Synthetic method of arbidol hydrochloride

Abstract

The invention provides a synthetic method of arbidol hydrochloride, and belongs to the technical field of organic chemistry. The method comprises the following steps: by taking 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester, glacial acetic acid, dimethylamine, formaldehyde, alkali, acetone, concentrated hydrochloric acid and a catalyst as raw materials, carrying out Mannich reaction and salt forming reaction to prepare arbidol hydrochloride; the catalyst is prepared by coupling UiO-66-OH and Fe3O4 (at) SiO2 nanospheres through phytic acid and loading phosphorus chloride, copper and zinc elements. The method is the final Mannich and salt forming reaction in the synthesis process of arbidol hydrochloride, the yield in the traditional reaction process is only 60-70%, through improvement, a proper catalyst is adopted for catalytic reaction, the reaction yield is greatly improved, conditions are milder, operation is easy, product aftertreatment is easy, and meanwhile, the method is suitable for industrial production. The catalyst can be recycled and regenerated, does not pollute the environment, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemistry, and particularly relates to a synthesis method of arbidol hydrochloride. Background Art

[0002] Arbidol hydrochloride (chemical structure is shown in Formula I). Its chemical name is ethyl 6-bromo-4-[(dimethylamino)methyl]-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylate hydrochloride. Arbidol can have a hydrophobic interaction with the binding site on the hemagglutinin (HA) on the cell surface, stabilize the structure of HA, prevent the conformational reorganization of HA caused by a decrease in pH value, avoid the exposure of the fusion peptide, thereby inhibiting virus-endosome membrane fusion and blocking virus invasion.

[0003]

[0004] Arbidol hydrochloride is mainly used clinically for the prevention and treatment of influenza and other acute viral respiratory infections, and is applicable to the prevention and treatment of influenza A, influenza B, acute viral respiratory infections, severe acute respiratory disease syndrome, and the prevention and treatment of complications of bronchitis and pneumonia in adults and children. The results of a clinical controlled trial comparing it with the neuraminidase inhibitor oseltamivir for patients positive for influenza A virus nucleic acid showed that the efficacy, treatment safety, and treatment cost of the two are comparable.

[0005] At present, there are many reports on the synthesis process of arbidol hydrochloride, including: using ethyl 3-aminocrotonate as a raw material, and obtaining arbidol hydrochloride through Nenitzescu reaction, acetylation, N-alkylation, bromination, condensation, Mannich reaction, and salification. The total yield of this method is relatively low (22.9%), mainly due to the low yield of the Mannich reaction, and carbon tetrachloride, a type of solvent, is used in the bromination reaction, which is not conducive to industrial production. Summary of the Invention

[0006] The purpose of the present invention is to propose a synthesis method of arbidol hydrochloride. The preparation method is simple, preventing the generation of carbon anode plate polarization, having advantages such as low porosity, less ash content, high mechanical strength, high bulk density, significantly improved lifespan, low resistivity, etc., and having broad application prospects.

[0007] The technical solution of the present invention is realized as follows:

[0008] The present invention provides a method for synthesizing arbidol hydrochloride. Using ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate, glacial acetic acid, dimethylamine, formaldehyde, a base, acetone, concentrated hydrochloric acid, and a catalyst as raw materials, arbidol hydrochloride is prepared through a Mannich reaction and a salt formation reaction. The catalyst is a catalyst obtained by coupling UiO-66-OH and Fe3O4@SiO2 nanospheres through phytic acid and loading phosphorus chloride and copper and zinc elements.

[0009] As a further improvement of the present invention, the method includes the following steps: adding an aqueous solution of dimethylamine to glacial acetic acid, stirring, adding an aqueous solution of formaldehyde, stirring at room temperature, adding ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate and the catalyst, heating and stirring for reaction, pouring the product into an alkaline solution, stirring and adding a base to adjust the pH value of the system, standing, adding acetone, heating and stirring, dropwise adding concentrated hydrochloric acid to adjust the pH value of the solution, stirring for reaction, cooling, standing, filtering, washing, and drying to obtain arbidol hydrochloride.

[0010] As a further improvement of the present invention, the concentration of the aqueous solution of dimethylamine is 30-35 wt%, the concentration of the aqueous solution of formaldehyde is 35-40 wt%, the concentration of the alkaline solution is 5-15 wt%, the stirring time is 1-1.5 h, the stirring time at room temperature is 0.5-1 h, the heating and stirring reaction temperature is 50-60 °C and the time is 2-3 h, the pH value of the system adjusted by adding a base is 9.5-10.5, the standing time is 1-2 h, the heating and stirring temperature is 45-55 °C and the time is 20-30 min, the pH value of the solution adjusted by dropwise adding concentrated hydrochloric acid is 0.5-1.5, and the stirring reaction time is 1-2 h.

[0011] As a further improvement of the present invention, the molar ratio of dimethylamine, formaldehyde, and ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate is 2:2-4:1-1.5, and the addition amount of the catalyst is 3-5 wt% of the mass of ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate.

