Preparation method of aldehyde compound, o-diketone compound and hydroxyquinolinone derivative

Abstract

The invention relates to the related technical field of organic synthesis, in particular to a preparation method of an aldehyde compound, an ortho-diketone compound and a hydroxyquinolinone derivative, which comprises the following steps: firstly, mixing a benzoyl methyl substituted triazole compound, water and a Fecatalyst in an oxygen atmosphere, and reacting under a heating condition; and then carrying out post-treatment on the reaction system to obtain the aldehyde compound, the o-diketone compound or the hydroxyquinolinone derivative. By introducing the Fecatalyst, the oxidation process of benzoylmethyl substituted triazole can be effectively catalyzed, so that the functionalization of triazole molecules is realized. The synthesis method is mild in reaction condition, simple and convenient to operate, high in product yield and low in cost, and has a good application prospect and popularization value.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of aldehyde compounds, o-diketone compounds and hydroxyquinolinone derivatives. BACKGROUND

[0002] The triazole skeleton as an important nitrogen-containing heterocyclic structure has attracted much attention due to its wide range of biological activities (such as anticancer, antibacterial, antituberculosis, antimalarial, and antimalarial properties) (Chu, X.-M.; Wang, C.; Wang, W.-L.; Liang, L.-L.; Liu, W.; Gong, K.-K.; Sun, K.-L. Eur. J. Med. Chem. 2019, 166, 206-223; Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.-C.; Chang, L.; Lv, Z.-S.; Feng, L.-S. Eur. J. Med. Chem. 2017, 138, 501-513). According to statistics, among the top 200 small molecule drugs on the market in 2023, the drug molecules containing triazole core skeleton account for a considerable proportion of the drugs already on the market. In addition to the significant application value in pharmacology, triazoles can also be used as multifunctional synthetic building blocks for the construction of complex and valuable organic skeletons. For example, pyridotriazoles have become a stable and safe alternative to diazocompounds (Akter, M.; Rupa, K.; Anbarasan, P. Chem. Rev. 2022, 122, 13108-13205; Chattopadhyay B.; Gevorgyan, V. Angew. Chem. Int. Ed. 2012, 51, 862-872.), which can be used as readily available and stable carbene precursors to participate in various photocatalytic and thermal transformation reactions (including cyclization reactions Helan, V.; Gulevich, A. V.; Gevorgyan, V. Chem. Sci. 2015, 6, 1928-1931; Zhang, Z.; Yadagiri, D.; Gevorgyan, V. Chem. Sci. 2019, 10, 8399-8404.), insertion reactions (Shi, Y.; Gulevich, A. V.; Gevorgyan, V. Angew. Chem. Int. Ed. 2014, 53, 14191-14195; Zhang, Z.; Yadagiri, D.; Gevorgyan, V. Chem. Sci. 2019, 10, 8399-8404.) and rearrangement reactions (Gao, Z.; Jiang, D.; Li, B.; Wang, B. Chem. Commun. 2022, 58, 1017-1020.).Therefore, developing efficient synthesis methods of triazole derivatives still has important and broad research prospects in the fields of medicinal chemistry and synthetic chemistry.

[0003] However, the existing synthesis methods based on triazole derivatives still have obvious limitations: on the one hand, most of the catalytic systems can only catalyze specific structure of triazole substrates and can only perform single conversion. When the structure of triazole changes, the efficiency of triazole derivatization reaction may be greatly reduced, which is difficult to meet the synthesis requirements of complex triazole derivatives; on the other hand, the current triazole derivatization strategy has significant limitations in realizing the late-stage modification of drug molecules with triazole structure, and it is difficult to accurately modify the structure of existing drug molecules. This directly leads to the diversity of product structure being severely restricted, and it is difficult to efficiently construct highly functionalized triazole derivatives. SUMMARY

[0004] The purpose of the present application is to provide a preparation method of aldehyde compounds, o-diketone compounds and hydroxyquinolinone derivatives, in order to solve the problem that the existing synthesis method based on triazole derivatives still has obvious limitations.

[0005] To achieve the above purpose, the present application provides the following technical scheme: a preparation method of aldehyde compounds, o-diketone compounds and hydroxyquinolinone derivatives, comprising the following steps: taking a benzoylmethyl-substituted triazole compound represented by formula (I) as a starting material, adding Fe 3+ catalyst, heating and mixing under an oxygen atmosphere, and then treating to obtain aldehyde compounds (II), o-diketone compounds (III) and hydroxyquinolinone derivatives (IV), and the reaction formula is as follows:

[0006]

[0007] Among them, the compound represented by formula (I) is a benzoylmethyl-substituted triazole.

