A method for synthesizing crude dotenorazole

Abstract

This invention belongs to the field of pharmaceutical technology, specifically providing a new method for synthesizing crude dotenoradine. This invention uses 2-aminobenzylthiol as the starting material, and obtains crude dotenoradine through cyclization reaction, first oxidation reaction, acylation reaction, and second oxidation reaction. It mainly utilizes the relatively weak oxidizing property of hydrogen peroxide, which makes it difficult to directly oxidize sulfide (1) to sulfone (2') in a high yield. Instead, relatively expensive m-chloroperoxybenzoic acid is still needed to complete the oxidation. This invention controls the oxidation of sulfide by controlling the amount of hydrogen peroxide and the composite catalyst and catalytic aid, so that most of the oxidation products remain in the sulfoxide structure (2) and are difficult to completely convert to the sulfone structure. After another oxidation reaction, the amount of m-chloroperoxybenzoic acid can be reduced relatively much, thus reducing the synthesis cost of crude dotenoradine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for synthesizing dotenoroxetine. Background Technology

[0002] Dotinurad is an active pharmaceutical ingredient (API) jointly developed by Fujiyama Pharmaceutical and Mochida Pharmaceutical in Japan for the treatment of hyperuricemia and gout. It was approved for marketing in Japan on January 23, 2020. Its mechanism of action is to target and inhibit the activity of urate reabsorption transporters, selectively inhibiting uric acid reabsorption transport proteins in the kidneys, thereby inhibiting uric acid reabsorption and lowering uric acid levels in the blood.

[0003] In January 2024, the National Medical Products Administration of China accepted the marketing application for dotenorazole. The Phase 3 clinical trial in China enrolled 451 patients with gout, and the results showed that dotenorazole significantly reduced blood uric acid levels within 24 weeks.

[0004] The original patent WO2011040449A1 reports a method for synthesizing dotenororil, using 2-aminophenylethanol as the starting material, which undergoes cyclization with formaldehyde or its equivalent to obtain benzothiazoline, followed by a condensation reaction with 3,5-dichloro-4-hydroxybenzoic acid or its phenolic hydroxyl-protected derivative, and finally oxidation with m-chloroperoxybenzoic acid to deprotect the group and obtain dotenororil. However, this process has drawbacks, including the large amount of m-chloroperoxybenzoic acid required (approximately 4.5 eq), the difficult operation, the difficulty in removing the large amount of m-chlorobenzoic acid after the reaction, and the difficulty in obtaining high yields of sulfone-based products with other oxidants.

[0005]

[0006] CN118580197A discloses a method for preparing dotenoroxetine and its application, which introduces ester groups into the route, avoiding the high-temperature reaction in the demethylation step of methoxy compounds in the prior art, and the dotenoroxetine prepared by this method has simple post-processing and high purity.

[0007]

[0008] Patent CN111662247A mentions first oxidizing benzothiazoline to a sulfone group, and then condensing it with 3,5-dichloro-4-hydroxybenzoic acid to obtain dotenoroxetine. However, the literature mentions that when hydrogen peroxide is selected as the oxidant, the reaction needs to be carried out at 90-100℃. The solvent for the reaction is acetic acid, and the actual substance involved in the reaction is peracetic acid. High temperature, high heat, metal ions and reducing agents can also cause peracetic acid to explode. Conducting experiments at such high temperatures poses a huge safety hazard.

[0009]

[0010] The method provided by patent CN111675675A involves directly acylating 2-aminobenzenethiol to obtain a mercapto-containing intermediate, followed by a cyclization reaction, and finally an oxidation reaction to obtain dotenoroxetine. However, the mercapto group in this process has high nucleophilicity, making it difficult to obtain a product that only reacts with the amino group during the acylation reaction, resulting in a low yield.

[0011] Summary of the Invention

[0012] In the process of oxidizing benzothiazole to sulfone, this invention found that only m-chloroperoxybenzoic acid is the most effective and can be completed in one step. Other oxidants are relatively unsatisfactory, and the resulting products are all mixtures of sulfoxide and sulfone.

[0013] This invention utilizes the unsatisfactory properties of other oxidants by dividing the oxidation reaction into two stages. The first oxidation reaction is relatively easy to carry out, and hydrogen peroxide, with its relatively weak oxidizing power and low cost, is chosen. The reaction can be conducted in water with a platinum / mesoporous alumina composite catalyst. The second oxidation reaction is completed after condensation. This is mainly because the oxidant in oxidation reaction II is m-chloroperoxybenzoic acid, which has poor solubility in water, and less m-chloroperoxybenzoic acid is needed after condensation.