[0012] As a further improvement of the present invention, the preparation method of the catalyst is as follows:

[0013] S1. Preparation of UiO-66-OH: Dissolve zirconium tetrachloride and 2-hydroxyterephthalic acid in N,N-dimethylformamide, add acetic acid under stirring at room temperature, raise the temperature for reaction, centrifuge, wash, and dry to obtain UiO-66-OH;

[0014] S2. Preparation of Fe3O4@SiO2 nanospheres: Under the protection of inert gas, ferric chloride and ferrous chloride are added to water, stirred and mixed evenly, ammonia water is added dropwise to adjust the pH value of the solution, heated and stirred for reaction, centrifuged, washed, dried, and calcined to obtain Fe3O4 nanoparticles; Fe3O4 nanoparticles and a hydrophilic emulsifier are added to water to obtain a suspension; an alkyl orthosilicate and a lipophilic emulsifier are added to an organic solvent to obtain an oil phase; the suspension is added dropwise to the oil phase, emulsified, the pH value of the solution is adjusted, stirred for reaction, separated by a magnet, washed, dried, and calcined to obtain Fe3O4@SiO2 nanospheres;

[0015] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: UiO-66-OH, phytic acid, Fe3O4@SiO2 nanospheres, and potassium dihydrogen phosphate are added to water, heated and stirred for reaction, heated under hydrothermal reaction, separated by a magnet, washed, and dried to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0016] S4. Loading of PCl3: UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and phosphorus trichloride are mixed and ball-milled, and the product is washed with dichloromethane and dried to obtain a modified catalyst loaded with PCl3;

[0017] S5. Preparation of the catalyst: An organic zinc salt and an organic copper salt are dissolved in dichloromethane, the modified catalyst loaded with PCl3 is added, stirred and impregnated, separated by a magnet, washed, and dried to obtain the catalyst.

[0018] As a further improvement of the present invention, in step S1, the mass ratio of zirconium tetrachloride, 2-hydroxyterephthalic acid, and acetic acid is 3-5:2-4:400-500, and the temperature of the temperature-raising reaction is 110-130°C and the time is 20-24 h.

[0019] As a further improvement of the present invention, in step S2, the molar ratio of ferric chloride to ferrous chloride is 2:1, the pH value of the solution is adjusted to 10 - 11 by dropping ammonia water, the temperature of the heating and stirring reaction is 80 - 90 °C, the time is 3 - 5 h, the temperature of the calcination is 500 - 600 °C, the time is 1 - 2 h, the mass ratio of the Fe3O4 nanoparticles, hydrophilic emulsifier, alkyl orthosilicate, and lipophilic emulsifier is 4 - 6:0.5 - 1:12 - 15:1 - 2, the hydrophilic emulsifier is selected from at least one of Tween - 20, Tween - 40, Tween - 60, Tween - 80, and Tween - 85, the lipophilic emulsifier is selected from at least one of Span - 20, Span - 40, Span - 60, Span - 80, and Span - 85, the pH value of the solution is adjusted to 10 - 11, the time of the stirring reaction is 10 - 12 h, the organic solvent is selected from at least one of ethyl acetate, propyl acetate, butyl acetate, dichloromethane, and chloroform, and the alkyl orthosilicate is methyl orthosilicate or ethyl orthosilicate.

[0020] As a further improvement of the present invention, in step S3, the mass ratio of UiO - 66 - OH, phytic acid, Fe3O4@SiO2 nanospheres, and potassium dihydrogen phosphate is 5 - 7:2 - 4:8 - 12:1 - 2, the temperature of the heating and stirring reaction is 90 - 100 °C, the time is 0.5 - 1.5 h, and the temperature of the temperature - rising hydrothermal reaction is 140 - 150 °C, the time is 9 - 10 h.

[0021] As a further improvement of the present invention, in step S4, the mass ratio of UiO - 66 - OH - phytic acid - Fe3O4@SiO2 nanospheres and phosphorus chloride is 10:2 - 3, and the time of the ball - milling is 30 - 40 min.

[0022] As a further improvement of the present invention, in step S5, the organic zinc salt is selected from at least one of diethyl zinc, zinc laurate, zinc oleate, and zinc propionate, the organic copper salt is selected from at least one of copper acetate and copper propionate, the mass ratio of the organic zinc salt, organic copper salt, and the modified catalyst loaded with PCl3 is 2 - 3:1 - 2:40 - 50, and the time of the stirring impregnation is 6 - 12 h.

[0023] The present invention has the following beneficial effects:

[0024] The catalyst prepared by the present invention greatly shortens the time of the Mannich reaction, has simple operation, easy product post - treatment, significantly improves the reaction yield. At the same time, the catalyst can be recycled and regenerated without polluting the environment.

[0025] The present invention first synthesizes magnetic iron oxide nanoparticles and coats a SiO2 shell layer on their surface. The SiO2 shell layer has a rich hydroxyl structure, which is convenient for subsequent reactions.

