Process for the preparation of a multiple tenofovir intermediate

Abstract

This invention discloses a method for preparing a dotenoroxetine intermediate, relating to the field of pharmaceutical intermediate synthesis technology. The method includes the following steps: Under a protective gas atmosphere, anhydrous ethanol, an ionic liquid, and a supported catalyst are mixed and stirred. Then, 2-aminothiophenol is added, and stirring continues. Next, slow-release formaldehyde is added in batches, and the reaction is carried out under controlled temperature and stirring. After post-treatment, the dotenoroxetine intermediate is obtained. This invention effectively improves the yield and purity of the dotenoroxetine intermediate through the synergistic effect of the supported catalyst, ionic liquid, and slow-release formaldehyde.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing dotenorazole intermediate. Background Technology

[0002] Dotenorazole, also known as dotenorazole, has the chemical name (3,5-dichloro-4-hydroxyphenyl)(1,1-dioxide-3(2H)-benzothiazolyl) methyl ketone, and its structural formula is as follows: .

[0003] Dotenorazole is a urate reabsorption inhibitor that targets and inhibits the activity of urate reabsorption transport proteins, thereby suppressing urate reabsorption and lowering blood uric acid levels. Benzothiazoline is a core intermediate in the synthesis of dotenorazole; its purity, yield, and the greenness and stability of its preparation process significantly impact the synthetic quality and production cost of the dotenorazole active pharmaceutical ingredient. Currently, the main synthetic route for benzothiazoline is the condensation cyclization of 2-aminothiophenol and formaldehyde.

[0004] Existing technologies often employ formaldehyde aqueous solutions or direct feeding of paraformaldehyde into the reaction. Excessive instantaneous formaldehyde concentration can easily trigger over-polymerization and intermolecular coupling, leading to a decrease in the yield, color, and purity of benzothiazoline. Furthermore, traditional processes utilize inorganic bases or small-molecule organic base catalytic systems, which suffer from poor catalytic selectivity, and strong inorganic bases readily induce side reactions such as formaldehyde disproportionation.

[0005] Therefore, how to overcome the shortcomings of existing technologies and achieve highly selective and high-purity preparation of benzothiazoline is of great research significance for the industrial production of dotenorazole. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a method for preparing dotenoroxetine intermediates.

[0007] The objective of this invention can be achieved through the following technical solutions: A method for preparing a dotenoroxetine intermediate includes the following steps: A protective gas is introduced, and anhydrous ethanol, ionic liquid, and supported catalyst are mixed and stirred. Then, 2-aminobenzylthiophenol is added and stirred again. Slow-release formaldehyde is added after stirring. After the addition is complete, the reaction is carried out under controlled temperature and stirred. The intermediate of dotenoroxetine is obtained after post-treatment.

[0008] A method for preparing a dotenoroxetine intermediate includes the following specific steps: A protective gas is introduced, and anhydrous ethanol, ionic liquid, and supported catalyst are mixed and stirred for 10-15 min. Then, 2-aminothiophenol is added, and stirring is continued for 15-20 min. Slow-release formaldehyde is added in three portions, with equal mass added each time and an interval of 3-5 min between each addition. After the addition is complete, the reaction is stirred at 10-15℃ for 3.5-4.0 h. The temperature is then lowered to 6-8℃, and the mixture is allowed to stand for 30-35 min. The supported catalyst is removed by filtration. The filtrate is rotary evaporated at -0.08 MPa to -0.06 MPa and 40-45℃ for 40-45 min. The concentrated solution is then cooled to 0-5℃, allowed to stand for 2-2.5 h, filtered, and the resulting crystals are washed twice with methyl tert-butyl ether at 0-5℃. The crystals are then vacuum dried at 35-40℃ for 8-9 h to obtain the dotenorazole intermediate.

[0009] Furthermore, the ratio of anhydrous ethanol, ionic liquid, supported catalyst, 2-aminothiophenol, and slow-release formaldehyde is 90-100mL: 9-12mL: 1.0-1.5g: 10g: 3.2-3.8g.