[0014] To address the above problems, this invention provides a method for synthesizing crude dotenoradine, comprising the following steps:

[0015] S1,2-aminobenzylthiol undergoes a cyclization reaction with a cyclizing agent to give intermediate 1, namely 2,3-dihydrobenzothiazole;

[0016] S2,2,3-dihydrobenzothiazole undergoes oxidation reaction I to generate intermediate 2, which has a sulfoxide structure;

[0017] S3, intermediate 2 reacts with the acyl chloride formed by 3,5-dichloro-4-hydroxybenzoic acid to give intermediate 3;

[0018] S3 and intermediate 3 undergo oxidation reaction II to produce crude dotenoradine.

[0019]

[0020] The synthesis method of this invention, in S1, involves the following steps: 80-150g of 2-aminobenzylthiol and 100-200g of the cyclizing reagent are added to 300-800mL of isopropyl ether and stirred. After the cyclization reaction is carried out at room temperature for 10-12 hours, 200-500mL of 10wt% sodium carbonate aqueous solution is taken to wash twice, followed by washing once with water, and the mixture is separated. 20-50g of anhydrous sodium sulfate is added and the mixture is dried under reduced pressure to obtain intermediate 1, namely 2,3-dihydrobenzothiazole.

[0021] The synthesis method described in this invention, in S2, oxidation reaction I is as follows: 80-100g of 2,3-dihydrobenzothiazole and 1-5g of platinum / mesoporous alumina composite catalyst are added to 100-200mL of ethanol and stirred until dissolved. Then, 100-120g of 30wt% hydrogen peroxide solution is added, and the mixture is heated to 30-40℃ and stirred for 10-15h. 30-80g of sodium bisulfite is added and stirring is continued for 1h. Then, 300-500mL of water is added, and the mixture is cooled to crystallize, yielding intermediate 2.

[0022] The synthesis method described in this invention involves the following steps: In step S3, the acyl chloride reaction is performed as follows: 60-110g of intermediate 2 is added to 300-550mL of dichloromethane for later use; 100-150g of 3,5-dichloro-4-hydroxybenzoic acid is added to 500-800mL of dichloromethane; 80-120g of thionyl chloride is slowly added dropwise at room temperature; the temperature is raised to 30-50℃ and maintained for 6 hours; then the temperature is lowered to 10-15℃ and 120-150g of triethylamine is added dropwise; a solution of intermediate 2 dissolved in dichloromethane is then slowly added dropwise; the temperature is raised to 30-40℃ and reacted for 2 hours; 800-1200mL of water is added and stirred; the mixture is extracted and separated; the aqueous phase is washed with 300-800mL of dichloromethane; and the solution is concentrated to obtain intermediate 3.

[0023] In the synthesis method described in this invention, oxidation reaction II in S4 is as follows: 1200-1800 mL of dichloromethane is added to 120-180 g of intermediate 3, followed by the slow addition of 150-200 g of m-chloroperoxybenzoic acid. After reacting at 30-50℃ for 4-5 hours, 40-50 g of sodium bisulfite is added and the reaction continues for 1 hour. 1200-1800 mL of water is added and mixed thoroughly. The mixture is separated, washed once with water, and the organic phase is evaporated to dryness. Then, 200-500 mL of 50 wt% ethanol aqueous solution is added, stirred, and slurried. After drying, the crude dotenoradine product is obtained.

[0024] The ring-closing reagent in S1 is formaldehyde or paraformaldehyde; paraformaldehyde is preferred.

[0025] The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method:

[0026] Calcination of 8-15g of mesoporous alumina at 400-600℃ for 2-6h, cooling to room temperature under nitrogen atmosphere, and then immersing in 80-120mL of 0.01-0.02mol / L chloroplatinic acid aqueous solution, followed by filtration and drying at 90-120℃ for 6-10h; calcination at 450-600℃ for 2-6h yields platinum / mesoporous alumina for later use; dissolving 0.1-1g of catalyst in 20-80mL of 0.1mol / L sodium bicarbonate buffer, adding 5-12g of platinum / mesoporous alumina, sonicating for 1-2h, filtering, and drying at 80-120℃ for 6-12h; calcination at 400-500℃ for 4-6h.

[0027] The catalyst is any one or two of sodium tungstate, sodium molybdate, sodium metavanadate, and ammonium molybdate.

[0028] The beneficial effects of this invention are:

[0029] 1. This invention provides a novel synthetic approach for dotenorazole. Utilizing the relatively weak oxidizing power of hydrogen peroxide, it addresses the difficulty of directly oxidizing sulfides to sulfone groups in high yields. m-chloroperoxybenzoic acid completes the conversion of sulfoxides to sulfones. Side reactions are controlled using a platinum / mesoporous alumina catalyst, resulting in fewer sulfone impurities. This approach is worthy of reference by those skilled in the art.

[0030] 2. Compared with the existing technology, the two oxidation reactions of the present invention greatly reduce the amount of m-chloroperoxybenzoic acid used, reduce the synthesis cost, and have strong controllability in terms of safety.