[0026] UiO-66 is a Zr-based MOFs material. Its crystal structure consists of zirconium oxide clusters [Zr6O4(OH)4], and this cluster is connected to 6 terephthalic acid linkers. In this invention, UiO-66 is modified by using terephthalic acid containing -OH functional groups as linkers, which improves the intrinsic structural properties of UiO-66 and the chemical state of active metals, thus improving its catalytic activity. At the same time, the hydroxyl groups on its surface can also be coupled with Fe3O4@SiO2 nanospheres by reacting with phytic acid, thereby preparing UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres, increasing the specific surface area of the catalyst, providing a reaction site for the catalytic reaction, making the reaction easier to proceed, improving the catalytic activity, and also providing a site for loading PCl3, zinc, and copper. At the same time, phytic acid also improves the acidity of the catalyst, thereby improving the catalytic activity, and can further improve the catalytic activity by forming complex bonds with subsequent zinc and copper to fix metal ions.

[0027] In this invention, the prepared UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres are reacted with phosphorus trichloride to prepare a Lewis acid catalyst loaded with PCl3, whose acidity is increased. Due to the principle of similar compatibility, the substrate can better interact with the catalyst, thus greatly improving the reaction activity of the catalyst. At the same time, since the core of the catalyst in this invention contains magnetic iron tetroxide, the separation ease of the catalyst is improved, overcoming the problem that traditional acidic catalysts cannot be recycled.

[0028] Furthermore, the prepared modified catalyst loaded with PCl3 is impregnated with copper and zinc metals through chemical bond complexation. During the reaction, it can provide electrons to the medium, thus promoting the smooth progress of the reaction, reducing the activation energy, making the reaction conditions milder, and having a higher reaction yield. The loading of the two metals has a synergistic effect.

[0029] This invention is for the final Mannich and salification reactions in the synthesis process of arbidol hydrochloride. In the traditional process of this reaction, the yield is only 60 - 70%. After the improvement of this invention, by using a suitable catalyst for the catalytic reaction, the reaction yield is greatly improved, the conditions are milder, the operation is simple, and the post-treatment of the product is easy. At the same time, the catalyst can be recycled and regenerated, without polluting the environment, and has broad application prospects. Detailed implementation manners

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0031] Preparation Example 1: Preparation of the catalyst

[0032] It includes the following steps:

[0033] S1. Preparation of UiO-66-OH: Dissolve 0.3 g of zirconium tetrachloride and 0.2 g of 2-hydroxyterephthalic acid in 200 mL of N,N-dimethylformamide, add 40 g of acetic acid under stirring at room temperature, heat up to 110 °C, stir and react for 20 h, centrifuge, wash, and dry to obtain UiO-66-OH;

[0034] S2. Preparation of Fe3O4@SiO2 nanospheres: Under nitrogen protection, add 0.02 mol of ferric chloride and 0.01 mol of ferrous chloride to 200 mL of water, stir and mix for 15 min, dropwise add ammonia water to adjust the pH value of the solution to 10, heat up to 80 °C, stir and react for 3 h, centrifuge, wash, and dry, calcine at 500 °C for 1 h to obtain Fe3O4 nanoparticles; Add 4 g of Fe3O4 nanoparticles and 0.5 g of Tween-40 to 100 mL of water to obtain a suspension; Add 12 g of methyl orthosilicate and 1 g of Span-40 to 200 mL of dichloromethane to obtain an oil phase; Drop the suspension into the oil phase, emulsify at 8000 r / min for 15 min, adjust the pH value of the solution to 10, stir and react for 10 h, separate with a magnet, wash, and dry, calcine at 500 °C for 1 h to obtain Fe3O4@SiO2 nanospheres;

[0035] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: Add 5 g of UiO-66-OH, 2 g of phytic acid, 8 g of Fe3O4@SiO2 nanospheres, and 1 g of potassium dihydrogen phosphate to 200 mL of water, heat up to 90 °C, stir and react for 0.5 h, then heat up to 140 °C and carry out a hydrothermal reaction for 9 h, separate with a magnet, wash, and dry to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0036] S4. Loading of PCl3: Mix 10 g of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and 2 g of phosphorus trichloride by ball milling for 30 min, wash the product with dichloromethane, and dry to obtain a modified catalyst loaded with PCl3;

[0037] S5. Preparation of the catalyst: Dissolve 2 g of diethylzinc and 1 g of copper propionate in 200 mL of dichloromethane, add 40 g of the modified catalyst loaded with PCl3, stir and impregnate for 6 h, separate with a magnet, wash, and dry to obtain the catalyst.