[0008] Preferably, the benzoylmethyl-substituted triazole compound is selected from any one of benzoylmethyl-substituted-1,2,3-pyridine triazole, benzoylmethyl-substituted-N-phenyl benzotriazole, benzoylmethyl-substituted-N-phenyl-1,2,3-triazole or benzoylmethyl-substituted-N-phenyl-1,2,4-triazole.

[0009] Preferably, the Fe 3+ catalyst is selected from FeCl3.

[0010] Preferably, the oxygen source of the oxygen atmosphere is selected from O2.

[0011] Preferably, in the mixing reaction, an additive and a solvent are mixed together, wherein the additive is selected from H2O and the solvent is selected from dimethyl sulfoxide.

[0012] Preferably, the molar ratio of the benzoylmethyl-substituted triazole compound to the iron ion catalyst is 1:0.01.

[0013] Preferably, the heating reaction is carried out at a temperature of 110-120°C for 8-24 hours.

[0014] Preferably, the post-treatment step comprises vacuum distillation, separation and purification to obtain the aldehyde compound, the o-diketone compound and the hydroxyquinolinone derivative.

[0015] Compared with the prior art, the present application has the following beneficial effects:

[0016] 1. By ingeniously utilizing the catalysis of Lewis acid, the precise conversion of benzoylmethyl-substituted triazole is realized, thereby a series of aldehyde compounds, o-diketone compounds and hydroxyquinolinone derivatives are efficiently synthesized, which provides a new strategy for the subsequent rational use of trivalent iron-catalyzed benzoylmethyl-substituted triazole.

[0017] 2. The synthesis method has simple reaction conditions, convenient treatment, wide substrate application range and various products, and is convenient for wide use. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0019] The embodiments of the present application are described below. The embodiments described below are exemplary and are only used to explain the present application, and cannot be understood as limiting the present application. If the specific technical conditions are not indicated in the embodiments, the technical conditions are carried out according to the technical conditions described in the literature in the art or according to the product instructions. If the reagents or instruments are not indicated by the manufacturer, they are all conventional products that can be obtained from the market.

[0020] Embodiment 1:

[0021]

[0022] In a 10 mL reaction tube, benzoylmethyl-substituted-1,2,3-pyridine triazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2.0 mL) were sequentially added. Under an oxygen atmosphere, heating to 120°C was carried out for 12 h with stirring, and the reaction was monitored by TLC. After the reaction was completed, extraction and vacuum concentration to remove the solvent were carried out, and column chromatography (silica gel column) was used for purification to obtain the corresponding aldehyde compound II (white solid, 20.3 mg, yield 91%).

[0023] 1 H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.81 (d, J = 7.0 Hz, 1H),8.13 (d, J = 7.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.74 – 7.70 (m, 2H), 7.60 –7.54 (m, 1H), 7.37 (dd, J = 9.0, 6.7 Hz, 1H), 7.09 (td, J = 6.9, 1.2 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 192.3, 135.2, 134.5, 134.0, 133.6, 132.4, 130.3,128.8, 128.7, 126.7, 125.8, 117.9, 115.9. HRMS (ESI) m / z calcd for C 13 H9N3OH[M+H] + : 224.0818; found: 224.0818.

[0024] Example 2:

[0025]

[0026] In a 10 mL reaction tube, benzoyl methyl substituted-N-phenylbenzotriazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2.0 mL) were added in sequence. Stirring at 120 °C for 12 h under an oxygen atmosphere, and the reaction was monitored by TLC. After the reaction was completed, extraction and concentration under reduced pressure to remove the solvent, and column chromatography (silica gel column) to purify the corresponding aldehyde compound II (yellow solid, 11.6 mg, yield 52%).

[0027] 1H NMR (500 MHz, CDCl3) δ 9.81 (s, 1H), 8.21 (td, J = 8.1, 1.3 Hz,2H), 7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.73 (tt, J = 7.6, 1.1 Hz, 1H), 7.66(dd, J = 8.0, 1.2 Hz, 1H), 7.61 – 7.57 (m, 1H), 7.54 – 7.51 (m, 1H), 7.51 –7.47 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 188.5, 146.3, 138.1, 135.0, 134.5,131.5, 130.2, 129.8, 129.1, 126.4, 125.0, 120.8, 109.9. HRMS (ESI) m / z calcdfor C 13 H9N3OH [M+H] + : 224.0818; found: 224.0818.