[0010] Furthermore, the ionic liquid is 1-ethyl-3-methylimidazolium tetrafluoroborate.

[0011] Furthermore, the reaction process for preparing the dotenorazole intermediate is as follows: .

[0012] Furthermore, the preparation method of the supported catalyst includes the following steps: Step (1): Mix mesoporous silica, hydrochloric acid solution, and ammonium fluoride, heat under reflux and stir, filter, wash, and dry to obtain activated mesoporous silica; Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, introduce a protective gas, add 3-chloropropyltriethoxysilane dropwise, heat and reflux with stirring, cool, filter, wash, and dry to obtain mesoporous silica with chloropropyl groups on the surface. Step (3): Mix mesoporous silica with chloropropyl groups on the surface and anhydrous n-butanol, stir, add ethylenediamine and triethylamine, introduce a protective gas, heat and stir, then heat and reflux and stir, cool, wash, filter, mix the filter cake with anhydrous toluene and hexamethyldisilazane, heat and stir in a protective gas atmosphere, filter, wash, dry, and obtain the supported catalyst.

[0013] Furthermore, the preparation method of the supported catalyst includes the following specific steps: Step (1): Mix mesoporous silica, hydrochloric acid solution and ammonium fluoride, heat to 70-75℃, reflux and stir for 3-3.5h, filter, wash with deionized water at 50-60℃ until the washing solution is neutral, then wash with anhydrous ethanol, dry the filter cake to obtain activated mesoporous silica. Furthermore, the ratio of mesoporous silica, hydrochloric acid solution, and ammonium fluoride is 10-11g: 150-155mL: 0.5-0.55g; the concentration of hydrochloric acid solution is 1.5-1.7mol / L.

[0014] Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, introduce a protective gas, add 3-chloropropyltriethoxysilane dropwise, control the addition of 3-chloropropyltriethoxysilane to be completed within 40-60 min, heat to 100-105℃, reflux and stir for 6-6.5 h, cool, filter, wash, and dry to obtain mesoporous silica with chloropropyl groups on the surface; Furthermore, the ratio of activated mesoporous silica, anhydrous isopropanol, deionized water, N-methylpiperidine, and 3-chloropropyltriethoxysilane is 8-8.5g: 120-125mL: 0.5-0.7mL: 2.5-3.0mL: 4.2-4.8mL.

[0015] Step (3): Mix mesoporous silica with chloropropyl groups on the surface and anhydrous n-butanol, stir for 20-30 min, add ethylenediamine and triethylamine, introduce a protective gas, heat to 60-65℃, stir for 2-2.5 h, then raise the temperature to 85-90℃, reflux and stir for 6-6.5 h, cool, filter, wash, filter again, mix the filter cake with anhydrous toluene and hexamethyldisilazane, heat to 90℃ in a protective gas atmosphere and stir for 3-3.5 h, filter, wash, dry to obtain the supported catalyst.

[0016] Furthermore, the ratio of surface-containing chloropropyl mesoporous silica, anhydrous n-butanol, ethylenediamine, and triethylamine is 9.0-10.0 g : 180-185 mL : 14-14.5 mL : 0.8-0.9 mL.

[0017] Furthermore, the method for preparing slow-release formaldehyde includes the following steps: The molecular sieve is calcined and cooled to obtain an activated molecular sieve. Paraformaldehyde, anhydrous methanol, and triethylamine are mixed, heated and stirred, cooled, and then the activated molecular sieve is added. The mixture is impregnated, filtered, and vacuum dried to obtain slow-release formaldehyde.

