Alpha-amido ketone compound and preparation method thereof

Abstract

The invention discloses a preparation method of an alpha-amido ketone compound. The method comprises the following steps: by taking trifluoroethanol, tert-butyl alcohol, hexafluoroisopropanol or water as a solvent, adding water at the temperature of 40-120 DEG C, stirring and reacting for 4-72 hours to obtain a reaction solution, removing the reaction solvent of the reaction solution, and purifying by thin layer chromatography / column chromatography to obtain the alpha-amido ketone compound. According to the method disclosed by the invention, the alpha-amido ketone compound is synthesized by taking N-alkynyl pyrrolidine-2-ketone alkyne amide as a raw material for the first time; the method has the advantages of simple operation, wide applicable substrate range, realization of synthesis of the alpha-amido ketone product in a gram scale, simple steps, convenient operation, high product yield, no use of an acid or transition metal catalyst, high atom economy, and environmental protection.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to an α-amido ketone compound and a preparation method thereof. Background Art

[0002] α-Amido ketone compounds, as a class of extremely crucial organic synthesis intermediates, play an indispensable role in the field of organic synthesis. They are the core raw materials for constructing numerous nitrogen-containing heterocyclic compounds, such as oxazoles, imidazoles, thiazoles, etc. that are widely used in the fields of drug research and development, materials science, etc. These nitrogen-containing heterocyclic compounds have shown great potential in the pharmaceutical industry, and many drug molecules with significant biological activities contain these heterocyclic structures.

[0003] Meanwhile, the structural fragments of α-amido ketone compounds frequently appear in numerous bioactive substances. In biomedical research, they are commonly found in various enzyme inhibitors, which can specifically bind to enzymes and regulate their activities, thereby affecting the physiological processes in organisms; in the agricultural field, the active ingredients of some herbicides also contain this structural fragment, achieving the purpose of weed control by interfering with the physiological metabolism process of weeds; in addition, in natural products, the α-amido ketone structural fragment also widely exists, providing a rich source of lead compounds for drug research and development. Given the importance of α-amido ketone compounds, scientific researchers have developed various preparation methods.

[0004] In 2011, the Bolm research group achieved the regioselective intermolecular hydroacylation reaction between enamide and salicylaldehyde under the conditions of using Rh(CO)2(acac) as a catalyst, PPh3 as a ligand, and toluene as a solvent for refluxing, and successfully prepared α-amido ketone compounds with a yield of 47 - 89% (H.-J. Zhang and C. Bolm, Org. Lett., 2011, 13, 3900 - 3903).

[0005] In 2014, the Gravel research group developed aaza-Benzoin reaction of aldehydes with phosphonylimines catalyzed by bis(amino)cyclopropenylidene (BAC), and obtained α-amido ketones with a yield of 27 - 96% (M.M.D. Wilde and M. Gravel, Org. Lett., 2014, 16, 5308 - 5311).

[0006] In 2015, the Zhang research group reported a radical cascade reaction of alkynes, N-fluoroarylsulfonimides, and alcohols, and through this operation, the corresponding α-amino-α-aryl ketones could be synthesized with a yield of 48 - 74% (G. Zheng, Y. Li, J. Han, T. Xiong and Q. Zhang, Nat. Commun., 2015, 6, 7011).

[0007] In 2016, the Park research group developed a method for the catalytic conversion of 1,2-azidoalcohol esters to α-amido ketones. This reaction uses 1,2-azidoalcohol esters as substrates. Under the condition of no external oxidant, ruthenium-catalyzed formation of N-H imines and release of nitrogen occur, and then an intramolecular migration of the acyl moiety takes place, thereby obtaining the corresponding α-amido ketones in a yield of 53-94% (Y. Kim, H. K. Pak, Y. H. Rhee and J. Park, Chem. Commun., 2016, 52, 6549-6552).

[0008] In 2019, Xu et al. developed a ring-opening reaction of palladium-catalyzed 2H-azirines with carboxylic acids for the preparation of α-amido ketone compounds. During this reaction process, 2,3-diaryl-2H-azirines and carboxylic acids first undergo nucleophilic addition, followed by cleavage of the C-N single bond, and then thermal rearrangement, finally obtaining the corresponding products in a yield of 43-92% (F. Xu, X.-J. Si, Y.-Y. Song, X.-D. Wang, C.-S. Liu, P.-F. Geng and M. Du, J. Org. Chem., 2019, 84, 2200-2208).

