A magnetic nano double acid catalyst, its preparation method and catalytic application

Abstract

The present invention relates to the technical field of the synthesis of benzodiazepine compounds, and specifically discloses a magnetic nano-bifunctional acid catalyst, a preparation method thereof, and a catalytic application. In the present invention, Fe3O4@SiO2 core-shell nanoparticles modified with a chlorosilane coupling agent are selected as the carrier, and an aminophosphonic acid compound is used as the grafting substance. Through the dehydrochlorination reaction between the Cl in the silane coupling agent and the NH2 in the aminophosphonic acid compound, the grafting of the aminophosphonic acid compound on the surface of the magnetic nanoparticles is realized. Then, with the aminophosphonic acid compound as the loading medium, the metal atom in the Lewis acid is coordinated with the N in the amino group and the O in the phosphoric acid group of the aminophosphonic acid compound respectively, forming a stable polycyclic structure, and the purpose of stably loading the transition metal Lewis acid and phosphonic acid on the surface of the magnetic nanoparticles is achieved. It has broad application prospects in the field of synthesizing 1,5-benzodiazepine compounds containing a spiro ring structure.

Description

Technical Field

[0001] The invention relates to the technical field of benzodiazepine compound synthesis, and in particular to a magnetic nanometer diacid catalyst and a preparation method and catalytic application thereof. Background Art

[0002] 1,5-Benzodiazepine compounds are important components of seven-membered heterocycles in medicinal chemistry. They are a class of compounds with important pharmacological and physiological activities, and are widely used in sedatives, anticonvulsants, antidepressants and anti-inflammatory drugs. Studies have shown that spiro compounds are organic compounds with pharmacological activity, and 1,3-indanedione spiro compounds have unique pharmacological and biological activities, are intermediates of many drugs, and have medical value. For example, fitramycin A has anti-tumor activity in vivo and in vitro, dihydropyrrole [2,1-a] isoquinoline B has good sedative and antihypertensive effects, and biphenyl spiro ketone C is a new type of anticancer drug. Therefore, the method of synthesizing benzodiazepine compounds containing spiro structures is of great significance and is also a challenging step.

[0003] However, most of the current synthesis of such compounds uses acidic catalysts, such as single liquid acids or solid acids. Such catalysts are non-renewable and cumbersome to separate. In order to improve the reusability of the catalyst, the methods for the catalytic synthesis of 1,5-benzodiazepine compounds that have been reported mostly use magnetic nanocatalysts whose active centers are directly loaded on the surface. However, the active centers of such catalysts are easily leached out in the reaction system. Moreover, the acid sites as active centers are mostly carboxyl groups, which have limited catalytic activity for reaction systems that require strong acids for catalytic synthesis, and cannot effectively catalyze the synthesis of 1,5-benzazepine compounds with spirocyclic structures, which is not conducive to the practical application of 1,5-benzazepine compounds. Therefore, it is of great significance to develop a catalyst with high catalytic activity, high selectivity and good stability for the synthesis of 1,5-benzazepine compounds containing spirocyclic structures. Summary of the invention

[0004] Aiming at the problem that the existing conventional catalysts for 1,5-benzazepine compounds are not suitable for synthesizing 1,5-benzazepine compounds containing spiro ring structures, the present invention provides a magnetic nanometer bis-acid catalyst and a preparation method and catalytic application thereof. The present invention not only significantly improves the catalytic activity and selectivity of the catalyst, but also significantly improves the stability of the catalyst by loading a transition metal Lewis acid and an aminophosphonic acid compound onto a ferroferric oxide magnetic carrier by chemical bonding. The catalytic activity of the catalyst does not significantly decrease after the catalyst is recycled for multiple times, which is of great significance for synthesizing 1,5-benzazepine compounds containing spiro ring structures or quinoxaline structures.

[0005] To solve the above technical problems, the technical solution provided by the present invention is as follows:

[0006] In the first aspect of the present application, a magnetic nano double acid catalyst is provided, and its raw materials include Fe modified by a chlorosilane coupling agent 3 O 4 @SiO 2 core-shell nanoparticles as carriers, and an aminophosphonic acid compound and a transition metal Lewis acid chemically bonded and loaded on the carriers;

[0007] Among them, the structure of the aminophosphonic acid compound is shown in formula (Ι):

[0008]

[0009] R 1 is a C1-C3 alkyl group;

[0010] The amino group in the aminophosphonic acid compound condenses with the Cl in the chlorosilane coupling agent on the surface of the carrier to form an aminomethyl bond; and the N of the amino group and the O of the phosphonic acid group in the aminophosphonic acid coordinate with the metal atom in the transition metal Lewis acid to form a polycyclic ring respectively.

[0011] Compared with the prior art, the present invention selects Fe modified by a chlorosilane coupling agent 3 O 4 @SiO 2 core-shell nanoparticles as carriers, uses an aminophosphonic acid compound as a grafting substance, and through the dehydrochlorination reaction of Cl in the silane coupling agent and NH in the aminophosphonic acid compound 2 to achieve the grafting of the aminophosphonic acid compound on the surface of the magnetic nanoparticles. Then, taking the aminophosphonic acid compound as a loading medium, the metal atom in the Lewis acid coordinates with the N in the amino group and the O in the phosphoric acid group of the aminophosphonic acid compound respectively to form a stable polycyclic ring structure, realizing the purpose of stably loading the transition metal Lewis acid and phosphonic acid on the surface of the magnetic nanoparticles; at the same time, in the double acid catalyst provided by the present invention, the P atom is in a stable polycyclic ring structure and is not easy to rotate, increasing the catalytic stability, and the hydroxyl hydrogen on the P atom can be used as an acid to provide hydrogen protons, increasing the electrophilic property of the carbonyl group, playing a role in catalytically activating the carbonyl group and promoting the progress of the reaction. The coordinated transition metal Lewis acid can effectively catalyze nucleophilic addition reactions and C-C coupling reactions, so that it shows excellent catalytic performance in a variety of organic chemical reactions.

[0012] The dual-acid magnetic catalyst provided by the present invention has high catalytic activity and can catalyze multiple organic reactions simultaneously. In particular, it is suitable for catalyzing the synthesis of 1,5-azacycle compounds with a spiro ring structure, and is a novel catalyst with great application value. It has very important value for expanding the application of 1,5-benzodiazepine compounds with a spiro ring structure in the fields of medicine and industrial production, and has a broad potential application field.

[0013] Preferably, the aminophosphonic acid compound is aminomethylphosphonic acid.