[0031] 3. This invention optimizes the structure of platinum and the mesoporous support, and then works synergistically with a catalytic promoter. After platinum is loaded, it interacts with the hydroxyl groups on the surface of mesoporous alumina. Acidic sites promote heterolytic cracking of precursors such as hydrogen peroxide to generate ·O- reactive oxygen species; at the same time, the d electrons of platinum shift towards tungsten, enhancing surface electronic defects, improving oxidation reaction kinetics, and preventing the formation of other impurities. Detailed Implementation

[0032] The parameters and sources of some substances in the examples are as follows:

[0033] Paraformaldehyde: CAS No.: 30525-89-4, molecular weight: 30.03 g / mol; product number: P6148; Vibio.

[0034] Mesoporous alumina: Particle size: 2.7±2.3 nm; Pore volume: 0.50-0.88 cm³ 3 / g; Specific surface area: 218±57m² 2 / g。 .

[0035] m-chloroperoxybenzoic acid: CAS No.: 937-14-4; purity: 70%.

[0036] Dotenoroxetine: CAS No.: 1285572-51-1, Molecular weight: 358.20 g / mol; Purity: 98%; Wedelie.

[0037] Example 1

[0038] A method for synthesizing crude dotenoroxetine is as follows:

[0039] Synthesis of S1,2,3-dihydrobenzothiazole:

[0040] 119.94 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. 100 g of 2-aminobenzylthiophenol was added and reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated and 30 g of anhydrous sodium sulfate was added and stirred to dry. 90.74 g of brown oily 2,3-dihydrobenzothiazole was obtained with a purity of 93.75% and a yield of 82.8%. 1 HNMR(400MHz, CDC13)7.17(d,J=7.4Hz,1H),6.99(t,J=7.6Hz,1H),6.81(t,J =7.4Hz,1H),6.75(d,J=7.8Hz,1H),4.88(d,J=2.2Hz,2H),3.94-4.02(m,1H)

[0041] Synthesis of S2 and intermediate 2:

[0042] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of sodium tungstate were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 84.72 g of off-white solid intermediate 2 with a purity of 89.5% and a yield of 84.30%, containing 4.2% sulfone impurities. 1HNMR (400MHz, CDC13)7.65(d,J=7.6Hz,1H),7.24(t,J=7.8Hz,1H),7.11(t, J=7.4Hz,1H),6.92(d,J=8.0Hz,1H),5.13(d,J=2.8Hz,2H),4.24-4.32(m,1H)

[0043] Synthesis of S3 and intermediate 3:

[0044] Dissolve 84.00 g of intermediate 2 in 420 mL of dichloromethane and set aside. Separately, add 113.50 g of 3,5-dichloro-4-hydroxybenzoic acid to 560 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride dropwise at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2 dropwise. Heat to 35 °C and react for 2 h. Add 980 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 148.97 g of pale yellow solid intermediate 3 with a purity of 91.7% and a yield of 79.40%. 1 H-NMR (400MHz, DMSO): 11.06 (s, 1H), 8.07 (d, J = 7.8Hz, 1H), 8.00 (d, J = 8.2Hz, 1H), 7.73 (s, 2H), 7.65-7.71 (m, 1H), 7.28-7.35 (m, 1H), 5.07 (s, 2H).

[0045] S4, Synthesis of crude dotenoroxetine:

[0046] 148.00 g of intermediate 3 was dissolved completely in 1480 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1480 mL of water was added, and the mixture was separated. The mixture was washed once again with 1480 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 128.77 g of crude dotenoroxetine with a purity of 97.8% and a yield of 83.1%. 0.13% of the product was monosubstituted intermediate 3. 1 HNMR (400MHz, DMSO) 11.01 (s, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.83-7.91 (m, 1H), 7.68-7.80 (m, 1H), 7.71 (s, 2H), 7.44 (t, J = 7.6Hz, 1H), 5.35 (s, 2H).

[0047] Comparative Example 1

[0048] A method for synthesizing crude dotenoroxetine is as follows:

[0049] Synthesis of S1,2,3-dihydrobenzothiazole:

[0050] 118.45 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. Then, 100 g of 2-aminobenzylthiophenol was added, and the mixture was reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred to dry the product. 90.09 g of brown oily 2,3-dihydrobenzothiazole was obtained with a purity of 93.12% and a yield of 82.2%.

[0051] Synthesis of S2 and intermediate 2:

[0052] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then, 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 80.10 g of off-white solid intermediate 2 with a purity of 91.1% and a yield of 79.73%, of which 2.7% contained sulfone impurities.

[0053] Synthesis of S3 and intermediate 3:

[0054] Dissolve 80.00 g of intermediate 2 in 400 mL of dichloromethane and set aside. Separately, add 108.27 g of 3,5-dichloro-4-hydroxybenzoic acid to 550 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride dropwise at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2 dropwise. Heat to 35 °C and react for 2 h. Add 950 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 141.29 g of pale yellow solid intermediate 3 with a purity of 90.5% and a yield of 79.06%.