[0018] Furthermore, the preparation method for slow-release formaldehyde includes the following specific steps: Molecular sieves are calcined at 550-560℃ for 4-4.5 hours and cooled to room temperature to obtain activated molecular sieves. Paraformaldehyde, anhydrous methanol, and triethylamine are mixed and stirred at 45-50℃ for 2-2.5 hours. After cooling, the activated molecular sieves are added and impregnated at room temperature for 12-13 hours. During impregnation, the mixture is stirred at 200-250 rpm for 3-5 minutes every 2.5-3 hours. The mixture is then filtered, and the filter cake is vacuum dried at 38-42℃ for 6-6.5 hours to obtain slow-release formaldehyde.

[0019] Furthermore, the ratio of paraformaldehyde, anhydrous methanol, triethylamine, and activated molecular sieve is 18-22g: 100-110mL: 0.1-0.3g: 40-45g.

[0020] The dotenorazole intermediate prepared by the above-mentioned method.

[0021] The beneficial effects of this invention are: This invention discloses a method for preparing a dotenorazole intermediate, which includes the following steps: In a protective gas atmosphere, anhydrous ethanol, an ionic liquid, and a supported catalyst are mixed, then 2-aminothiophenol is added, followed by batches of slow-release formaldehyde. After temperature-controlled stirring and reaction, the dotenorazole intermediate (i.e., benzothiazoline) is obtained through post-treatment. The supported catalyst used in this invention is prepared using mesoporous silica as a carrier, which undergoes fluorine-assisted hydrochloric acid pore-expansion activation, silane grafting with chloropropyl groups, ethylenediamine amination to introduce weakly basic active sites, and subsequent post-treatment processes such as surface residual silanol capping. Alternatively, this invention uses molecular sieves as a carrier, impregnating a mixture of paraformaldehyde, anhydrous methanol, and triethylamine to prepare slow-release formaldehyde.

[0022] This invention uses molecular sieve-supported slow-release formaldehyde as the reactant, which slowly releases formaldehyde in the reaction system, avoiding excessively high instantaneous formaldehyde concentrations and inhibiting side reactions such as substrate polymerization and intermolecular coupling, thereby improving product yield and purity. This invention uses ionic liquids to improve mass transfer at the liquid-solid interface and stabilize cyclic intermediates during the reaction, reducing the activation energy of side reactions. The supported catalyst provides highly selective, long-lasting basic active sites for directional catalysis of cyclization and ring-closure reactions, avoiding formaldehyde disproportionation side reactions initiated by inorganic strong bases. Through the synergistic effect of the supported catalyst and ionic liquid, the selectivity of the cyclization reaction and the conversion efficiency of the reactants can be improved. Combined with slow-release formaldehyde and a protective gas atmosphere, impurity formation can be synergistically suppressed, improving the yield and purity of the dotenorphine intermediate. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] The chromatographic purity of the dotenorazole intermediates (i.e., benzothiazoline) prepared in Examples 7-9 and Comparative Examples 1-5 of this invention was determined by high performance liquid chromatography (HPLC) using the external standard method, and denoted as purity P. The purity was determined based on the mass m0 of 2-aminothiophenol, the relative molecular weight of 2-aminothiophenol (125.19 g / mol), the purity P of the dotenorazole intermediate, and the mass m of the crude dotenorazole intermediate obtained after filtration, washing, and drying in the preparation process. 粗 The relative molecular weight of benzothiazoline is 137.20 g / mol. Calculate the yield Y of the dotenorazine intermediate using the formula: Y = (m 粗 ×P×125.19) / (m0×137.20)×100%.

[0025] Example 1: The preparation method of the supported catalyst includes the following steps: Step (1): Mix mesoporous silica (supplier: Qinghe County Chaotai Metal Materials Co., Ltd., grade: SF90), hydrochloric acid solution, and ammonium fluoride, heat to 70℃, reflux and stir for 3h, filter, wash with 50℃ deionized water until the washing solution is neutral, then wash three times with anhydrous ethanol, dry the filter cake at 40℃ for 4h, and then vacuum dry at 80℃ for 8h to obtain activated mesoporous silica; the ratio of mesoporous silica, hydrochloric acid solution, and ammonium fluoride is 10g:150mL:0.5g; the concentration of hydrochloric acid solution is 1.5mol / L.