[0009] In 2020, the Willis research group reported a method for the synthesis of α-amido ketones by rhodium-catalyzed intermolecular alkyne hydroacylation of β-aldehyde amides. This reaction uses [Rh(dppe)(C6H5F)][BAr F 4] as a catalyst and CH2Cl2 as a solvent, and the corresponding products are obtained in a yield of 47-95% under the condition of 40 °C (R. Pal, S. C. O’Brien and M. C. Willis, Chem.-Eur. J., 2020, 26, 11710-11714).

[0010] Although the above methods can achieve the preparation of α-amido ketone compounds to a certain extent, there are still many deficiencies. Some methods require the use of expensive transition metal catalysts, which not only increases the production cost but also may lead to the problem of metal residues in the products, affecting the product quality and application scope. There are also some methods that adopt multi-step synthesis routes, with complex reaction processes, requiring multiple separation and purification operations, reducing the production efficiency and increasing the time and labor costs. In addition, the preparation of some substrates is difficult and requires special synthesis methods and conditions, further limiting the wide application of these methods.

[0011] In summary, it is extremely attractive to develop a green, efficient, economical and widely applicable method for the preparation of α-amido ketone compounds. Summary of the Invention

[0012] To overcome the disadvantages and deficiencies of the prior art, the object of the present invention is to provide a method for preparing α-amido ketone compounds, aiming to solve the problem that the use of N-alkynylpyrrolidin-2-one alkynamides as raw materials to assist in the synthesis of α-amido ketone compounds through neighboring group participation has not been involved in the existing literature.

[0013] The present invention is implemented as follows. A method for preparing α-amido ketone compounds includes the following steps:

[0014] (1) Water and alkynamide are successively added to a reaction solvent, and after stirring and reacting at 50-120 °C for 4-72 hours, a reaction solution is obtained; wherein, the molar volume ratios of the alkynamide, water, and reaction solvent are respectively (0.2-0.4) mmol : (0.2-2.0) mmol : (2-6) mL.

[0015] (2) After monitoring the reaction to completion by TLC, the reaction solution obtained in step (1) is removed of the solvent and purified to obtain an α-amido ketone compound, whose chemical structural formula is:

[0016] Preferably, in step (1), the alkynamide is an N-alkynylpyrrolidin-2-one compound, and its chemical structural formula is:

[0017] Preferably, the alkynamide is selected from any one of Table 1.

[0018] Table 1

[0019]

[0020]

[0021] Preferably, in step (1), the reaction solvent is selected from any one of trifluoroethanol, hexafluoroisopropanol, tert-butanol, and water. Preferably, the reaction solvent is trifluoroethanol.

[0022] Preferably, in step (1), the molar volume ratios of the alkynamide, water, and reaction solvent are 0.2-0.4 mmol : 0.2-2.0 mmol : 2-6 mL.

[0023] Preferably, in step (1), the reaction temperature is any temperature in the range of 40-120 °C. Preferably, the reaction temperature is 90 °C.

[0024] The present invention further provides the α-amido ketone compounds obtained by the above preparation method.

[0025] Compared with the disadvantages and deficiencies of the prior art, the present invention has the following beneficial effects:

[0026] (1) The present method uses easily accessible alkynyl amides as raw materials, which can be obtained through commercial channels or by coupling alkynyl copper reagents with corresponding amides via carbon-nitrogen bond coupling, with low cost; and the reaction has a wide range of applicability, for example, the substrate can be various aryl- or alkyl-substituted alkynyl amides;

[0027] (2) The present method uses solvents that are inexpensive, stable, and easy to store as reaction solvents, and can be recycled in large quantities;

[0028] (3) The present method does not require the additional addition of acids, transition metal catalysts, bases, oxidants, etc., which is environmentally friendly and economical. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the compound in Example 1 of the present invention;

[0030] Figure 2 is the nuclear magnetic resonance carbon spectrum of the compound in Example 1 of the present invention

[0031] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of the compound in Example 2 of the present invention;

[0032] Figure 4 is the nuclear magnetic resonance carbon spectrum of the compound in Example 2 of the present invention;

