Preparation method of alpha-ketoamide compound

Abstract

The invention provides a preparation method of an alpha-ketoamide compound, and belongs to the technical field of preparation of carbonyl acid amide. The preparation method comprises the following steps: mixing and dissolving compounds shown in a formula (I), a formula (II) and a formula (III) in an organic solvent, adding a metal catalyst, alkali and oxygen, and reacting to obtain the alpha-ketoamide compound shown in a formula (IV). The alpha-ketoamide compound prepared by the method disclosed by the invention can be used as a multipurpose intermediate and precursor in organic synthesis, has a strong anti-cancer effect, and has a very wide application prospect in the field of preparation of anti-cancer drugs.

Description

Technical Field

[0001] The present application relates to a preparation method of α-ketoamide compounds, belonging to the technical field of the preparation of carboxylic acid amides. Background Art

[0002] α-Ketoamide compounds have various biological activities, such as: inhibiting coronaviruses, HCV proteases, and T-cell proliferation blockers. Currently, the synthesis methods of α-ketoamide compounds have been fully developed, including the oxidation reaction of corresponding hydroxy or amino compounds, the dicarbonyl amination reaction using carbon monoxide as the carbonyl source, the coupling reaction of acyl halides, and the amidation reaction of α-ketoacid derivatives. However, these synthesis methods all have certain limitations. For example, the need to additionally add strong oxidants makes the reaction less green. In addition, when using carbon monoxide as the carbonyl source, the reaction often requires high temperature and high pressure to avoid the generation of monocarbonyl insertion by-products. In the amidation reaction method of α-ketoacids, the synthesis of α-ketoacids is relatively complex. Therefore, there are great limitations in the diversity of products obtained by amidation to α-ketoamide compounds. Summary of the Invention

[0003] In view of this, the present application provides a preparation method of α-ketoamide compounds. This method has mild conditions and a wide application range, and can rapidly construct α-ketoamide compounds with diverse structures.

[0004] Specifically, the present application is achieved through the following solutions:

[0005] A preparation method of α-ketoamide compounds, characterized in that: the compounds shown in formula (I), formula (II), and formula (III) are mixed and dissolved in an organic solvent, and a metal catalyst, a base, and oxygen are added, and the reaction obtains the α-ketoamide compound shown in formula (IV).

[0006]

[0007] Wherein, R is phenyl, substituted phenyl, C 1～8 alkyl, cyclic alkyl; R 1 is hydrogen, phenyl, substituted phenyl, C 1～4 linear alkyl, C 3～6 cycloalkyl, sulfur-containing heterocyclic group, nitrogen-containing heterocyclic group, or oxygen-containing heterocyclic group; R 2 is hydrogen, phenyl, substituted phenyl, C 1～4 linear alkyl, C 3～6 cycloalkyl, sulfur-containing heterocyclic group, nitrogen-containing heterocyclic group, or oxygen-containing heterocyclic group, and R 1 and R 2 are not simultaneously hydrogen.

[0008] The above preparation method has the advantages of easy separation, easy preparation of raw materials, high efficiency, mild reaction conditions, high atom economy and wide substrate adaptability. Oxygen is used as an oxidant in this reaction process, which is a new type of green preparation method.

[0009] Furthermore, as a preference:

[0010] The base is any one or several of sodium fluoride, sodium methoxide, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine.

[0011] The metal catalyst is Cu(MeCN) 4 PF 6 、Pd(OAc) 2 、Rh 2 (OAc) 4 、Rh 2 (esp) 2 、Rh 2 (OPiv) 4 、Rh 2 (TFA) 4 、any one or several of FeTPPCl.

[0012] The organic solvent is any one or several of tetrahydrofuran, dichloromethane, tert-butyl methyl ether, toluene, ethyl acetate.

[0013] The reaction molar ratio of the compound shown in formula (I), the compound shown in formula (II), the compound shown in formula (III), the metal catalyst and the base is 1-2:1.2-2.0:1.2-2.0:0.01-0.05:1.2-4.0. Preferably, at this time, the concentration of the compound shown in formula (III) in the organic solvent is 40.0-60.0 mol / L, and more preferably, the concentration of the compound shown in formula (III) in the organic solvent is 50.0 mol / L.

