Preparation methods of cobutrecalcet and its intermediates

Abstract

The present invention discloses a preparation method of cobutrecin calcium and its intermediate, which relates to the technical field of medicine. The method includes the steps of dissolving compound 2 in water, performing vacuum distillation, and stopping the distillation when the pH of the residue is 5.5 - 6.5; mixing the residue with water, adding cation resin, stirring, filtering, and collecting the mother liquor to obtain a solution containing compound 3; mixing the solution containing compound 3 with calcium carbonate, reacting, cooling, performing vacuum distillation, adding a solvent to the residue, keeping warm, cooling, separating the precipitated product, and drying to obtain cobutrecin calcium. The present invention has less solid waste. The process of free intermediate butanol ammonium salt to cobutrecin calcium can be prepared by a one-pot method, which reduces the cost, simplifies the process, and has high yield and purity.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a method for preparing cobutamol calcium and its intermediates. Background Art

[0002] Cobutamol calcium is one of the excipients of gadobutrol, a calcium coordination compound composed of calcium and the macrocyclic ligand dihydroxy-hydroxy-methylpropyl-tetraazacyclododecane-triacetic acid (butrol), which can solve the problem of free gadolinium release in gadobutrol preparations, and thus effectively solve the toxicity problem of gadolinium ions in the preparations.

[0003] Chinese Patent CN113272284A discloses a method for producing butrol by a simple production method, then producing high-purity butrol through a purification process, and then producing high-purity cobutamol calcium using the high-purity butrol. The method includes: the first step: reacting cyclen (1,4,7,10-tetraazacyclododecane) with 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane to obtain 3-(1,4,7,10-tetraazacyclododecan-1-yl)butane-1,2,4-triol, and then reacting it with haloacetic acid to generate crude butrol; the second step: preliminarily purifying the crude butrol using an ion exchange resin; the third step: performing secondary purification on the preliminarily purified crude butrol by crystallization. This method requires adsorbing butrol with a cation resin column, eluting with a large amount of ammonia water, freeing with a cation resin, dissolving to precipitate butrol, and adding calcium carbonate for complexation to obtain cobutamol calcium. A large amount of cation resin is used in the above process, resulting in high costs and a cumbersome purification process.

[0004] Chinese Patent CN114573522A discloses a new crystal form of cobutamol calcium and its preparation method, including the steps of adding 3600 g of purified water, 1200 g of gadobutrol, and 475 g of oxalic acid dihydrate to a reaction flask. Reacting at 90°C; after the reaction, filtering by suction, slowly adding 285 g of sodium hydroxide to the filtrate, filtering by suction, and transferring the filtrate to a reaction flask. Adding 9800 g of absolute ethanol dropwise at 85°C, filtering by suction; concentrating the filtrate under reduced pressure, adding 520 g of purified water and 1600 g of absolute ethanol, pulping, then transferring the slurry to a reaction flask and stirring evenly at 85°C, and adding 3600 g of ethanol dropwise. Filtering by suction and drying to obtain 750 g of ligand sodium salt, with a molar yield of 75.4%. This method involves nanofiltration to remove sodium chloride, making it difficult to achieve large-scale production and having high costs.

[0005] Chinese Patent CN109803958A discloses a method for producing a crystal form of cobutamol calcium variant A. The gadolinium complex (gadobutrol) of dihydroxy-hydroxy-methylpropyl-tetraazacyclododecane-triacetic acid is decoordinated, the precipitated gadolinium salt is removed, and then the solution containing the free ligand is bound to an acidic ion exchanger, then eluted with an alkaline aqueous solution, then complexed with calcium ions, crystallized from an aqueous ethanol solution, and then the product is dried and separated. Gadobutrol is first decoordinated to remove gadolinium and then purified through an ion exchange column, with a cumbersome process and high cost.

[0006] In view of this, the present invention provides a method for preparing cobutamol calcium intermediates and cobutamol calcium with low cost, simple process, high yield and high purity. Summary of the Invention

[0007] The object of the present invention is to provide a method for preparing cobutamol calcium and its intermediates, which avoids using high-value gadobutrol as a raw material, avoids the use of ion exchange columns and a large amount of ion exchange resins, has a high yield and less solid waste. The process from the free intermediate butol ammonium salt to cobutamol calcium can be prepared by a one-pot method, without the need to obtain solid butol in the middle, reducing costs, simplifying the process, and having a high yield and high purity.