[0014] Preferably, aminomethylphosphonic acid has high catalytic activity and catalytic efficiency for the synthesis reaction of 1,5-benzazepine compounds with a spiro ring structure.

[0015] Preferably, the transition metal Lewis acid is cerium trichloride, copper acetate, nickel chloride or palladium acetate.

[0016] More preferably, the transition metal Lewis acid is cerium trichloride.

[0017] Preferably, the Lewis acid has high coordination ability and can form strong coordination bonds with N in the amino group and O in the phosphate group of the aminophosphonic acid compound, thereby forming a stable polycyclic structure, which is beneficial to improving the activity and stability of the catalyst.

[0018] Preferably, the chlorosilane coupling agent is (3-chloropropyl)trimethoxysilane or (3-chloropropyl)triethoxysilane.

[0019] Preferably, the silane coupling agent can react fully with the hydroxyl groups on the surface of silica in the magnetic nanoparticles to achieve surface modification of the magnetic nanoparticles, which is beneficial to subsequent chemical bonding and loading of aminophosphonic acid compounds.

[0020] Preferably, the structure of the magnetic nano dual-acid catalyst is shown in formula (Ⅱ):

[0021]

[0022] Among them, n = 1-3; R is CH 3 or CH 2 CH 3 ; M is CeCl 3 , Cu(OAC) 2 , NiCl 2 or Pd(OAC) 2 .

[0023] More preferably, the structure of the magnetic nano dual-acid catalyst is as follows:

[0024]

[0025] Among them, R is CH 3 or CH 2 CH 3 .

[0026] The second aspect of the present application provides a preparation method of the above-mentioned magnetic nano double acid catalyst, including the following steps:

[0027] Step a, prepare Fe 3 O 4 @SiO 2 core-shell nanoparticles;

[0028] Step b, disperse the Fe 3 O 4 @SiO 2 core-shell nanoparticles in a first organic solvent, add a chlorosilane coupling agent, mix evenly, heat and react, separate the product, wash, and dry to obtain the chlorosilane coupling agent-modified Fe 3 O 4 @SiO 2 core-shell nanoparticles;

[0029] Step c, disperse the chlorosilane coupling agent-modified Fe 3 O 4 @SiO 2 core-shell nanoparticles in a second organic solvent, adjust the pH to 8-9, add an aminophosphonic acid compound, react, separate the product, wash, and dry to obtain the Fe loaded with aminophosphonic acid 3 O 4 @SiO 2 core-shell nanoparticles;

[0030] Step d, disperse the Fe 3 O 4 @SiO 2 core-shell nanoparticles loaded with aminophosphonic acid and the transition metal Lewis acid in a third organic solvent, react, separate the product, wash, and dry to obtain the magnetic nano double acid catalyst.

[0031] Compared with the prior art, the present invention first uses silica to coat the magnetic iron oxide particles to form core-shell structured Fe 3 O 4 @SiO 2 nanoparticles, which not only reduces the aggregation of magnetic nanoparticles, expands the specific surface area of magnetic nanoparticles, increases the loading sites, but also the hydroxyl groups on the silica surface can provide reactive groups for further surface modification; through the de-alcohol reaction of the OH on the silica surface with the alkoxy groups in the chlorosilane coupling agent, the modified Fe 3 O 4 @SiO 2Core-shell magnetic nanoparticles; furthermore, by using NH in the aminophosphonic acid compound 2 to undergo a dehydrochlorination reaction with Cl in the chlorosilane coupling agent, grafting of the aminophosphonic acid compound onto the surface of the magnetic nanoparticles was achieved; furthermore, with the grafted aminophosphonic acid compound as the loading medium, through coordination of the metal atom in the transition metal Lewis acid with N in the amino group and O in the phosphoric acid group of the aminophosphonic acid compound, a stable polycyclic structure was formed, and finally a series of magnetic nano-bifunctional catalysts were prepared.

[0032] The preparation method of the magnetic nano-bifunctional catalyst provided by the present invention is simple in operation, the raw materials are easily available, and no stabilizers and surfactants are required to stabilize the active components during the preparation process. The prepared catalyst has many active centers on the surface, high reaction activity, and the active components are loaded onto the surface of the carrier in the form of chemical bonding, with good stability. It can be separated by magnetic adsorption, and has the advantages of easy recovery and multiple reuse, which is of great significance for the catalytic synthesis of 1,5-benzodiazepine compounds containing a spiro ring structure.

[0033] Preferably, in step b, the mass ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles to the chlorosilane coupling agent is 1-2:2-3.

[0034] Preferably, in step b, the mass-volume ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles to the first organic solvent is 1-2:50-100, where the unit of mass is grams and the unit of volume is milliliters.

[0035] Preferably, in step b, the first organic solvent is toluene or n-hexane.

[0036] The preferred raw material ratio and the addition amount of the organic solvent are conducive to the full reaction of the chlorosilane coupling agent with the hydroxyl groups on the surface of the Fe 3 O 4 @SiO 2 core-shell nanoparticles, realizing the functionalization of the nano surface.

[0037] Exemplarily, in step b, the reaction is a reflux reaction, and the reaction time is 20h-24h.

[0038] Exemplarily, in step b, the washing is to wash 3-4 times with anhydrous ethanol and deionized water respectively; the drying is vacuum drying at 80°C-90°C for 20h-24h.

[0039] Preferably, in step c, the Fe modified with the chlorosilane coupling agent 3 O4 @SiO 2 The mass ratio of the core-shell nanoparticles to the aminophosphonic acid compound is 1:1 - 1.5.

[0040] Preferably, in step c, the Fe modified by the chlorosilane coupling agent 3 O 4 @SiO 2 The mass-volume ratio of the core-shell nanoparticles to the second organic solvent is 1:20 - 30, where the unit of mass is grams and the unit of volume is milliliters.

[0041] Preferably, in step c, the second organic solvent is anhydrous ethanol.

[0042] The preferred raw material ratio and the addition amount of the organic solvent can promote the reaction of NH in the aminophosphonic acid compound 2 with the functionalized Fe 3 O 4 @SiO 2 to fully react with the Cl on the surface of the core-shell nanoparticles, realizing the grafting of the aminophosphonic acid compound and improving the grafting rate of the aminophosphonic acid compound.

[0043] Exemplarily, in step c, the reaction temperature is 15°C - 40°C and the reaction time is 24h - 48h.

[0044] Exemplarily, in step c, triethylamine is used to adjust the pH to 8 - 9.

[0045] Exemplarily, in step c, the washing is carried out by washing 3 - 4 times with anhydrous ethanol and deionized water respectively; the drying is carried out by vacuum drying at 80°C - 90°C for 20h - 24h.

