A preparation method of marbofloxacin

Abstract

The present invention relates to a preparation method of marbofloxacin. The preparation method of the present invention is that under alkaline conditions, ethyl 2,3,4,5-tetrafluorobenzoate reacts with acetonitrile to prepare intermediate (I), intermediate (I) reacts with triethyl orthoformate and acetic anhydride and then reacts with formylhydrazine to prepare intermediate (II), intermediate (II) cyclizes under alkaline conditions to prepare intermediate (III), intermediate (III) is hydrolyzed with base and then cyclizes with formaldehyde to prepare intermediate (IV), and intermediate (IV) reacts with N -methylpiperazine and then through N -methylation to prepare marbofloxacin. The raw materials of the present invention are cheap, the reaction conditions are mild, the operation is easy, the product yield and purity are high, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the fields of pharmaceutical synthesis and organic synthesis, and particularly relates to a preparation method of marbofloxacin. Background Art

[0002] Marbofloxacin is a third-generation veterinary fluoroquinolone antibacterial drug, which was first developed by Roche and further developed by Virbac in France and launched in Europe. Marbofloxacin has strong antibacterial activity, a long elimination half-life, a bioavailability close to 100%, and almost no residue in animal blood, feces and tissues, and is very popular in the market. Currently, the typical synthesis route of marbofloxacin is as follows:

[0003] The synthesis route of marbofloxacin disclosed in EP4801584:

[0004]

[0005] The product yield of this route is relatively low, and complex diethyl ethoxyvinylmalonate (EMME) and expensive methyl iodide reagents are used, resulting in high industrial production costs.

[0006] CN107383058 discloses the following synthesis route:

[0007]

[0008] This route involves the preparation problem of the intermediate 1,1,1-trichloro-4-(4-methylpiperazin-1-yl)but-3-en-2-one, the process is relatively complex, there are environmental pollution problems, and the product yield is not high.

[0009] CN107522718 uses 2,4,5-trifluoro-3-methoxybenzoyl chloride as the starting material, and prepares marbofloxacin through side chain connection, amination, cyclization, piperazine condensation, hydrolysis, re-cyclization, and then alkali dissolution and acid adjustment. There is also the problem that the intermediate used is not easily commercially available.

[0010]

[0011] The other reported synthesis routes are basically evolutions of the above several routes and will not be elaborated. In short, the existing synthesis routes of marbofloxacin all have some drawbacks, and it is necessary to develop a new preparation method of marbofloxacin. Summary of the Invention

[0012] The object of the present invention is to provide a preparation method of marbofloxacin with commercially available and inexpensive raw materials, less environmental pollution in the preparation process, simple operation, high yield and high purity.

[0013] To achieve the above object, the technical solution adopted by the present invention is: a preparation method of marbofloxacin, the preparation method comprising the following steps:

[0014]

[0015] Wherein, M is K, Na; the base is NaH, EtONa, t BuOK.

[0016] As a preferred embodiment of the preparation method of the present invention, the specific operation of the step (1) is: adding ethyl 2,3,4,5-tetrafluorobenzoate, acetonitrile and a base into anhydrous toluene, refluxing for 3 - 4 h, distilling off the alcohol, cooling to room temperature, filtering, washing with toluene, adding water to the filter cake, stirring to dissolve, adjusting the pH to 2 - 3 with dilute hydrochloric acid, extracting with dichloromethane, drying with anhydrous sodium sulfate, filtering, concentrating, and recrystallizing with toluene to obtain the intermediate (I).

[0017] As a preferred embodiment of the preparation method of the present invention, the specific operation of the step (2) is: successively adding the intermediate (I), acetic anhydride, and triethyl orthoformate into a reaction kettle, stirring and heating to 110 °C, reacting for 1 - 2 h, then heating to 130 °C, reacting for 4 - 5 h, distilling off the generated ethyl acetate during the reaction, after the reaction is completed, evaporating to dryness under reduced pressure, adding toluene to dissolve, stirring at room temperature, dropping a toluene solution of formylhydrazine, reacting for 24 h, evaporating to dryness under reduced pressure, and recrystallizing with ethanol to obtain the intermediate (II).

