Nitrogen-doped porous carbon supported cobalt monatomic catalyst and preparation method and application thereof

Abstract

The invention discloses a nitrogen-doped porous carbon supported cobalt monatomic catalyst as well as a preparation method and application thereof, and belongs to the technical field of monatomic catalysts. According to the preparation method, 2-methylimidazole, organic amine, cobalt and zinc metal are used for preparing a ZIF precursor, and the precursor is subjected to high-temperature calcination to obtain the nitrogen-doped porous carbon supported cobalt monatomic catalyst. According to the method, the quinazoline and quinazolinone compounds can be synthesized through oxidative dehydrogenation condensation at the temperature of 100 DEG C. The yield of quinazoline and quinazolinone in the reaction can reach 90% or above through the catalyst, dehydrogenation of fatty alcohol can be effectively promoted, compared with a traditional synthesis method, the catalyst is stable in performance, high in catalytic activity and capable of being recycled, use of precious metal, organic solvents and alkali is avoided, reaction raw materials are cheap and stable, substrate tolerance is good, and the method is suitable for industrial production. Various drug intermediates and candidate drugs are synthesized.

Description

Technical Field

[0001] The present invention belongs to the technical field of single-atom catalysts, and in particular relates to a nitrogen-doped porous carbon-supported cobalt single-atom catalyst and a preparation method and application thereof. Background Art

[0002] Quinazoline and quinazolinone derivatives are an important class of nitrogen-containing heterocyclic compounds with a wide range of pharmacological and biological activities. They are widely found in naturally occurring alkaloids, such as lotonin A, lotonin F, (+)-vasidone, buchardine, etc. ( Tetrahedron 2006, 62, 9787-9826; Arab. J. Chem. 2023, 16, 105190). As a special N-heterocycle, quinazoline and quinazolinone derivatives have attracted widespread attention as a new drug delivery technology and are used as anti-tumor, anti-defibrillator, analgesics, diuretics, central nervous system stimulants, antihistamines, antihypertensives and vasodilators, and are also used as inhibitors of various enzymes ( Front. Chem. 2023, 11, 1140562.).

[0003] In view of the wide application of quinazoline and quinazolinone derivatives in medicine, pesticides and industry, their synthesis has always been at the forefront of modern organic chemistry research. In recent years, the synthesis of these two skeleton structures is mainly carried out through two-component coupling cyclization reactions: (1) Cheap and low-toxic aromatic alcohols (aldehydes or ketones) are used as coupling partners to react with aromatic substrates with two nitrogen-containing groups (cyano, amide, methylamine, amino or nitro) to form the corresponding N-heterocyclic compounds ( Synlett 2009,2010, 101-106; Tetrahedron Lett. 2010, 51, 758-760; Adv. Synth. Catal. 2012, 354, 2899-2904). (2) Arylcarbonitrile (methylamine or formamide) reacts with aromatic alcohol (aldehyde) with a nitrogen-containing group at the ortho position to generate the corresponding product ( Chem. Commun. 2011, 47, 9513-9515; Org. Biomol. Chem. 2017, 15,5781; ChemistrySelect 2017, 2, 5735-5739; ACS Sustainable Chem. Eng. 2020, 8, 267-277). In addition, using an additional nitrogen source (NH3·H2O or NH4OAc), a one-pot three-component reaction has been developed for the preparation of quinazoline derivatives. For example, Wang et al. reported an iodine-catalyzed and TBHP-mediated C(sp 3 )-H bond with o-aminoaryl ketone to prepare quinazoline ( Angew. Chem., Int. Ed.2012, 51, 8077-8081); Wu et al. reported a copper-catalyzed cascade reaction of o-aminoaryl methanol and aromatic aldehydes to prepare quinazolines ( J. Org. Chem. 2013, 78, 11342-11348); Lin et al. reported a method for synthesizing quinazoline from o-aminoaryl ketones and aromatic alcohols catalyzed by iron ( Catal. Sci. Technol. 2022, 12, 7018-7026). A three-component method for the synthesis of quinazolinone compounds has also been achieved by coupling isatoic anhydride with organic amines and alcohols [25I] ( ChemistrySelect 2024, 9 , e202305001).

