A method for the preparation of a pharmaceutical intermediate benzothiazolo[2,3-b]quinazolinone derivative and a renewable catalytic system

Abstract

The present application relates to the field of pharmaceutical intermediates, and specifically discloses a method for preparing a pharmaceutical intermediate benzothiazolo[2,3-b]quinazolinone derivative and a renewable catalytic system, which comprises condensation reaction of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole as reaction raw materials under the condition of heating and in a catalytic system formed by glycerol-derived carbon-based solid sulfonic acid and dimethylformamide-ethanol-[Bmim]BF4 to prepare the benzothiazolo[2,3-b]quinazolinone derivative. The catalytic system can not only achieve the purpose of recycling without any treatment, but also can be regenerated by simple organic solvent washing when the product cannot meet the requirements of pharmaceutical intermediate grade. Compared with other preparation methods of benzothiazolo[2,3-b]quinazolinone derivative, the product purification process of the present application is relatively simple, and continuous, economical, environmentally friendly and large-scale production can be easily achieved.

Description

Technical Field

[0001] This invention relates to a method for preparing pharmaceutical intermediates, specifically to a method and a regenerative catalytic system for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative, which belongs to the field of pharmaceutical intermediate preparation. Background Technology

[0002] Quinazolinones are an important class of nitrogen-containing heterocyclic compounds, forming the skeletal structure of many natural products. They also possess a wide range of pharmacological activities, and are used in everyday life as hypnotics, sedatives, anticonvulsants, antibacterial agents, antidiabetic drugs, anti-inflammatory drugs, and antitumor drugs. Furthermore, compounds containing the benzothiazole structure are also an important class of fused heterocyclic compounds with broad biological activities. Coupled with their low toxicity, high efficiency, environmental friendliness, and diverse structural variations, they have wide applications in the pharmaceutical industry and have become a hot topic in drug development. Therefore, benzothiazo[2,3-b]quinazolinone derivatives, which contain both benzothiazole and quinazolinone structures, possess both of the aforementioned biological activities and are gradually becoming a research focus for organic chemists and medicinal chemists. To date, these compounds can be used as parent structures to synthesize cyclin-dependent kinase CDK and GSK-3 inhibitors (Synthesis and evaluation of the antiproliferative activity of novel thiazoloquinazolinone kinases inhibitors[J], Journal of Enzyme Inhibition and Medicinal Chemistry, 2005, 20(6): 557-568; Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3[J], Bioorganic & Medicinal Chemistry Letters, 2006, 16: 3419-3423).

[0003] In recent years, a research method for preparing benzothiazo[2,3-b]quinazolinone derivatives via a three-component one-pot method using 2-aminobenzothiazolium, 1,3-cyclohexanedione derivatives, and aromatic aldehydes has begun to develop abroad, but progress has been limited and there are many drawbacks. For example, in 2008, Rajendra P. Pawar et al. used an anhydrous zinc chloride catalyst and dimethylformamide as a solvent to catalyze the synthesis of a series of benzothiazo[2,3-b]quinazolinone derivatives from different aromatic aldehydes, 2-aminobenzothiazolium derivatives, and 1,3-cyclohexanedione (Anhydrous zinc chloride: an efficient catalyst for one pot synthesis of 2,3,4,12-tetrahydro-benzo-[4,5]-thiazolo-[2,3-b]-quinazolin-1-ones[J], ARKIVOC, 2008, (XVII): 241-247). Although this preparation method has the advantages of simplicity and high efficiency, it also has disadvantages such as the inability to recycle the catalyst (anhydrous zinc chloride is easily hydrolyzed), high reaction temperature (120℃), and relatively complex product purification process (column chromatography). In 2012, MAZAAHIR Kidwai et al. used Amberlyst-15 as a heterogeneous catalyst and PEG-400 as a reaction solvent to catalyze the reaction of different aldehydes, 2-aminobenzothiazole derivatives and 1,3-cyclohexanedione derivatives to prepare different benzothiazolo-[2,3-b]quinazolinone derivatives (Amberlyst-15 in PEG: anovel catalytic system for the facile and efficient one-pot synthesis of benzothiazolo-[2,3-b]-quinazolinone derivatives[J], Science China, 2012, 55(10): 2154~2160). This preparation method greatly reduces the reaction temperature and reaction time while also improving the yield of the corresponding products. Furthermore, and more importantly, the catalytic system composed of Amberlyst-15 and PEG-400 can be recycled. However, the above method also has the disadvantages of the catalytic system not being able to be regenerated after recycling, the product purification process still being complex, and the catalyst preparation being cumbersome and lacking in selectivity. Summary of the Invention

[0004] To achieve the above objectives, this invention aims to provide a method for preparing benzothiazo[2,3-b]quinazolinone derivatives using aldehydes, 2-aminobenzothiazolium, and 1,3-cyclohexanedione derivatives as reactants. The method utilizes a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent as the catalytic system, thereby achieving continuous recycling and regeneration of the catalytic system, simplifying the product purification process, and improving reaction selectivity.

[0005] The objective of this invention can be achieved through the following technical solutions:

[0006] A method for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative, wherein the reaction formula of the preparation method is as follows:

[0007]

[0008] The above reaction steps are as follows: under heating conditions, and in a catalytic system formed by glycerol-derived carbon-based solid sulfonic acid and dimethylformamide-ethanol-[Bmim]BF4, aldehydes, 1,3-cyclohexanedione derivatives and 2-aminobenzothiazole are used as reactants to carry out a condensation reaction to prepare benzothiazo[2,3-b]quinazolinone derivatives.

[0009] Optionally, the aldehyde in the reaction raw materials is selected from:

[0010]

[0011] Any one of them.