[0008] To achieve the above-mentioned invention object, the technical solution of the present invention is as follows:

[0009] On the one hand, the present invention provides a method for preparing cobutamol calcium, comprising the following steps:

[0010]

[0011] (1) Dissolve compound 2 in water, distill under reduced pressure until the pH of the residue is 5.5 - 6.5 and stop distillation to obtain residue 1;

[0012] (2) Mix the residue 1 obtained in step (1) with water, add a cation resin, stir, filter, and collect the mother liquor to obtain a solution containing compound 3 (butol solution);

[0013] (3) Mix the solution containing compound 3 obtained in step (2) with calcium carbonate, react, cool down, and distill under reduced pressure to collect residue 2;

[0014] (4) Heat the residue 2 obtained in step (3), add a solvent, keep warm, cool down, separate the precipitated substance, and dry the precipitated substance to obtain cobutamol calcium,

[0015] Wherein, the purity of the compound 2 is ≥99.0%, preferably ≥99.5%.

[0016] Preferably, in step (1), the mass ratio of the compound 2 to water is 1:4 - 8, and more preferably 1:6.

[0017] Preferably, in step (1), the conditions for vacuum distillation are: temperature ≤ 50°C, vacuum degree -0.08 to -0.1 MPa.

[0018] Preferably, in step (1), the pH of the residue is 6.

[0019] Preferably, in step (2), the mass ratio of water to compound 2 in step (1) is 1 - 3:1, more preferably 2:1.

[0020] Preferably, in step (2), the cation exchange resin is selected from at least one of Amberlite IR120H, FPC22, FPC11, FPC23UPS, CR99K / 310, and most preferably Amberlite IR120.

[0021] Preferably, in step (2), the mass ratio of the cation exchange resin to compound 2 in step (1) is 5 - 15:5 - 15, more preferably 7.1:10.

[0022] Preferably, in step (2), the method of adding the cation exchange resin is: adding in portions, the mass ratios of the first three additions are 3:3:1, and the additional amount for each subsequent addition is 1% of the mass of compound 2 until pH ≤ 3.8.

[0023] Preferably, in step (2), to ensure complete collection, the steps after filtration further include: rinsing with water.

[0024] Preferably, in step (3), the mass ratio of calcium carbonate to compound 2 in step (1) is 1 - 3:10, more preferably 1.9:10.

[0025] Preferably, in step (3), the conditions for the reaction are: reacting at 80 - 90°C for 1 - 2 h, more preferably reacting at 85°C for 1.5 h.

[0026] Preferably, in step (3), the cooling means cooling to ≤ 50°C.

[0027] Preferably, in step (3), the conditions for vacuum distillation are: temperature ≤ 50°C, vacuum degree -0.08 to -0.1 MPa.

[0028] Preferably, in step (3), stop distillation when the mass of the distilled fraction is 14 - 19 times the mass of calcium carbonate; more preferably, stop distillation when the ratio of the mass of the distilled fraction to the mass of calcium carbonate is 30:1.9.

[0029] Preferably, in step (4), the heating temperature is 65 - 85°C, more preferably 75°C.

[0030] Preferably, in step (4), the solvent is at least one of absolute ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, and methanol, and more preferably absolute ethanol.

[0031] Even more preferably, in step (4), the mass ratio of the absolute ethanol to compound 2 in step (1) is 10:70 - 90, and further preferably 10:80.

[0032] Preferably, in step (4), the conditions for heat preservation are: heat preservation at 65 - 85 °C for 0.5 - 1.5 h, and more preferably: heat preservation at 70 - 80 °C for 1 h.

[0033] Preferably, in step (4), the cooling means cooling to 18 - 20 °C.

[0034] Preferably, in step (4), the separation specifically is: centrifugation, rinsing with ethanol to obtain a wet filter cake.

[0035] Preferably, in step (4), the drying specifically is: drying with hot air at 45 - 60 °C for 14 - 20 hours, and more preferably drying with hot air at 50 °C for 16 hours.