[0038] Preparation Example 2: Preparation of the catalyst

[0039] It includes the following steps:

[0040] S1. Preparation of UiO-66-OH: Dissolve 0.5 g of zirconium tetrachloride and 0.4 g of 2-hydroxyterephthalic acid in 200 mL of N,N-dimethylformamide, add 50 g of acetic acid under stirring at room temperature, heat up to 130 °C, stir and react for 24 h, centrifuge, wash, and dry to obtain UiO-66-OH;

[0041] S2. Preparation of Fe3O4@SiO2 nanospheres: Under nitrogen protection, add 0.02 mol of ferric chloride and 0.01 mol of ferrous chloride to 200 mL of water, stir and mix for 15 min, dropwise add ammonia water to adjust the pH value of the solution to 11, heat up to 90 °C, stir and react for 5 h, centrifuge, wash, and dry, calcine at 600 °C for 2 h to obtain Fe3O4 nanoparticles; Add 6 g of Fe3O4 nanoparticles and 1 g of Span-60 to 100 mL of water to obtain a suspension; Add 15 g of tetraethyl orthosilicate and 2 g of Tween-80 to 200 mL of propyl acetate to obtain an oil phase; Drop the suspension into the oil phase, emulsify at 8000 r / min for 15 min, adjust the pH value of the solution to 11, stir and react for 12 h, separate with a magnet, wash, and dry, calcine at 600 °C for 2 h to obtain Fe3O4@SiO2 nanospheres;

[0042] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: Add 7 g of UiO-66-OH, 4 g of phytic acid, 12 g of Fe3O4@SiO2 nanospheres, and 2 g of potassium dihydrogen phosphate to 200 mL of water, heat up to 100 °C, stir and react for 1.5 h, then heat up to 150 °C and carry out a hydrothermal reaction for 10 h, separate with a magnet, wash, and dry to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0043] S4. Loading of PCl3: Mix 10 g of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and 3 g of phosphorus trichloride by ball milling for 40 min, wash the product with dichloromethane, and dry to obtain a modified catalyst loaded with PCl3;

[0044] S5. Preparation of the catalyst: Dissolve 3 g of zinc propionate and 2 g of copper propionate in 200 mL of dichloromethane, add 50 g of the modified catalyst loaded with PCl3, stir and impregnate for 12 h, separate with a magnet, wash, and dry to obtain the catalyst.

[0045] Preparation Example 3 Preparation of the catalyst

[0046] It includes the following steps:

[0047] S1. Preparation of UiO-66-OH: Dissolve 0.4 g of zirconium tetrachloride and 0.3 g of 2-hydroxyterephthalic acid in 200 mL of N,N-dimethylformamide. Add 45 g of acetic acid under stirring at room temperature, heat up to 120 °C, stir and react for 22 h, centrifuge, wash, and dry to obtain UiO-66-OH;

[0048] S2. Preparation of Fe3O4@SiO2 nanospheres: Under nitrogen protection, add 0.02 mol of ferric chloride and 0.01 mol of ferrous chloride to 200 mL of water, stir and mix for 15 min, add ammonia water dropwise to adjust the pH value of the solution to 10.5, heat up to 85 °C, stir and react for 4 h, centrifuge, wash, and dry, then calcine at 550 °C for 1.5 h to obtain Fe3O4 nanoparticles; Add 5 g of Fe3O4 nanoparticles and 0.7 g of Tween-85 to 100 mL of water to obtain a suspension; Add 13 g of tetraethyl orthosilicate and 1.5 g of Span-85 to 200 mL of ethyl acetate to obtain an oil phase; Drop the suspension into the oil phase, emulsify at 8000 r / min for 15 min, adjust the pH value of the solution to 10.5, stir and react for 11 h, separate by magnet, wash, and dry, then calcine at 550 °C for 1.5 h to obtain Fe3O4@SiO2 nanospheres;

[0049] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: Add 6 g of UiO-66-OH, 3 g of phytic acid, 10 g of Fe3O4@SiO2 nanospheres, and 1.5 g of potassium dihydrogen phosphate to 200 mL of water, heat up to 95 °C, stir and react for 1 h, then heat up to 145 °C and carry out hydrothermal reaction for 9.5 h, separate by magnet, wash, and dry to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0050] S4. Loading PCl3: Mix 10 g of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and 2.5 g of phosphorus trichloride by ball milling for 35 min, wash the product with dichloromethane, and dry to obtain the modified catalyst loaded with PCl3;

[0051] S5. Preparation of the catalyst: Dissolve 2.5 g of zinc propionate and 1.5 g of copper acetate in 200 mL of dichloromethane, add 45 g of the modified catalyst loaded with PCl3, stir and impregnate for 9 h, separate by magnet, wash, and dry to obtain the catalyst.

[0052] Comparative Preparation Example 1

[0053] Compared with Preparation Example 3, the difference is that phytic acid is not added in step S3.

[0054] Specifically as follows:

[0055] S3. Preparation of the mixture of UiO-66-OH and Fe3O4@SiO2 nanospheres: 6 g of UiO-66-OH, 3 g of phytic acid, and 10 g of Fe3O4@SiO2 nanospheres were stirred and mixed for 10 min to obtain the mixture of UiO-66-OH and Fe3O4@SiO2 nanospheres.

[0056] Comparative Preparation Example 2

[0057] Compared with Preparation Example 3, the difference lies in that UiO-66-OH was not added in step S3.