[0012] Optionally, the catalytic system consists of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent, wherein [Bmim]BF4 is a tetrafluoroborate 1-butyl-3-methylimidazolium salt.

[0013] Optionally, the 1,3-cyclohexanedione derivative is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

[0014] Optionally, the molar ratio of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole in the reaction raw materials is 1:1:1.

[0015] Optionally, the mass of the glycerol-derived carbon-based solid sulfonic acid catalyst in the reaction is 5 to 9% of the molar amount of the aldehyde used.

[0016] Optionally, the volume of dimethylformamide-ethanol-[Bmim]BF4 solvent used in the reaction is 6 to 10 times the amount of the aldehyde substance in millimoles.

[0017] Optionally, the volume ratio of dimethylformamide, ethanol and [Bmim]BF4 in the dimethylformamide-ethanol-[Bmim]BF4 solvent in the reaction is 7:(1.3-2.4):(0.5-1.2).

[0018] Optionally, after adding a predetermined amount of reaction raw materials to a catalytic system composed of dimethylformamide-ethanol-[Bmim]BF4 solvent and a glycerol-derived carbon-based solid sulfonic acid catalyst at room temperature, the mixture needs to be stirred to form a mixed solution, heated to a predetermined temperature and kept at that temperature for reaction, then subjected to a first filtration while hot, followed by cooling and crystallization of the first filtrate, crushing the crystals and allowing it to stand, then subjected to a second filtration and purification of the filter residue, and finally subjected to a third filtration and vacuum drying of the filter residue to obtain the benzothiazo[2,3-b]quinazolinone derivative.

[0019] Mixing and stirring to form a mixed solution: First, the glycerol-derived carbon-based solid sulfonic acid catalyst is added to a reaction flask equipped with a thermometer, magnetic stir bar and spherical condenser, containing dimethylformamide-ethanol-[Bmim]BF4 solvent in a preset volume ratio. The catalytic system is formed by magnetic stirring at room temperature. Then, the reaction raw materials are added to the reaction flask in the order of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole and the preset amount of substance. The mixture is stirred at room temperature to form a mixed solution.

[0020] Heating to a preset temperature and holding for reaction: The mixed solution is heated to a preset temperature in a methyl silicone oil bath under magnetic stirring, and this temperature is maintained until the reaction is complete. Stirring is continued during the holding process. The preset temperature is 53-71℃ and the holding time is 24-39 min.

[0021] Perform the first filtration while the reaction is still hot: immediately after the reaction is completed, filter the reaction solution to obtain the first filter residue and the first filtrate;

[0022] First filtrate cooling and crystallization, crushing crystals and standing: The first filtrate was first cooled naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large number of crystals. The crystals were then crushed and left to stand in the ice-water bath for 6 hours.

[0023] Second filtration and purification of filter residue: The liquid containing a large number of crystals after standing is filtered to obtain a second filtrate and a second filter residue. The second filter residue is dissolved in hot ethanol and then naturally cooled to room temperature to precipitate a large number of crystals.

[0024] Third filtration and vacuum drying of filter residue: Perform a third filtration to obtain a third filter residue, and then place the third filter residue in a vacuum drying oven and dry it at 75°C for 12 hours to obtain the benzothiazo[2,3-b]quinazolinone derivative.

[0025] A regenerable catalytic system for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative, wherein the catalytic system consisting of the first filter residue being added to the second filtrate can be recycled or regenerated;

[0026] The specific operating procedure for recycling the catalytic system is as follows:

[0027] The first filter residue without any treatment is placed into the second filtrate, and magnetic stirring is used to form a catalytic system. Then, the reaction raw materials are directly added to carry out the next round of reaction. The system is recycled multiple times. The purity of the benzothiazo[2,3-b]quinazolinone derivative of each product is monitored by high performance liquid chromatography and its yield is calculated. Considering the requirements of the pharmaceutical intermediate industry or economic factors, when its liquid chromatography purity is lower than 98.5% or the yield decreases by more than 5%, the catalytic system is stopped from being recycled and enters the regeneration process.

[0028] The specific operation procedure for regenerating the catalytic system is as follows:

[0029] The first filter residue from the final recycling experiment was extracted with petroleum ether (boiling range 60–90 °C) using a Soxhlet extractor and then vacuum dried at 85 °C to constant weight to obtain the regenerated catalyst. The second filtrate was rotary evaporated to remove dimethylformamide and ethanol, and then transferred to a separatory funnel. Petroleum ether (boiling range 60–90 °C) was added, and the mixture was shaken and washed. The mixture was then separated again, and petroleum ether (boiling range 60–90 °C) was added to the lower layer of liquid for shaking and washing. This process was repeated three times. The lower layer of liquid was then vacuum dried at 85 °C to constant weight and added to the previously evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system. Attached Figure Description

[0030] To facilitate understanding by those skilled in the art, the present invention will be further described below with reference to the accompanying drawings.

[0031] Figure 1 This is a simplified process flow diagram for preparing benzothiazo[2,3-b]quinazolinone derivatives according to the present invention.

[0032] Figure 2 This is a simplified process flow diagram of the catalytic system of the present invention for recycling.

[0033] Figure 3 This is a simplified process flow diagram for the regeneration of the catalytic system of the present invention.

[0034] The beneficial effects of this invention are:

[0035] This invention discloses a method and regenerable catalytic system for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative. Using aldehydes, 1,3-cyclohexanedione derivatives, and 2-aminobenzothiazolium as reactants, a catalytic system composed of a highly selective and stable glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent is employed to prepare high-purity benzothiazo[2,3-b]quinazolinone derivatives. This catalytic system not only allows for recycling without any pretreatment, improving the atom economy of the reactants, but also enables regeneration through simple organic solvent washing when the product does not meet pharmaceutical intermediate standards. Furthermore, compared to other methods for preparing benzothiazo[2,3-b]quinazolinone derivatives, the product purification process of this invention is relatively simple, allowing for easy continuous, economical, environmentally friendly, and large-scale production. Detailed Implementation

[0036] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. 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.