[0004] However, most of these previous strategies are carried out in a noble metal-catalyzed homogeneous system and use an excess of base or oxidant, which lacks economy and recyclability. In addition, in previous reports, whether it is a two-component or three-component synthesis strategy, the alcohol substrate is aromatic alcohol, and the activation of aliphatic alcohols has always been a difficult problem to overcome in dehydrogenative coupling reactions. Therefore, it is necessary to provide a greener and more efficient method to synthesize quinazoline and quinazolinone derivatives. Summary of the invention

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and to provide a nitrogen-doped porous carbon material-supported cobalt catalyst which is recyclable, highly stable, has good catalytic activity and is simple to prepare, and a preparation method and application thereof. The cobalt single-atom catalyst prepared by the method can efficiently and low-costly catalyze 2-aminobenzyl alcohol derivatives, 2-aminobenzophenone derivatives or isatoic anhydride derivatives, fatty alcohols, and ammonia water to synthesize quinazolines and quinazolinone compounds, synthesize a variety of drug intermediates and candidate drugs, and has a long service life and stability.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows: The present invention provides a method for preparing a nitrogen-doped porous carbon-supported cobalt single-atom catalyst, comprising the following steps: Step 1: dispersing 2-methylimidazole and an organic amine in a solvent to obtain a first mixture; Step 2: Dispersing Co(NO3)2·6H2O and Zn(NO3)2·6H2O in a solvent to obtain a second mixture; Step 3: adding the second mixture obtained in step 2 dropwise to the first mixture obtained in step 1, stirring and reacting at a certain temperature, washing and drying the obtained mixture to obtain precursor ZIFs; Step 4: calcining the precursor ZIFs obtained in step 3 to prepare the nitrogen-doped porous carbon-supported cobalt single-atom catalyst.

[0007] Furthermore, the organic amine in step 1 is aniline or benzylamine.

[0008] Furthermore, the molar ratio of the 2-methylimidazole to the organic amine in step 1 is 1:0.5 to 1:1.5; In step 2, the molar ratio of Co(NO3)2·6H2O to Zn(NO3)2·6H2O is 1:10-50; The reaction temperature in step 3 is 25° C., and the reaction time is 4-10 h. The solvent in steps 1 and 3 is deionized water.

[0009] The present invention also provides a nitrogen-doped porous carbon-supported cobalt single-atom catalyst prepared by any of the above-mentioned methods for preparing the nitrogen-doped porous carbon-supported cobalt single-atom catalyst.

[0010] The invention also provides application of nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation to synthesize quinazoline and quinazolinone compounds.

[0011] Furthermore, the use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in the oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds comprises the following steps: adding 2-aminobenzyl alcohol derivatives, 2-aminobenzophenone derivatives or isatoic anhydride derivatives, fatty alcohols, ammonia water, and a nitrogen-doped porous carbon material-supported cobalt catalyst into a reactor, reacting at 80-140° C. for 4-20 hours, cooling after the reaction is completed, separating the catalyst and the reaction liquid, purifying the crude product by column chromatography to obtain the target product, and recycling the nitrogen-doped porous carbon-supported cobalt single-atom catalyst after the reaction is completed.

[0012] Furthermore, the 2-aminobenzyl alcohol derivative is 2-aminobenzyl alcohol, 2-amino-5-methoxybenzyl alcohol, 2-amino-3-methylbenzyl alcohol, 2-amino-5-fluorobenzyl alcohol, 2-amino-5-chlorobenzyl alcohol, 2-amino-3-pyridinemethanol or 1-(2-aminophenyl)ethanol.

[0013] Furthermore, the 2-aminobenzophenone derivative is 2-aminobenzophenone, 2-amino-5-chlorobenzophenone, 2-amino-4-fluorobenzophenone, 2-amino-4-chlorobenzophenone, 2-amino-4-bromobenzophenone or 2-amino-5-nitrobenzophenone.

[0014] Furthermore, the isatoic anhydride derivative is isatoic anhydride, 6-methylisatoic anhydride, 7-methylisatoic anhydride, 4,5-dimethoxyisatoic anhydride, 4-fluoroisatoic anhydride, 4-chloroisatoic anhydride, 4-bromoisatoic anhydride or 4-nitroisatoic anhydride; the fatty alcohol is methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, isoheptanol or isopropanol.