[0046] Preferably, in step d, the mass ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles loaded with aminophosphonic acid to the transition metal Lewis acid is 1:1 - 1.5.

[0047] Preferably, in step d, the mass-volume ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles loaded with aminophosphonic acid to the third organic solvent is 1:20 - 30, where the unit of mass is grams and the unit of volume is milliliters.

[0048] Preferably, in step d, the third organic solvent is anhydrous ethanol or acetone.

[0049] Preferred organic solvents can promote the coordination of the Lewis acid of transition metals with N and O in aminophosphonic acid compounds, thus facilitating the formation of a stable polycyclic structure.

[0050] Exemplarily, in step d, the temperature of the reaction is 15°C - 78°C, and the reaction time is 24 h - 48 h.

[0051] Preferably, Fe 3 O 4 @SiO 2 The preparation method of the core-shell nanoparticles specifically includes the following steps:

[0052] Dissolve ferrous chloride and ferric chloride in deionized water, heat up to 80°C - 90°C, adjust the pH to 9 - 12, keep the temperature for reaction for 1 h - 2 h, separate the product, wash, and dry to obtain Fe 3 O 4 nanoparticles;

[0053] Disperse the Fe 3 O 4 nanoparticles in an ethanol aqueous solution, sequentially add ammonia water and tetraethyl orthosilicate, stir and react at 15°C - 40°C for 20 h - 24 h, separate the product, wash, and dry to obtain the Fe 3 O 4 @SiO 2 core-shell nanoparticles.

[0054] Exemplarily, in combination with the above, ammonia water is used to adjust the pH to 9 - 12.

[0055] Preferably, the molar ratio of ferrous chloride to ferric chloride is 1:2 - 4.

[0056] Preferably, the mass-volume ratio of the Fe 3 O 4 nanoparticles to the ethanol aqueous solution is 1 - 3:80 - 120, where the unit of mass is gram and the unit of volume is milliliter; among them, the volume ratio of ethanol to water in the ethanol aqueous solution is 2 - 5:1.

[0057] Preferably, the mass-volume ratio of the Fe 3 O 4 nanoparticles to ammonia water is 1 - 2:1 - 2, where the unit of mass is gram and the unit of volume is milliliter.

[0058] Exemplarily, the mass concentration of the ammonia water is 25% - 28%.

[0059] Preferably, the mass ratio of the Fe 3 O 4 nanoparticles to tetraethyl orthosilicate is 1 - 2:1 - 2.

[0060] In the above preparation process, the method for separating products all selects the method of magnetic adsorption separation.

[0061] The third aspect of the present application also provides the application of the magnetic nanobisacid catalyst described in any one of the above in the synthesis of 1,5-benzodiazepine compounds containing a spiro ring structure.

[0062] Furthermore, using the substituted o-phenylenediamine, diketone compound, and ninhydrin shown in formula (III) as raw materials, and using the magnetic nanobisacid catalyst described in any one of the above as a catalyst, reacting to obtain 1,5-benzodiazepine compounds with a spiro ring structure shown in formula (IV) - formula (VII);

[0063]

[0064] Among them, the diketone compound is cyclopentanedione or 1,3-indanedione;

[0065] When R 1 = H, R 2 = H, CH 3 , Cl, Br or OCH 3 ;

[0066] When R 1 = CH 3 , R 2 = CH 3 .

[0067] The magnetic nanobisacid catalyst provided by the present invention can be applied to the following reactions for preparing 1,5-benzodiazepine compounds containing a spiro ring structure:

[0068]

[0069] When R 1 = H, R 2 = H, CH 3 , Cl, Br, OCH 3 ;

[0070] When R 1 = CH 3 , R 2 = CH 3 .

[0071] Specifically, when using the bisacid catalyst provided by the present invention to prepare 1,5-benzodiazepine compounds containing a spiro ring structure shown in formula (IV), the specific steps are as follows:

[0072] The substituted o-phenylenediamine shown in formula (III) and cyclopentanedione are added to anhydrous ethanol and mixed evenly. The above-mentioned double acid catalyst is added, and the reaction is monitored by TLC until the reaction ends. Ninhydrin is added to the reaction solution, and the reaction is monitored by TLC until the reaction ends. Then, separation, washing, and drying are carried out to obtain the 1,5-benzodiazepine compound containing a spiro ring structure shown in formula (IV).

[0073] Exemplarily, the reaction temperature of the above synthesis reaction of the 1,5-benzodiazepine compound containing a spiro ring structure is 15°C - 40°C.

[0074] Specifically, when the double acid catalyst provided by the present invention is used to prepare the 1,5-benzodiazepine compound containing a spiro ring structure shown in formula (V), the following steps are specifically included:

[0075] The substituted o-phenylenediamine shown in formula (III) and 1,3-indanedione are added to anhydrous ethanol and mixed evenly. The above-mentioned double acid catalyst is added, and the reaction is monitored by TLC until the reaction ends. Ninhydrin is added to the reaction solution, and the reaction is monitored by TLC until the reaction ends. Then, separation, washing, and drying are carried out to obtain the 1,5-benzodiazepine compound containing a spiro ring structure shown in formula (V).

[0076] Exemplarily, the reaction temperature of the above reaction is 15°C - 40°C.

[0077] The magnetic nano double acid catalyst provided by the present invention can also be applied to the following reaction for preparing the 1,5-benzodiazepine compound containing a spiro ring and quinoxaline structure:

[0078]

[0079] When R 1 = H, R 2 = H, CH 3 , Cl, Br, OCH 3 ;

[0080] When R 1 = CH 3 ), R 2 = CH 3 .

[0081] Specifically, when the double acid catalyst provided by the present invention is used to prepare the 1,5-benzodiazepine compound containing a spiro ring structure shown in formula (VI), the following steps are specifically included:

[0082] The substituted o-phenylenediamine shown in formula (III) and cyclopentanedione are added to anhydrous ethanol, mixed evenly, the above-mentioned double acid catalyst is added, and after reaction, separation, washing, and drying are carried out to obtain intermediate A;

[0083] Add the substituted o - phenylenediamine shown in formula (Ⅲ) and ninhydrin into absolute ethanol, mix evenly, react, separate, wash, and dry to obtain intermediate B;

[0084] Add intermediate A and intermediate B into absolute ethanol, mix evenly, add the above - mentioned double - acid catalyst, monitor the reaction by TLC until the reaction ends, separate, wash, and dry to obtain the spiro - ring - containing 1,5 - benzodiazepine compound shown in formula (Ⅵ).