[0036] On the other hand, the present invention provides a preparation method of cobutrecin calcium intermediate (compound 2), comprising the following steps:

[0037]

[0038] (1) Mix compound 1, an acid, and water, heat up to reflux for reaction to obtain mixture 1, sequentially add ammonia water, methanol, and ethanol to mixture 1, stir until it becomes turbid, continue stirring at 15 - 25 °C for 20 - 24 hours, separate and dry to obtain a crude product of compound 2;

[0039] (2) Dissolve the crude product of compound 2 obtained in step (1) with a solvent, sequentially add methanol and ethanol, stir until it becomes turbid, continue stirring at 15 - 25 °C for 20 - 24 hours, separate and dry to obtain the cobutrecin calcium intermediate with a purity ≥ 99.5%,

[0040] Wherein,

[0041] In step (1), the mass ratio of compound 1, ammonia water, methanol, and ethanol is 15 - 19:10 - 15:80 - 90:250 - 260, and preferably 17:11.8:85:255;

[0042] In step (2), the mass ratio of the crude product of compound 2, the solvent, methanol, and ethanol is 12 - 14:30 - 40:50 - 65:160 - 180, and more preferably 13.5:34.5:57.5:172.5.

[0043] Preferably, in step (1), the acid is selected from hydrochloric acid, and more preferably hydrochloric acid with a mass concentration of 37%.

[0044] Preferably, in step (1), the mass ratio of compound 1, acid and water is 15 - 20:5 - 8:40 - 50, and more preferably 17:7.64:44.5.

[0045] Preferably, in step (1), the reaction is carried out under nitrogen protection for 1 - 3 h; more preferably, the time is 2 h.

[0046] Preferably, in step (1), the volume concentration of the ammonia water is 26%.

[0047] Preferably, in step (1), the sequential addition of ammonia water, methanol, and ethanol is specifically as follows:

[0048] Dropwise add ammonia water, control the temperature not exceeding 25°C, finish dropping in 1.0 - 2.0 h, stir at 15 - 25°C for 10 - 20 min after dropping, add methanol at one time, and then dropwise add ethanol, finish dropping in 1.5 - 3.5 h.

[0049] Preferably, in step (2), the solvent is selected from at least one of water, DMSO, and DMF, and more preferably water.

[0050] Preferably, in step (2), the sequential addition of methanol and ethanol is specifically as follows: Add methanol at one time, and then dropwise add ethanol, finish dropping in 1.5 - 3.5 h.

[0051] Preferably, in step (2), the separation and drying are specifically as follows: Centrifuge to dryness, and dry the wet filter cake at 45 - 65°C with forced air for 14 - 20 h, and more preferably centrifuge to dryness, and dry the wet filter cake at 50°C with forced air for 16 h.

[0052] The beneficial effects of the present invention are as follows:

[0053] (1) The present invention uses high - purity bucol ammonium salt to prepare bucol after dissociation, and defines specific process conditions, realizing the preparation of cobutrecalcium by one - pot method without separation, simplifying the process and being beneficial to industrial production.

[0054] (2) The synthesis method of the present invention is easy to purify, only requires a small amount of resin to complete purification, saves costs, has high product yield and purity, and less solid waste.

[0055] (3) Through the selection of a specific crystallization solvent (a specific ratio mixture of methanol and ethanol) and the selection of the amount of ammonia water used, the preparation of high - purity bucol ammonium salt is realized for further preparation of cobutrecalcium. Brief Description of the Drawings

[0056] Figure 1Crude product spectrum of Compound 2 of the present invention;

[0057] Figure 2 Fine product spectrum of Compound 2 of the present invention;

[0058] Figure 3 NMR spectrum of Compound 2 of the present invention;

[0059] Figure 4 Spectrum of cobutrecin calcium prepared by the present invention;

[0060] Figure 1 、 Figure 2 、 Figure 4 In , ,

[0061] , ,

[0062] , ,

[0063] , ,

[0064] , "CAD" represents the peak of the target compound. Detailed implementation manners

[0061] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and it should also fall within the scope claimed by this application.