[0058] Specifically as follows:

[0059] S3. Preparation of phytic acid-Fe3O4@SiO2 nanospheres: 3 g of phytic acid, 16 g of Fe3O4@SiO2 nanospheres, and 1.5 g of potassium dihydrogen phosphate were added to 200 mL of water, heated to 95 °C, stirred and reacted for 1 h, heated to 145 °C, and hydrothermally reacted for 9.5 h. After magnetic separation, washing, and drying, phytic acid-Fe3O4@SiO2 nanospheres were obtained.

[0060] Comparative Preparation Example 3

[0061] Compared with Preparation Example 3, the difference lies in that Fe3O4@SiO2 nanospheres were not added in step S3.

[0062] Specifically as follows:

[0063] S3. Preparation of phytic acid-UiO-66-OH nanoparticles: 16 g of UiO-66-OH, 3 g of phytic acid, and 1.5 g of potassium dihydrogen phosphate were added to 200 mL of water, heated to 95 °C, stirred and reacted for 1 h, heated to 145 °C, and hydrothermally reacted for 9.5 h. After magnetic separation, washing, and drying, phytic acid-UiO-66-OH nanoparticles were obtained.

[0064] Comparative Preparation Example 4

[0065] Compared with Preparation Example 3, the difference lies in that step S4 was not carried out.

[0066] Specifically as follows:

[0067] S1. Preparation of UiO-66-OH: 0.4 g of zirconium tetrachloride and 0.3 g of 2-hydroxyterephthalic acid were dissolved in 200 mL of N,N-dimethylformamide. 45 g of acetic acid was added under stirring at room temperature, and the temperature was raised to 120 °C, followed by stirring and reacting for 22 h. After centrifugation, washing, and drying, UiO-66-OH was obtained;

[0068] S2. Preparation of Fe3O4@SiO2 nanospheres: Under nitrogen protection, 0.02 mol of ferric chloride and 0.01 mol of ferrous chloride were added to 200 mL of water, stirred and mixed for 15 min, ammonia water was added dropwise to adjust the pH value of the solution to 10.5, heated to 85 °C, stirred and reacted for 4 h, centrifuged, washed, dried, and calcined at 550 °C for 1.5 h to obtain Fe3O4 nanoparticles; 5 g of Fe3O4 nanoparticles and 0.7 g of Tween-85 were added to 100 mL of water to obtain a suspension; 13 g of tetraethyl orthosilicate and 1.5 g of Span-85 were added to 200 mL of ethyl acetate to obtain an oil phase; the suspension was added dropwise to the oil phase, emulsified at 8000 r / min for 15 min, the pH value of the solution was adjusted to 10.5, stirred and reacted for 11 h, separated by a magnet, washed, dried, and calcined at 550 °C for 1.5 h to obtain Fe3O4@SiO2 nanospheres;

[0069] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: 6 g of UiO-66-OH, 3 g of phytic acid, 10 g of Fe3O4@SiO2 nanospheres, and 1.5 g of potassium dihydrogen phosphate were added to 200 mL of water, heated to 95 °C, stirred and reacted for 1 h, heated to 145 °C, and hydrothermally reacted for 9.5 h, separated by a magnet, washed, dried, to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0070] S4. Preparation of the catalyst: 2.5 g of zinc propionate and 1.5 g of copper acetate were dissolved in 200 mL of dichloromethane, 45 g of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres were added, stirred and impregnated for 9 h, separated by a magnet, washed, dried, to obtain the catalyst.

[0071] Comparative Preparation Example 5

[0072] Compared with Preparation Example 3, the difference is that zinc propionate was not added in step S5.

[0073] Specifically as follows:

[0074] S5. Preparation of the catalyst: 4 g of copper acetate was dissolved in 200 mL of dichloromethane, 45 g of the modified catalyst loaded with PCl3 was added, stirred and impregnated for 9 h, separated by a magnet, washed, dried, to obtain the catalyst.

[0075] Comparative Preparation Example 6

[0076] Compared with Preparation Example 3, the difference is that copper acetate was not added in step S5.

[0077] Specifically as follows:

[0078] S5. Preparation of catalyst: Dissolve 4 g of propionic acid in 200 mL of dichloromethane, add 45 g of the modified catalyst loaded with PCl3, stir and impregnate for 9 h, separate by magnet, wash, and dry to obtain the catalyst.

[0079] Comparative Preparation Example 7

[0080] Compared with Preparation Example 3, the difference lies in that step S5 is not carried out.