[0085] Specifically, when the double - acid catalyst provided by the present invention is used to prepare the spiro - ring - containing 1,5 - benzodiazepine compound shown in formula (Ⅶ), the following steps are specifically included:

[0086] Add the substituted o - phenylenediamine shown in formula (Ⅲ) and indane - 1,3 - dione into absolute ethanol, mix evenly, add the above - mentioned double - acid catalyst, react, separate, wash, and dry to obtain intermediate A;

[0087] Add the substituted o - phenylenediamine shown in formula (Ⅲ) and ninhydrin into absolute ethanol, mix evenly, react, separate, wash, and dry to obtain intermediate B;

[0088] Add intermediate A and intermediate B into absolute ethanol, mix evenly, add the above - mentioned double - acid catalyst, monitor the reaction by TLC until the reaction ends, separate, wash, and dry to obtain the spiro - ring - containing 1,5 - benzodiazepine compound shown in formula (Ⅶ).

[0089] Exemplarily, the reaction temperature of the above reactions is all 15 °C - 40 °C.

[0090] The double - acid - loaded catalyst provided by the present invention can catalyze the organic reactions of different types of spiro - ring - containing 1,5 - benzodiazepine compounds, and has high catalytic activity and selectivity, is easy to separate from the reaction system. At the same time, the catalyst has good stability and can be reused, and has broad application prospects in the field of synthesizing spiro - ring - containing 1,5 - benzodiazepine compounds. Brief Description of the Drawings

[0091] Figure 1 It is the Fourier transform infrared spectrum (FT - IR) of the reaction products of each step prepared in Example 1 of the present invention, where a: Fe 3 O 4 b: Fe 3 O 4 @SiO 2 c: Fe 3 O 4 @SiO 2 @CPTES, d: Fe 3 O 4 @SiO 2@CPTES@APA, e: Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 ;

[0092] Figure 2 This is the X-ray diffraction pattern (XRD) of the reaction products at each step prepared in Example 1 of the present invention. Among them, a: Fe 3 O 4 , b: Fe 3 O 4 @SiO 2 , c: Fe 3 O 4 @SiO 2 @CPTES, d: Fe 3 O 4 @SiO 2 @CPTES@APA, e: Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 ;

[0093] Figure 3 This is the X-ray diffraction pattern (XRD) of aminomethylphosphonic acid;

[0094] Figure 4 This is the scanning electron microscopy image (SEM) of Fe 3 O 4 and Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 prepared in Example 1 of the present invention. Among them, a: Fe 3 O 4 , b: Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 ;

[0095] Figure 5 This is the transmission electron microscopy image (TEM) of Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 prepared in Example 1 of the present invention;

[0096] Figure 6 This is the Fe 3 O 4 @SiO 2@CPTES@APA@CeCl 3 X-ray energy dispersive spectroscopy (EDS) pattern of

[0097] Figure 7a Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 X-ray photoelectron spectroscopy (XPS) pattern of

[0098] Figure 7b Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 Fe2p electron binding energy spectrum of

[0099] Figure 7c Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 C1s electron binding energy spectrum of

[0100] Figure 7d Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 O1s electron binding energy spectrum of

[0101] Figure 7e Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 N1s electron binding energy spectrum of

[0102] Figure 7f Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 P2p electron binding energy spectrum of

[0103] Figure 7g Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 Ce3d electron binding energy spectrum of

[0104] Figure 8 The Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 The low-temperature physical adsorption and desorption graph (BET), where the upper left inset is a schematic diagram of the pore size distribution; 2

[0105] Figure 9 The VSM graph of the reaction products of each step prepared in Example 1 of the present invention, where: a: Fe 3 O 4 ; b: Fe 3 O 4 @SiO 2 @CPTES@APA, c: Fe 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 ; The actual separation effect diagram of the product with an external magnet is shown in the lower right corner;

[0106] Figure 10 The Fe prepared in Example 1 of the present invention 3 O 4 @SiO 2 @CPTES@APA@CeCl 3 The cyclic use performance graph. Detailed implementation manners

[0107] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0108] To better illustrate the present invention, further examples are given below by way of examples.

[0109] All reagents in the following examples are commercially available reagents unless otherwise specified, and all experimental methods are existing experimental methods unless otherwise specified.

[0110] The concentrated ammonia water used in the examples all refers to industrial ammonia water with a mass concentration of 25%-28%. Room temperature in the following examples all refers to 25°C - 30°C.

[0111] Example 1

[0112] A magnetic nano double acid catalyst (Fe 3 O 4 @SiO 2 ​@CPTES@PAP@CeCl 3 Preparation method of

[0113] Step a, Preparation of Fe 3 O 4 nanoparticles:

[0114] Weigh 3.0 g of FeCl 3 ·6H 2 O and 1.5 g of FeCl 2 ·4H 2 O and dissolve them in 50 mL of deionized water. Ultrasonically disperse for 40 min, gradually heat up to 80 °C, slowly add concentrated ammonia water under stirring to adjust the pH to 10, keep stirring and reacting at 80 °C for 1 h, cool to room temperature, separate the Fe 3 O 4 nanoparticles by an external magnet, then wash them 3 times with absolute ethanol and deionized water successively, and dry them in vacuum at 85 °C for 24 h to obtain Fe 3 O 4 nanoparticles.

[0115] Step b, Preparation of Fe 3 O 4 @SiO 2 magnetic nanoparticles:

[0116] Weigh 1 g of the above-prepared Fe 3 O 4 nanoparticles, add them to a mixed solution of 40 mL of absolute ethanol and 10 mL of deionized water, ultrasonically disperse for 40 min, then slowly add concentrated ammonia water under stirring to adjust the pH to 11, dropwise add 1 g of tetraethyl orthosilicate, stir and react at room temperature for 24 h, separate the product with an external magnet, and wash it 3 times with absolute ethanol and deionized water, dry it in vacuum at 85 °C for 24 h to obtain Fe 3 O 4 @SiO 2 magnetic nanoparticles.

[0117] Step c, Preparation of functionalized Fe 3 O 4 @SiO 2 magnetic nanoparticles:

[0118] Weigh 1 g of the above-prepared Fe 3 O 4 @SiO 2 magnetic nanoparticles, add them to 50 mL of toluene, disperse evenly, add 1.1 g of (3-chloropropyl)triethoxysilane, reflux and react for 24 h, cool to room temperature, separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol, dry it in vacuum at 85 °C for 24 h to obtain functionalized Fe 3 O4 @SiO 2 Magnetic nanoparticles (CoFe 2 O 4 @SiO 2 @CPTES).