[0037] In the following examples, the 1H NMR characterization of the reaction product benzothiazo[2,3-b]quinazolinone derivative was performed using an AVANCE II 400MHz NMR spectrometer from Bruker GmbH, Germany; infrared spectroscopy was performed using an EQUINOX 55 infrared spectrometer (KBr pellet) from Bruker GmbH, Germany; high performance liquid chromatography purity was determined using a Water 2695 high performance liquid chromatograph from Waters Corporation, USA; and melting point was determined using a capillary melting point apparatus from Shanghai Jiahang Instruments Co., Ltd.

[0038] The glycerol-derived carbon-based solid sulfonic acid catalyst used in this invention was prepared with reference to the following literature:

[0039] Glycerol derived carbon-SO3H: a green recyclable catalyst toward the access of functionalized 2,5-dihydrofuran-3-carboxylates[J], Polycyclic Aromatic Compounds, 2023, 43(2): 1722-1734. Its preparation process requires the following steps:

[0040]

[0041] The -SO3H content in the carbon-based solid sulfonic acid catalyst of the prepared glycerol derivative was determined to be 2.68 mmol / g by acid-base potentiometric titration.

[0042] The [Bmim]BF4 used in this invention was prepared via a two-step substitution and exchange method, referring to the following literature:

[0043] Improved preparation and use of room-temperature ionic liquids inlipase-catalyzed enantio-and regioselective acylations[J], Journal of Organic Chemistry, 2001, 66(25): 8395~8401, the preparation process is:

[0044]

[0045] Other reagents or instruments used without a specified manufacturer are all commercially available products.

[0046] A method for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative, wherein the reaction formula of the preparation method is as follows:

[0047]

[0048] The above reaction steps are as follows: under heating conditions, and in a catalytic system formed by glycerol-derived carbon-based solid sulfonic acid and dimethylformamide-ethanol-[Bmim]BF4, aldehydes, 1,3-cyclohexanedione derivatives and 2-aminobenzothiazole are used as reactants to carry out a condensation reaction to prepare benzothiazo[2,3-b]quinazolinone derivatives.

[0049] As a technical optimization of the present invention, the aldehyde in the reaction raw materials is selected from:

[0050]

[0051] Any one of them.

[0052] As an optimized technical solution of the present invention, the catalytic system is composed of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent, wherein [Bmim]BF4 is a tetrafluoroborated 1-butyl-3-methylimidazolium salt.

[0053] As a technical optimization of the present invention, the 1,3-cyclohexanedione derivative is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione.

[0054] As a technical optimization scheme of the present invention, the molar ratio of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole in the reaction raw materials is 1:1:1.

[0055] As a technical optimization of the present invention, the mass of the glycerol-derived carbon-based solid sulfonic acid catalyst in the reaction is 5 to 9% of the molar amount of the aldehyde used.

[0056] As a technical optimization of the present invention, the volume of dimethylformamide-ethanol-[Bmim]BF4 solvent used in the reaction is 6 to 10 times the amount of aldehyde substance in millimoles.

[0057] As a technical optimization scheme of the present invention, the volume ratio of dimethylformamide, ethanol and [Bmim]BF4 in the dimethylformamide-ethanol-[Bmim]BF4 solvent in the reaction is 7:(1.3~2.4):(0.5~1.2).

[0058] As a technical optimization of the present invention, after adding a predetermined amount of reaction raw materials to a catalytic system composed of dimethylformamide-ethanol-[Bmim]BF4 solvent and glycerol-derived carbon-based solid sulfonic acid catalyst at room temperature, it is necessary to mix and stir to form a mixed solution → heat to a predetermined temperature and keep it warm for reaction → perform the first filtration while hot → cool the first filtrate to crystallize, crush the crystals and let it stand → perform the second filtration and purify the filter residue → perform the third filtration and vacuum dry the filter residue to obtain the benzothiazo[2,3-b]quinazolinone derivative;

[0059] Mixing and stirring to form a mixed solution: First, the glycerol-derived carbon-based solid sulfonic acid catalyst is added to a reaction flask equipped with a thermometer, magnetic stir bar and spherical condenser, containing dimethylformamide-ethanol-[Bmim]BF4 solvent in a preset volume ratio. The catalytic system is formed by magnetic stirring at room temperature. Then, the reaction raw materials are added to the reaction flask in the order of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole and the preset amount of substance. The mixture is stirred at room temperature to form a mixed solution.

[0060] Heating to a preset temperature and holding for reaction: The mixed solution is heated to a preset temperature in a methyl silicone oil bath under magnetic stirring, and this temperature is maintained until the reaction is complete. Stirring is continued during the holding process. The preset temperature is 53-71℃ and the holding time is 24-39 min.

[0061] Perform the first filtration while the reaction is still hot: immediately after the reaction is completed, filter the reaction solution to obtain the first filter residue and the first filtrate;

[0062] First filtrate cooling and crystallization, crushing crystals and standing: The first filtrate was first cooled naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large number of crystals. The crystals were then crushed and left to stand in the ice-water bath for 6 hours.

[0063] Second filtration and purification of filter residue: The liquid containing a large number of crystals after standing is filtered to obtain a second filtrate and a second filter residue. The second filter residue is dissolved in hot ethanol and then naturally cooled to room temperature to precipitate a large number of crystals.