[0055] S4, Synthesis of crude dotenoroxetine:

[0056] 141.00 g of intermediate 3 was dissolved completely in 1410 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1410 mL of water was added, and the mixture was separated. The mixture was washed once again with 1410 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 115.69 g of crude dotenoroxetine with a purity of 96.3% and a yield of 78.4%. 0.17% of the product was monosubstituted intermediate 3.

[0057] The platinum / mesoporous alumina catalyst in S2 is prepared as follows:

[0058] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under nitrogen atmosphere, immersed in 100mL of 0.02mol / L chloroplatinic acid aqueous solution, dried at 110℃ for 8h, and calcined at 500℃ for 4h to obtain the final product.

[0059] Example 2

[0060] A method for synthesizing crude dotenoroxetine is as follows:

[0061] Synthesis of S1,2,3-dihydrobenzothiazole:

[0062] 120.26 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. 100 g of 2-aminobenzylthiophenol was then added, and the mixture was reacted at room temperature for 10 h. The solution was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred until dry. 91.18 g of brown oily 2,3-dihydrobenzothiazole was obtained. Purity: 93.34%, Yield: 83.2%.

[0063] Synthesis of S2 and intermediate 2:

[0064] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then, 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 86.02 g of off-white solid intermediate 2 with a purity of 92.4% and a yield of 85.6%, containing 1.4% sulfone impurities.

[0065] Synthesis of S3 and intermediate 3:

[0066] Dissolve 85.00 g of intermediate 2 in 425 mL of dichloromethane and set aside. Separately, add 114.90 g of 3,5-dichloro-4-hydroxybenzoic acid to 580 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride dropwise at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 1005 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 147.69 g of pale yellow solid intermediate 3 with a purity of 90.8% and a yield of 77.8%.

[0067] S4, Synthesis of crude dotenoroxetine:

[0068] 147.00 g of intermediate 3 was dissolved completely in 1470 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1470 mL of water was added, and the mixture was separated. The mixture was washed once again with 1470 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 127.84 g of crude dotenoroxetine with a purity of 97.1% and a yield of 82.5%. The purity of the monosubstituted intermediate 3 was 0.12%.

[0069] The platinum / mesoporous alumina composite catalyst in S2 is prepared as follows:

[0070] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under nitrogen atmosphere, and then immersed in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. It was dried at 110℃ for 8h and calcined at 500℃ for 4h for later use. 0.5g of sodium molybdate was dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, dried at 110℃ for 8h, and then calcined at 450℃ for 4h to obtain the final product.

[0071] Example 3

[0072] A method for synthesizing crude dotenoroxetine is as follows:

[0073] Synthesis of S1,2,3-dihydrobenzothiazole:

[0074] 119.02 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. 100 g of 2-aminobenzylthiophenol was then added, and the mixture was reacted at room temperature for 10 h. The solution was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred until dry. 90.30 g of brown oily 2,3-dihydrobenzothiazole was obtained. Purity: 93.41%, Yield: 82.4%.

[0075] Synthesis of S2 and intermediate 2:

[0076] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then, 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 86.48 g of off-white solid intermediate 2 with a purity of 92.1% and a yield of 86.08%, containing 1.5% sulfone impurities.

[0077] Synthesis of S3 and intermediate 3:

[0078] Dissolve 86.00 g of intermediate 2 in 430 mL of dichloromethane and set aside. Separately, add 116.23 g of 3,5-dichloro-4-hydroxybenzoic acid to 590 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride dropwise at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 1020 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 149.14 g of pale yellow solid intermediate 3 with a purity of 91.2% and a yield of 77.63%.

[0079] S4, Synthesis of crude dotenoroxetine:

[0080] 149.00 g of intermediate 3 was dissolved completely in 1490 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1490 mL of water was added, and the mixture was separated. The mixture was washed once again with 1490 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 129.13 g of crude dotenoroxetine with a purity of 96.8% and a yield of 82.80%. The purity of the monosubstituted intermediate 3 was 0.14%.

[0081] The platinum / mesoporous alumina composite catalyst in S2 is prepared as follows:

[0082] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then added to a solution of 100mL of 0.02mol / L chloroplatinic acid. The alumina was dried at 110℃ for 8h and calcined at 500℃ for 4h. 0.5g of sodium metavanadate was dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, dried at 110℃ for 8h, and then calcined at 450℃ for 4h to obtain the final product.

[0083] Example 4

[0084] A method for synthesizing crude dotenoroxetine is as follows:

[0085] Synthesis of S1,2,3-dihydrobenzothiazole:

[0086] 120.07 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. Then, 100 g of 2-aminobenzylthiophenol was added, and the mixture was reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred to dry the product. 91.29 g of brown oily 2,3-dihydrobenzothiazole was obtained with a purity of 93.07% and a yield of 83.3%.