[0119] Step d, prepare Fe@SiO core-shell nanoparticles loaded with phosphonic acid: 3 O 4 @SiO 2 Weigh 1 g of the prepared CoFe

[0120] O@SiO@CPTES and add it to 25 mL of absolute ethanol. Ultrasonically disperse for 40 min, add triethylamine to adjust the pH to 8, add 1 g of aminomethylphosphonic acid, stir and react at room temperature for 48 h. Separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol. Dry it in vacuum at 85 °C for 24 h to obtain Fe@SiO core-shell nanoparticles loaded with phosphonic acid (Fe@SiO@CPTES@PAP). 2 O 4 @SiO 2 @CPTES and add it to 25 mL of absolute ethanol. Ultrasonically disperse for 40 min, add triethylamine to adjust the pH to 8, add 1 g of aminomethylphosphonic acid, stir and react at room temperature for 48 h. Separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol. Dry it in vacuum at 85 °C for 24 h to obtain Fe@SiO core-shell nanoparticles loaded with phosphonic acid (Fe@SiO@CPTES@PAP). 3 O 4 @SiO 2 core-shell nanoparticles (Fe 3 O 4 @SiO 2 @CPTES@PAP).

[0121] Step e, prepare a dual-acid catalyst:

[0122] Weigh 1 g of the prepared CoFe 2 O 4 @SiO 2 @CPTES@PAP and add it to 20 mL of absolute ethanol. Ultrasonically disperse for 30 min, then add 1 g of CeCl 3 ·7H 2 O, stir and react at room temperature for 48 h. Separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol. Dry it in vacuum at 85 °C for 24 h to obtain a dual-acid catalyst (CoFe 2 O 4 @SiO 2 @CPTES@PAP@CeCl 3 ).

[0123] The specific reaction equations are as follows:

[0124]

[0125] Figure 1 This is the Fourier transform infrared spectrum (FT-IR) of the reaction products prepared in each step of this example. In the spectrum of the magnetic nanoparticles of Fe 3 O 4 (a), located at 586 cm-1 The strong absorption peak that appears at can be attributed to Fe 3 O 4 The Fe-O stretching vibration absorption peak of, at 3435 cm -1 is the characteristic peak caused by the H-O-H bond in H 2 O. In Fe 3 O 4 @SiO 2 As can be seen from the spectrum of the magnetic nanoparticles (b), the absorption peaks of Si-O-Si bonds appear at 1035 cm -1 and 806 cm -1 which proves that SiO 2 is successfully coated on the surface of the Fe 3 O 4 magnetic core. In the spectrum of the magnetic nanoparticles Fe 3 O 4 @SiO 2 @CPTES (c), it can be seen that broad absorption bands appear at 2984 cm -1 and 2852 cm -1 The absorption vibration of the C-H peak at corresponds to (CH 2 ) 3 Cl, which verifies the bonding of the silane coupling agent with the Fe 3 O 4 @SiO 2 nanocomposite. In the spectrum of the magnetic nanoparticles Fe 3 O 4 @SiO 2 @CPTES@PAP (d), it can be seen that the absorption peak of P=O is at 1286 cm -1 , the absorption peak of O-H appears at 1629 cm -1 , and the absorption peak at 1528 cm -1 is the stretching vibration absorption peak of N-H, which proves that aminomethylphosphonic acid (APA) is successfully grafted onto the surface of the nanoparticles in the form of chemical bonds. Figure 1 (e) Compared with Figure 1 (d), the P=O absorption peak shifts to a lower field, which is due to the successful coordination of CeCl 3 .

[0126] Figure 2 This is the X-ray diffraction pattern (XRD) of the reaction products prepared in each step of this example. For the XRD patterns shown in a-c, the Fe 3 O 4 nanoparticle structure has six different characteristic peaks, among which the characteristic peaks conform to (JCPDS#75-0033), confirming the existence of the nanomagnetite structure. Among them, 30.21°, 35.55°, 43.32°, 53.69°, 57.22° correspond to Fe3 O 4 (220), (331), (400), (422), (511), (400) crystal planes correspond. It shows that during the functionalization process from step a to step c, the structure of Fe 3 O 4 remains intact. Figure 3 is the XRD pattern of aminomethylphosphonic acid. Comparing Figure 2 (d), it can be seen that the grafting of aminomethylphosphonic acid has caused a large change in the phase of the magnetic nanoparticles, indicating that the catalyst prepared in this example is a heterogeneous catalyst.

[0127] Figure 4 is the Fe 3 O 4 nanoparticles and Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 nanoparticles' scanning electron micrograph (SEM). It can be seen from the figure that the Fe 3 O 4 nanoparticles and Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 are both nanoscale quasi-spherical structures, proving that there is no obvious change in the morphology of the functionalized catalyst. The average particle size of the Fe 3 O 4 prepared in this example is about 15.49 nm, and the Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 is a quasi-spherical particle with an average particle size of about 24.79 nm, which may be due to the increase in particle size during the coating and grafting processes.

[0128] Figure 5 is the transmission electron micrograph (TEM) of the Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 nanoparticles prepared in this example. It can be seen from the figure that the final morphology of the catalyst prepared in this example is a core-shell structure with a coating layer, which may be the organic chains formed during the functionalization process. The partial aggregation of the particles in the TEM can be attributed to the hydrogen bonds formed between the -PO 3 H groups grafted on the catalyst surface.

[0129] Figure 6 is the Fe prepared in this example3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 X-ray energy dispersive spectroscopy (EDS) of the nanoparticles. All expected major elements, including C, N, O, Si, P, Cl, Fe, and Ce, were detected by energy dispersive spectrometer. Among them, the presence of P element provides evidence for the successful grafting of phosphonic acid, and the presence of Ce element also indicates that CeCl 3 was successfully loaded on the catalyst surface. To further accurately analyze the contents of these two important elements, we tested them by ICP-AES. The results show that the content of P element is 7.9508 Wt%, and the content of Ce element is 8.2244 Wt%, which also provides evidence for the coordination of ligand and donor in a 1:1 ratio.