[0062] The present invention will be further described below by way of specific examples. All chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are mass contents. Unless otherwise specified, it is understood to be carried out at room temperature. In the present invention, the water used can be selected from purified water, ultrapure water, distilled water, drinking water, etc. As specific examples of the present invention, purified water is used.

[0063] In the following examples, the mass concentration of hydrochloric acid used is 37%, the volume concentration of ammonia water used is 26%, the cation resin used is hydrogen type, purchased from Shanghai Titan Technology Co., Ltd., and the model is Amberlite IR120.

[0064] Example 1 Preparation of Compound 2

[0065]

[0066] (1) Add 37% hydrochloric acid (7.64 kg, 75 mol) and purified water (44.5 kg) to a 100 L reactor, and mix them evenly. Add Compound 1 (17.0 kg), turn on the condensing circulating water, start stirring, and protect with nitrogen. Open the steam valve, heat up to reflux, and keep the reaction at a constant temperature for 2 hours. Turn off the steam and cool down to 10 °C. Dropwise add ammonia water (26%, 11.8 kg), control the temperature not to exceed 25 °C, and finish dropping within 1.0 - 2.0 hours. After the feeding is completed, stir at 15 - 25 °C for 15 minutes, transfer the liquid material to a 500 L reactor, and add methanol (85.0 kg) at one time. Dropwise add ethanol (255.0 kg), and finish dropping in about 2 - 3 hours. After dropping, start to become turbid after stirring for about 1 hour. Continue to stir at 15 - 25 °C for 20 - 24 hours, connect the bottom valve of the reactor to a centrifuge, and centrifuge until dry to obtain the crude product of butanol ammonium salt (Compound 2) (13.5 kg), with an HPLC purity of 98.45%. The chromatogram of the crude product of Compound 2 is as shown in Figure 1 , and in the figure, the specific peak elution data are as shown in the following table:

[0067] Table 1

[0068]

[0069] (2) Transfer the crude product of butanol ammonium salt back to the 500 L reactor, add purified water (34.5 kg), stir to dissolve, add methanol (57.5 kg) at one time, dropwise add ethanol (172.5 kg), and finish dropping in about 2 - 3 hours. After dropping, start to become turbid after stirring for about 1 hour. Continue to stir at 20 °C for 22 hours, connect the bottom valve of the reactor to a centrifuge, and centrifuge until dry. Weigh the wet filter cake after drying in a blast dryer at 50 °C for 16 hours to obtain 10.5 kg of the refined product of butanol ammonium salt (Compound 2), with a yield of 81% and an HPLC purity of 99.71%.

[0070] 1H NMR (400 MHz, D 2 O) δ2.28 - 3.09 (m, 16H), 3.33 - 3.53 (m, 8H), 3.67 - 3.70 (m, 4H).

[0071] LC_MS: (ES+): m / z 451.85[M + H]+. tR = 0.590 min.

[0072] The chromatogram of the refined product of Compound 2 is as shown in Figure 2 、 Figure 3 , and in the figure, the peak elution results are as shown in the following table:

[0073] Table 2

[0074]

[0075] Example 2 Preparation of Cobutamide Calcium

[0076]

[0077] (1) Add purified water (60 kg) and butanol ammonium salt (Compound 2) (10.0 kg) to a 100 L reaction kettle, stir to dissolve, measure the pH to be 8 - 9, and perform vacuum distillation (temperature ≤ 50 °C, vacuum degree -0.08 ~ -0.1 MPa). Stop distillation after collecting 45 kg of distillate, and measure the pH of the residue to be 6.

[0078] (2) Dilute the collected residue with 20 kg of water, add cation resin (3.0 kg + 3.0 kg + 1 kg) in batches and stir for 10 minutes. Measure the pH of the supernatant to be 4.1. Add another 0.1 kg of cation resin and stir for 10 minutes. Measure the pH of the supernatant to be 3.8. Filter, rinse the kettle wall with purified water (10 kg) and wash the filter cake, and collect 51.2 kg of mother liquor, which is the butanol solution.

[0079] (3) Pour the butanol solution into a 200 L reaction kettle, start stirring, add 1.9 kg of calcium carbonate, heat, and react for 1.5 hours after the temperature rises to 85 °C. Cool down, perform vacuum distillation, and stop distillation after collecting 30 kg of distillate.