[0018] As a preferred embodiment of the preparation method of the present invention, the specific operation of the step (3) is: heating a mixture of anhydrous toluene and anhydrous K2CO3 to 110 °C, dropping an anhydrous toluene solution of the intermediate (II), refluxing for 1.5 - 3 h, cooling to room temperature, filtering, concentrating the filtrate to dryness under reduced pressure, and recrystallizing with toluene / methanol to obtain the intermediate (III).

[0019] As a preferred embodiment of the preparation method of the present invention, the specific operation of the step (4) is: under nitrogen protection, mixing the intermediate (III), dioxane and a 7 - 9% KOH or NaOH solution, stirring and heating to 100 °C, simultaneously distilling off ethanol, sealing the reaction kettle, heating to 110 - 125 °C, reacting for 15 - 24 h, cooling to 40 - 50 °C, adding concentrated hydrochloric acid to the reaction solution until the pH is 5 - 6, adding a 37% formaldehyde solution, refluxing for 2 - 3 h, evaporating to dryness under reduced pressure, removing inorganic salts, and recrystallizing with ethanol to obtain the intermediate (IV);

[0020] As a preferred embodiment of the preparation method of the present invention, the specific operation of the step (5) is: dissolving the intermediate (IV) in DMF, adding K2CO3 and N -methylpiperazine, reacting at 120 °C for 4 - 5 h, after the reaction is completed, recovering DMF and the excessive N -methylpiperazine under reduced pressure, and recrystallizing the residue with 95% ethanol to obtain the intermediate (V);

[0021] As a preferred embodiment of the preparation method of the present invention, the specific operation of step (6) is as follows: Add intermediate (V) to water, stir, add 10% NaOH solution dropwise to dissolve, control the pH of the reaction solution at 8.5 - 9.0, add dimethyl sulfate dropwise at 30 - 35°C, react for 2 - 3 h, cool to room temperature, adjust the pH of the reaction solution to 10 - 11 with 10% NaOH solution, extract with ethyl acetate, remove water-insoluble substances, adjust the pH of the aqueous phase to 7 - 7.5 with dilute hydrochloric acid, extract with ethyl acetate, dry, filter, concentrate under reduced pressure to dryness, recrystallize with 95% ethanol, and dry under reduced pressure at 60°C to obtain marbofloxacin.

[0022] As a preferred embodiment of the preparation method of the present invention, in step (1), the molar ratio of ethyl 2,3,4,5 - tetrafluorobenzoate, acetonitrile and base is 1:1.3 - 2:1.25 - 1.5; in step (2), the molar ratio of intermediate (I), triethyl orthoformate, acetic anhydride and formylhydrazine is 1:2 - 2.2:5 - 5.5:1 - 1.05; in step (3), the molar ratio of intermediate (II) and K2CO3 is 1:1.5 - 2.0; in step (4), the molar ratio of intermediate (III), KOH or NaOH and formaldehyde is 1:3.1 - 3.3:1.5 - 2.0; in step (5), the molar ratio of intermediate (IV), K2CO3 and N -methylpiperazine is 1:1:2.3 - 2.5; in step (6), the molar ratio of intermediate (V) and dimethyl sulfate is 1:1.05 - 1.1.

[0023] Compared with the prior art, the beneficial effects and advantages of the present invention are as follows:

[0024] The present invention develops a new preparation method of marbofloxacin. Using the technical scheme of the present invention to prepare marbofloxacin, the yield and purity of the product are superior to the existing preparation technologies. The raw materials used are cheap and easily available, the reaction conditions are mild, the operation is simple, the environmental pollution is small, and it is suitable for industrial production. Embodiment

[0025] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto. Example 1

[0026] 22.2 g (0.1 mol) of ethyl 2,3,4,5-tetrafluorobenzoate, 6.6 mL of acetonitrile and 3 g (0.125 mol) of NaH were added to 100 mL of anhydrous toluene, and the mixture was refluxed for 3 h, cooled to room temperature, filtered, washed with toluene, the filter cake was added with water, stirred to dissolve, the pH was adjusted to 2 - 3 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was recrystallized from toluene to obtain intermediate (I) with a yield of 70.9%. ESI-MS (m / z): 217 [M] + 。 Example 2