[0064] Third filtration and vacuum drying of filter residue: Perform a third filtration to obtain a third filter residue, and then place the third filter residue in a vacuum drying oven and dry it at 75°C for 12 hours to obtain the benzothiazo[2,3-b]quinazolinone derivative.

[0065] A regenerable catalytic system for preparing the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative, wherein the catalytic system consisting of the first filter residue being added to the second filtrate can be recycled or regenerated;

[0066] The specific operating procedure for recycling the catalytic system is as follows:

[0067] The first filter residue without any treatment is placed into the second filtrate, and magnetic stirring is used to form a catalytic system. Then, the reaction raw materials are directly added to carry out the next round of reaction. The system is recycled multiple times. The purity of the benzothiazo[2,3-b]quinazolinone derivative of each product is monitored by high performance liquid chromatography and its yield is calculated. Considering the requirements of the pharmaceutical intermediate industry or economic factors, when its liquid chromatography purity is lower than 98.5% or the yield decreases by more than 5%, the catalytic system is stopped from being recycled and enters the regeneration process.

[0068] The specific operation procedure for regenerating the catalytic system is as follows:

[0069] The first filter residue from the final recycling experiment was extracted with petroleum ether (boiling range 60–90 °C) using a Soxhlet extractor and then vacuum dried at 85 °C to constant weight to obtain the regenerated catalyst. The second filtrate was rotary evaporated to remove dimethylformamide and ethanol, and then transferred to a separatory funnel. Petroleum ether (boiling range 60–90 °C) was added, and the mixture was shaken and washed. The mixture was then separated again, and petroleum ether (boiling range 60–90 °C) was added to the lower layer of liquid for shaking and washing. This process was repeated three times. The lower layer of liquid was then vacuum dried at 85 °C to constant weight and added to the previously evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

[0070] The present invention will be further described below with reference to specific embodiments.

[0071] Example 1

[0072]

[0073] First, 0.07 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 6 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:1.3:0.7). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of benzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 3 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 58 °C in a methyl silicone oil bath under stirring and maintained at this temperature for 29 min. The reaction was detected by TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1). Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was cooled naturally to room temperature, then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 hours, and then filtered to obtain a second residue and a second filtrate. The second residue was dissolved in 2 mL of hot ethanol, then cooled naturally to room temperature, resulting in the precipitation of a large amount of crystals. This was then filtered to obtain a third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried under vacuum at 75°C for 12 hours to obtain 0.31 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-phenyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.2%. Calculations showed that the yield of the product 12-phenyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 93%.

[0074] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0075] The detection data of the product 12-phenyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 231~233℃; 1 H NMR (400MHz, TMS, CDCl3): δ=7.24~7.53(m, 4H), 7.12~7.23(m, 5H), 5.44(s, 1H), 2.51~2.62(m, 2 H), 2.35~2.44(m, 2H), 1.96~2.03(m, 2H); IR(KBr): ν=3319, 2954, 1727, 1594, 1535, 1377, 752cm -1.

[0076] Example 2

[0077]

[0078] First, 0.08 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 7 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:1.5:0.9). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of p-chlorobenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 3 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 62 °C in a methyl silicone oil bath under stirring and maintained at this temperature for 31 min. The reaction was detected by TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1). Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was cooled naturally to room temperature, then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, and the mixture was allowed to stand in the ice-water bath for 6 hours before being filtered to obtain a second residue and a second filtrate. The second residue was dissolved in 3 mL of hot ethanol, then cooled naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered to obtain a third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried at 75°C for 12 hours to obtain 0.34 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.4%. Calculations showed that the yield of the product 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 91%.

[0079] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0080] The detection data of the product 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 212~214℃; 1H NMR (400MHz, TMS, CDCl3): δ=7.27~7.80 (m, 4H), 6.99~7.19 (m, 4H), 5.41 (s, 1H), 2.57~2.64 (m, 2 H), 2.33~2.49 (m, 2H), 1.94~2.00 (m, 2H); IR (KBr): ν=3324, 2957, 1723, 1591, 1530, 1374, 539cm -1 .

[0081] Example 3

[0082]

[0083] First, 0.08 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 8 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:1.7:1.0). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of p-methylbenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 3 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 66 °C in a methyl silicone oil bath under stirring and maintained at this temperature for 34 min. The reaction was detected by TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1). Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was cooled naturally to room temperature, then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 hours, and then filtered to obtain a second residue and a second filtrate. The second residue was dissolved in 4 mL of hot ethanol, then cooled naturally to room temperature, resulting in the precipitation of a large amount of crystals. This was then filtered to obtain a third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried under vacuum at 75°C for 12 hours to obtain 0.31 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-(4-methylphenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.1%. Calculations showed that the yield of the product 12-(4-methylphenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 90%.

[0084] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0085] The detection data of the product 12-(4-methylphenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 146~148℃; 1 H NMR (400MHz, TMS, CDCl3): δ=7.15~7.79(m, 4H), 6.92~7.03(m, 4H), 5.37(s, 1H), 2.55~2.64(m, 2H), 2. 37 ~ 2.48 (m, 2H), 2.30 (s, 3H), 1.96 ~ 2.02 (m, 2H); IR (KBr): ν = 3341, 2950, ​​1719, 1638, 1600, 1369, 753cm -1 .