[0033] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of the compound in Example 3 of the present invention;

[0034] Figure 6 is the nuclear magnetic resonance carbon spectrum of the compound in Example 3 of the present invention;

[0035] Figure 7 is the nuclear magnetic resonance hydrogen spectrum of the compound in Example 4 of the present invention;

[0036] Figure 8 is the nuclear magnetic resonance carbon spectrum of the compound in Example 4 of the present invention;

[0037] Figure 9 is the nuclear magnetic resonance hydrogen spectrum of the compound in Example 5 of the present invention;

[0038] Figure 10 is the nuclear magnetic resonance carbon spectrum of the compound in Example 5 of the present invention; DETAILED DESCRIPTION OF THE INVENTION

[0039] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and 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.

[0040] Example 1

[0041] (1) In a 10 mL Schlenk tube, 0.2 mmol of 1-(ferrocenylethynyl)pyrrolidin-2-one, 0.2 mmol of water, and 2 mL of trifluoroethanol were added, and the mixture was stirred and reacted at 90 °C for 6 h. The reaction equation is as follows:

[0042]

[0043] (2) After monitoring the completion of the reaction by TLC, the solvent was removed by a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a red solid compound with a yield of 99%.

[0044] The compound was characterized, and the data are as follows:

[0045] 1 H NMR (400 MHz, CDCl3) δ 4.82 (s, 2H), 4.55 (s, 2H), 4.46 (s, 2H), 4.29 (s, 5H), 3.52 (t, J = 7.0 Hz, 2H), 2.48 (t, J = 8.1 Hz, 2H), 2.17 - 2.05 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 197.9, 175.6, 76.0, 72.6, 70.2, 68.9, 49.3, 48.1, 30.4, 18.0.

[0046] The NMR spectra are as Figures 1 - 2 shown. The above characterization results indicate the compound 1-(2-oxo-2-ferrocenylethyl)pyrrolidin-2-one.

[0047] Example 2

[0048] (1) In a 10 mL Schlenk tube, 0.2 mmol of 1-(1-heptynyl)pyrrolidin-2-one, 0.4 mmol of water, and 2 mL of hexafluoroisopropanol were added, and the mixture was stirred and reacted at 90 °C for 6 h. The reaction equation is as follows:

[0049]

[0050] (2) After monitoring the completion of the reaction by TLC, the solvent was removed by a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was a petroleum ether / ethyl acetate system (5 / 1). The product was a yellow oily compound with a yield of 79%.

[0051] The compound was characterized, and the data are as follows:

[0052] 1 H NMR (400 MHz, CDCl3) δ 4.09 (s, 2H), 3.44 (t, J = 7.1 Hz, 2H), 2.48 - 2.37 (m, 4H), 2.14 - 2.02 (m, 2H), 1.66 - 1.54 (m, 2H), 1.39 - 1.21 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 205.2, 175.6, 51.7, 47.9, 39.9, 31.2, 30.2, 23.1, 22.3, 18.0, 13.8.

[0053] The NMR spectra are as shown in Figures 3 - 4 The above characterization results indicate that the compound is 1-(2-oxoheptyl)pyrrolidin-2-one.

[0054] Example 3

[0055] (1) In a 10 mL Schlenk tube, 0.2 mmol of 1-(1-decynyl)pyrrolidin-2-one, 0.6 mmol of water, and 2 mL of tert-butanol were added, and the mixture was stirred at 60 °C for 12 h. The reaction equation is:

[0056]

[0057] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was a petroleum ether / ethyl acetate system (5 / 1). The product was a yellow oily compound with a yield of 81%.

[0058] The compound was characterized, and the data are as follows:

[0059] 1 H NMR (400 MHz, CDCl3) δ 4.09 (s, 2H), 3.43 (t, J = 7.1 Hz, 2H), 2.48 - 2.37 (m, 4H), 2.14 - 2.02 (m, 2H), 1.65 - 1.53 (m, 2H), 1.27 (t, J = 4.8 Hz, 10H), 0.92 - 0.84 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 205.2, 175.5, 51.7, 47.8, 40.0, 31.7, 30.2, 29.2, 29.1, 29.0, 23.4, 22.6, 18.0, 14.0.