[0027] 22.2 g (0.1 mol) of ethyl 2,3,4,5-tetrafluorobenzoate, 9.8 mL of acetonitrile and 10.2 g (0.15 mol) of EtONa were added to 100 mL of anhydrous toluene, and the mixture was refluxed for 4 h, ethanol was distilled off, cooled to room temperature, filtered, washed with toluene, the filter cake was added with water, stirred to dissolve, the pH was adjusted to 2 - 3 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was recrystallized from toluene to obtain intermediate (I) with a yield of 75.3%. Example 3

[0028] 22.2 g (0.1 mol) of ethyl 2,3,4,5-tetrafluorobenzoate, 9.8 mL of acetonitrile and 16.8 g (0.15 mol) of KOBu t were added to 100 mL of anhydrous toluene, and the mixture was refluxed for 4 h, tert-butanol was distilled off, cooled to room temperature, filtered, washed with toluene, the filter cake was added with water, stirred to dissolve, the pH was adjusted to 2 - 3 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was recrystallized from toluene to obtain intermediate (I) with a yield of 76.2%. Example 4

[0029] 21.7 g (0.1 mol) of intermediate (I), 51 g (0.5 mol) of acetic anhydride and 29.6 g (0.2 mol) of triethyl orthoformate were successively added to a reaction kettle, stirred and heated to 110 °C, reacted for 1 h, then heated to 130 °C and reacted for 5 h. Ethyl acetate formed during the reaction was distilled off simultaneously. After the reaction was completed, it was evaporated to dryness under reduced pressure, 100 mL of toluene was added and stirred to dissolve, and a toluene solution of 6.3 g (0.105 mol) of formylhydrazine was added dropwise at room temperature, reacted for 24 h, evaporated to dryness under reduced pressure, and recrystallized from ethanol to obtain intermediate (II) with a yield of 85.7%. ESI-MS (m / z): 287 [M] + ; 1 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.96 (s,1H), 7.87 (s, 1H), 7.25 (s, 1H), 3.85 (s, 1H). Example 5

[0030] In a reaction kettle, 21.7 g (0.1 mol) of intermediate (I), 56.1 g (0.55 mol) of acetic anhydride, and 32.5 g (0.22 mol) of triethyl orthoformate were added in sequence. The mixture was stirred and heated to 110 °C and reacted for 2 h, then heated to 130 °C and reacted for 4 h. During the reaction, the generated ethyl acetate was distilled out. After the reaction was completed, it was evaporated to dryness under reduced pressure, dissolved in 100 mL of toluene, and a toluene solution of 6 g (0.1 mol) of formylhydrazine was added dropwise with stirring at room temperature. The reaction was carried out for 24 h, then evaporated to dryness under reduced pressure, and recrystallized from ethanol to obtain intermediate (II) with a yield of 86.6%. Example 6

[0031] In a reaction kettle, 21.7 g (0.1 mol) of intermediate (I), 54 g (0.53 mol) of acetic anhydride, and 31.1 g (0.21 mol) of triethyl orthoformate were added in sequence. The mixture was stirred and heated to 110 °C and reacted for 1 h, then heated to 130 °C and reacted for 5 h. During the reaction, the generated ethyl acetate was distilled out. After the reaction was completed, it was evaporated to dryness under reduced pressure, dissolved in 100 mL of toluene, and a toluene solution of 6.1 g (0.102 mol) of formylhydrazine was added dropwise with stirring at room temperature. The reaction was carried out for 24 h, then evaporated to dryness under reduced pressure, and recrystallized from ethanol to obtain intermediate (II) with a yield of 86.4%. Example 7

[0032] A mixture of 100 mL of anhydrous toluene and 20.7 g (0.15 mol) of anhydrous K2CO3 was heated to 110 °C, and a solution of 28.7 g (0.1 mol) of intermediate (II) in anhydrous toluene was added dropwise. The mixture was refluxed for 1.5 h, cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure and recrystallized from toluene / methanol to obtain intermediate (III) with a yield of 97.9%. ESI-MS (m / z): 267[M] + ; 1 H NMR(400MHz, CDCl3) δ 8.34 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.98 (s, 1H). Example 8