[0026] Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, purge with nitrogen, and add 3-chloropropyltriethoxysilane dropwise, controlling the addition of 3-chloropropyltriethoxysilane to be completed within 40 min. Heat to 100℃, reflux and stir for 6 h, cool to room temperature, filter, wash the filter cake three times with anhydrous ethanol, and vacuum dry at 60℃ for 6 h to obtain mesoporous silica with chloropropyl groups on the surface; the ratio of activated mesoporous silica, anhydrous isopropanol, deionized water, N-methylpiperidine, and 3-chloropropyltriethoxysilane is 8 g: 120 mL: 0.5 mL: 2.5 mL: 4.2 mL.

[0027] Step (3): Mix the surface-containing chloropropyl mesoporous silica and anhydrous n-butanol, stir for 20 min, add ethylenediamine and triethylamine, purge with nitrogen, heat to 60°C, stir for 2 h, then heat to 85°C, reflux and stir for 6 h, cool to room temperature, filter, wash three times with n-butanol at 80°C, then wash twice with diethyl ether, filter again, mix the filter cake with 100 mL of anhydrous toluene and 4 mL of hexamethyldisilazane, heat to 90°C in a nitrogen atmosphere and stir for 3 h, filter, wash three times each with toluene and ethanol, first place at 40°C and vacuum dry for 6 h, then heat to 70°C and continue vacuum drying for 4 h to obtain the supported catalyst; the ratio of surface-containing chloropropyl mesoporous silica, anhydrous n-butanol, ethylenediamine and triethylamine is 9.0 g: 180 mL: 14 mL: 0.8 mL.

[0028] Example 2: The preparation method of the supported catalyst includes the following steps: Step (1): Mix mesoporous silica (supplier: Qinghe County Chaotai Metal Materials Co., Ltd., grade: SF90), hydrochloric acid solution, and ammonium fluoride, heat to 73℃, reflux and stir for 3.3h, filter, wash with deionized water at 55℃ until the washing solution is neutral, then wash three times with anhydrous ethanol, dry the filter cake at 40℃ for 4h, and then vacuum dry at 80℃ for 8h to obtain activated mesoporous silica; the ratio of mesoporous silica, hydrochloric acid solution, and ammonium fluoride is 10.5g:153mL:0.53g; the concentration of hydrochloric acid solution is 1.6mol / L.

[0029] Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, purge with nitrogen, and add 3-chloropropyltriethoxysilane dropwise, ensuring the addition of 3-chloropropyltriethoxysilane is completed within 50 min. Heat to 103 °C, reflux and stir for 6.3 h, cool to room temperature, filter, wash the filter cake three times with anhydrous ethanol, and vacuum dry at 60 °C for 6 h to obtain mesoporous silica with chloropropyl groups on the surface. The ratio of activated mesoporous silica, anhydrous isopropanol, deionized water, N-methylpiperidine, and 3-chloropropyltriethoxysilane is 8.3 g: 123 mL: 0.6 mL: 2.8 mL: 4.5 mL.

[0030] Step (3): Mix the surface-containing chloropropyl mesoporous silica and anhydrous n-butanol, stir for 25 min, add ethylenediamine and triethylamine, purge with nitrogen, heat to 63℃, stir for 2.3 h, then heat to 88℃, reflux and stir for 6.3 h, cool to room temperature, filter, wash three times with n-butanol at 80℃, then wash twice with diethyl ether, filter again, mix the filter cake with 100 mL of anhydrous toluene and 4 mL of hexamethyldisilazane, heat to 90℃ in a nitrogen atmosphere and stir for 3.3 h, filter, wash three times each with toluene and ethanol, first place at 40℃ and vacuum dry for 6 h, then heat to 70℃ and continue vacuum drying for 4 h to obtain the supported catalyst; the ratio of surface-containing chloropropyl mesoporous silica, anhydrous n-butanol, ethylenediamine and triethylamine is 9.5 g: 183 mL: 14.3 mL: 0.85 mL.