[0080] (4) Heat the collected distillate to 75 °C, control the temperature at 70 - 80 °C and dropwise add anhydrous ethanol (80 kg). After the addition, solids precipitate. Continue to keep warm for 1 hour, then cool down to 18 - 20 °C, centrifuge, wash with ethanol (5 kg), and dry the wet filter cake at 50 °C with forced air for 16 hours to obtain 8.7 kg of product, with a yield of 89% and HPLC purity: 99.72%.

[0081] (5) Characterization data: 1H NMR (400 MHz, D 2 O) δ2.12 - 2.34 (m, 4H), 2.62 - 2.80 (m,4H), 3.04 - 3.31 (m, 9H), 3.40 - 3.55 (m, 5H), 3.63 - 3.80 (m, 5H), 3.86 - 4.06 (m,1H).

[0082] LC_MS: (ES+): m / z 489.60[M + H] +. tR = 0.648min.

[0083] The cobutrel calcium spectrum is as Figure 4 , and in the figure, the peak emergence results are as follows in the table:

[0084] Table 3

[0085]

[0086] Example 3 Preparation of Compound 2

[0087] Different from Example 1, in step (1), 90 kg of methanol was added at one time, and 250 kg of ethanol was added dropwise, and the other conditions were the same.

[0088] Example 4 Preparation of Compound 2

[0089] Different from Example 1, in step (1), 80 kg of methanol was added at one time, and 260 kg of ethanol was added dropwise, and the other conditions were the same.

[0090] Example 5 Preparation of Compound 2

[0091] Different from Example 1, in step (2), 50 kg of methanol was added, and 180 kg of ethanol was added dropwise, and the other conditions were the same.

[0092] Example 6 Preparation of Compound 2

[0093] Different from Example 1, in step (2), 65 kg of methanol was added, and 160 kg of ethanol was added dropwise, and the other conditions were the same.

[0094] Example 7 Preparation of Compound 2

[0095] Different from Example 1, in step (2), 15 kg of ammonia water was added, and the other conditions were the same.

[0096] Example 8

[0097] Using Compound 2 prepared by the method of Example 1 as the raw material, cobutamol calcium was further prepared. Different from Example 2, in step (3), the distillation was stopped after collecting 35 kg of the distillate, and the rest was the same.

[0098] Comparative Example 1 Preparation of Compound 2

[0099] Different from Example 1, in step (1), 100 kg of methanol was added at one time, and 240 kg of ethanol was added dropwise, and the other conditions were the same.

[0100] Comparative Example 2 Preparation of Compound 2

[0101] Different from Example 1, in step (1), 255 kg of methanol was added at one time, and 85 kg of ethanol was added dropwise, and the other conditions were the same.

[0102] Comparative Example 3 Preparation of Compound 2

[0103] Different from Example 1, in step (2), 20 kg of ammonia water was added, and the other conditions were the same.

[0104] Following the same method as in Example 2, Cobutramide Calcium was prepared successively using the compounds 2 prepared in Examples 3 - 7 and Comparative Examples 1 - 3.

[0105] Formula for calculating the yield of Compound 2: (Amount of Compound 2 obtained) / ((501.58 ÷ 658.88) × Amount of Compound 1 charged) × 100%;

[0106] Formula for calculating the yield of Cobutramide Calcium: (Amount of Cobutramide Calcium obtained / Theoretical amount) × 100%;

[0107] Wherein, the theoretical amount = 0.975 × Amount of Compound 2 charged.

[0108] The purity detection method is: HPLC.

[0109] The results are as follows:

[0110] Table 4

[0111]

[0112] Comparative Example 4

[0113] Refer to the preparation method of Example 2, and it was prepared using Compound 2 with a purity of 89.2%, and the rest were the same.

[0114] Comparative Example 5

[0115] Using the Compound 2 prepared by the method of Example 1 as the raw material, Cobutramide Calcium was further prepared. Different from Example 2, in step (1), the distillation was stopped when the pH of the residue was detected to be 7, and the rest were the same.

[0116] Comparative Example 6

[0117] Using the Compound 2 prepared by the method of Example 1 as the raw material, Cobutramide Calcium was further prepared. Different from Example 2, in step (2), the addition amounts of the cation resin for the first three times were 12 kg + 12 kg + 10 kg, and the rest were the same.