[0087] Synthesis of S2 and intermediate 2:

[0088] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then, 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 88.68 g of off-white solid intermediate 2 with a purity of 92.3% and a yield of 88.27%, containing 1.1% sulfone impurities.

[0089] Synthesis of S3 and intermediate 3:

[0090] Dissolve 88.00 g of intermediate 2 in 440 mL of dichloromethane and set aside. Separately, add 119.87 g of 3,5-dichloro-4-hydroxybenzoic acid to 600 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride dropwise at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 1040 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 149.03 g of pale yellow solid intermediate 3 with a purity of 92.1% and a yield of 75.81%.

[0091] S4, Synthesis of crude dotenoroxetine:

[0092] 149.00 g of intermediate 3 was dissolved completely in 1490 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1490 mL of water was added, and the mixture was separated. The mixture was washed once again with 1530-490 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 129.02 g of crude dotenoroxetine with a purity of 96.3% and a yield of 83.71%. The purity of monosubstituted intermediate 3 was 0.10%.

[0093] The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method:

[0094] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then impregnated in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. After filtration, it was dried at 110℃ for 8h. After calcination at 500℃ for 4h, platinum / mesoporous alumina was obtained and set aside. 0.5g of sodium tungstate was dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, filtered, and dried at 110℃ for 8h. After calcination at 450℃ for 4h, the final product was obtained.

[0095] Example 5

[0096] A method for synthesizing crude dotenoroxetine is as follows:

[0097] Synthesis of S1,2,3-dihydrobenzothiazole:

[0098] 119.28 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. Then, 100 g of 2-aminobenzylthiophenol was added, and the mixture was reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred to dry the product. 91.36 g of brown oily 2,3-dihydrobenzothiazole was obtained with a purity of 94.14% and a yield of 83.4%.

[0099] Synthesis of S2 and intermediate 2:

[0100] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to crystallize, yielding 90.02 g of off-white solid intermediate 2 with a purity of 92.85% and a yield of 89.60%, containing 1.0% sulfone impurities.

[0101] Synthesis of S3 and intermediate 3:

[0102] Dissolve 90.00 g of intermediate 2 in 450 mL of dichloromethane and set aside. Separately, add 121.70 g of 3,5-dichloro-4-hydroxybenzoic acid to 610 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 1060 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 150.67 g of pale yellow solid intermediate 3 with a purity of 92.4% and a yield of 74.72%.

[0103] S4, Synthesis of crude dotenoroxetine:

[0104] 150.00 g of intermediate 3 was dissolved completely in 1500 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1500 mL of water was added, and the mixture was separated. The mixture was washed once again with 1500 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 131.41 g of crude dotenoroxetine with a purity of 97.1% and a yield of 83.68%. The purity of the monosubstituted intermediate 3 was 0.09%.

[0105] The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method:

[0106] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then immersed in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. After filtration, it was dried at 110℃ for 8h. After calcination at 500℃ for 4h, platinum / mesoporous alumina was obtained and set aside. 0.38g of sodium metavanadate and 0.29g of sodium tungstate were dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, filtered, and dried at 110℃ for 8h. After calcination at 450℃ for 4h, the final product was obtained.

[0107] Comparative Example 2

[0108] A method for synthesizing crude dotenoroxetine is as follows:

[0109] Synthesis of S1,2,3-dihydrobenzothiazole:

[0110] 121.31 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. Then, 100 g of 2-aminobenzylthiophenol was added, and the mixture was reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated, and 30 g of anhydrous sodium sulfate was added and stirred until dry. 90.25 g of brown oily 2,3-dihydrobenzothiazole was obtained with a purity of 93.29% and a yield of 82.32%.

[0111] Synthesis of S2 and intermediate 2:

[0112] 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then 41.00 g of sodium bisulfite was added and stirring was continued for 1 h. 360 mL of water was added, and the mixture was cooled to crystallize, yielding 83.27 g of off-white solid intermediate 2 with a purity of 91.3% and a yield of 84.52%, of which 1.6% contained sulfone impurities.

[0113] Synthesis of S3 and intermediate 3:

[0114] Dissolve 83.00 g of intermediate 2 in 415 mL of dichloromethane and set aside. Separately, add 112.19 g of 3,5-dichloro-4-hydroxybenzoic acid to 565 mL of dichloromethane. Slowly add 98.51 g of thionyl chloride at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 980 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 142.18 g of pale yellow solid intermediate 3 with a purity of 90.054% and a yield of 76.46%.

[0115] S4, Synthesis of crude dotenoroxetine:

[0116] 142.00 g of intermediate 3 was dissolved completely in 1420 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1420 mL of water was added, and the mixture was separated. The mixture was washed once again with 1420 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 122.56 g of crude dotenoroxetine with a purity of 96.4% and a yield of 82.44%. The purity of the monosubstituted intermediate 3 was 0.14%.