[0014] The reaction temperature is -20°C to 80°C, and the time is 3-24 h.

[0015] The product obtained from the above reaction is separated and purified to obtain an α-ketoamide compound. The separation and purification specifically is: the reaction solution is first concentrated under reduced pressure to remove the solvent, and then column chromatography is carried out with a mixed solution of ethyl acetate and petroleum ether to obtain the α-ketoamide compound. Preferably, the volume ratio of ethyl acetate to petroleum ether is 1:15-40.

[0016] The α-ketoamide compound is any one of the following structures:

[0017]

[0018] The α-ketoamide compounds can not only be used as versatile intermediates and precursors in organic synthesis, but also have potent anti-cancer effects. Therefore, they can also be used to prepare anti-cancer agents or inhibitors of coronaviruses, HCV proteases, and T cell proliferation blockers, such as anti-lung cancer drugs, anti-liver cancer drugs, anti-prostate cancer drugs, or anti-colorectal cancer drugs, and they have broad application prospects in the field of preparing anti-cancer drugs.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] (1) The preparation method of the α-ketoamide compounds provided by the present invention has the advantages of easy separation, easy preparation of raw materials, high efficiency, mild reaction conditions, wide atom economy, and wide substrate adaptation range. Oxygen is used as an oxidant in the reaction process, which is a new type of green preparation method. The α-ketoamide compounds prepared by this preparation method have high purity and biological activity.

[0021] (2) The α-ketoamide compounds provided by the present invention have various biological activities, such as inhibitors of coronaviruses, HCV proteases, and T cell proliferation blockers. At the same time, they can be used as versatile intermediates and precursors in organic synthesis. The α-ketoamide compounds are also potential potent anti-cancer drugs and have broad application prospects in the field of preparing anti-cancer drugs.

[0022] The following further explains with reference to the accompanying drawings and specific embodiments. Description of the Drawings

[0023] Figure 1 1H NMR spectrum of the product IV-a prepared in Example 1;

[0024] Figure 2 13C NMR spectrum of the product IV-a prepared in Example 1;

[0025] Figure 3 1H NMR spectrum of the product IV-b prepared in Example 2;

[0026] Figure 4 13C NMR spectrum of the product IV-b prepared in Example 2;

[0027] Figure 5 1H NMR spectrum of the product IV-c prepared in Example 3;

[0028] Figure 6 13C NMR spectrum of the product IV-c prepared in Example 3;

[0029] Figure 7 1H NMR spectrum of the product IV-d prepared in Example 4;

[0030] Figure 8 13C NMR spectrum of the product IV-d prepared in Example 4;

[0031] Figure 9 It is the 1H NMR spectrum of Product IV-e prepared in Example 5;

[0032] Figure 10 It is the 13C NMR spectrum of Product IV-e prepared in Example 5;

[0033] Figure 11 It is the 1H NMR spectrum of Product IV-f prepared in Example 6;

[0034] Figure 12 It is the 13C NMR spectrum of Product IV-f prepared in Example 6;

[0035] Figure 13 It is the 1H NMR spectrum of Product IV-g prepared in Example 7;

[0036] Figure 14 It is the 13C NMR spectrum of Product IV-g prepared in Example 7;

[0037] Figure 15 It is the 1H NMR spectrum of Product IV-h prepared in Example 8;

[0038] Figure 16 It is the 13C NMR spectrum of Product IV-h prepared in Example 8;

[0039] Figure 17 It is the 1H NMR spectrum of Product IV-i prepared in Example 9;

[0040] Figure 18 It is the 13C NMR spectrum of Product IV-i prepared in Example 9;

[0041] Figure 19 It is the 1H NMR spectrum of Product IV-j prepared in Example 10;

[0042] Figure 20 It is the 13C NMR spectrum of Product IV-j prepared in Example 10;

[0043] Figure 21 It is the 1H NMR spectrum of Product IV-k prepared in Example 11;

[0044] Figure 22 It is the 13C NMR spectrum of Product IV-k prepared in Example 11. Detailed Embodiments

[0045] The following further describes the detailed embodiments of the present invention. It should be noted here that the description of these embodiments is for helping to understand the present invention, but does not constitute a limitation to the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0046] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available through conventional channels unless otherwise specified.