[0015] Furthermore, the molar ratio of the 2-aminobenzyl alcohol derivative, 2-aminobenzophenone derivative or isatoic anhydride derivative to the fatty alcohol, aqueous ammonia and catalyst is 1:6-50:3-15:0.025.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] First, the present invention effectively improves the electronic structure of the Co center, adjusts the specific surface area and pore structure of the catalyst, is conducive to the adsorption of reactants, improves the catalytic efficiency, and enables the reaction to be completed more gently and in a short time; Second, the nitrogen-doped porous carbon material-supported cobalt single-atom catalyst of the present invention exhibits excellent catalytic performance in the condensation reaction of 2-aminobenzyl alcohol derivatives, 2-aminobenzophenone derivatives or isatoic anhydride derivatives, fatty alcohols, and ammonia water to generate quinazoline and quinazolinone, and the quinazoline yield can be as high as more than 90%, which can effectively promote the dehydrogenation of fatty alcohols, has high yield, is economical and environmentally friendly, and avoids the use of precious metal catalysts, toxic solvents, and alkaline additives; Third, the substrate of the present invention has a wide range of applications and can react with a variety of fatty alcohols under mild conditions, can be used for the synthesis of pharmaceutical intermediates, and the catalyst can be recovered and reused after the reaction is completed.