[0117] The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method:

[0118] 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then impregnated in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. After filtration, it was dried at 110℃ for 8h. After calcination at 500℃ for 4h, platinum / mesoporous alumina was obtained and set aside. 0.31g of ammonium molybdate and 0.59g of sodium tungstate were dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, filtered, and dried at 110℃ for 8h. After calcination at 450℃ for 4h, the final product was obtained.

[0119] Test Example 1

[0120] Residual reactive oxygen species test

[0121] Sample preparation: Take 1.0 g of intermediate 2 obtained in Examples 1-5 and Comparative Examples 1-2 respectively, add it to 50 mL of a chloroform-glacial acetic acid mixture with a volume ratio of 3:2, dissolve completely, and then make up to 100 mL and let stand for later use.

[0122] Sample testing: Take 10 mL of the prepared test sample and add 20 mL of freshly prepared 10% (w / v) potassium iodide solution and 10 mL of 1 mol / L sulfuric acid solution. Let it stand in the dark for 15 min. Titrate with 0.1 M sodium thiosulfate standard solution until the blue color disappears. The blank is 10 mL of a 3:2 mixture of chloroform and glacial acetic acid. Repeat the above steps, record and calculate the residual oxidizing activity.

[0123] The calculation formula is as follows:

[0124]

[0125] Table 1 Results of Residual Reactive Oxygen Species Test

[0126] Residual reactive oxygen species / % Example 1 1.04 Comparative Example 1 1.56 Example 2 0.79 Example 3 0.86 Example 4 0.67 Example 5 0.41 Comparative Example 2 1.13

[0127] Residual reactive oxygen species refer to those not consumed after the reaction, such as ·OH and O2. - Reactive oxygen species continuously attack the organic framework, leading to the formation of non-selective oxidation products and potential side reactions. This verifies whether the catalyst can "precisely control the degree of oxidation reaction".

[0128] The residual active oxygen in Comparative Example 1 and Example 1 was lower than that in Examples 2-5. This may be because platinum / mesoporous alumina, as a supported catalyst, results in insufficient activity in the oxidation of sulfide when sodium tungstate is added alone or when a supported catalyst is added, making it difficult to activate reactant molecules. Therefore, it is necessary to rely on auxiliary agents to optimize the interfacial reaction kinetics. Comparative Example 2 simultaneously introduced molybdenum and tungsten, which resulted in competitive adsorption on the support surface, reducing dispersion. Furthermore, the metal particles agglomerated, reducing the number of effective active sites.

[0129] Furthermore, compared to Examples 1-4, Example 5 contains less V in its sodium metavanadate. 5+ With W in sodium tungstate 6+ The formation of a co-doped structure enhances its activation ability for hydrogen peroxide through electron transfer, promotes the generation and stabilization of active oxygen species such as nitronium ions, and promotes the selective oxidation of sulfide to sulfone groups; in particular, sodium tungstate forms a dispersion layer on the surface of mesoporous alumina, inhibits the sintering of platinum particles, and prolongs the catalyst lifetime.

[0130] In Example 5, the catalyst exhibited low and stable residual active oxygen levels, indicating the highest utilization rate of hydrogen peroxide. This did not affect the maintenance of subsequent product purity and yield during the first oxidation reaction. The shift of platinum's d electrons towards tungsten enhanced the electronic defects on the platinum surface, improving its adsorption capacity for reactants. Simultaneously, sodium tungstate provided Lewis acidic sites, promoting CH bond activation, while sodium metavanadate accelerated proton transfer through surface hydroxyl groups, thereby reducing impurity formation and ensuring the stability of subsequent reactions.

[0131] Test Example 2

[0132] Thermal stability test

[0133] Programmable temperature recovery

[0134] Take 50 mg of the platinum / mesoporous alumina composite catalysts from Examples 2-5 and Comparative Examples 1-2, and dry them in argon at 200 °C for 1 h beforehand. Use a Micromeritics AutoChem II chemisorption analyzer, set the carrier gas to a 10% H2 / Ar mixture and the flow rate to 30 mL / min, increase the temperature to 120 °C at 10 °C / min and hold for 30 min, then switch to reducing gas and increase the temperature to 500 °C at 5 °C / min. Record the results using a TCD detector.

[0135] High temperature aging test

[0136] Take 0.1 g of the platinum / mesoporous alumina composite catalyst from Examples 2-5 and Comparative Examples 1-2, grind it evenly, load it into a quartz tube, place it in a muffle furnace at 500℃, and calcine it in air atmosphere for 4 h. Observe the particle size distribution of platinum particles before and after high-temperature treatment, calculate and record the data. The results are shown in Table 2.