[0130] Figure 7 is the Fe prepared in this example 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 X-ray photoelectron spectroscopy (XPS) of the nanoparticles. Figure 7a of Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 The full spectrum of the nanocatalyst confirmed the coexistence of Fe, C, N, O, Si, Ce, and Cl elements, which is consistent with the results of EDS. Figure 7b The two peaks represent the split spin-orbit components of Fe 2p3 / 2 and Fe 2p1 / 2, and the corresponding binding energy diffraction peaks appear at 710.1 eV and 724.13 eV. Figure 7c This is the spectrum of C1s. The peaks at 283.2 eV, 283.5 eV, 283.7 eV, 284.3 eV, 285.1 eV, and 288.5 eV are the binding energies of C1s in each chemical environment of C-Si, C-H, C-P, C-C, C-N, respectively. Figure 7d This is the spectrum of O1s, showing that the peaks at 529.7 eV, 531.1 eV, 532.1 eV, and 533.29 eV correspond to Fe-O, O=P-O, Si-O, and C-O, respectively. Figure 7e This is the spectrum of N1s. The binding energy of C-N appears at 400.4 eV, which can effectively prove that aminomethylphosphonic acid and (3-chloropropyl)trimethoxysilane undergo dehydrochlorination reaction and are grafted onto the catalyst surface by chemical bond. Figure 7f This is the spectrum of P 2p. The binding energy diffraction peak of P=O appears at 131.5 eV. Figure 7g This is the spectrum of Ce 3d. There are two main peaks in the figure, which are Ce 3d5 / 2 and Ce 3d 2 / 3 The split spin - orbit components, corresponding to 885.1 eV and 903.3 eV, also prove that Ce(Ⅲ) is successfully loaded on the catalyst surface.

[0131] Figure 8 For the Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 nanoparticles, the 2 low - temperature physical adsorption - desorption isotherm (BET) and pore size distribution diagram. According to the IUPAC classification, the 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 nanoparticles' adsorption isotherm belongs to type Ⅳ and has an obvious H1 hysteresis loop, indicating that the magnetic nanoparticles have mesoporous characteristics. The specific surface area, total pore volume, and average pore diameter of the magnetic nanoparticles are 38.0575 m 2 ·g -1 −1, 0.1962 cc·g -1 −1 and 10.31 nm respectively.

[0132] Figure 9 are the VSM diagrams of the reaction products prepared in each step of this example. Among them, Figure 9 (a), 9(b), 9(c) are the magnetization curves of 3 O 4 Fe 3 O 4 Fe 2 @SiO 3 O 4 @SiO 2 @CPTES@APA, 3 Fe 3 O 4 Fe 3 O 4 @SiO 2 @CPTES@APA, 3 O 4 Fe 2 @SiO 3The saturation magnetization values are 86.19 emu / g, 33.56 emu / g, and 33.90 emu / g respectively. For the three samples, no hysteresis phenomenon appears, and the magnetization curve increases significantly with the increase of the applied magnetic field, thus confirming the typical superparamagnetic characteristics of the magnetic nanomaterials. Due to the grafting of functional groups on the surface of the magnetic nanoparticles, Fe 3 O 4 @SiO 2 @CPTES@APA and Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 have a lower saturation magnetization value than Fe 3 O 4 . However, as shown in the inset of Figure 9 , they can still be effectively and easily separated from the reaction mixture using an external magnetic field. Additionally, it can be seen that due to the synergistic effect between Ce and Fe metals and their oxides, the magnetic properties of Fe 3 O 4 @SiO 2 @CPTES@APA are improved after coordination with CeCl 3 .

[0133] Example 2

[0134] This example provides a method for preparing a magnetic nanobifunctional catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@Cu(OAc) 2 ), wherein steps a - d are exactly the same as those in Example 1, and step e is specifically as follows:

[0135] Weigh 1 g of the prepared Fe 3 O 4 @SiO 2 @CPTES@PAP and add it to 20 mL of absolute ethanol. Ultrasonically disperse for 30 min, then add 1 g of Cu(OAc) 2 , heat to 70 °C and stir for 24 h. Separate the product using an external magnet, and wash it 3 times with deionized water and absolute ethanol. Dry it in vacuum at 85 °C for 24 h to obtain the bifunctional catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@Cu(OAc) 2 ).

[0136] Example 3

[0137] This example provides a magnetic nanobifunctional catalyst (Fe 3O 4 @SiO 2 @CPTES@PAP@Pd(OAc) 2 ) The preparation method, wherein steps a - d are exactly the same as those in Example 1, and step e is specifically as follows:

[0138] Weigh 1 g of the prepared Fe 3 O 4 @SiO 2 @CPTES@PAP and add it to 20 mL of acetone, ultrasonically disperse for 30 min, then add 1 g of Pd(OAc) 2 , heat to 78 °C and stir - react for 24 h, separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol, and dry it in vacuum at 85 °C for 24 h to obtain the dual - acid catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@Pd(OAc) 2 ).

[0139] Example 4

[0140] This example provides a preparation method of a magnetic nano - dual - acid catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@NiCl 2 ), wherein steps a - d are exactly the same as those in Example 1, and step e is specifically as follows:

[0141] Weigh 1 g of the prepared Fe 3 O 4 @SiO 2 @CPTES@PAP and add it to 20 mL of absolute ethanol, ultrasonically disperse for 30 min, then add 1 g of NiCl 2 ·6H 2 O, heat to 78 °C and stir - react for 24 h, separate the product with an external magnet, and wash it 3 times with deionized water and absolute ethanol, and dry it in vacuum at 85 °C for 24 h to obtain the dual - acid catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@NiCl 2 ).

[0142] Catalytic activity evaluation:

[0143] 1. The dual - acid catalysts prepared in Examples 1 - 4 can be applied as catalysts for the reaction of preparing a class of 1,5 - benzodiazepine compounds containing a spiro - ring structure as follows:

[0144]

[0145] When R 1 = H, R 2 = H, CH 3 , Cl, Br, OCH 3 ; when R 1 = CH 3 , R 2 = CH 3 .

[0146] 1.1 Taking the 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,2'-indene]-1,1',3'-trione compound as an example, the catalytic activity of the prepared double acid catalyst was evaluated.

[0147] Twelve clean 50 mL round-bottom flasks were taken, and 2 mmol of o-phenylenediamine, 2 mmol of cyclopentanedione and 20 mL of absolute ethanol were added simultaneously. 0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg of the Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 prepared in Example 1, as well as p-toluenesulfonic acid and cerium trichloride (the addition amount thereof was 1% of the molar amount of o-phenylenediamine), were respectively added to the above 12 round-bottom flasks. The obtained mixture was stirred and reacted at room temperature. After the reaction was completed as indicated by TLC, 2 mmol of ninhydrin was added, and the reaction continued at different temperatures. After the reaction was completed as indicated by TLC, the catalyst was separated using an external magnet and washed three times with absolute ethanol and deionized water respectively, and then vacuum dried at 85 °C for 24 h for recycling. Solids precipitated in the round-bottom flask were washed with absolute ethanol, filtered by suction, and dried to obtain the 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,2'-indene]-1,1',3'-trione compound. The specific reaction equation is as follows:

[0148]

[0149] The results of the catalyst activity evaluation are shown in Table 1.