[0018] Fourth, compared with the traditional synthesis method, the present invention can realize oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds at 100°C, and the catalyst of the present invention has stable performance, high catalytic activity, and can be recycled. The reaction raw materials are cheap and stable, and the substrate tolerance is good, so it can be used for the synthesis of drug intermediates. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 XRD diagram of the nitrogen-doped porous carbon material loaded with cobalt catalyst prepared in Examples 1 and 2 of the present invention; Figure 2 N2 adsorption isotherms of nitrogen-doped porous carbon materials loaded with cobalt catalysts prepared in Examples 1 and 2 of the present invention; Figure 3 TEM images of nitrogen-doped porous carbon materials loaded with cobalt catalysts prepared in Examples 1 and 2 of the present invention; Figure 4 This is a HAADF-STEM-EDS image of the nitrogen-doped porous carbon material loaded with cobalt single atom catalyst prepared in Example 1 of the present invention; Figure 5a This is a XANES graph of the nitrogen-doped porous carbon material loaded with cobalt single atom catalyst prepared in Example 1 of the present invention; Figure 5bThis is an EXAFS graph of the nitrogen-doped porous carbon material loaded with cobalt single atom catalyst prepared in Example 1 of the present invention; Figure 6 The product of 4a of the present invention 1 H NMR spectrum; 4a is a white solid, 1 H NMR (500 MHz, CDCl3): δ9.39 (s, 1H), 8.01–8.03 (d, 1H), 7.96-7.92 (t, 2H), 7.67-7.64 (t, 1H), 2.97(s, 3H). Figure 7 The product of the present invention 1 H NMR spectrum; 41 is a white solid, 1 H NMR (500 MHz, CDCl3): δ9.36 (s, 1H), 8.07-8.05 (d, 1H), 7.66-7.63 (dd, 1H), 7.22 (d, 1H), 4.02 (s,3H) 2.99 (s, 3H). Figure 8 The 4m product of the present invention 1 H NMR spectrum; 4m is a white solid, 1 H NMR (500 MHz, CDCl3): δ9.33 (s, 1H), 7.77-7.76 (d, 2H), 7.54-7.51 (t, 1H), 2.97 (s, 3H) 2.81 (s,3H). Fig. 9 The 4n product of the present invention 1 H NMR spectrum; 4n is a white solid, 1 H NMR (500 MHz, CDCl3): δ9.37 (s, 1H), 8.07-8.04 (m, 1H), 7.73-7.70 (m, 1H), 7.58-7.56 (dd, 1H) 2.96 (s, 3H). Fig.10 The product of the present invention 1 H NMR spectrum; 4o is a white solid, 1 H NMR (500 MHz, CDCl3): δ9.32 (s, 1H), 7.97-7.93 (t, 2H), 7.87-7.85 (t, 1H) 2.95 (s, 3H). Fig.11 The 4q product of the present invention 1H NMR spectrum; 4q is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.13-8.12 (d, 1H), 8.04-8.01 (t, 1H), 7.95-7.90 (m, 1H), 7.66-7.62 (m, 1H)3.00 (s, 3H), 2.92 (s, 3H). Fig.12 The product of 6a of the present invention 1 H NMR spectrum; 6a is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.10-8.05 (m, 2H), 7.93-7.89 (m, 1H), 7.80-7.78 (m, 2H), 7.61-7.56 (m, 4H), 3.00-2.99 (d, 3H). Fig.13 The product of 6b of the present invention 1 H NMR spectrum; 6b is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.06 (d, 1H), 8.01-8.00 (m, 1H), 7.84-7.82 (dd, 1H), 7.77 (m, 2H), 7.63-7.62(t, 3H), 2.98 (s, 3H). Fig.14 The product of 6c of the present invention 1 H NMR spectrum; 6c is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.08-8.06 (t, 2H), 7.94-7.91 (t, 1H), 7.83-7.80 (m, 2H), 7.61-7.58 (t, 3H),7.33-7.29 (m, 2H), 2.99 (s, 3H). Fig.15 The product of 6d of the present invention 1 H NMR spectrum; 6d is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.07-8.03 (m, 2H), 7.93-7.90 (t, 1H), 7.76-7.74 (d, 2H), 7.60-7.56 (m, 3H), 2.98 (s, 3H). Fig.16 The product of 6e of the present invention 1H NMR spectrum; 6e is a white solid, 1 H NMR (500 MHz, CDCl3): δ8.08-8.04 (m, 2H), 7.94-7.91 (t, 1H), 7.77-7.75 (d, 2H), 7.70-7.68 (d, 2H),7.60-7.57 (t, 1H), 2.99 (s, 3H). Fig.17 For 6g of the product of the present invention 1 H NMR chart; 6g is a light yellow solid, 1 H NMR (500 MHz, CDCl3): δ8.05-8.03 (d, 1H), 7.89-7.86 (t, 1H), 7.61-7.55 (m, 2H), 7.52-7.44 (m, 4H), 2.97 (s, 3H). Fig.18 The product of 8a of the present invention 1 H NMR spectrum; 8a is a white solid, 1 H NMR (500 MHz, DMSO): δ12.18 (s, 1H), 8.07-8.06 (d, 1H), 7.77-7.73 (t, 1H), 7.57-7.55 (d, 1H), 7.45-7.42 (m, 1H), 2.34 (d, 3H). Fig.19 The 8d product of the present invention 1 H NMR spectrum; 8d is a white solid, 1 H NMR (500 MHz, CDCl3): δ11.16 (s, 1H), 8.29-8.27 (d, 1H), 7.78-7.69 (m, 2H), 7.48-7.45 (t, 1H), 2.77-2.74 (t, 2H), 1.95-1.87 (m, 2H), 1.09-1.06 (t, 3H). Fig. 20 The product of 8e of the present invention 1 H NMR spectrum; 8e is a white solid, 1 H NMR (500 MHz, DMSO): δ12.09 (s, 1H), 7.86 (s, 1H), 7.59-7.57 (d, 1H), 7.47-7.46 (d, 1H), 2.41 (s,3H), 2.33 (s, 3H). Fig.21The product of 8f of the present invention 1 H NMR spectrum; 8f is a white solid, 1 H NMR (500 MHz, CDCl3): δ11.62 (s, 1H), 8.12 (s, 1H), 7.63 (s, 2H), 2.63 (s, 3H), 2.55 (s, 3H). Fig. 22 For 8g of the product of the present invention 1 H NMR chart; 8g is a light yellow solid, 1 H NMR (500 MHz, CDCl3): δ11.44 (s, 1H), 7.58 (s, 1H), 7.10 (s, 1H), 4.02-4.00 (d, 6H). Fig.23 The 8aa product of the present invention 1 H NMR spectrum; 8aa is a light yellow solid, 1 H NMR (500 MHz, DMSO): δ 8.12-8.10 (d, 1H), 7.92-7.89 (t, 1H), 7.79-7.77 (d, 1H), 7.62-7.59 (t, 1H), 2.56 (s, 3H). Fig.24 The 8ac product of the present invention 1 H NMR spectrum; 8ab is a light yellow solid. 1 H NMR (500 MHz, CDCl3): δ 7.74-7.72 (d, 1H), 7.53-7.50 (t, 1H), 7.12-7.10 (d, 2H), 7.02-7.00 (d, 1H), 6.97-6.95 (t, 1H), 6.91-6.89 (d, 2H), 3.83 (s, 3H), 3.58 (s, 3H), 2.72 (s, 3H). DETAILED DESCRIPTION