[0047] Example 1

[0048] The diazo compound (0.15 mmol) shown in formula (I), water (0.15 mmol) shown in formula (II), and Rh 2 (esp) 2 (0.01 mmol) were weighed into a test tube. Then, 2 mL of anhydrous tetrahydrofuran was added to the reaction system, and the reaction was stirred at 30 °C for about 3 hours until the diazo compound shown in formula (I) was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and triethylamine were added to the reaction system until the amine compound shown in (III) was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-a.

[0049] The reaction equation for the above process is as follows:

[0050]

[0051] Example 2

[0052] The diazo compound (0.2 mmol) shown in formula (I), water (0.15 mmol) shown in formula (II), and CuCl 2 (0.1 mmol) were weighed into a test tube. Then, 2 mL of anhydrous tetrahydrofuran was added to the reaction system, and the reaction was stirred at 30 °C for 5 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and sodium methoxide were added to the reaction system, and the reaction was continued to be stirred under this condition for 2 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-b.

[0053] The reaction equation for the above process is as follows:

[0054]

[0055] Example 3

[0056] The diazo compound shown in formula (I) (0.2 mmol), water shown in formula (II) (0.15 mmol), and FeTPPCl (0.05 mmol) were weighed into a test tube. Then, 2 mL of anhydrous tetrahydrofuran was added to the reaction system, and the reaction was stirred at 40 °C for about 5 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and triethylamine were added to the reaction system, and the reaction was continued to be stirred under this condition for 3 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-c.

[0057] The reaction equation for the above process is as follows:

[0058]

[0059] Example 4

[0060] The diazo compound shown in formula (I) (0.15 mmol), water shown in formula (II) (0.15 mmol), and Rh 2 (OPiv) 4 (0.02 mmol) were weighed into a test tube. Then, 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at 35 °C for about 4 h until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and sodium fluoride were added to the reaction system, and the reaction was continued to be stirred under this condition for 10 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-d.

[0061] The reaction equation for the above process is as follows:

[0062]

[0063] Example 5

[0064] The diazo compound shown in formula (I) (0.15 mmol), water shown in formula (II) (0.15 mmol), and Rh 2 (OAc) 4 (0.02 mmol) were weighed into a test tube. Then, 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at 10 °C for about 4 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and triethylamine were added to the reaction system, and the reaction was continued to be stirred under this condition for 12 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-e.

[0065] The reaction equation of the above process is as follows:

[0066]

[0067] Example 6

[0068] The diazo compound (0.15 mmol) shown in formula (I), water (0.15 mmol) shown in formula (II), and Pd(OAc) 2 (0.05 mmol) were weighed into a test tube. Then, 2 mL of anhydrous ethyl acetate was added to the reaction system, and the mixture was stirred at 60 °C for about 4 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and 4-dimethylaminopyridine were added to the reaction system, and the mixture was continuously stirred at this condition for 8 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, that is, the α-ketoamide compound, denoted as IV-f.

[0069] The reaction equation of the above process is as follows:

[0070]

[0071] Example 7

[0072] The diazo compound (0.15 mmol) shown in formula (I), water (0.15 mmol) shown in formula (II), and Rh 2 (TFA) 4 (0.01 mmol) were weighed into a test tube. Then, 2 mL of anhydrous ethyl acetate was added to the reaction system, and the mixture was stirred at -20 °C for 1 hour until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and N,N-diisopropylethylamine were added to the reaction system, and the mixture was continuously stirred at this condition for 6 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, that is, the α-ketoamide compound, denoted as IV-g.

[0073] The reaction equation of the above process is as follows:

[0074]

[0075] Example 8

[0076] The diazo compound (0.15 mmol) shown in formula (I), water (0.15 mmol) shown in formula (II), and Rh 2 (OAc) 4(0.02 mmol) was weighed into a test tube, then 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at 40 °C for 2 - 4 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and sodium fluoride were added to the reaction system, and the reaction was continued to stir at this condition for 3 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-h.