[0137] Table 2 Results of hygroscopicity and loss on drying tests

[0138]

[0139] The reduction peak temperature refers to the temperature at which hydrogen consumption reaches its peak during a temperature-programmed reduction test when the active components such as platinum and sodium tungstate in the catalyst undergo a reduction reaction with a reducing gas such as H2. A higher reduction peak temperature indicates a stronger bond between the active components and the support / auxiliary agent, resulting in greater catalyst stability during high-temperature reactions.

[0140] Hydrogen consumption is a key parameter reflecting the reducibility of active components and the number of active sites. The lower the consumption, the stronger the interaction between the active components and the support / auxiliary agent, and the less likely it is to be reduced and deactivated at high temperatures.

[0141] Platinum particle size variation is one of the core indicators for measuring the thermal stability of a catalyst. A small increase in particle size indicates that the support / auxiliary stabilizes the platinum particles through steric hindrance or electronic effects.

[0142] In Comparative Example 2, a composite catalyst of ammonium molybdate and sodium tungstate was used. Ammonium molybdate preferentially adsorbs onto the acidic sites of mesoporous alumina, reducing the contact opportunities between sodium tungstate and platinum, thus preventing platinum from forming a stable bond with sodium tungstate. In Example 2, the electron matching between ammonium molybdate and platinum was poor, resulting in insufficient interaction strength. In Example 3, the redox synergy between sodium metavanadate and platinum was limited, leading to a low reduction peak temperature and failing to sufficiently suppress the reducibility of platinum. In Example 4, through the synergistic effect of the pore confinement of mesoporous alumina and the strong electron anchoring of sodium tungstate, platinum was highly dispersed and bonded to sodium tungstate, resulting in relatively stable active sites.

[0143] Furthermore, in Example 5, the mismatch of valence states between W6+ and V5+ accelerates the generation cycle of active oxygen species in the catalyst, lowering the reduction peak temperature and maintaining a high density of active sites. The tungsten-vanadium composite system, through its surface WVO structure, reduces the adsorption energy of the carbon deposition precursor, showing better performance compared to the ammonium molybdate system. The dual-auxiliary-supported system catalyzes the oxidation of hydrogen peroxide combined with m-chloroperoxybenzoic acid, achieving high purity, low impurities, and good hygroscopicity, meeting the stability requirements for industrial application.

Claims

1. A method for synthesizing crude dotenoroxetine, characterized in that, The synthesis method includes the following steps: S1,2-aminobenzylthiol undergoes a cyclization reaction with a cyclizing agent to give 2,3-dihydrobenzothiazole; S2,2,3-dihydrobenzothiazole is oxidized by a platinum / mesoporous alumina composite catalyst to generate intermediate 2 with a sulfoxide structure in reaction I; S3, intermediate 2 reacts with the acyl chloride formed by 3,5-dichloro-4-hydroxybenzoic acid to give intermediate 3; S4 and intermediate 3 are subjected to oxidation reaction II to obtain crude dotenoroxetine; The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method: 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then immersed in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. After filtration, it was dried at 110℃ for 8h. After calcination at 500℃ for 4h, platinum / mesoporous alumina was obtained and set aside. 0.38g of sodium metavanadate and 0.29g of sodium tungstate were dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, filtered, and dried at 110℃ for 8h. After calcination at 450℃ for 4h, the final product was obtained.

2. The method for synthesizing crude dotenorazole according to claim 1, characterized in that, The cyclization reaction in S1 is as follows: 80-150g of 2-aminobenzylthiol and 100-200g of the cyclizing reagent are added to 300-800mL of isopropyl ether and stirred. After cyclization reaction at room temperature for 10-12h, the mixture is washed twice with 200-500mL of 10wt% sodium carbonate aqueous solution and once with water. The mixture is then separated. 20-50g of anhydrous sodium sulfate is added and the mixture is dried under reduced pressure to obtain intermediate 1, namely 2,3-dihydrobenzothiazole.

3. The method for synthesizing crude dotenoradine according to claim 1, characterized in that, The oxidation reaction I in S2 is as follows: 80-100g of 2,3-dihydrobenzothiazole and 1-5g of platinum / mesoporous alumina composite catalyst are added to 100-200mL of ethanol and stirred until dissolved. Then, 100-120g of 30wt% hydrogen peroxide solution is added, and the mixture is heated to 30-40℃ and stirred for 10-15h. 30-80g of sodium bisulfite is added and stirring is continued for 1h. Then, 300-500mL of water is added, the mixture is cooled to crystallize, filtered, and intermediate 2 is obtained.