[0020] The present invention is further described in detail below in conjunction with embodiments.

[0021] Those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, they are carried out according to the techniques or conditions described in the literature in this area or according to the product instructions. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased.

[0022] Example 1

[0023] This embodiment provides a method for preparing a nitrogen-doped porous carbon material supported cobalt single atom catalyst, the method comprising the following steps: Step 1: Dissolve 2-methylimidazole (24 mmol) and benzylamine (24 mmol) in deionized water (80 mL) to obtain solution A; Step 2: Dissolve cobalt nitrate hexahydrate (0.12 mmol) and zinc nitrate hexahydrate (6 mmol) in deionized water (80 mL) to obtain solution B; Step 3: Add solution B dropwise into solution A, stir and react at 25 °C for 4 h, wash the mixture with deionized water and methanol and dry to obtain CoZn@BZIF-50; Step 4: The precursor CoZn@BZIF-50 was heated to 900°C in a tube furnace under nitrogen atmosphere at a heating rate of 5°C / min and calcined for 2h to obtain Co1@NC-50, wherein the Co content was 1.5 wt.%.

[0024] Example 2

[0025] This embodiment provides a method for preparing a nitrogen-doped porous carbon material-supported cobalt nanoparticle catalyst, the method comprising the following steps: Step 1: Dissolve 2-methylimidazole (24 mmol) and benzylamine (24 mmol) in deionized water (80 mL) to obtain solution A; Step 2: Dissolve cobalt nitrate hexahydrate (0.6 mmol) and zinc nitrate hexahydrate (6 mmol) in deionized water (80 mL) to obtain solution B; Step 3: Add solution B dropwise into solution A, stir and react at 25°C for 4 h, wash the mixture with deionized water and methanol and dry to obtain the precursor CoZn@BZIF-10; Step 4: The precursor CoZn@BZIF-10 was heated to 900°C at a heating rate of 5°C / min in a tubular furnace under a nitrogen atmosphere and calcined for 2 h to obtain Co@NC-10.

[0026] Depend on Figure 1 It can be seen that there are two broad peaks at 24° and 43°, which are attributed to the (002) and (101) crystal planes of graphite carbon materials, respectively. No diffraction peaks of cobalt substances were detected in the Co1@NC-50 catalyst, indicating that cobalt may exist in the catalyst in the form of single atoms. The diffraction peaks of cobalt particles were detected in the XRD spectrum of Co@NC-10, indicating that crystalline cobalt particles exist in the catalyst.

[0027] Depend on Figure 2It can be seen that the specific surface area of ​​Co1@NC-50 catalyst is larger than that of Co@NC-10.

[0028] Depend on Figure 3 It can be seen that no Co particles were observed in the Co1@NC-50 catalyst, indicating that cobalt may exist in the catalyst in the form of single atoms. Obvious Co was observed in the TEM spectrum of Co@NC-10, which is consistent with the XRD results.

[0029] Depend on Figure 4 It can be seen that in the HAADF-STEM-EDS image, a large number of bright spots marked with circles represent isolated cobalt atoms. The EDX element mapping image shows uniformly distributed N, C, and Co signals, indicating that Co and N have been successfully doped into the carbon matrix.

[0030] Depend on Figure 5a and 5b It can be seen that cobalt exists in the material in the form of a single atom, there are 4 nitrogen atoms outside the first shell, the catalytic active center is a Co-N4 structure, and the valence state of Co is between +2 and +3.