[0077] The reaction equation for the above process is as follows:

[0078]

[0079] Example 9

[0080] The diazo compound (0.15 mmol) shown in formula (I) in the following reaction formula, water (0.15 mmol) shown in formula (II), and Rh 2 (esp) 2 (0.01 mmol) was weighed into a test tube, then 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at -10 °C for 2 hours until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and sodium fluoride were added to the reaction system, and the reaction was continued to stir at this condition for 4 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-i.

[0081] The reaction equation for the above process is as follows:

[0082]

[0083] Example 10

[0084] The diazo compound (0.15 mmol) shown in formula (I) in the following reaction formula, water (0.15 mmol) shown in formula (II), and Rh 2 (esp) 2 (0.01 mmol) was weighed into a test tube, then 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at 0 °C for 1 hour until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown in formula (III) and triethylamine were added to the reaction system, and the reaction was continued to stir at this condition for 9 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain the pure target product, namely α-ketoamide compound, denoted as IV-j.

[0085] The reaction equation for the above process is as follows:

[0086]

[0087] Example 11

[0088] The diazo compound (0.15 mmol) shown by formula (I) above, water (0.15 mmol) shown by formula (II), and Rh 2 (esp) 2 (0.01 mmol) were weighed in a test tube. Then, 2 mL of anhydrous ethyl acetate was added to the reaction system, and the reaction was stirred at 25 °C for 1 hour until the diazo compound was completely consumed. Then, in an oxygen atmosphere, the amine compound shown by formula (III) and sodium methoxide were added to the reaction system, and the reaction was continued to be stirred under this condition for 18 hours until the amine compound was completely consumed. The reaction solution was filtered and purified by column chromatography to obtain a pure target product, that is, an α-ketoamide compound, denoted as IV-k.

[0089] The reaction equation for the above process is as follows:

[0090]

[0091] The specific spectral data of compounds IV-a to IV-k are as follows:

[0092] Spectral data of compound IV-a: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.95 (s, 1H), 8.49–8.37 (m, 2H), 7.73–7.69 (m, 2H), 7.68–7.63 (m, 1H), 7.54–7.48 (m, 2H), 7.44–7.36 (m, 2H), 7.24–7.16 (m, 1H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 187.6, 159.0, 136.8, 134.8, 133.3, 131.6, 129.4, 128.7, 125.5, 120.1.

[0093] Spectral data of compound IV-b: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.37–8.23 (m, 2H), 7.66–7.60 (m, 1H), 7.57 (d, J = 4.7 Hz, 1H), 7.51–7.45 (m, 2H), 4.74–4.57 (m, 1H), 3.79 (s, 3H), 1.66–1.42 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3 )(δ, ppm) 187.1, 172.6, 161.3, 134.6, 133.3, 131.3, 128.7, 52.8, 48.3, 18.2。

[0094] Spectral data of Compound IV-c: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.34–8.29 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.67–7.61 (m, 1H), 7.53–7.45 (m, 2H), 7.33–7.27 (comp, 4H), 7.25–7.20 (m, 1H), 4.98–4.71 (m, 1H), 3.78 (s, 3H), 3.76 (s, 2H), 3.14–2.82 (m, 2H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 186.9, 170.5, 161.6, 137.5, 134.7, 133.2, 131.3, 129.1, 128.8, 128.7, 127.5, 53.0, 51.9, 36.7, 33.1。

[0095] Spectral data of Compound IV-d: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.36–8.27 (m, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.66–7.57 (m, 1H), 7.53–7.42 (m, 2H), 4.98–4.67 (m, 1H), 3.80 (s, 3H), 2.57 (t, J = 7.4 Hz, 2H), 2.33–2.23 (m, 1H), 2.16–2.07 (comp, 4H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 186.9, 171.6, 161.6, 134.7, 133.2, 131.3, 128.7, 52.9, 51.7, 31.6, 30.1, 15.6。

[0096] Spectral data of Compound IV-e: 1 H NMR (400 MHz, CDCl 3)(δ, ppm) 8.37–8.26 (m, 2H), 7.66–7.56 (m, 1H), 7.52–7.43 (m, 2H), 7.24 (s, 1H), 3.96–3.88 (m, 2H), 3.70–3.62 (m, 1H), 2.35 (s, 1H), 1.01 (s, 9H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 188.1, 162.9, 134.6, 133.4, 131.4, 128.7, 62.7, 60.1, 34.0, 27.0.