[0118] The results are as follows:

[0119] Table 5

[0120]

[0121] The results show that the purity of Compound 2 has an obvious influence on the purity and yield of the subsequent Cobutramide Calcium product; while controlling the pH value of the residue in step (1) and the addition amount of the cation resin for the first three times in step (2) have an obvious influence on the yield of the Cobutramide Calcium product.

[0122] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing calcobutrol, characterized in that: The following steps are involved: (1) Compound 2 was dissolved in water and distilled under reduced pressure until the pH of the residue was 5.5-6.5 and then distillation was stopped to obtain residue 1; (2) Mixing the residue 1 obtained in step (1) with water, adding a cationic resin, stirring, filtering, and collecting the mother liquor to obtain a solution containing compound 3; the mass ratio of the cationic resin to the compound 2 in step (1) is 5-15:5-15, and the cationic resin is added in batches, the mass ratio of the first three additions is 3:3:1, and the amount of each subsequent addition is 1% of the mass of the compound 2 until the pH is ≤3.8; (3) mixing the solution containing compound 3 obtained in step (2) with calcium carbonate, reacting, cooling, and distilling under reduced pressure to collect the residue 2; (4) heating the residue 2 obtained in step (3), adding a solvent, maintaining the temperature, cooling, separating to obtain a precipitate, and drying the precipitate to obtain calcobutrol calcium. Wherein, the purity of compound 2 is ≥99.0%; The preparation method of the compound 2 comprises the following steps: (a) Compound 1, acid and water are mixed, heated to reflux, reacted to obtain a mixture 1, aqueous ammonia, methanol and ethanol are added to the mixture 1 in sequence, stirred until cloudy, stirred at 15-25° C. for 20-24 hours, separated and dried to obtain a crude compound 2; (b) dissolving the crude compound 2 obtained in step (a) in a solvent, adding methanol and ethanol in sequence, stirring until it becomes turbid, continuing to stir at 15-25° C. for 20-24 hours, separating and drying to obtain the calcobutrol intermediate. in, In step (a), the mass ratio of compound 1, aqueous ammonia, methanol and ethanol is 15-19:10-15:80-90:250-260; In step (b), the mass ratio of the crude compound 2, the solvent, methanol and ethanol is 12-14:30-40:50-65:160-180.

2. The preparation method according to claim 1, characterized in that: In step (1), the mass ratio of the compound 2 to water is 1:4-8; in step (2), the mass ratio of the residue 1 to water is 2-3:1-4.

3. The preparation method according to claim 1, characterized in that: In step (2), after filtering, the method further comprises the step of rinsing with water.

4. The preparation method according to claim 1, characterized in that: In step (3), the mass ratio of calcium carbonate to compound 2 in step (1) is 1-3:10; the reaction conditions are 80-90° C. for 1-2 hours; and the distillation is stopped when the mass of the distillate is 14-19 times the mass of calcium carbonate.

5. The preparation method according to claim 1, characterized in that: In step (4), the heating temperature is 65-85° C.; the solvent is anhydrous ethanol; and the mass ratio of the anhydrous ethanol to the compound 2 in step (1) is 10:70-90.

6. The preparation method according to claim 1, characterized in that: In step (a), the acid is hydrochloric acid; the mass ratio of the compound 1, the acid and water is 15-20:5-8:40-50; the reaction is carried out under nitrogen protection for 1-3 hours.

7. The preparation method according to claim 1, characterized in that: In step (a), the sequential addition of ammonia water, methanol and ethanol is specifically as follows: Add ammonia water dropwise, control the temperature not to exceed 25°C, stir at 15-25°C for 10-20 minutes after the addition is completed, add methanol all at once, and then add ethanol dropwise, and complete the addition in 1.5-3.5 hours.

8. The preparation method according to claim 1, characterized in that: In step (b), the solvent is water.

9. The preparation method according to claim 1, characterized in that: In step (b), the sequential addition of methanol and ethanol specifically includes: adding methanol at one time, and then adding ethanol dropwise, and the addition is completed within 1.5-3.5 hours.

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