[0060] The NMR spectra are as shown in Figures 5 - 6As shown above, the above characterization results indicate that the compound is 1-(2-oxodecyl)pyrrolidin-2-one.

[0061] Example 4

[0062] (1) In a 10 mL Schlenk tube, 0.2 mmol of 1-(o-tolylethynyl)pyrrolidin-2-one, 0.8 mmol of water, and 2 mL of tert-butanol were added, and the mixture was stirred at 60 °C for 12 h. The reaction equation is as follows:

[0063]

[0064] (2) After monitoring the reaction to completion by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate, and the product was a colorless oily compound with a yield of 98%.

[0065] The compound was characterized, and the data are as follows:

[0066] M 1 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 7.3, 1.7 Hz, 1H), 7.41 (td, J = 7.3, 1.4 Hz, 1H), 7.32 - 7.24 (m, 2H), 4.62 (s, 2H), 3.50 (t, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.47 (t, J = 8.1 Hz, 2H), 2.16 - 2.06 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 197.1, 175.6, 139.0, 134.9, 132.2, 132.0, 128.5, 125.7, 50.7, 47.8, 30.3, 21.3, 17.9.

[0067] The NMR spectra are as Figures 7 - 8 shown above. The above characterization results indicate that the compound is 1-(2-oxo-2-(o-tolyl)ethyl)pyrrolidin-2-one.

[0068] Example 5

[0069] (1) In a 10 mL Schlenk tube, 0.2 mmol of 1-(m-tolylethynyl)pyrrolidin-2-one, 1.0 mmol of water, and 4 mL of trifluoroethanol were added, and the mixture was stirred at 40 °C for 72 h. The reaction equation is as follows:

[0070]

[0071] (2) After monitoring the reaction to completion by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate, and the product was a colorless oily compound with a yield of 96%.

[0072] The compound was characterized, and the data are as follows:

[0073] 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.69 (m, 2H), 7.48 - 7.31 (m, 2H), 4.72 (s, 2H), 3.50 (t, J = 7.0 Hz, 2H), 2.48 (t, J = 8.1 Hz, 2H), 2.41 (s, 3H), 2.17 - 2.05 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 193.9, 175.7, 138.5, 134.8, 134.4, 128.6, 128.4, 125.1, 49.0, 47.8, 30.3, 21.2, 17.9.

[0074] The NMR spectra are as Figures 9 - 10 shown. The above characterization results indicate that the compound is 1-(2-oxo-2-(m-tolyl)ethyl)pyrrolidin-2-one.

[0075] Example 6

[0076] (1) In a 10 mL Schlenk tube, 0.4 mmol of 1-(1-cyclohexenylethynyl)pyrrolidin-2-one, 2.0 mmol of water, and 6 mL of tert-butanol were added, and the mixture was stirred at 40 °C for 72 h. The reaction equation is as follows:

[0077]

[0078] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a white solid compound with a yield of 98%.

[0079] The compound was characterized, and the data are as follows:

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.00 - 6.94 (m, 1H), 4.42 (s, 2H), 3.44 (t, J = 7.1 Hz, 2H), 2.44 (t, J = 8.1 Hz, 2H), 2.31 - 2.20 (m, 4H), 2.13 - 2.04 (m, 2H), 1.69 - 1.56 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 194.1, 175.6, 141.1, 137.6, 47.9, 47.7, 30.4, 26.0, 22.8, 21.6, 21.3, 17.9.

[0081] The above characterization results indicate that the compound is 1-[2-(1-cyclohexen-1-yl)-2-oxoethyl]pyrrolidin-2-one.

[0082] Example 7

[0083] (1) In a 10 mL Schlenk tube, 0.4 mmol of 1-(2-thienylethynyl)pyrrolidin-2-one and 6 mL of water were added, and the mixture was stirred at 120 °C for 4 h. The reaction equation is as follows:

[0084]

[0085] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a yellow solid compound with a yield of 99%.

[0086] The compound was characterized, and the data are as follows:

[0087] 1 H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 3.8, 1.1 Hz, 1H), 7.69 (dd, J = 5.0, 1.1 Hz, 1H), 7.16 (dd, J = 5.0, 3.8 Hz, 1H), 4.65 (s, 2H), 3.52 (d, J = 7.1 Hz, 2H), 2.47 (d, J = 8.0 Hz, 2H), 2.19 - 2.05 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 186.9, 175.6, 141.3, 134.3, 132.5, 128.3, 49.0, 47.8, 30.3, 17.9.