[0097] Spectral data of Compound IV-f: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.38–8.12 (m, 2H), 7.65–7.58 (m, 1H), 7.50–7.42 (m, 2H), 7.37–7.28 (comp, 3H), 7.28–7.21 (comp, 3H), 4.37–4.26 (m, 1H), 3.78 (dd, J = 11.1, 3.6 Hz, 1H), 3.69 (dd, J = 11.1, 4.8 Hz, 1H), 3.04–2.88 (m, 2H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 187.9, 162.1, 137.3, 134.6, 133.3, 131.3, 129.4, 128.9, 128.6, 127.0, 63.7, 53.0, 37.1.

[0098] Spectral data of Compound IV-g: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 7.70–7.58 (comp, 4H), 7.58–7.48 (m, 1H), 7.42–7.35 (comp, 4H), 6.96–6.89 (m, 1H), 6.77–6.73 (m, 1H), 6.70–6.63 (m, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H), 2.16 (s, 3H), 2.09 (s, 3H); 13 C NMR (100 MHz, CDCl 3)(δ, ppm) 190.7, 167.1, 142.5, 138.3, 137.3, 136.9, 134.3, 133.7, 130.6, 129.7, 129.4, 129.2 (d, J = 32.3 Hz), 128.8, 128.7, 125.5 (q, J = 3.6 Hz), 125.1, 124.4 (q, J = 272.4 Hz), 48.8, 33.6, 19.7, 19.4; 19 F NMR (376 MHz, CDCl 3 )(δ, ppm) -62.31 (s).

[0099] Spectral data of compound IV-h: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.93 (s, 1H), 8.65–8.41 (m, 2H), 7.78 (d, J = 7.8 Hz, 2H), 7.57–7.53 (m, 1H), 7.50–7.44 (m, 2H), 7.44–7.37 (m, 2H), 7.36–7.32 (m, 1H), 7.32–7.26 (m, 1H), 7.23–7.14 (m, 1H), 6.92–6.79 (m, 1H), 5.11 (s, 2H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 186.6, 159.6, 158.2, 137.6, 136.8, 135.9, 135.7 (q, J = 32.9 Hz), 131.9, 130.2, 128.8, 128.2, 127.7, 125.7 (q, J = 3.6 Hz), 123.6 (q, J = 272.9 Hz), 112.6, 112.4, 106.7, 70.2; 19 F NMR (376 MHz, CDCl 3 )(δ, ppm) -63.38 (s).

[0100] Spectral data of compound IV-i: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.73 (s, 1H), 7.67–7.59 (m, 2H), 7.40–7.28 (comp, 7H), 7.21–7.14 (m, 1H), 4.31 (s, 2H); 13 C NMR (100 MHz, CDCl 3)(δ, ppm) 196.4, 157.5, 136.4, 132.6, 130.0, 129.4, 128.9, 127.5, 125.5, 119.9, 42.8。

[0101] Spectral data of compound IV-j: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.36–8.27 (m, 2H), 7.68–7.56 (m, 1H), 7.54–7.42 (m, 2H), 7.04 (s, 1H), 4.41–4.20 (m, 1H), 2.11–2.00 (m, 2H), 1.79–1.70 (m, 2H), 1.69–1.60 (m, 2H), 1.58–1.47 (m, 2H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 188.1, 161.4, 134.4, 133.5, 131.4, 128.6, 51.3, 33.1, 23.9。

[0102] Spectral data of compound IV-k: 1 H NMR (400 MHz, CDCl 3 )(δ, ppm) 8.43–8.28 (m, 2H), 7.66–7.58 (m, 1H), 7.52–7.44 (m, 2H), 7.06 (d, J = 5.5 Hz, 1H), 4.12–4.04 (m, 1H), 4.03–3.95 (m, 2H), 3.56–3.45 (m, 2H), 1.98–1.93 (m, 2H), 1.65–1.56 (m, 2H); 13 C NMR (100 MHz, CDCl 3 )(δ, ppm) 187.8, 161.1, 134.6, 133.4, 131.3, 128.6, 66.7, 46.1, 32.8。