[0028] Example 3:

[0029]

[0030] In a 10 mL reaction tube, benzoyl methyl substituted-N-phenyl-1,2,3-triazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2.0 mL) were added in sequence. Stirring at 120 °C for 12 h under an oxygen atmosphere, and monitoring the reaction by TLC. After the reaction was completed, extraction and concentration under reduced pressure to remove the solvent, and column chromatography (silica gel column) to purify the corresponding aldehyde compound II (white solid, 13.2 mg, yield 76%).

[0031] 1 H NMR (600 MHz, CDCl3) δ 9.86 (s, 1H), 8.11 – 8.08 (m, 1H), 7.99 (d,J = 1.2 Hz, 1H), 7.91 (d, J = 1.2 Hz, 1H), 7.77 (td, J = 7.7, 1.6 Hz, 1H),7.67 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 188.6, 138.4, 134.8, 134.6, 130.6, 130.2, 129.7, 125.8, 125.6. HRMS (ESI) m / z calcd for C9H7N3OH [M+H] + : 174.0662; found: 174.0663.

[0032] Example 4:

[0033]

[0034] In a 10 mL reaction tube, benzoyl methyl substituted-N-phenyl-1,2,3-triazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2 mL) were added in sequence. Stirring at 120 °C for 8 h under an oxygen atmosphere, and monitoring the reaction by TLC. After the reaction was completed, extraction and concentration under reduced pressure to remove the solvent, and column chromatography (silica gel column) to purify the corresponding aldehyde compound III (white solid, 5.8 mg, yield 20%).

[0035] 1 H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 7.8, 1.5 Hz, 1H), 8.01 – 7.97(m, 3H), 7.77 (td, J = 7.7, 1.6 Hz, 1H), 7.70 – 7.67 (m, 2H), 7.63 – 7.60 (m,1H), 7.50 – 7.46 (m, 3H). 13 C NMR (150 MHz, CDCl3) δ 190.5, 188.5, 136.1,135.9, 134.4, 133.8, 132.3, 131.9, 130.9, 130.8, 129.9, 128.5, 124.2, 122.8.HRMS (ESI) m / z calcd for C 16 H 11 N3O2H [M+H] + : 278.0924; found: 278.0923.

[0036] Example 5:

[0037]

[0038] In a 10 mL reaction tube, benzoylmethyl substituted-N-phenyl-1,2,4-triazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2 mL) were added successively. Stirring at 120 °C for 12 h under an oxygen atmosphere, and the reaction was monitored by TLC. After the reaction was completed, extraction and concentration under reduced pressure to remove the solvent, and column chromatography (silica gel column) to purify the corresponding hydroxyquinolinone compound IV (white solid, 17.2 mg, yield 62%).

[0039] 1 H NMR (600 MHz, CDCl3) δ 8.05 (s, 1H), 8.02 (dd, J = 8.2, 1.0 Hz,1H), 7.95 (dd, J = 7.8, 1.5 Hz, 1H), 7.75 (td, J = 7.8, 1.5 Hz, 1H), 7.38(td, J = 7.6, 1.1 Hz, 1H), 7.26 – 7.20 (m, 3H), 7.15 – 7.12 (m, 2H), 6.17 (s,1H). 13 C NMR (150 MHz, CDCl3) δ 193.2, 155.6, 152.7, 138.2, 136.9, 136.8,129.4, 129.2, 127.8, 125.9, 120.5, 116.6. HRMS (ESI) m / z calcd for C 16 H 11 N3OH[M+H] + : 262.0975; found: 262.0976.

[0040] Example 6:

[0041]

[0042] In a 10 mL reaction tube, benzoylmethyl substituted-N-phenyl-1,2,4-triazole (0.1 mmol), FeCl3(0.01 mmol), H2O (0.1 mmol) and DMSO (2 mL) were added successively. Stirring at 120 °C for 12 h under an oxygen atmosphere, and the reaction was monitored by TLC. After the reaction was completed, extraction and concentration under reduced pressure to remove the solvent, and column chromatography (silica gel column) to purify the corresponding hydroxyquinolinone compound IV (white solid, 17.2 mg, yield 62%).