[0081] Specifically as follows:

[0082] S1. Preparation of UiO-66-OH: Dissolve 0.4 g of zirconium tetrachloride and 0.3 g of 2-hydroxyterephthalic acid in 200 mL of N,N-dimethylformamide, add 45 g of acetic acid under stirring at room temperature, heat up to 120 °C, stir and react for 22 h, centrifuge, wash, and dry to obtain UiO-66-OH;

[0083] S2. Preparation of Fe3O4@SiO2 nanospheres: Under nitrogen protection, add 0.02 mol of ferric chloride and 0.01 mol of ferrous chloride to 200 mL of water, stir and mix for 15 min, dropwise add ammonia water to adjust the pH value of the solution to 10.5, heat up to 85 °C, stir and react for 4 h, centrifuge, wash, and dry, calcine at 550 °C for 1.5 h to obtain Fe3O4 nanoparticles; Add 5 g of Fe3O4 nanoparticles and 0.7 g of Tween-85 to 100 mL of water to obtain a suspension; Add 13 g of tetraethyl orthosilicate and 1.5 g of Span-85 to 200 mL of ethyl acetate to obtain an oil phase; Drop the suspension into the oil phase, emulsify at 8000 r / min for 15 min, adjust the pH value of the solution to 10.5, stir and react for 11 h, separate by magnet, wash, and dry, calcine at 550 °C for 1.5 h to obtain Fe3O4@SiO2 nanospheres;

[0084] S3. Preparation of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres: Add 6 g of UiO-66-OH, 3 g of phytic acid, 10 g of Fe3O4@SiO2 nanospheres, and 1.5 g of potassium dihydrogen phosphate to 200 mL of water, heat up to 95 °C, stir and react for 1 h, heat up to 145 °C, carry out hydrothermal reaction for 9.5 h, separate by magnet, wash, and dry to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres;

[0085] S4. Loading of PCl3: Mix 10 g of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and 2.5 g of phosphorus chloride by ball milling for 35 min, wash the product with dichloromethane, and dry to obtain the modified catalyst loaded with PCl3, which is the catalyst.

[0086] Test Example 1

[0087] The specific surface area and total pore volume of the catalysts prepared in Preparation Examples 1-3 and Comparative Preparation Examples 1-7 were measured using a 3-FLEX 3500 multi-station high-throughput gas adsorption instrument, and the results are shown in Table 1.

[0088] Table 1 Group <![CDATA[Specific surface area (m 2 / g)]]> <![CDATA[Total pore volume (cm 3 / g)]]> Example 1 805.2 0.711 Example 2 807.9 0.712 Example 3 810.1 0.714 Comparative Example 1 668.9 0.567 Comparative Example 2 724.8 0.675 Comparative Example 3 710.9 0.669 Comparative Example 4 792.7 0.702 Comparative Example 5 798.6 0.707 Comparative Example 6 795.4 0.705 Comparative Example 7 790.1 0.701

[0089] As can be seen from the above table, the catalysts prepared in Preparation Examples 1-3 of the present invention have a larger specific surface area and total pore volume.

[0090] Example 1

[0091] This example provides a method for synthesizing arbidol hydrochloride, which includes the following steps: adding 30 wt% aqueous dimethylamine solution to glacial acetic acid, stirring for 1 h, adding 35 wt% aqueous formaldehyde solution, stirring at room temperature for 0.5 h, adding ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate and the catalyst prepared in Preparation Example 1, heating to 50 °C, stirring and reacting for 2 h, separating the catalyst by magnetic separation, washing, drying the catalyst, recycling it for reuse, pouring the product into 5 wt% aqueous NaOH solution, stirring and adding NaOH to adjust the pH value of the system to 9.5, standing for 1 h, adding acetone, heating to 45 °C, stirring for 20 min, dropping concentrated hydrochloric acid to adjust the pH value of the solution to 0.5, stirring and reacting for 1 h, cooling, standing for 1 h, filtering, washing, and drying to obtain arbidol hydrochloride;

[0092] Among them, the molar ratio of dimethylamine, formaldehyde, and ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate is 2:2:1, and the addition amount of the catalyst is 3 wt% of the mass of ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate.

[0093] Example 2

[0094] This example provides a method for synthesizing arbidol hydrochloride, which includes the following steps: adding 35 wt% aqueous dimethylamine solution to glacial acetic acid, stirring for 1.5 h, adding 40 wt% aqueous formaldehyde solution, stirring at room temperature for 1 h, adding ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate and the catalyst prepared in Preparation Example 2, heating to 60 °C, stirring and reacting for 3 h, separating the catalyst by magnetic separation, washing, drying the catalyst, recycling it for reuse, pouring the product into 15 wt% aqueous KOH solution, stirring and adding KOH to adjust the pH value of the system to 10.5, standing for 2 h, adding acetone, heating to 55 °C, stirring for 30 min, dropping concentrated hydrochloric acid to adjust the pH value of the solution to 1.5, stirring and reacting for 2 h, cooling, standing for 2 h, filtering, washing, and drying to obtain arbidol hydrochloride;

[0095] Among them, the molar ratio of the dimethylamine, formaldehyde, and ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1H-indole-3-carboxylate is 2:4:1.5, and the addition amount of the catalyst is 5 wt% of the mass of the ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1H-indole-3-carboxylate.