[0103] In summary, the α-ketoamide compounds provided by the present invention are widely distributed in natural products and bioactive molecules. It has a variety of biological activities, such as inhibiting coronaviruses, HCV proteases, and T-cell proliferation blockers. At the same time, it can be used as a versatile intermediate and precursor in organic synthesis. The α-ketoamide compound is also a potential potent anti-cancer drug and has broad application prospects in the field of preparing anti-cancer drugs.

[0104] Moreover, the present invention provides a method for preparing α-ketoamide compounds. It has the advantages of easy separation, readily available raw materials, high efficiency, mild reaction conditions, high atom economy and a wide substrate scope. Oxygen is used as an oxidant in this reaction process, which is a new type of green preparation method. The α-ketoamide compounds prepared by this preparation method have high purity and biological activity.

[0105] Obviously, the above-mentioned embodiments of the present invention are merely examples for clearly illustrating the present invention, rather than limitations on the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing an α-ketoamide compound, characterized in that: The compounds represented by formula (I), formula (II) and formula (III) are mixed and dissolved in an organic solvent, and a metal catalyst, a base and oxygen are added to react to obtain an α-ketoamide compound represented by formula (IV). Wherein, R is phenyl, substituted phenyl, C 1～8 Alkyl, cyclic alkyl; R 1 is hydrogen, phenyl, substituted phenyl, C 1～4 Straight chain alkyl, C 3～6 Cycloalkyl, S-containing heterocyclic group, N-containing heterocyclic group or O-containing heterocyclic group; R 2 is hydrogen, phenyl, substituted phenyl, C 1～4 Straight chain alkyl, C 3～6 cycloalkyl, S-containing heterocyclic group, N-containing heterocyclic group or O-containing heterocyclic group, and R 1 , R 2 Not hydrogen at the same time.

2. The method for preparing an α-ketoamide compound according to claim 1, characterized in that: The base is any one or more of sodium fluoride, sodium methoxide, triethylamine, 4-dimethylaminopyridine and N,N-diisopropylethylamine.

3. The method for preparing an α-ketoamide compound according to claim 1, characterized in that: The metal catalyst is any one or more of Cu(MeCN)4PF6, Pd(OAc)2, Rh2(OAc)4, Rh2(esp)2, Rh2(OPiv)4, Rh2(TFA)4, and FeTPPCl.

4. The method for preparing an α-ketoamide compound according to claim 1, characterized in that: The organic solvent is any one or more of tetrahydrofuran, dichloromethane, tert-butyl methyl ether, toluene and ethyl acetate.

5. The method for preparing an α-ketoamide compound according to claim 1, characterized in that: The reaction molar ratio of the compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the metal catalyst and the base is 1-2:1.2-2.0:1.2-2.0:0.01-0.05:1.2-4.

0.

6. The method for preparing an α-ketoamide compound according to claim 5, characterized in that: The concentration of the compound represented by formula (III) in the organic solvent is 40.0 to 60.0 mol / L.

7. The method for preparing an α-ketoamide compound according to claim 1, characterized in that: The reaction temperature is -20°C to 80°C, and the reaction time is 3 to 24 hours.

8. The method for preparing an α-ketoamide compound according to any one of claims 1 to 7, characterized in that: The α-ketoamide compound is any one of the following structures:

9. The method for preparing an α-ketoamide compound according to claim 8, characterized in that: The α-ketoamide compounds are used to prepare anticancer preparations or inhibitors for inhibiting coronavirus, HCV protease and T cell proliferation; or the α-ketoamide compounds are used as precursors or intermediates of chemical products.

10. The method for preparing an α-ketoamide compound according to claim 9, characterized in that: The anticancer preparation is an anti-lung cancer drug, an anti-liver cancer drug, an anti-prostate cancer drug or an anti-colorectal cancer drug.

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