[0031] Example 3

[0032] This embodiment provides a method for preparing a nitrogen-doped porous carbon material, the method comprising the following steps: Step 1: Dissolve 2-methylimidazole (24 mmol) and benzylamine (24 mmol) in deionized water (80 mL) to obtain a homogeneous solution A; Step 2: Dissolve zinc nitrate hexahydrate (6 mmol) in deionized water (80 mL) to obtain a homogeneous solution B; Step 3: Add solution B dropwise into solution A, stir and react at 25°C for 4 h, wash the mixture with deionized water and methanol and dry to obtain precursor ZIFs; Step 4: The precursor ZIFs were heated to 900 °C at a heating rate of 5 °C / min in a tube furnace under a nitrogen atmosphere and calcined for 2 h to obtain NC.

[0033] Example 4

[0034] This embodiment provides a method for preparing a carbon material-supported cobalt catalyst, the method comprising the following steps: Step 1: Grind carbon black (200 mg) and cobalt nitrate hexahydrate (0.07 mmol) in a mortar to obtain the precursor Co(NO3)2@C; Step 2: The precursor Co(NO3)2@C was heated to 900°C at a heating rate of 5°C / min in a tubular furnace under a nitrogen atmosphere and calcined for 2 h to obtain Co@C.

[0035] Example 5

[0036] This embodiment provides a preparation process of 2-methylquinazoline by condensation of o-aminobenzyl alcohol, ethanol and ammonia catalyzed by Co1@NC-50, specifically: 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia water and Co1@NC-50 (2.5 mol% Co) were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, the sealed tube was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain a crude product, which was concentrated under reduced pressure. The crude product was diluted with ethyl acetate, and quantitatively analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) with mesitylene as the internal standard, and the yield of 4a was 97%. It was purified by silica gel column chromatography with petroleum ether / ethyl acetate as the eluent, and the polarity was gradually increased from 20% (ethyl acetate / petroleum ether, v / v = 2:8) to 70% (ethyl acetate / petroleum ether, v / v = 7:3), and the isolated yield of the purified product 4a was 92%.

[0037] The reaction process is as follows:

[0038] Comparative Example 1

[0039] The steps for preparing the catalyst were the same as in Example 2, and Co@NC-10 was used for the catalytic reaction.

[0040] 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia and Co@NC-10 (2.5 mol% Co) were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, the sealed tube was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain the reaction mixture, which was concentrated under reduced pressure to obtain a crude product. The crude product was diluted with ethyl acetate, and quantitatively analyzed by GC and GC-MS using mesitylene as the internal standard, and the yield of 4a was 48%.

[0041] Comparative Example 2

[0042] The steps for preparing the catalyst were the same as in Example 3, and NC was used for the catalytic reaction.

[0043] 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia water and 20 mg NC were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, the sealed tube was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain a crude product. The crude product was diluted with ethyl acetate and quantitatively analyzed by GC and GC-MS using mesitylene as an internal standard, and the yield of 4a was 24%.

[0044] Comparative Example 3

[0045] The steps for preparing the catalyst were the same as in Example 4, and Co@C was used for the catalytic reaction.

[0046] 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia water and Co@C (2.5 mol% Co) were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, the sealed tube was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain the reaction mixture, which was concentrated under reduced pressure to obtain a crude product. The crude product was diluted with ethyl acetate, and quantitatively analyzed by GC and GC-MS using mesitylene as the internal standard, and the yield of 4a was 9%.

[0047] Comparative Example 4

[0048] The steps for preparing the catalyst are the same as those in Example 1, except that in the preparation method described in Example 1, benzylamine is replaced by aniline, the precursor is named CoZn@BZIFs-50-PhA, and Co@NC-50-PhA is obtained by calcination.

[0049] 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia water and Co@NC-50-PhA (2.5 mol% Co) were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, the sealed tube was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain a crude product, which was concentrated under reduced pressure. The crude product was diluted with ethyl acetate, and quantitatively analyzed by GC and GC-MS using mesitylene as an internal standard, and the yield of 4a was 73%. The crude product was purified by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent, and the polarity was gradually increased from 20% (ethyl acetate / petroleum ether, v / v = 2:8) to 70% (ethyl acetate / petroleum ether, v / v = 7:3), and the isolated yield of the purified product 4a was 68%.