[0033] A mixture of 100 mL of anhydrous toluene and 27.6 g (0.2 mol) of anhydrous K2CO3 was heated to 110 °C, and a solution of 28.7 g (0.1 mol) of intermediate (II) in anhydrous toluene was added dropwise. The mixture was refluxed for 2 h, cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure and recrystallized from toluene / methanol to obtain intermediate (III) with a yield of 98.7%. Example 9

[0034] A mixture of 100 mL of anhydrous toluene and 24.8 g (0.18 mol) of anhydrous K2CO3 was heated to 110 °C, and a solution of 28.7 g (0.1 mol) of intermediate (II) in anhydrous toluene was added dropwise. The mixture was refluxed for 3 h, cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Recrystallization from toluene / methanol gave intermediate (III) with a yield of 98.7%. Example 10

[0035] Under nitrogen protection, 26.7 g (0.1 mol) of intermediate (III), 100 mL of dioxane, and 12.4 g (0.31 mol) of 7% NaOH solution were mixed. The mixture was stirred and heated to 100 °C while ethanol was distilled off. The reaction kettle was sealed and heated to 110 °C for 24 h. After cooling to 40 °C, concentrated hydrochloric acid was added until the pH of the reaction solution reached 5 - 6. Then 12.2 g of 37% formaldehyde solution was added, and the mixture was refluxed for 3 h. After evaporation to dryness under reduced pressure, recrystallization from ethanol gave intermediate (IV) with a yield of 93.1%. Intermediate (IV, base) ESI-MS (m / z): 268 [M] + ; 1 1H NMR (400 MHz, CDCl3) δ 11.04 (br, 1H), 8.66 (s, 1H), 7.71 (s, 1H), 5.10 (s, 2H), 4.11 (s, 1H). Example 11

[0036] Under nitrogen protection, 26.7 g (0.1 mol) of intermediate (III), 100 mL of dioxane, and 18.5 g (0.33 mol) of 9% KOH solution were mixed. The mixture was stirred and heated to 100 °C while ethanol was distilled off. The reaction kettle was sealed and heated to 120 °C for 18 h. After cooling to 50 °C, concentrated hydrochloric acid was added until the pH of the reaction solution reached 5 - 6. Then 16.2 g of 37% formaldehyde solution was added, and the mixture was refluxed for 2 h. After evaporation to dryness under reduced pressure, recrystallization from ethanol gave intermediate (IV) with a yield of 93.6%. Example 12

[0037] Under nitrogen protection, 26.7 g (0.1 mol) of intermediate (III), 100 mL of dioxane, and 17.9 g (0.32 mol) of 8% KOH solution were mixed. The mixture was stirred and heated to 100 °C while ethanol was distilled off. The reaction kettle was sealed and heated to 125 °C for 15 h. After cooling to 45 °C, concentrated hydrochloric acid was added until the pH of the reaction solution reached 5 - 6. Then 13.8 g of 37% formaldehyde solution was added, and the mixture was refluxed for 3 h. After evaporation to dryness under reduced pressure, recrystallization from ethanol gave intermediate (IV) with a yield of 93.8%. Example 13

[0038] Dissolve 34.1 g (0.1 mol) of intermediate (IV) in 120 mL of DMF, add 13.8 g (0.1 mol) of K2CO3 and 23 g (0.23 mol) N of N-methylpiperazine, react at 120 °C for 5 h. After the reaction is completed, cool to room temperature, filter, recover DMF and excess N N-methylpiperazine under reduced pressure. Recrystallize the residue from 95% ethanol to obtain intermediate (V) with a yield of 86.2%; ESI-MS (m / z): 348 [M] + ; 1 1H NMR (400 MHz, CDCl3) δ 11.02 (br, 1H), 8.65 (s, 1H), 7.71 (s, 1H), 5.09 (s, 2H), 4.10 (s, 1H), 3.44 (m, 4H), 2.56 (m, 4H), 2.37 (s, 3H). Example 14