[0096] Example 3

[0097] This example provides a method for synthesizing arbidol hydrochloride, which includes the following steps: adding an aqueous solution of 32 wt% dimethylamine to glacial acetic acid, stirring for 1.5 h, adding an aqueous solution of 37 wt% formaldehyde, stirring at room temperature for 1 h, adding ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1H-indole-3-carboxylate and the catalyst prepared in Preparation Example 3, heating to 55 °C, stirring and reacting for 2.5 h, separating the catalyst by magnetic separation, washing the catalyst, drying it, recycling it for reuse, pouring the product into a 10 wt% aqueous NaOH solution, stirring and adding NaOH to adjust the pH value of the system to 10, standing for 1.5 h, adding acetone, heating to 50 °C, stirring for 25 min, dropping concentrated hydrochloric acid to adjust the pH value of the solution to 1, stirring and reacting for 1.5 h, cooling, standing for 1.5 h, filtering, washing, and drying to obtain arbidol hydrochloride;

[0098] Among them, the molar ratio of the dimethylamine, formaldehyde, and ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1H-indole-3-carboxylate is 2:3:1.2, and the addition amount of the catalyst is 4 wt% of the mass of the ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)-1H-indole-3-carboxylate.

[0099] Comparative Example 1

[0100] Compared with Example 3, the difference is that the catalyst is prepared from Comparative Preparation Example 1.

[0101] Comparative Example 2

[0102] Compared with Example 3, the difference is that the catalyst is prepared from Comparative Preparation Example 2.

[0103] Comparative Example 3

[0104] Compared with Example 3, the difference is that the catalyst is prepared from Comparative Preparation Example 3.

[0105] Comparative Example 4

[0106] Compared with Example 3, the difference is that the catalyst is prepared from Comparative Preparation Example 4.

[0107] Comparative Example 5

[0108] Compared with Example 3, the difference is that the catalyst is prepared from Comparative Preparation Example 5.

[0109] Comparative Example 6

[0110] Compared with Example 3, the difference lies in that the catalyst is prepared from Comparative Preparation Example 6.

[0111] Comparative Example 7

[0112] Compared with Example 3, the difference lies in that the catalyst is prepared from Comparative Preparation Example 7.

[0113] Test Example 2

[0114] The reactions in Examples 1 - 3 and Comparative Examples 1 - 7 were evaluated, and the results are shown in Table 2.

[0115] Table 2 Group Yield of Arbidol Hydrochloride (%) Purity of Arbidol Hydrochloride (%) Example 1 96.75 99.82 Example 2 96.88 99.90 Example 3 97.10 99.94 Comparative Example 1 91.41 97.10 Comparative Example 2 90.12 98.57 Comparative Example 3 92.95 98.72 Comparative Example 4 89.10 97.89 Comparative Example 5 92.24 98.33 Comparative Example 6 93.15 97.92 Comparative Example 7 86.89 96.82

[0116] As can be seen from the above table, the abidol hydrochloride prepared by the reactions in Examples 1 - 3 of the present invention has high purity and high yield.

[0117] Test Example 3

[0118] The catalyst separated in Example 3 was used to continue catalyzing the reaction 5 times, and the effects of the 5 reactions were recorded. The results are shown in Table 3.

[0119] Table 3 Number of Reactions Yield of Arbidol Hydrochloride (%) Purity of Arbidol Hydrochloride (%) First Time 96.87 99.91 Second Time 96.44 99.90 Third Time 96.10 99.87 Fourth Time 95.89 99.82 Fifth Time 95.11 99.75

[0120] As can be seen from the above table, the catalyst in Example 3 of the present invention can still maintain high catalytic activity after repeated catalysis in multiple experiments.

[0121] 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 in the protection scope of the present invention.

Claims

1. A synthetic method of arbidol hydrochloride, characterized in that, Taking ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate, glacial acetic acid, dimethylamine, formaldehyde, a base, acetone, concentrated hydrochloric acid, and a catalyst as raw materials, arbidol hydrochloride is prepared through a Mannich reaction and a salt formation reaction; the catalyst is a catalyst obtained by coupling UiO-66-OH and Fe3O4@SiO2 nanospheres through phytic acid and loading phosphorus chloride, copper, and zinc elements.

2. The synthesis method according to claim 1, characterized in that, It includes the following steps: adding an aqueous solution of dimethylamine to glacial acetic acid, stirring, adding an aqueous solution of formaldehyde, stirring at room temperature, adding ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate and the catalyst, heating and stirring for reaction, pouring the product into an alkaline solution, stirring and adding a base to adjust the pH value of the system, standing, adding acetone, heating and stirring, dropwise adding concentrated hydrochloric acid to adjust the pH value of the solution, stirring for reaction, cooling, standing, filtering, washing, and drying to obtain arbidol hydrochloride.

3. The synthesis method according to claim 2, characterized in that, The concentration of the aqueous solution of dimethylamine is 30 - 35 wt%, the concentration of the aqueous solution of formaldehyde is 35 - 40 wt%, the concentration of the alkaline solution is 5 - 15 wt%, the stirring time is 1 - 1.5 h, the stirring time at room temperature is 0.5 - 1 h, the temperature for heating and stirring the reaction is 50 - 60 °C, and the time is 2 - 3 h. The pH value of the system adjusted by adding a base is 9.5 - 10.5, the standing time is 1 - 2 h, the temperature for heating and stirring is 45 - 55 °C, and the time is 20 - 30 min. The pH value of the solution adjusted by dropwise adding concentrated hydrochloric acid is 0.5 - 1.5, and the stirring time for the reaction is 1 - 2 h.