[0150] Table 1

[0151]

[0152]

[0153] Note: The reaction temperature and reaction time in the table refer to the reaction temperature and reaction time for the reaction with ninhydrin.

[0154] The results showed that the magnetic nano-bifunctional acid catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 ) prepared in Example 1 demonstrated excellent catalytic performance in the reaction of three-component tandem catalytic synthesis of spiro-containing 1,5-benzodiazepine compounds. When the optimal catalyst dosage was 25 mg, the reaction could be completed in 0.4 h, and the reaction could be carried out at room temperature. The yield of the target product could reach 95%, and the purity of the prepared product could reach 96%.

[0155] The catalyst recovered from the above reaction system was reused in the catalytic synthesis of 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,2'-indene]-1,1',3'-trione compounds according to the above method. The catalyst dosage was 25 mg, the reaction time was 0.4 h, and the reaction temperature was room temperature. After each reaction, the catalyst was separated by an external magnet and washed three times with absolute ethanol and deionized water, and used as the catalyst for the next catalytic reaction. After being reused 7 times, it still maintained high catalytic activity. The yield of the 7th cycle was 89%, as Figure 10 shown. It was proved that the magnetic nano-bifunctional acid catalyst prepared in this example had high catalytic activity for the catalytic synthesis of spiro-containing 1,5-benzodiazepine compounds, was easy to recover and had good recyclability.

[0156] Replacing the reaction temperature, reaction time, raw material dosage and reaction solvent in steps a to d of Example 1 of the present invention with other conditions defined in the present invention could achieve technical effects equivalent to those of Example 1.

[0157] The catalytic activities of the magnetic nano-bifunctional acid catalysts prepared in Examples 2-4 were evaluated according to the same method as above. The catalyst dosage was 25 mg, the reaction time was 0.4 h, and the reaction temperature was room temperature. The other reaction conditions were exactly the same. The results are shown in Table 2.

[0158] Table 2

[0159] Example 2 Example 3 Example 4 Yield (%) 85 83 87

[0160] The purity of 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,2'-indene]-1,1',3'-trione compounds prepared using the bifunctional acid catalysts prepared in Examples 2-4 as catalysts could reach 95%. After being recycled 6 times, the yield could still reach about 85%.

[0161] 1.2 Taking the preparation of 5,10-dihydro-12H-spiro[benzo[b]indeno[1,2-e][1,4]diazepine-11,2'-indene]-1',3',12-trione compound as an example, the catalytic activity of the prepared double acid catalyst was evaluated.

[0162] Another clean 50 mL round-bottom flask was taken, 2 mmol of o-phenylenediamine, 2 mmol of 1,3-indanedione and 20 mL of absolute ethanol were added, and 25 mg of Fe prepared in Example 1 was added. 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 was reacted at room temperature. After the reaction was completed by TLC detection, 2 mmol of ninhydrin was added and reacted at room temperature for 20 min. The catalyst was separated using an external magnet and washed three times with absolute ethanol and deionized water respectively, and then dried in vacuo at 90 °C for 24 h for recycling. Solids precipitated in the round-bottom flask were washed with absolute ethanol, filtered by suction and dried to obtain 5,10-dihydro-12H-spiro[benzo[b]indeno[1,2-e][1,4]diazepine-11,2'-indene]-1',3',12-trione compound with a yield of 94% and a purity of 95%.

[0163] 2. The double acid catalysts prepared in Examples 1-4 can be applied as catalysts for the preparation of a class of 1,5-benzodiazepines containing spiro ring and quinoxaline structures as follows:

[0164]

[0165] When R 1 = H, R 2 = H, CH 3 , Cl, Br, OCH 3 ;

[0166] When R 1 = CH 3 , R 2 = CH 3 .

[0167] 2.1 Taking 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,11'-indeno[1,2-b]quinoxaline]-1-one as an example, the catalytic activity of the prepared double acid catalyst was evaluated.

[0168] Twelve clean 50 mL round-bottom flasks were taken, 2 mmol of o-phenylenediamine, 2 mmol of cyclopentanedione and 20 mL of absolute ethanol were added simultaneously, and then 25 mg of Fe prepared in Example 1 was added. 3 O 4 @SiO2 @CPTES@PAP@CeCl 3 , react at room temperature for 10 min to obtain intermediate A;

[0169] Take another 50 mL round-bottom flask, add 2 mmol of o-phenylenediamine, 2 mmol of ninhydrin and 20 mL of absolute ethanol simultaneously, react at room temperature for 10 min to obtain intermediate B;

[0170] Add 1 mmol of intermediate A and 1 mmol of intermediate B into a 50 mL round-bottom flask, add 10 mL of absolute ethanol, add different types of catalysts respectively, detect by TLC until the reaction ends, separate the catalyst using an external magnet, and wash it three times with absolute ethanol and deionized water respectively, then dry it under vacuum at 90 °C for 24 h for recycling. Solids precipitate in the round-bottom flask, wash it with absolute ethanol, filter by suction, and dry it to obtain 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,11'-indeno[1,2-b]quinoxalin]-1-one compound. The specific reaction equation is as follows:

[0171]

[0172] The results of the catalyst activity evaluation are shown in Table 3.

[0173] Table 3

[0174]

[0175]

[0176] Note: The reaction temperature and reaction time in the table refer to the reaction temperature and reaction time of intermediate A and intermediate B.

[0177] The results prove that the magnetic nano-bifunctional acid catalyst (Fe 3 O 4 @SiO 2 @CPTES@PAP@CeCl 3 ) prepared in Example 1 demonstrated excellent catalytic performance in the reaction of three-component tandem catalytic synthesis of 1,5-benzodiazepine compounds containing spirocyclic and quinoxaline structures. When the optimal catalyst dosage was 25 mg, the reaction could be completed in 0.5 h, and the reaction could be carried out at room temperature. The yield of the target product could reach 97%, and the purity of the prepared product could reach 98%.

[0178] The catalyst recovered from the above reaction system was reused in the catalytic synthesis of 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,11'-indeno[1,2-b]quinoxalin]-1-one compound according to the above method. The amount of the catalyst used was 25 mg, the reaction time was 0.5 h, and the reaction temperature was room temperature. After each reaction, the catalyst was separated by an external magnet and washed three times with absolute ethanol and deionized water, and then used as the catalyst for the next catalytic reaction. After being reused six times, it still maintained high catalytic activity, and the yield of the sixth cycle was 86%. It was proved that the magnetic nano-bisacid catalyst prepared in this example had high catalytic activity in the catalytic synthesis of 1,5-benzodiazepine compounds with spiro and quinoxaline structures, was easy to recover, and had good recyclability.