[0039] Dissolve 34.1 g (0.1 mol) of intermediate (IV) in 120 mL of DMF, add 13.8 g (0.1 mol) of K2CO3 and 25 g (0.25 mol) N of N-methylpiperazine, react at 120 °C for 4 h. After the reaction is completed, cool to room temperature, filter, recover DMF and excess N N-methylpiperazine under reduced pressure. Recrystallize the residue from 95% ethanol to obtain intermediate (V) with a yield of 86.7%. Example 15

[0040] Dissolve 34.1 g (0.1 mol) of intermediate (IV) in 120 mL of DMF, add 13.8 g (0.1 mol) of K2CO3 and 24 g (0.24 mol) N of N-methylpiperazine, react at 120 °C for 4 h. After the reaction is completed, cool to room temperature, filter, recover DMF and excess N N-methylpiperazine under reduced pressure. Recrystallize the residue from 95% ethanol to obtain intermediate (V) with a yield of 86.8%. Example 16

[0041] 34.8 g (0.1 mol) of intermediate (V) was added to water, stirred, and 10% NaOH solution was added dropwise for dissolution. The pH of the reaction solution was controlled at 8.5 - 9.0. At 30 °C, 13.2 g (0.105 mol) of dimethyl sulfate was added dropwise, and the reaction was carried out for 3 h. After cooling to room temperature, the pH of the reaction solution was adjusted to 10 with 10% NaOH solution, and then extracted with ethyl acetate. The water-insoluble substances were removed. The pH of the aqueous phase was adjusted to 7 - 7.5 with dilute hydrochloric acid, and then extracted with ethyl acetate. After drying over anhydrous sodium sulfate, filtration was carried out, and the solution was concentrated under reduced pressure to dryness. Recrystallization was carried out with 95% ethanol, and drying was carried out under reduced pressure at 60 °C to obtain marbofloxacin, with an overall yield of 51.6% (calculated based on ethyl 2,3,4,5-tetrafluorobenzoate), a purity of 99.9%, m.p. 269 - 272 °C, and ESI-MS (m / z): 362 [M] + ; 1 1H NMR (400 MHz, CDCl3) δ 14.0 (br, 1H), 8.65 (s, 1H), 7.70 (s, 1H), 5.09(s, 2H), 3.48 (m, 4H), 3.30 (s, 3H), 2.66 (m, 4H), 2.42 (s, 3H). Example 17

[0042] 34.8 g (0.1 mol) of intermediate (V) was added to water, stirred, and 10% NaOH solution was added dropwise for dissolution. The pH of the reaction solution was controlled at 8.5 - 9.0. At 35 °C, 13.6 g (0.108 mol) of dimethyl sulfate was added dropwise, and the reaction was carried out for 2 h. After cooling to room temperature, the pH of the reaction solution was adjusted to 11 with 10% NaOH solution, and then extracted with ethyl acetate. The water-insoluble substances were removed. The pH of the aqueous phase was adjusted to 7 - 7.5 with dilute hydrochloric acid, and then extracted with ethyl acetate. After drying over anhydrous sodium sulfate, filtration was carried out, and the solution was concentrated under reduced pressure to dryness. Recrystallization was carried out with 95% ethanol, and drying was carried out under reduced pressure at 60 °C to obtain marbofloxacin, with an overall yield of 51.4% (calculated based on ethyl 2,3,4,5-tetrafluorobenzoate), a purity of 99.9%, and m.p. 270 - 272 °C. Example 18

[0043] 34.8 g (0.1 mol) of intermediate (V) was added to water, stirred, and 10% NaOH solution was added dropwise for dissolution. The pH of the reaction solution was controlled at 8.5 - 9.0. At 35 °C, 13.9 g (0.11 mol) of dimethyl sulfate was added dropwise, and the reaction was carried out for 2 h. After cooling to room temperature, the pH of the reaction solution was adjusted to 11 with 10% NaOH solution, and then extracted with ethyl acetate. The water-insoluble substances were removed. The pH of the aqueous phase was adjusted to 7 - 7.5 with dilute hydrochloric acid, and then extracted with ethyl acetate. After drying over anhydrous sodium sulfate, filtration was carried out, and the solution was concentrated under reduced pressure to dryness. Recrystallization was carried out with 95% ethanol, and drying was carried out under reduced pressure at 60 °C to obtain marbofloxacin, with an overall yield of 51.3% (calculated based on ethyl 2,3,4,5-tetrafluorobenzoate), a purity of 99.8%, and m.p. 269 - 272 °C.