4. The synthesis method according to claim 2, characterized in that, The molar ratio of dimethylamine, formaldehyde, and ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate is 2:2 - 4:1 - 1.5, and the addition amount of the catalyst is 3 - 5 wt% of the mass of ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylthio)methylindole-3-carboxylate.

5. The synthesis method according to claim 1, wherein, The preparation method of the catalyst is as follows: S1. Preparation of UiO-66-OH: Dissolving zirconium tetrachloride and 2-hydroxyterephthalic acid in N,N-dimethylformamide, adding acetic acid under stirring at room temperature, heating for reaction, centrifuging, washing, and drying to obtain UiO-66-OH; S2. Preparation of Fe3O4@SiO2 nanospheres: Under the protection of an inert gas, adding ferric chloride and ferrous chloride to water, stirring and mixing evenly, dropwise adding ammonia water to adjust the pH value of the solution, heating and stirring for reaction, centrifuging, washing, drying, and calcining to obtain Fe3O4 nanoparticles; adding the Fe3O4 nanoparticles and a hydrophilic emulsifier to water to obtain a suspension; adding an alkyl orthosilicate and a lipophilic emulsifier to an organic solvent to obtain an oil phase; dropping the suspension into the oil phase, emulsifying, adjusting the pH value of the solution, stirring for reaction, separating with a magnet, washing, drying, and calcining to obtain Fe3O4@SiO2 nanospheres; S3. Preparation of UiO-66-OH-Phytic Acid-Fe3O4@SiO2 Nanospheres: Add UiO-66-OH, phytic acid, Fe3O4@SiO2 nanospheres, and potassium dihydrogen phosphate into water, heat and stir for reaction, carry out hydrothermal reaction under heating, separate by magnet, wash, and dry to obtain UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres; S4. Loading PCl3: Mix and ball-mill UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and phosphorus chloride, wash the product with dichloromethane, and dry to obtain a modified catalyst loaded with PCl3; S5. Preparation of the Catalyst: Dissolve organic zinc salt and organic copper salt in dichloromethane, add the modified catalyst loaded with PCl3, stir and impregnate, separate by magnet, wash, and dry to obtain the catalyst.

6. The synthesis method according to claim 5, characterized in that, In step S1, the mass ratio of zirconium tetrachloride, 2-hydroxyterephthalic acid, and acetic acid is 3-5:2-4:400-500, the temperature of the temperature-rising reaction is 110-130 °C, and the time is 20-24 h.

7. The synthesis method according to claim 5, characterized in that, In step S2, the molar ratio of ferric chloride to ferrous chloride is 2:1, the pH value of the solution is adjusted to 10-11 by dropping ammonia water, the temperature of the heating and stirring reaction is 80-90 °C, the time is 3-5 h, the temperature of the calcination is 500-600 °C, the time is 1-2 h, the mass ratio of Fe3O4 nanoparticles, hydrophilic emulsifier, alkyl orthosilicate, and lipophilic emulsifier is 4-6:0.5-1:12-15:1-2, the hydrophilic emulsifier is selected from at least one of Tween-20, Tween-40, Tween-60, Tween-80, and Tween-85, the lipophilic emulsifier is selected from at least one of Span-20, Span-40, Span-60, Span-80, and Span-85, the pH value of the solution is adjusted to 10-11, the stirring reaction time is 10-12 h, the organic solvent is selected from at least one of ethyl acetate, propyl acetate, butyl acetate, dichloromethane, and chloroform, and the alkyl orthosilicate is methyl orthosilicate or ethyl orthosilicate.

8. The synthesis method according to claim 5, characterized in that, In step S3, the mass ratio of UiO-66-OH, phytic acid, Fe3O4@SiO2 nanospheres, and potassium dihydrogen phosphate is 5-7:2-4:8-12:1-2, the temperature of the heating and stirring reaction is 90-100 °C, the time is 0.5-1.5 h, and the temperature of the temperature-rising hydrothermal reaction is 140-150 °C, the time is 9-10 h.

9. The synthesis method according to claim 5, characterized in that, In step S4, the mass ratio of UiO-66-OH-phytic acid-Fe3O4@SiO2 nanospheres and phosphorus chloride is 10:2-3, and the ball-milling time is 30-40 min.

10. The synthesis method according to claim 5, wherein In step S5, the organic zinc salt is selected from at least one of diethyl zinc, zinc laurate, zinc oleate, and zinc propionate, the organic copper salt is selected from at least one of copper acetate and copper propionate, the mass ratio of the organic zinc salt, organic copper salt, and the modified catalyst loaded with PCl3 is 2-3:1-2:40-50, and the stirring impregnation time is 6-12 h.

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