent or without a solvent, and the organic solvent includes one or more of a benzene solvent and a nitrile solvent.

6. The preparation method according to claim 4, characterized in that: The reduction catalyst includes one or more of a palladium catalyst, a nickel catalyst, a cobalt catalyst, sodium borohydride, potassium borohydride, sodium cyanoborohydride and sodium triacetylborohydride; the mass ratio of the compound ZJT-1 to the solid reduction catalyst is 1:0.01-1; The reducing agent includes hydrogen and a solid reducing agent; the pressure of the hydrogen is 1 to 5 MPa; the solid reducing agent includes borohydride; the molar ratio of the compound ZJT-1 to the reducing agent is 1:0.5 to 6; The reduction reaction temperature is 5 to 150° C. and the time is 8 to 80 hours; The reduction reaction is carried out under the condition of an organic solvent, and the organic solvent includes an alcohol solvent.

7. The preparation method according to claim 1, characterized in that: The chiral separation reaction is carried out with or without a resolving agent; The resolving agent includes one or more of D-(+)-di-p-methylbenzoyl tartar, mandelic acid, glycine and malic acid; The mass ratio of the compound ZJT-2 to the resolving agent is 1:0.2-3.

8. The preparation method according to claim 1 or 7, characterized in that: The temperature of the chiral separation reaction is 80-85° C. and the time is 0.5-12 h.

9. The preparation method according to claim 1, characterized in that: The methylating agent includes one or more of methyl iodide, methyl chloride, methyl bromide, dimethyl sulfate and dimethyl carbonate; The molar ratio of the compound ZJT-3 to the methylating agent is 1:0.5-2.

10. The preparation method according to claim 1 or 9, characterized in that: The methylation reaction is carried out under the condition of an alkaline reagent, wherein the alkaline reagent includes at least one of a carbonate and a hydroxide; the molar ratio of the compound ZJT-3 to the alkaline reagent is 1:0.5-3; The methylation reaction is carried out under solvent conditions, and the solvent includes one or more of an amide solvent, a ketone solvent, a nitrile solvent and water; The temperature of the methylation reaction is 0-90° C. and the time is 0.5-6 hours.

Images