[0044] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A preparation method of marbofloxacin, characterized in that, The preparation method comprises the following steps: Wherein, M is K, Na; the base is EtONa, t BuOK.

2. The preparation method according to claim 1, characterized in that, The specific operation of step (1) is as follows: Ethyl 2,3,4,5-tetrafluorobenzoate, acetonitrile and a base are added to anhydrous toluene, and the mixture is refluxed for 3 - 4 h. The alcohol is distilled off, cooled to room temperature, filtered, washed with toluene, the filter cake is stirred and dissolved in water, the pH is adjusted to 2 - 3 with dilute hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from toluene to obtain intermediate (I).

3. The preparation method according to claim 1, wherein The specific operation of step (2) is as follows: Intermediate (I), acetic anhydride and triethyl orthoformate are successively added to a reaction kettle, stirred and heated to 110 °C, reacted for 1 - 2 h, then heated to 130 °C and reacted for 4 - 5 h. Ethyl acetate formed during the reaction is distilled off simultaneously. After distilling to dryness under reduced pressure, it is dissolved in toluene, stirred at room temperature, and a toluene solution of formylhydrazine is added dropwise, reacted for 24 h, distilled to dryness under reduced pressure, and recrystallized from ethanol to obtain intermediate (II).

4. The preparation method according to claim 1, characterized in that, The specific operation of step (3) is as follows: A mixture of anhydrous toluene and anhydrous K2CO3 is heated to 110 °C, a toluene solution of intermediate (II) is added dropwise, refluxed for 1.5 - 3 h, cooled to room temperature, filtered, the filtrate is concentrated to dryness under reduced pressure, and recrystallized from toluene / methanol to obtain intermediate (III).

5. The preparation method according to claim 1, characterized in that, The specific operation of step (5) is as follows: Intermediate (IV) is dissolved in DMF, K2CO3 and N-methylpiperazine are added, reacted at 120 °C for 4 - 5 h. After the reaction is completed, it is cooled to room temperature, filtered, DMF and excessive N-methylpiperazine are recovered under reduced pressure, and the residue is recrystallized from 95% ethanol to obtain intermediate (V).

6. The preparation method according to claim 1, wherein, The specific operation of step (6) is as follows: Intermediate (V) is added to water, stirred, and a 10% NaOH solution is added dropwise to dissolve it. The pH of the reaction solution is controlled at 8.5 - 9.0, and dimethyl sulfate is added dropwise at 30 - 35 °C, reacted for 2 - 3 h, cooled to room temperature, the pH of the reaction solution is adjusted to 10 - 11 with a 10% NaOH solution, extracted with ethyl acetate, the water-insoluble substances are removed, the pH of the aqueous phase is adjusted to 7 - 7.5 with dilute hydrochloric acid, extracted with ethyl acetate, dried, filtered, distilled to dryness under reduced pressure, recrystallized from 95% ethanol, and dried under reduced pressure at 60 °C to obtain marbofloxacin.

7. The preparation method according to claim 1, wherein, In step (1), the molar ratio of ethyl 2,3,4,5-tetrafluorobenzoate, acetonitrile and the base is 1:1.3 - 2:1.25 - 1.5; in step (2), the molar ratio of intermediate (I), triethyl orthoformate, acetic anhydride and formylhydrazine is 1:2 - 2.2:5 - 5.5:1 - 1.05; in step (3), the molar ratio of intermediate (II) and K2CO3 is 1:1.5 - 2.0; in step (4), the molar ratio of intermediate (III), KOH or NaOH and formaldehyde is 1:3.1 - 3.3:1.5 - 2.0; in step (5), the molar ratio of intermediate (IV), K2CO3 and N-methylpiperazine is 1:1:2.3 - 2.5; in step (6), the molar ratio of intermediate (V) and dimethyl sulfate is 1:1.05 - 1.1.

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