[0031] Example 3: The preparation method of the supported catalyst includes the following steps: Step (1): Mix mesoporous silica (supplier: Qinghe County Chaotai Metal Materials Co., Ltd., grade: SF90), hydrochloric acid solution, and ammonium fluoride, heat to 75℃, reflux and stir for 3.5h, filter, wash with deionized water at 60℃ until the washing solution is neutral, then wash three times with anhydrous ethanol, dry the filter cake at 40℃ for 4h, and then vacuum dry at 80℃ for 8h to obtain activated mesoporous silica; the ratio of mesoporous silica, hydrochloric acid solution, and ammonium fluoride is 11g:155mL:0.55g; the concentration of hydrochloric acid solution is 1.7mol / L.

[0032] Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, purge with nitrogen, and add 3-chloropropyltriethoxysilane dropwise, ensuring the addition of 3-chloropropyltriethoxysilane is completed within 60 min. Heat to 105 °C, reflux and stir for 6.5 h, cool to room temperature, filter, wash the filter cake three times with anhydrous ethanol, and vacuum dry at 60 °C for 6 h to obtain mesoporous silica with chloropropyl groups on the surface. The ratio of activated mesoporous silica, anhydrous isopropanol, deionized water, N-methylpiperidine, and 3-chloropropyltriethoxysilane is 8.5 g: 125 mL: 0.7 mL: 3.0 mL: 4.8 mL.

[0033] Step (3): Mix the surface-containing chloropropyl mesoporous silica and anhydrous n-butanol, stir for 30 min, add ethylenediamine and triethylamine, purge with nitrogen, heat to 65℃, stir for 2.5 h, then heat to 90℃, reflux and stir for 6.5 h, cool to room temperature, filter, wash three times with n-butanol at 80℃, then wash twice with diethyl ether, filter again, mix the filter cake with 100 mL of anhydrous toluene and 4 mL of hexamethyldisilazane, heat to 90℃ in a nitrogen atmosphere and stir for 3.5 h, filter, wash three times each with toluene and ethanol, first place at 40℃ and vacuum dry for 6 h, then heat to 70℃ and continue vacuum drying for 4 h to obtain the supported catalyst; the ratio of surface-containing chloropropyl mesoporous silica, anhydrous n-butanol, ethylenediamine and triethylamine is 10.0 g: 185 mL: 14.5 mL: 0.9 mL.

[0034] Example 4: The preparation method of slow-release formaldehyde includes the following steps: Molecular sieves (supplier: Pingxiang Hexing Chemical Packing Equipment Co., Ltd., model: 4A) were calcined at 550℃ for 4 hours and cooled to room temperature to obtain activated molecular sieves. Paraformaldehyde (supplier: Jinan Jiewei Chemical Technology Co., Ltd., net weight: 25kg), anhydrous methanol, and triethylamine were mixed and stirred at 45℃ for 2 hours. After cooling to room temperature, the activated molecular sieves were added and impregnated at room temperature for 12 hours. During the impregnation period, the mixture was stirred at 200 rpm for 3 minutes every 2.5 hours. The mixture was filtered, and the filter cake was vacuum dried at 38℃ for 6 hours to obtain slow-release formaldehyde. The ratio of paraformaldehyde, anhydrous methanol, triethylamine, and activated molecular sieves was 18g:100mL:0.1g:40g.

[0035] Example 5: The preparation method of slow-release formaldehyde includes the following steps: Molecular sieves (supplier: Pingxiang Hexing Chemical Packing Equipment Co., Ltd., model: 4A) were calcined at 555℃ for 4.3h and cooled to room temperature to obtain activated molecular sieves. Paraformaldehyde (supplier: Jinan Jiewei Chemical Technology Co., Ltd., net weight: 25kg), anhydrous methanol, and triethylamine were mixed and stirred at 48℃ for 2.3h. After cooling to room temperature, the activated molecular sieves were added, and the mixture was impregnated at room temperature for 12.5h. During the impregnation period, the mixture was stirred at 220rpm for 4min every 2.8h. The mixture was filtered, and the filter cake was vacuum dried at 40℃ for 6.3h to obtain slow-release formaldehyde. The ratio of paraformaldehyde, anhydrous methanol, triethylamine, and activated molecular sieves was 20g:105mL:0.2g:43g.