[0086] Example 4

[0087]

[0088] First, 0.05 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 7 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:1.5:0.5). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of m-nitrobenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 3 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 53 °C in a methyl silicone oil bath with stirring. This temperature was maintained for 24 min. The reaction was detected by TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1). Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was filtered while still hot to obtain the first residue and the first filtrate. The first filtrate was cooled naturally to room temperature, then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, and the mixture was allowed to stand in the ice-water bath for 6 hours before being filtered to obtain a second residue and a second filtrate. The second residue was dissolved in 3 mL of hot ethanol, then cooled naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered to obtain a third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried under vacuum at 75°C for 12 hours to obtain 0.36 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-(3-nitrophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.5%. Calculations showed the yield of the product 12-(3-nitrophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one to be 94%.

[0089] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0090] The detection data of the product 12-(3-nitrophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 161~163℃; 1H NMR (400MHz, TMS, CDCl3): δ=7.63~7.97(m, 4H), 7.12~7.56(m, 4H), 5.42(s, 1H), 2.58~2.68(m, 2 H), 2.44~2.49 (m, 2H), 1.93~2.03 (m, 2H); IR (KBr): ν=3308, 2961, 1723, 1604, 1518, 1349, 750cm -1 .

[0091] Example 5

[0092]

[0093] First, 0.08 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 9 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:1.8:1.2). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of piperine, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 4 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 68 °C in a methyl silicone oil bath with stirring. This temperature was maintained for 37 min. The reaction was detected by TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1). Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was filtered while still hot to obtain the first residue and the first filtrate. The first filtrate was naturally cooled to room temperature, then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, and the mixture was allowed to stand in the ice-water bath for 6 hours before being filtered to obtain a second residue and a second filtrate. The second residue was dissolved in 5 mL of hot ethanol, then naturally cooled to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered to obtain a third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried at 75°C for 12 hours to obtain 0.34 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-benzo[1,3]dioxo-5-yl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.5%. Calculations showed that the yield of the product 12-benzo[1,3]dioxo-5-yl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 89%.

[0094] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0095] The detection data of the product 12-benzo[1,3]dioxo-5-yl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 217~219℃; 1 H NMR (400MHz, TMS, CDCl3): δ=6.74~7.51(m, 3H), 6.55~6.73(m, 4H), 5.89(s, 2H), 5.39(s, 1H), 2.51~2.58( m, 2H), 2.46 ~ 2.49 (m, 2H), 1.99 ~ 2.03 (m, 2H); IR (KBr): ν = 3298, 2960, 1717, 1604, 1482, 1379, 1238, 774cm -1 .

[0096] Example 6

[0097]

[0098] First, 0.07 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 8 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:2:1.1). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of o-hydroxybenzaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 3 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 59°C in a methyl silicone oil bath with stirring, and the reaction was maintained at this temperature for 32 min. TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1) was used for detection. Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was allowed to cool naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 h, and then filtered again to obtain the second residue and the second filtrate. The second residue was dissolved in 5 mL of hot ethanol, then allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered again to obtain the third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried at 75°C for 12 hours to obtain 0.34 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 12-(2-hydroxyphenyl)-3,3-dimethyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.4%. Calculations showed that the yield of the product 12-(2-hydroxyphenyl)-3,3-dimethyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 89%.

[0099] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0100] The detection data of the product 12-(2-hydroxyphenyl)-3,3-dimethyl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 161~163℃; 1H NMR (400MHz, TMS, CDCl3): δ=7.49~7.57(m, 4H), 7.15~7.33(m, 4H), 6.72(s, 1H), 4.74(br s, 1H), 3.68 (t, J=20.8Hz, 2H), 2.26 (s, 2H), 0.95 (s, 6H); IR (KBr): ν=3176, 2949, 1643, 1597, 1371, 1258, 753cm -1 .

[0101] Example 7

[0102]

[0103] First, 0.08 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 8 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:2.1:1.0). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of 2-thiophenecarboxaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 4 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 65°C in a methyl silicone oil bath with stirring, and the reaction was maintained at this temperature for 34 min. TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1) was used for detection. Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was allowed to cool naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 h, and then filtered again to obtain the second residue and the second filtrate. The second residue was dissolved in 4 mL of hot ethanol, then allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered again to obtain the third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried at 75°C for 12 hours to obtain 0.32 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 3,3-dimethyl-12-(thienyl-2-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.3%. Calculations showed that the yield of the product 3,3-dimethyl-12-(thienyl-2-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 86%.

[0104] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0105] The detection data of the product 3,3-dimethyl-12-(thienyl-2-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 135~137℃; 1 H NMR (400MHz, TMS, CDCl3): δ=7.26~7.52(m, 4H), 6.58~7.04(m, 3H), 5.62(s, 1H), 3.65(t, J=21.4Hz, 2H), 2.38 (s, 2H), 1.14 (s, 6H); IR (KBr): ν=2963, 2641, 1592, 1372, 1257, 728cm -1 .

[0106] Example 8

[0107]

[0108] First, 0.09 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 10 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:2.4:1.2). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of 1-naphthaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially under stirring at room temperature. The mixture was stirred for another 6 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 71°C in a methyl silicone oil bath with stirring, and the reaction was maintained at this temperature for 39 min. TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1) was used for detection. Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was allowed to cool naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 h, and then filtered again to obtain the second residue and the second filtrate. The second residue was dissolved in 5 mL of hot ethanol, then allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered again to obtain the third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried under vacuum at 75°C for 12 hours to obtain 0.34 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 3,3-dimethyl-12-(naphthyl-1-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.1%. Calculations showed that the yield of the product 3,3-dimethyl-12-(naphthyl-1-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 83%.

[0109] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0110] The detection data of the product 3,3-dimethyl-12-(naphthyl-1-yl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 286~288℃; 1H NMR (400MHz, TMS, CDCl3): δ=7.45~8.02(m, 7H), 7.12~7.39(m, 4H), 6.12(s, 1H), 3.47(t, J=24.6Hz, 2H), 2.30 (s, 2H), 1.11 (s, 6H); IR (KBr): ν=2997, 1642, 1474, 1172, 1129, 748cm -1 .