[0043] 1H NMR (600 MHz, CDCl3) δ 9.77 (s, 1H), 7.90 (dd, J = 6.5, 1.9 Hz,1H), 7.79 (s, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.26(s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.3, 2.2 Hz, 1H), 4.42 (d, J= 14.8 Hz, 1H), 4.15 (d, J = 14.2 Hz, 1H), 4.08 (dd, J = 14.8, 7.8 Hz, 1H),3.98 (q, J = 7.2 Hz, 1H), 3.64 – 3.59 (m, 1H), 3.46 – 3.36 (m, 1H), 3.12 –3.03 (m, 1H), 2.50 (d, J = 15.6 Hz, 3H), 2.25 – 2.19 (m, 1H), 1.65 (dt, J =16.7, 8.9 Hz, 1H), 1.20 (d, J = 6.5 Hz, 2H), 1.07 (d, J = 6.7 Hz, 1H). 13 C NMR(150 MHz, CDCl3) δ 188.7, 167.5, 162.9, 147.5, 144.6, 140.0, 136.5, 136.3,133.4, 133.0, 132.3, 131.3, 129.7, 129.5, 120.5, 116.3, 109.3, 52.3, 47.1,43.8, 41.2, 29.3, 20.1, 14.2. HRMS (ESI) m / z calcd for C 24 H 23 ClN6O3H [M+H] + :479.1593; found: 479.1591.

[0044] Example 7:

[0045]

[0046] In a 10 mL reaction tube, benzoylmethyl-substituted suvorexant (0.1 mmol), FeCl3 (0.01 mmol), H2O (0.1 mmol) and DMSO (2 mL) were added in sequence. Under an oxygen atmosphere, it was heated to 120 °C and stirred for 24 h, and the reaction was monitored by TLC. After the reaction was completed, it was extracted and the solvent was removed by concentration under reduced pressure, and purified by column chromatography (silica gel column) to obtain the corresponding aldehyde compound III (white solid, 18.0 mg, yield 31%).

[0047] 1 H NMR (600 MHz, CDCl3) δ 8.03 – 8.01 (m, 2H), 7.77(dd, J = 12.3, 1.9Hz, 1H). 7.62 – 7.59 (m, 1H), 7.47 (t, J = 7.8 Hz, 3H), 7.37(s, 1H), 7.29 (s,2H), 7.16-7.14(m, 1H), 7.00-6.97(m, 1H), 4.49 – 4.37 (m, 1H), 4.17(d, J =14.6 Hz 1H), 4.07 (d, J = 12.3 Hz, 1H), 3.98 (dt, J = 14.2, 3.6 Hz, 1H), 3.84(dd, J = 14.9, 9.0 Hz, 1H), 3.59 – 3.54 (m, 1H), 3.13 (ddd, J = 13.4, 11.3,1.8 Hz, 1H), 2.52(d, J = 50 Hz, 3H), 2.31 (dt J =14.9, 5.9 Hz, 1H), 1.70 (dt,J = 15.7, 8.9 Hz, 1H), 1.25 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCl3) δ168.1, 162.9, 147.5, 136.6, 134.0, 133.6, 132.6, 131.6, 130.7, 128.3, 120.4,116.2, 52.4, 47.0, 43.9, 41.4, 36.4, 20.1. HRMS (ESI) m / z calcd forC 31 H 27 ClN6O4H [M+H] + : 583.1855; found: 583.1855.

[0048] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives, characterized in that, Includes the following steps: Using benzoylmethyl-substituted triazole compounds as shown in formula (I) as starting materials, Fe was added. 3+ The catalyst, under an oxygen atmosphere, was heated to carry out a mixed reaction, and post-treatment yielded aldehyde compound (II), o-diketone compound (III), and hydroxyquinolinone derivative (IV), as shown in the following reaction formula: Among them, the compound shown in formula (I) is a benzoylmethyl substituted triazole.

2. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The benzoylmethyl-substituted triazole compound is selected from any one of benzoylmethyl-substituted-1,2,3-pyridinetriazole, benzoylmethyl-substituted-N-phenylbenzotriazole, benzoylmethyl-substituted-N-phenyl-1,2,3-triazole or benzoylmethyl-substituted-N-phenyl-1,2,4-triazole.

3. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The Fe 3+ The catalyst was selected from FeCl3.

4. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The oxygen source for the oxygen atmosphere is selected from O2.

5. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, In the mixing reaction, an additive and a solvent are added and mixed together, wherein the additive is selected from H2O and the solvent is selected from dimethyl sulfoxide.

6. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The molar ratio of the benzoylmethyl substituted triazole compound to the iron ion catalyst is 1:0.

01.

7. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The heating reaction is carried out at a temperature of 110~120℃ for 8~24 hours.

8. The method for preparing aldehyde compounds, o-dione compounds, and hydroxyquinoline ketone derivatives according to claim 1, characterized in that, The post-processing steps include: vacuum distillation, separation and purification to obtain aldehyde compounds, o-dione compounds and hydroxyquinoline ketone derivatives.

Images