[0036] Example 6: The preparation method of slow-release formaldehyde includes the following steps: Molecular sieves (supplier: Pingxiang Hexing Chemical Packing Equipment Co., Ltd., model: 4A) were calcined at 560℃ for 4.5h and cooled to room temperature to obtain activated molecular sieves. Paraformaldehyde (supplier: Jinan Jiewei Chemical Technology Co., Ltd., net weight: 25kg), anhydrous methanol, and triethylamine were mixed and stirred at 50℃ for 2.5h. After cooling to room temperature, the activated molecular sieves were added and impregnated at room temperature for 13h. During the impregnation period, the mixture was stirred at 250rpm for 5min every 3h. The mixture was filtered, and the filter cake was vacuum dried at 42℃ for 6.5h to obtain slow-release formaldehyde. The ratio of paraformaldehyde, anhydrous methanol, triethylamine, and activated molecular sieves was 22g:110mL:0.3g:45g.

[0037] Example 7: A method for preparing a dotenoroxetine intermediate includes the following steps: Nitrogen gas was introduced, and anhydrous ethanol, ionic liquid, and the supported catalyst obtained in Example 1 were mixed and stirred at room temperature for 10 min. Then, 2-aminothiophenol was added, and stirring was continued for 15 min. The slow-release formaldehyde obtained in Example 4 was added in three portions, with equal mass added each time and an interval of 3 min between each addition. After the addition was completed, the mixture was stirred at 10°C for 3.5 h, cooled to 6°C, and allowed to stand for 30 min. The supported catalyst was removed by filtration, and the filtrate was rotary evaporated at -0.08 MPa and 40°C for 40 min. The concentrated solution was cooled to 0°C, allowed to stand for 2 h, and filtered. The resulting crystals were washed twice with 3 mL of methyl tert-butyl ether at 0°C, and then vacuum dried at 35°C for 8 h to obtain the dotenorazole intermediate. The ratio of anhydrous ethanol, ionic liquid, supported catalyst, 2-aminothiophenol, and slow-release formaldehyde was 90 mL: 9 mL: 1.0 g: 10 g: 3.2 g. The ionic liquid was 1-ethyl-3-methylimidazolium tetrafluoroborate.

[0038] The purity (P) of the dotenoroxetine intermediate was 99.4%; the yield (Y) was 92.8%.

[0039] Example 8: A method for preparing a dotenoroxetine intermediate includes the following steps: Nitrogen gas was introduced, and anhydrous ethanol, ionic liquid, and the supported catalyst obtained in Example 2 were mixed and stirred at room temperature for 13 min. Then, 2-aminothiophenol was added, and stirring was continued for 18 min. The slow-release formaldehyde obtained in Example 5 was added in three equal portions, with each addition spaced 4 min apart. After the addition was complete, the mixture was stirred at 13°C for 3.8 h, cooled to 7°C, and allowed to stand for 33 min. The supported catalyst was removed by filtration, and the filtrate was subjected to a rotary osmosis at -0.07 MPa and 43°C. The solution was steamed for 43 min, cooled to 3 °C, allowed to stand for 2.3 h, filtered, and the resulting crystals were washed twice with 4 mL of methyl tert-butyl ether at 3 °C. Then, the solution was vacuum dried at 38 °C for 8.5 h to obtain the dotenorazole intermediate. The ratio of anhydrous ethanol, ionic liquid, supported catalyst, 2-aminobenzylthiophenol, and slow-release formaldehyde was 95 mL: 10.5 mL: 1.3 g: 10 g: 3.5 g. The ionic liquid was 1-ethyl-3-methylimidazolium tetrafluoroborate.