4. The method for synthesizing crude dotenorazole according to claim 1, characterized in that, The S3 acyl chloride reaction is as follows: 60-110g of intermediate 2 is added to 300-550mL of dichloromethane and set aside; 100-150g of 3,5-dichloro-4-hydroxybenzoic acid is added to 500-800mL of dichloromethane, and 80-120g of thionyl chloride is slowly added dropwise at room temperature. The temperature is raised to 30-50℃ and the reaction is maintained for 6 hours. Then, the temperature is lowered to 10-15℃ and 120-150g of triethylamine is added dropwise. The prepared solution is then slowly added dropwise, and the temperature is raised to 30-40℃ and the reaction is carried out for 2 hours. 800-1200mL of water is added and stirred. The mixture is extracted and separated. The aqueous phase is washed with 300-800mL of dichloromethane and concentrated to obtain intermediate 3.

5. The method for synthesizing crude dotenorazole according to claim 1, characterized in that, The oxidation reaction II in S4 is as follows: 1200-1800 mL of dichloromethane is added to 120-180 g of intermediate 3, followed by the slow addition of 150-200 g of m-chloroperoxybenzoic acid. After reacting at 30-50℃ for 4-5 hours, 40-50 g of sodium bisulfite is added and the reaction continues for 1 hour. 1200-1800 mL of water is added and mixed thoroughly. The mixture is separated, washed once with water, and the organic phase is evaporated to dryness. Then, 200-500 mL of 50wt% ethanol aqueous solution is added, stirred, and slurried. After drying, the crude product of dotenoroxetine is obtained.

6. The method for synthesizing crude dotenorazole according to claim 2, characterized in that, The cyclization reagent in step S1 is either formaldehyde or paraformaldehyde.

7. The method for synthesizing crude dotenoradine according to claim 1, characterized in that, Includes the following steps: Synthesis of S1,2,3-dihydrobenzothiazole: 119.28 g of paraformaldehyde was added to 500 mL of isopropyl ether and stirred. 100 g of 2-aminobenzylthiophenol was added and reacted at room temperature for 10 h. The mixture was washed twice with 300 mL of 10 wt% sodium carbonate aqueous solution and once with water. The mixture was separated and 30 g of anhydrous sodium sulfate was added and stirred to dry. 91.36 g of brown oily 2,3-dihydrobenzothiazole was obtained. Synthesis of S2 and intermediate 2: 90.00 g of 2,3-dihydrobenzothiazole and 1.35 g of platinum / mesoporous alumina composite catalyst were added to 180 mL of ethanol and stirred until dissolved. 111.56 g of 30 wt% hydrogen peroxide was added dropwise, and the mixture was heated to 30 °C and stirred for 12 h. Then 41.00 g of sodium bisulfite was added and the mixture was stirred for another 1 h. 360 mL of water was added, and the mixture was cooled to allow crystallization, yielding 90.02 g of off-white solid intermediate 2. Synthesis of S3 and intermediate 3: Dissolve 90.00 g of intermediate 2 in 450 mL of dichloromethane and set aside. Separately, dissolve 121.70 g of 3,5-dichloro-4-hydroxybenzoic acid in 610 mL of dichloromethane. Slowly add 98.51 g of sulfoxide at room temperature, then heat to 40 °C and maintain the temperature for 6 h. Adjust the temperature to 12 °C, add 138.70 g of triethylamine, and then slowly add the prepared dichloromethane solution of intermediate 2. Heat to 35 °C and react for 2 h. Add 1060 mL of water and mix. Extract and separate the liquid. Wash the aqueous phase with 500 mL of dichloromethane, concentrate and dry to obtain 150.67 g of pale yellow solid intermediate 3. S4, Synthesis of crude dotenoroxetine: 150.00 g of intermediate 3 was dissolved completely in 1500 mL of dichloromethane. 192.00 g of m-chloroperoxybenzoic acid was slowly added, and the reaction was carried out at 40 °C for 4 h. 45.00 g of sodium bisulfite was then added, and the reaction was continued for another 1 h. 1500 mL of water was added, and the mixture was separated. The mixture was washed once again with 1500 mL of water, and the organic phase was evaporated to dryness. The obtained solid was stirred and slurried with 300 mL of 50 wt% ethanol aqueous solution, and dried to obtain 131.41 g of crude dotenoroxetine. The platinum / mesoporous alumina composite catalyst in S2 is prepared by the following method: 10g of mesoporous alumina was calcined at 450℃ for 4h, cooled to room temperature under a nitrogen atmosphere, and then immersed in 100mL of 0.02mol / L chloroplatinic acid aqueous solution. After filtration, it was dried at 110℃ for 8h. After calcination at 500℃ for 4h, platinum / mesoporous alumina was obtained and set aside. 0.38g of sodium metavanadate and 0.29g of sodium tungstate were dissolved in 50mL of 0.1mol / L sodium bicarbonate buffer solution, and 8g of the prepared platinum / mesoporous alumina was added. The mixture was sonicated for 1h, filtered, and dried at 110℃ for 8h. After calcination at 450℃ for 4h, the final product was obtained.

Images