[0050] Example 6-39

[0051] Example 6-39 provides a preparation process for condensing a 2-aminobenzyl alcohol derivative, a 2-aminobenzophenone or an isatoic anhydride derivative, a fatty alcohol and ammonia water to generate a quinazoline or quinazolinone derivative. The difference from Example 5 is that only one or two of the 2-aminobenzyl alcohol derivative, the 2-aminobenzophenone derivative or the isatoic anhydride derivative, and the fatty alcohol are changed. For specific results, see Scheme 1, Scheme 2, and Scheme 3.

[0052] Solution 1 is as follows:

[0053] Solution 2 is as follows:

[0054] Solution 3 is as follows:

[0055] Embodiment 40:

[0056] This example provides a method for preparing ER176 intermediate 6g, specifically: 0.2 mmol (2-aminophenyl)(2-chlorophenyl)methanone, 2 mL ethanol, 1 mL ammonia and Co@C (2.5 mol% Co) were placed in a 25 mL sealed tube, placed in an oil bath preheated to 100 °C, and stirred for 6 h. After the reaction was completed, it was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain a reaction mixture, which was concentrated under reduced pressure to obtain a crude product. Purification was performed by silica gel column chromatography with ethyl acetate / petroleum ether as the eluent, and the polarity was gradually increased from 20% (ethyl acetate / petroleum ether, v / v = 2:8) to 70% (ethyl acetate / petroleum ether, v / v = 7:3), and the isolated yield of the purified product 6g was 84%.

[0057]

[0058] Embodiment 41:

[0059] This example provides a method for preparing the candidate drug Verubulin, specifically: Step i: 0.5 mmol 8a, 0.75 mmol NN-diisopropylethylamine, and 2 mL toluene were placed in a reactor, refluxed for 1 h, and then cooled to room temperature. After cooling, 0.75 mmol tripolyphosphine was added to the reaction solution, and the reaction was continued at 80 °C for 2 h. After cooling, it was diluted with ethyl acetate, washed with ice water, saturated sodium bicarbonate, sodium citrate, and saturated sodium chloride, and the organic phase was collected. The organic layer was then dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain a crude product. Purification was performed by silica gel column chromatography with ethyl acetate / petroleum ether as the eluent, and the polarity was gradually increased from 20% (ethyl acetate / petroleum ether, v / v = 2:8) to 70% (ethyl acetate / petroleum ether, v / v = 7:3), and the yield of the purified product 8aa was 61%.

[0060] Step ii: 0.5 mmol 8aa, 0.55 mmol 8ab, 30 μL concentrated hydrochloric acid and 2 mL isopropanol were placed in a reactor and stirred at room temperature for 12 h. After the reaction was completed, it was cooled to room temperature, ethyl acetate was added to dilute the reaction mixture, and the reaction mixture was filtered through a silica gel short column to obtain a reaction mixture, which was concentrated under reduced pressure to obtain a crude product. Purification was performed by silica gel column chromatography using ethyl acetate / petroleum ether as the eluent, and the polarity was gradually increased from 20% (ethyl acetate / petroleum ether, v / v = 2:8) to 70% (ethyl acetate / petroleum ether, v / v = 7:3). The isolated yield of the purified product 8ab was 63%.

[0061]

[0062] Example 42: Catalyst Reuse Activity Test

[0063] 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, 1 mL ammonia water, and Co1@NC-50 (2.5 mol% Co) were placed in a 25 mL sealed tube, heated to 100 °C, and reacted for 2 h. After the reaction was completed, the sealed tube was cooled to room temperature, centrifuged, and the catalyst and solution were separated. The catalyst was washed with a small amount of water and ethyl acetate and dried, then transferred to a 25 mL sealed tube, 0.2 mmol o-aminobenzyl alcohol, 2 mL ethanol, and 1 mL ammonia water were added, heated to 100 °C, and reacted for 2 h. After the reaction was completed, the sealed tube was cooled to room temperature, and the catalyst recovery and re-use feeding operations were repeated. According to gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) analysis, the yields of the target product 4a in the reactions of fresh catalyst use and re-use 1-5 times were as follows: 70%, 70%, 67%, 69%, 67%, 65%, respectively, and the catalyst activity did not significantly decay.