[0179] When the reaction temperature, reaction time, raw material dosage, and reaction solvent in steps a to d of Example 1 of the present invention were replaced with other conditions defined in the present invention, the catalysts prepared were used to prepare the above 1,5-benzodiazepine compounds with spiro and quinoxaline structures, and the technical effects equivalent to those of Example 1 could be achieved.

[0180] The catalytic activities of the magnetic nano-bisacid catalysts prepared in Examples 2-4 were evaluated according to the same method as above. The amount of the catalyst used was 25 mg, the reaction time was 0.5 h, and the reaction temperature was room temperature, and the other reaction conditions were exactly the same. The results are shown in Table 4.

[0181] Table 4

[0182] Example 2 Example 3 Example 4 Yield (%) 90 86 85

[0183] The purity of the 2,3,4,9-tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,11'-indeno[1,2-b]quinoxalin]-1-one compounds prepared using the bisacid catalysts prepared in Examples 2-4 as catalysts could reach 93%-98%. After being recycled six times, the yield could still reach about 85%-90%.

[0184] Using the Fe 3 O 4 @TEOS@CPTES@APA@CeCl 3 nano-bisacid catalyst prepared in Example 1 of the present invention to catalyze the synthesis of other 1,5-benzodiazepine compounds with spiro structures defined above could make the yield of the final product reach 85%-97% and the purity reach 93%-98%.

[0185] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A magnetic nano double acid catalyst, characterized in that, Its raw materials include Fe modified by chlorosilane coupling agent 3 O 4 @SiO 2 core-shell nanoparticle carriers, and aminophosphonic acid compounds and transition metal Lewis acids chemically bonded and loaded on the carriers; wherein, the structure of the aminophosphonic acid compound is shown in formula (Ι): (Ι); R 1 is a C1-C3 alkyl group; The amino group in the aminophosphonic acid compound undergoes a dehydrochlorination reaction with the Cl in the surface chlorosilane coupling agent of the carrier; and the N of the amino group and the O of the phosphonic acid group in the aminophosphonic acid compound coordinate with the metal atom in the transition metal Lewis acid to form a polycyclic ring.

2. The magnetic nano double acid catalyst according to claim 1, characterized in that, the transition metal Lewis acid is cerium trichloride, copper acetate, nickel chloride or palladium acetate; and / or the chlorosilane coupling agent is (3-chloropropyl)trimethoxysilane or (3-chloropropyl)triethoxysilane.

3. The magnetic nano double acid catalyst according to claim 1, characterized in that, the transition metal Lewis acid is cerium trichloride; and / or the aminophosphonic acid compound is aminomethylphosphonic acid.

4. The magnetic nano double acid catalyst according to claim 1, characterized in that, the structure of the magnetic nano double acid catalyst is shown in formula (Ⅱ): （Ⅱ） Among them, n = 1, 2, 3; R is CH 3 or CH 2 CH 3 ; M is CeCl 3 , Cu(OAC) 2 , NiCl 2 or Pd(OAC) 2 .

5. The preparation method of the magnetic nano double acid catalyst according to any one of claims 1-4, characterized in that, comprises the following steps: Step a, prepare Fe 3 O 4 @SiO 2 core-shell nanoparticles; Step b, disperse the Fe 3 O 4 @SiO 2 core-shell nanoparticles in a first organic solvent, add a chlorosilane coupling agent, mix evenly, heat and react, separate the product, wash, and dry to obtain the chlorosilane coupling agent-modified Fe 3 O 4 @SiO 2 core-shell nanoparticles; Step c, disperse the Fe 3 O 4 @SiO 2 core-shell nanoparticles in a second organic solvent, adjust the pH to 8-9, add an aminophosphonic acid compound, react, separate the product, wash, and dry to obtain the Fe 3 O 4 @SiO 2 core-shell nanoparticles loaded with aminophosphonic acid; Step d, dispersing the Fe 3 O 4 @SiO 2 core-shell nanoparticles and the transition metal Lewis acid in a third organic solvent, reacting, separating the product, washing, and drying to obtain the magnetic nano double acid catalyst.

6. The preparation method of the magnetic nano double acid catalyst according to claim 5, characterized in that, In step b, the mass ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles to the chlorosilane coupling agent is 1-2:2-3; and / or In step c, the mass ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles to the aminophosphonic acid compound is 1:1 - 1.5; and / or In step d, the mass ratio of the Fe 3 O 4 @SiO 2 core-shell nanoparticles loaded with aminophosphonic acid to the transition metal Lewis acid is 1:1 - 1.

5.

7. The preparation method of the magnetic nano double acid catalyst according to claim 5 or 6, characterized in that, in step b, the first organic solvent is toluene or n-hexane; and / or in step c, the second organic solvent is absolute ethanol; and / or in step d, the third organic solvent is absolute ethanol or acetone.

8. The preparation method of the magnetic nano double acid catalyst according to claim 5, characterized in that, The described Fe 3 O 4 @SiO 2 The preparation method of the core-shell nanoparticles specifically includes the following steps: Dissolve ferrous chloride and ferric chloride in deionized water, heat up to 80 °C - 90 °C, adjust the pH to 9 - 12, keep the temperature for reaction for 1 h - 2 h, separate the product, wash and dry to obtain Fe 3 O 4 nanoparticles; Disperse the Fe 3 O 4 nanoparticles in an ethanol aqueous solution, sequentially add ammonia water and tetraethyl orthosilicate, and stir and react at 15 °C - 40 °C for 20 h - 24 h. Separate the product, wash it, and dry it to obtain the Fe 3 O 4 @SiO 2 core-shell nanoparticles.

9. The application of the magnetic nano double acid catalyst according to any one of claims 1-4 in the synthesis of 1,5-benzodiazepine compounds with a spiro ring structure.

10. The application according to claim 9, characterized in that, using the substituted o-phenylenediamine, diketone compound and ninhydrin shown in formula (Ⅲ) as raw materials, and using the magnetic nano double acid catalyst according to any one of claims 1-4 as a catalyst, reacting to obtain 1,5-benzodiazepine compounds with a spiro ring structure shown in formula (Ⅳ)-(Ⅶ); wherein, the diketone compound is cyclopentanedione or 1,3-indanedione; When R 1 = H, R 2 = H, CH 3 , Cl, Br or OCH 3 ; When R 1 =CH 3 , R 2 =CH 3 .

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