[0040] The purity P of the dotenoroxetine intermediate was 99.1%; the yield Y was 92.3%.

[0041] Example 9: A method for preparing a dotenoroxetine intermediate includes the following steps: Nitrogen gas was introduced, and anhydrous ethanol, ionic liquid, and the supported catalyst obtained in Example 3 were mixed and stirred at room temperature for 15 min. Then, 2-aminobenzylthiophenol was added, and stirring was continued for 20 min. The slow-release formaldehyde obtained in Example 6 was added in three portions, with equal mass added each time and an interval of 5 min between each addition. After the addition was completed, the mixture was stirred at 15°C for 4.0 h, cooled to 8°C, and allowed to stand for 35 min. The supported catalyst was removed by filtration, and the filtrate was rotary evaporated at -0.06 MPa and 45°C for 45 min. The concentrated solution was cooled to 5°C, allowed to stand for 2.5 h, filtered, and the resulting crystals were washed twice with 5 mL of methyl tert-butyl ether at 5°C. Then, the crystals were vacuum dried at 40°C for 9 h to obtain the dotenorazole intermediate. The ratio of anhydrous ethanol, ionic liquid, supported catalyst, 2-aminobenzylthiophenol, and slow-release formaldehyde was 100 mL: 12 mL: 1.5 g: 10 g: 3.8 g. The ionic liquid was 1-ethyl-3-methylimidazolium tetrafluoroborate.

[0042] The purity P of the dotenoroxetine intermediate was 99.5%; the yield Y was 93.1%.

[0043] Comparative Example 1 Compared with Example 9, the slow-release formaldehyde was replaced by a 37% formaldehyde aqueous solution, while the rest was exactly the same as in Example 9, and finally, a dotenoroxetine intermediate was prepared.

[0044] The purity P of the dotenoroxetine intermediate was 79.5%; the yield Y was 96.7%.

[0045] Comparative Example 2 Compared with Example 9, the supported catalyst was replaced with potassium carbonate by the same mass, and everything else was exactly the same as in Example 9. Finally, a dotenoroxetine intermediate was prepared.

[0046] The purity (P) of the dotenoroxetine intermediate was 84.3%; the yield (Y) was 97.4%.

[0047] Comparative Example 3 Compared with Example 9, no ionic liquid was used, but everything else was exactly the same as in Example 9, and finally a dotenoroxetine intermediate was prepared.

[0048] The purity P of the dotenoroxetine intermediate was 85.5%; the yield Y was 97.7%.

[0049] Comparative Example 4 Compared with Example 9, the ionic liquid was replaced with DMSO in equal mass, and everything else was exactly the same as in Example 9, finally producing a dotenoroxetine intermediate.

[0050] The purity (P) of the dotenororil intermediate was 83.7%; the yield (Y) was 95.2%.

[0051] Comparative Example 5 Compared with Example 9, no supported catalyst was used, but everything else was exactly the same as in Example 9, and finally a dotenorox intermediate was prepared.

[0052] The purity P of the dotenororic intermediate was 62.2%; the yield Y was 93.4%.

[0053] Comparative Example 6 Compared with Example 9, triethylamine was not used in the preparation of sustained-release formaldehyde, but everything else was exactly the same as in Example 9, and finally, dotenoradine intermediate was prepared.

[0054] The purity (P) of the dotenoroxetine intermediate was 85.1%; the yield (Y) was 97.9%.

[0055] Comparative Example 7 Compared with Example 9, the supported catalyst was replaced by an equal mass of mesoporous silica with chloropropyl groups on the surface, while the rest was exactly the same as in Example 9, and finally a dotenorox intermediate was prepared.

[0056] The purity (P) of the dotenoroxetine intermediate was 75.1%; the yield (Y) was 93.9%.