[0111] Example 9

[0112]

[0113] First, 0.09 g of glycerol-derived carbon-based solid sulfonic acid was added to a 50 mL four-necked flask equipped with a magnetic stirrer, a spherical condenser, and a thermometer, containing 9 mL of dimethylformamide-ethanol-[Bmim]BF4 (the volume ratio of dimethylformamide, ethanol, and [Bmim]BF4 was 7:2.4:0.8). The mixture was stirred at room temperature to form a suspension catalytic system. Then, 1.0 mmol of cinnamaldehyde, 1.0 mmol of 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were added sequentially with stirring at room temperature. The mixture was stirred for another 5 min at room temperature to ensure complete dissolution of the reactants. Next, the mixture was uniformly heated to 68°C in a methyl silicone oil bath with stirring, and the reaction was maintained at this temperature for 37 min. TLC (thin-plate chromatography, developing solvent: V(dichloromethane):V(ethyl acetate) = 3:1) was used for detection. Once the starting material spot disappeared, stirring was immediately stopped, and the four-necked flask was removed from the oil bath. The mixture was then filtered while hot to obtain the first residue and the first filtrate. The first filtrate was allowed to cool naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large amount of crystals. The crystals were then crushed, allowed to stand in the ice-water bath for 6 h, and then filtered again to obtain the second residue and the second filtrate. The second residue was dissolved in 5 mL of hot ethanol, then allowed to cool naturally to room temperature, resulting in the precipitation of a large amount of crystals. This residue was then filtered again to obtain the third residue. Finally, the third filter residue was placed in a vacuum drying oven and dried under vacuum at 75°C for 12 hours to obtain 0.34 g of solid. Nuclear magnetic resonance (NMR) and infrared spectroscopy analysis revealed it to be 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one. High performance liquid chromatography (HPLC) (mobile phase: V(methanol):V(distilled water) = 7:3) determined its purity to be 99.7%. Calculations showed that the yield of the product 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one was 87%.

[0114] The first filter residue was added to the second filtrate without any treatment and mixed with magnetic stirring at room temperature to form a suspended catalytic system for recycling.

[0115] The detection data of the product 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one obtained in this example: MP: 164~166℃; 1 H NMR (400MHz, TMS, CDCl3): δ=7.26~7.58 (m, 9H), 7.14 (d, J=15.3Hz, 1H), 7.06 (m, 1H), 5.98 (m, 1H), 2.51 (s, 2 H), 2.34 (t, J=17.2Hz, 2H), 1.14 (s, 3H), 1.01 (s, 3H); IR (KBr): ν=3449, 2961, 1618, 1459, 1393, 1235, 750cm -1 .

[0116] Example 10

[0117] The performance of the catalytic system in recycling

[0118] Taking the catalytic system of Example 2, which consists of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent, as an example: 1.0 mmol of p-chlorobenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were directly added to the circulating catalytic system in Example 2. The catalytic system was then recycled in accordance with the operating steps and reaction conditions of Example 2, for a total of 7 times. The changes in the liquid chromatography purity and yield of the reaction product 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 1.

[0119]

[0120] Table 1

[0121] As can be seen from the data in Table 1, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the new catalytic system without regeneration in Example 2 can be used up to 6 times.

[0122] Example 11

[0123] First regeneration of the catalytic system

[0124] Taking the catalytic system of glycerol-derived carbon-based solid sulfonic acid catalyst and dimethylformamide-ethanol-[Bmim]BF4 solvent, which has been used 7 times in Example 10, as an example: the first filter residue from the 7th cycle experiment in Example 10 was extracted with petroleum ether (boiling range 60-90°C) using a Soxhlet extractor and dried under vacuum at 75°C to constant weight to obtain the regenerated catalyst; after the dimethylformamide and ethanol were evaporated from the second filtrate by rotary evaporation, it was transferred to a separatory funnel, 5 ml of petroleum ether (boiling range 60-90°C) was added, and the mixture was shaken and washed, and then separated. Then, 5 ml of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid and the mixture was shaken and washed, for a total of 3 times. The lower layer liquid was then dried under vacuum at 85°C to constant weight, and then added to the previously evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

[0125] Example 12

[0126] The performance of the catalytic system after the first regeneration for recycling

[0127] Taking the catalytic system composed of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent from Example 11 as an example: 1.0 mmol of p-chlorobenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione, and 1.0 mmol of 2-aminobenzothiazole were directly added to the catalytic system regenerated in Example 11. Then, the regenerated catalytic system was recycled according to the operating steps of Example 10, and used a total of 6 times. The changes in the liquid chromatography purity and yield of the reaction product 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 2.

[0128]

[0129] Table 2

[0130] As can be seen from the data in Table 2, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the catalytic system after the first regeneration in Example 2 can be used up to 5 times.

[0131] Example 13

[0132] Second regeneration of the catalytic system

[0133] Taking the catalytic system of glycerol-derived carbon-based solid sulfonic acid catalyst and dimethylformamide-ethanol-[Bmim]BF4 solvent, which has been used 6 times in Example 12, as an example: the first filter residue from the 6th cycle experiment in Example 12 was extracted with petroleum ether (boiling range 60-90°C) using a Soxhlet extractor and then vacuum dried at 85°C to constant weight to obtain the regenerated catalyst; after dimethylformamide and ethanol were evaporated from the second filtrate by rotary evaporation, it was transferred to a separatory funnel, 5 ml of petroleum ether (boiling range 60-90°C) was added, and the mixture was shaken and washed, and then separated. Then, 5 ml of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid and the mixture was shaken and washed, for a total of 3 times. The lower layer liquid was then vacuum dried at 85°C to constant weight, and then added to the previously evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

[0134] Example 14

[0135] The performance of the catalytic system after the second regeneration for recycling

[0136] Taking the catalytic system composed of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent after the second regeneration in Example 13 as an example: 1.0 mmol of p-chlorobenzaldehyde, 1.0 mmol of 1,3-cyclohexanedione and 1.0 mmol of 2-aminobenzothiazole were directly added to the catalytic system after the second regeneration in Example 13. Then, the regenerated catalytic system was recycled according to the operating steps of Example 10, and used a total of 5 times. The changes in the liquid chromatography purity and yield of the reaction product 12-(4-chlorophenyl)-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 3.