[0064] The above embodiments describe the implementation methods of the present invention in detail, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the field without departing from the purpose of the present invention. The above description is only a preferred feasible embodiment of the present invention, and does not limit the scope of rights of the present invention. All equivalent structural changes made by using the contents of the present invention specification are included in the scope of rights of the present invention.

Claims

1. A method for preparing a nitrogen-doped porous carbon-supported cobalt single-atom catalyst, characterized in that: The steps include: Step 1: dispersing 2-methylimidazole and an organic amine in a solvent to obtain a first mixture; Step 2: Dispersing Co(NO3)2·6H2O and Zn(NO3)2·6H2O in a solvent to obtain a second mixture; Step 3: adding the second mixture obtained in step 2 dropwise to the first mixture obtained in step 1, stirring and reacting at a certain temperature, washing and drying the obtained mixture to obtain precursor ZIFs; Step 4: calcining the precursor ZIFs obtained in step 3 to prepare the nitrogen-doped porous carbon-supported cobalt single-atom catalyst.

2. The method for preparing the nitrogen-doped porous carbon-supported cobalt single-atom catalyst according to claim 1, characterized in that: The organic amine in step 1 is aniline or benzylamine.

3. The method for preparing the nitrogen-doped porous carbon-supported cobalt single-atom catalyst according to claim 1, characterized in that: The molar ratio of 2-methylimidazole to the organic amine in step 1 is 1:0.5 to 1:1.5; In step 2, the molar ratio of Co(NO3)2·6H2O to Zn(NO3)2·6H2O is 1:10-50; The reaction temperature in step 3 is 25° C., and the reaction time is 4-10 h. The solvent in steps 1 and 3 is deionized water.

4. A nitrogen-doped porous carbon-supported cobalt single-atom catalyst prepared by the method for preparing a nitrogen-doped porous carbon-supported cobalt single-atom catalyst according to any one of claims 1 to 3.

5. Application of nitrogen-doped porous carbon-supported cobalt single-atom catalyst in the oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds.

6. Use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds according to claim 5, characterized in that: The method comprises the following steps: adding 2-aminobenzyl alcohol derivatives, 2-aminobenzophenone derivatives or isatoic anhydride derivatives, fatty alcohols, ammonia water, and a nitrogen-doped porous carbon material-supported cobalt catalyst into a reactor, reacting at 80-140° C. for 4-20 hours, cooling after the reaction is completed, separating the catalyst and the reaction liquid, purifying the crude product by column chromatography to obtain the target product, and recycling the nitrogen-doped porous carbon-supported cobalt single-atom catalyst after the reaction is completed.

7. Use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds according to claim 6, characterized in that: The 2-aminobenzyl alcohol derivative is 2-aminobenzyl alcohol, 2-amino-5-methoxybenzyl alcohol, 2-amino-3-methylbenzyl alcohol, 2-amino-5-fluorobenzyl alcohol, 2-amino-5-chlorobenzyl alcohol, 2-amino-3-pyridinemethanol or 1-(2-aminophenyl)ethanol.

8. Use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds according to claim 6, characterized in that: The 2-aminobenzophenone derivative is 2-aminobenzophenone, 2-amino-5-chlorobenzophenone, 2-amino-4-fluorobenzophenone, 2-amino-4-chlorobenzophenone, 2-amino-4-bromobenzophenone or 2-amino-5-nitrobenzophenone.

9. Use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds according to claim 6, characterized in that: The isatoic anhydride derivative is isatoic anhydride, 6-methylisatoic anhydride, 7-methylisatoic anhydride, 4,5-dimethoxyisatoic anhydride, 4-fluoroisatoic anhydride, 4-chloroisatoic anhydride, 4-bromoisatoic anhydride or 4-nitroisatoic anhydride; the fatty alcohol is methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, isoheptanol or isopropanol.

10. Use of the nitrogen-doped porous carbon-supported cobalt single-atom catalyst in oxidative dehydrogenation condensation synthesis of quinazoline and quinazolinone compounds according to claim 6, characterized in that: The molar ratio of the 2-aminobenzyl alcohol derivative, 2-aminobenzophenone derivative or isatoic anhydride derivative to the fatty alcohol, ammonia water and catalyst is 1:6-50:3-15:0.025.

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