[0057] The above description is merely an example and illustration of the concept of the present invention. Those skilled in the art can make various modifications or additions to the specific embodiments described or use similar methods to replace them, as long as they do not deviate from the concept of the invention or exceed the scope defined in the claims, they should all fall within the protection scope of the present invention.

Claims

1. A method for preparing a dotenoroxetine intermediate, characterized in that: Includes the following steps: A protective gas is introduced, and anhydrous ethanol, ionic liquid, and supported catalyst are mixed and stirred. Then, 2-aminobenzylthiophenol is added and stirred again. Slow-release formaldehyde is added after stirring. After the addition is complete, the reaction is carried out under controlled temperature and stirred. The intermediate of dotenoroxetine is obtained after post-treatment.

2. The method for preparing a dotenorphine intermediate according to claim 1, characterized in that: The ratio of anhydrous ethanol, ionic liquid, supported catalyst, 2-aminothiophenol, and slow-release formaldehyde is 90-100 mL: 9-12 mL: 1.0-1.5 g: 10 g: 3.2-3.8 g.

3. The method for preparing a dotenorphine intermediate according to claim 1, characterized in that: The preparation process of the dotenoroxetine intermediate is as follows: 。 4. The method for preparing a dotenorphine intermediate according to claim 1, characterized in that: The preparation method of the supported catalyst includes the following steps: Step (1): Mix mesoporous silica, hydrochloric acid solution, and ammonium fluoride, heat under reflux and stir, filter, wash, and dry to obtain activated mesoporous silica; Step (2): Mix activated mesoporous silica, anhydrous isopropanol, deionized water, and N-methylpiperidine, introduce a protective gas, add 3-chloropropyltriethoxysilane dropwise, heat and reflux with stirring, cool, filter, wash, and dry to obtain mesoporous silica with chloropropyl groups on the surface. Step (3): Mix mesoporous silica with chloropropyl groups on the surface and anhydrous n-butanol, stir, add ethylenediamine and triethylamine, introduce a protective gas, heat and stir, then heat and reflux and stir, cool, wash, filter, mix the filter cake with anhydrous toluene and hexamethyldisilazane, heat and stir in a protective gas atmosphere, filter, wash, dry, and obtain the supported catalyst.

5. The method for preparing a dotenoroxetine intermediate according to claim 4, characterized in that: In step (1), the ratio of the amount of mesoporous silica, hydrochloric acid solution, and ammonium fluoride is 10-11g: 150-155mL: 0.5-0.55g; The concentration of the hydrochloric acid solution is 1.5-1.7 mol / L.

6. The method for preparing a dotenoroxetine intermediate according to claim 4, characterized in that: In step (2), the ratio of activated mesoporous silica, anhydrous isopropanol, deionized water, N-methylpiperidine, and 3-chloropropyltriethoxysilane is 8-8.5g: 120-125mL: 0.5-0.7mL: 2.5-3.0mL: 4.2-4.8mL.

7. The method for preparing a dotenoroxetine intermediate according to claim 4, characterized in that: In step (3), the ratio of the amount of the surface-containing chloropropyl mesoporous silica, anhydrous n-butanol, ethylenediamine, and triethylamine is 9.0-10.0g: 180-185mL: 14-14.5mL: 0.8-0.9mL.

8. The method for preparing a dotenorphine intermediate according to claim 1, characterized in that: The slow-release formaldehyde is prepared by the following steps: The molecular sieve is calcined and cooled to obtain an activated molecular sieve. Paraformaldehyde, anhydrous methanol, and triethylamine are mixed, heated and stirred, cooled, and then the activated molecular sieve is added. The mixture is impregnated, filtered, and vacuum dried to obtain slow-release formaldehyde.

9. The method for preparing a dotenoroxetine intermediate according to claim 8, characterized in that: The ratio of paraformaldehyde, anhydrous methanol, triethylamine, and activated molecular sieve is 18-22g: 100-110mL: 0.1-0.3g: 40-45g.

10. A dotenorazole intermediate prepared by a method according to any one of claims 1-9.

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