[0137]

[0138] Table 3

[0139] As can be seen from the data in Table 3, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the catalytic system after the second regeneration in Example 2 can be used up to 4 times.

[0140] Example 15

[0141] The performance of the catalytic system in recycling

[0142] Taking the catalytic system of Example 9, which consists of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent, as an example: 1.0 mmol cinnamaldehyde, 1.0 mmol 5,5-dimethyl-1,3-cyclohexanedione, and 1.0 mmol 2-aminobenzothiazole were directly added to the circulating catalytic system in Example 9. The catalytic system was then recycled in accordance with the operating steps and reaction conditions of Example 9 for a total of 9 times. The changes in the liquid chromatography purity and yield of the reaction product 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 4.

[0143]

[0144]

[0145] Table 4

[0146] As can be seen from the data in Table 4, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the new catalytic system without regeneration in Example 9 can be used up to 8 times.

[0147] Example 16

[0148] First regeneration of the catalytic system

[0149] Taking the catalytic system of glycerol-derived carbon-based solid sulfonic acid catalyst and dimethylformamide-ethanol-[Bmim]BF4 solvent, which has been used 9 times in Example 15, as an example: the first filter residue from the 9th cycle experiment in Example 15 was extracted with petroleum ether (boiling range 60-90°C) using a Soxhlet extractor and then vacuum dried at 85°C to constant weight to obtain the regenerated catalyst; after the dimethylformamide and ethanol were removed by rotary evaporation of the second filtrate, it was transferred to a separatory funnel, 6 ml of petroleum ether (boiling range 60-90°C) was added, and the mixture was shaken and washed, and then separated. Then, 6 ml of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid and the mixture was shaken and washed, for a total of 3 times. The lower layer liquid was then vacuum dried at 85°C to constant weight, and then added to the previously rotary-evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

[0150] Example 17

[0151] The performance of the catalytic system after the first regeneration for recycling

[0152] Taking the catalytic system composed of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent from Example 16 as an example: 1.0 mmol cinnamaldehyde, 1.0 mmol 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol 2-aminobenzothiazole were directly added to the catalytic system regenerated in Example 16. Then, the regenerated catalytic system was recycled according to the operating steps of Example 15, and used a total of 7 times. The changes in the liquid chromatography purity and yield of the reaction product 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 5.

[0153]

[0154] Table 5

[0155] As can be seen from the data in Table 5, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the catalytic system after the first regeneration in Example 9 can be used up to 6 times.

[0156] Example 18

[0157] Second regeneration of the catalytic system

[0158] Taking the catalytic system of glycerol-derived carbon-based solid sulfonic acid catalyst and dimethylformamide-ethanol-[Bmim]BF4 solvent, which has been used 7 times in Example 17, as an example: the first filter residue from the 7th cycle experiment in Example 17 was extracted with petroleum ether (boiling range 60-90°C) using a Soxhlet extractor and then vacuum dried at 85°C to constant weight to obtain the regenerated catalyst; after dimethylformamide and ethanol were removed by rotary evaporation of the second filtrate, it was transferred to a separatory funnel, 6 ml of petroleum ether (boiling range 60-90°C) was added, and the mixture was shaken and washed, and then separated. Then, 6 ml of petroleum ether (boiling range 60-90°C) was added to the lower layer liquid and the mixture was shaken and washed, for a total of 3 times. The lower layer liquid was then vacuum dried at 85°C to constant weight, and then added to the previously rotary-evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

[0159] Example 19

[0160] The performance of the catalytic system after the second regeneration for recycling

[0161] Taking the catalytic system composed of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent after the second regeneration in Example 18 as an example: 1.0 mmol cinnamaldehyde, 1.0 mmol 5,5-dimethyl-1,3-cyclohexanedione and 1.0 mmol 2-aminobenzothiazole were directly added to the catalytic system after the second regeneration in Example 18. Then, the regenerated catalytic system was recycled according to the operating steps of Example 15, and used a total of 5 times. The changes in the liquid chromatography purity and yield of the reaction product 3,3-dimethyl-12-styryl-2,3,4,12-tetrahydrobenzo[4,5]thiazo[2,3-b]quinazolin-1-one are shown in Table 6.

[0162]

[0163] Table 6

[0164] As can be seen from the data in Table 6, according to the recommendation that the catalytic system should not be recycled when the purity of the pharmaceutical intermediate benzothiazo[2,3-b]quinazolinone derivative in liquid chromatography is less than 98.5% or the yield decreases by more than 5%, the catalytic system after the second regeneration in Example 9 can be used up to 4 times.

[0165] The preferred embodiments do not describe all details exhaustively, nor do they limit the invention to the specific embodiments described. Clearly, many modifications and variations can be made based on the content of this specification. These embodiments have been selected and specifically described in this specification to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing the pharmaceutical intermediate benzothiazo[2,3- b The method for quinazolinone derivatives is characterized by, The reaction formula for this preparation method is: The above reaction steps are as follows: Under heating conditions, and in a catalytic system formed by glycerol-derived carbon-based solid sulfonic acid and dimethylformamide-ethanol-[Bmim]BF4, aldehydes, 1,3-cyclohexanedione derivatives, and 2-aminobenzothiazole are used as reactants to undergo a condensation reaction to prepare benzothiazole[2,3- b Quinazolinone derivatives; The aldehydes in the reaction raw materials are selected from: any one of them; The catalytic system consists of a glycerol-derived carbon-based solid sulfonic acid catalyst and a dimethylformamide-ethanol-[Bmim]BF4 solvent, wherein [Bmim]BF4 is a tetrafluoroborated 1-butyl-3-methylimidazolium salt; The 1,3-cyclohexanedione derivative is 1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione; The mass of the glycerol-derived carbon-based solid sulfonic acid catalyst in the reaction is 5–9% of the molar amount of the aldehyde used. In the reaction, the volume of dimethylformamide-ethanol-[Bmim]BF4 solvent used, in milliliters, is 6 to 10 times the amount of aldehyde substance in millimoles. In the reaction, the volume ratio of dimethylformamide, ethanol and [Bmim]BF4 in the dimethylformamide-ethanol-[Bmim]BF4 solvent is 7: (1.3~2.4): (0.5~1.2).

2. The method for preparing the pharmaceutical intermediate benzothiazo[2,3-] according to claim 1 b The method for quinazolinone derivatives is characterized by, The molar ratio of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole in the reaction raw materials is 1:1:

1.

3. The method for preparing the pharmaceutical intermediate benzothiazo[2,3-] according to claim 2 b The method for quinazolinone derivatives is characterized by, After adding the predetermined amount of reactants to the catalytic system composed of dimethylformamide-ethanol-[Bmim]BF4 solvent and glycerol-derived carbon-based solid sulfonic acid catalyst at room temperature, the mixture needs to be stirred to form a mixed solution, heated to the predetermined temperature and kept at that temperature for reaction, then subjected to the first filtration while hot, followed by cooling and crystallization of the first filtrate, crushing the crystals and allowing it to stand, then subjected to the second filtration and purification of the filter residue, and finally subjected to the third filtration and vacuum drying of the filter residue to obtain benzothiazo[2,3- b Quinazolinone derivatives; Mixing and stirring to form a mixed solution: First, the glycerol-derived carbon-based solid sulfonic acid catalyst is added to a reaction flask equipped with a thermometer, magnetic stir bar and spherical condenser, containing dimethylformamide-ethanol-[Bmim]BF4 solvent in a preset volume ratio. The catalytic system is formed by magnetic stirring at room temperature. Then, the reaction raw materials are added to the reaction flask in the order of aldehyde, 1,3-cyclohexanedione derivative and 2-aminobenzothiazole and the preset amount of substance. The mixture is stirred at room temperature to form a mixed solution. Heating to a preset temperature and holding for reaction: The mixed solution is heated to a preset temperature in a methyl silicone oil bath under magnetic stirring, and this temperature is maintained until the reaction is complete. Stirring is continued during the holding process. The preset temperature is 53-71℃ and the holding time is 24-39 min. Perform the first filtration while the reaction is still hot: immediately after the reaction is completed, filter the reaction solution to obtain the first filter residue and the first filtrate; First filtrate cooling and crystallization, crushing crystals and standing: The first filtrate was first cooled naturally to room temperature, and then placed in an ice-water bath for further cooling, resulting in the precipitation of a large number of crystals. The crystals were then crushed and left to stand in the ice-water bath for 6 hours. Second filtration and purification of filter residue: The liquid containing a large number of crystals after standing is filtered to obtain a second filtrate and a second filter residue. The second filter residue is dissolved in hot ethanol and then naturally cooled to room temperature to precipitate a large number of crystals. Third filtration and vacuum drying of filter residue: A third filtration is performed to obtain a third filter residue. This residue is then placed in a vacuum drying oven and dried at 75°C for 12 hours to obtain benzothiazo[2,3-] b Quinazolinone derivatives.

4. A method for preparing the pharmaceutical intermediate benzothiazo[2,3-] according to claim 3. b The method for quinazolinone derivatives is characterized by, The catalytic system formed by adding the first filter residue to the second filtrate can be recycled or regenerated. The specific operating procedure for recycling the catalytic system is as follows: The untreated first filter residue was added to the second filtrate, and magnetic stirring was used to form a catalytic system. Then, reactants were directly added for the next round of reaction. This process was repeated multiple times, and the product benzothiazo[2,3-] was monitored by high-performance liquid chromatography. b The purity of the quinazolinone derivative was determined and its yield was calculated. When the liquid chromatography purity was lower than 98.5% or the yield decreased by more than 5%, the catalytic system was stopped from being recycled and entered the regeneration process. The specific operation procedure for regenerating the catalytic system is as follows: The first filter residue from the final recycling experiment was extracted with petroleum ether (boiling range 60–90 °C) using a Soxhlet extractor and then vacuum dried at 85 °C to constant weight to obtain the regenerated catalyst. The second filtrate, after rotary evaporation to remove dimethylformamide and ethanol, was transferred to a separatory funnel. Petroleum ether (boiling range 60–90 °C) was added, followed by shaking and washing. The mixture was then separated, and the lower layer was washed with petroleum ether (boiling range 60–90 °C) for a total of three times. The lower layer was then vacuum dried at 85 °C to constant weight and added to the previously evaporated dimethylformamide and ethanol to form the regenerated solvent. Finally, the regenerated catalyst was added to the regenerated solvent and magnetically stirred to form the regenerated catalytic system.

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