[0088] The above characterization results indicate that the compound is 1-(2-oxo-2-(thienyl)ethyl)pyrrolidin-2-one.

[0089] Example 8

[0090] (1) In a 10 mL Schlenk tube, 0.3 mmol of 5-methyl-1-(phenylethynyl)pyrrolidin-2-one and 4 mL of water were added, and the mixture was stirred at 120 °C for 4 h. The reaction equation is as follows:

[0091]

[0092] (2) After monitoring the completion of the reaction by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a yellow solid compound with a yield of 85%.

[0093] The compound was characterized, and the data are as follows:

[0094] 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 5.09 (d, J = 17.6 Hz, 1H), 4.36 (d, J = 17.7 Hz, 1H), 3.95 - 3.82 (m, 1H), 2.49 (t, J = 8.0 Hz, 2H), 2.38 - 2.25 (m, 1H), 1.72 - 1.58 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 193.9, 175.6, 134.8, 133.7, 128.7, 127.9, 53.9, 46.5, 30.0, 27.0, 19.4.

[0095] The above characterization results indicate that the compound is 1-(2-oxo-2-phenylethyl)-5-methylpyrrolidin-2-one.

[0096] Example 9

[0097] (1) In a 10 mL Schlenk tube, 0.3 mmol of 4-methyl-1-(phenylethynyl)pyrrolidin-2-one, 0.3 mmol of water, and 2 mL of trifluoroethanol were added, and the mixture was stirred at 90 °C for 6 h. The reaction equation is as follows:

[0098]

[0099] (2) After monitoring the reaction to completion by TLC, the solvent was removed using a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a yellow solid compound with a yield of 92%.

[0100] The compound was characterized, and the data are as follows:

[0101] 1 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 4.82 - 4.66 (m, 2H), 3.64 - 3.56 (m, 1H), 3.15 - 3.07 (m, 1H), 2.70 - 2.47 (m, 2H), 2.19 - 2.09 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 193.9, 175.3, 134.8, 133.7, 128.8, 127.9, 55.1, 48.8, 38.8, 26.6, 19.7.

[0102] The above characterization results indicate that the compound is 1-(2-oxo-2-phenylethyl)-4-methylpyrrolidin-2-one.

[0103] Example 10

[0104] (1) In a 10 mL Schlenk tube, 0.2 mmol of 4,4-dimethyl-1-(phenylethynyl)pyrrolidin-2-one, 0.5 mmol of water, and 3 mL of hexafluoropropanol were added, and the mixture was stirred at 90 °C for 4 h. The reaction equation is as follows:

[0105]

[0106] (2) After monitoring the completion of the reaction by TLC, the solvent was removed by a rotary evaporator under vacuum, and the product was separated by column chromatography. The eluent was ethyl acetate. The product was a colorless oily compound with a yield of 85%.

[0107] The compound was characterized, and the data are as follows:

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.99 - 7.92 (m, 2H), 7.64 - 7.56 (m, 1H), 7.48 (t, J = 7.7 Hz, 2H), 4.73 (s, 2H), 3.22 (s, 2H), 2.31 (s, 2H), 1.21 (s, 6H). 13 C NMR (100 MHz, CDCl3) δ 194.0, 175.0, 134.8, 133.7, 128.8, 127.9, 60.9, 48.7, 45.6, 33.1, 27.8.

[0109] The above characterization results indicate that the compound is 1-(2-oxo-2-phenylethyl)-4,4-dimethylpyrrolidin-2-one.

[0110] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing an α-amido ketone compound, characterized in that, The method comprises the following steps: (1) Add the alkynyl amide and the additive to the reaction solvent in sequence, and stir and react for 4 to 72 hours at 40 to 120 °C to obtain a reaction solution; wherein, The chemical structural formula of the alkynyl amide is: The structural formula of the α-amido ketone compound is: (2) After monitoring the reaction to completion by TLC, filter the reaction solution obtained in step (1), remove the solvent, and purify to obtain an α-amido ketone compound; The alkynylamide is selected from any one of those in Table 1. It should be noted that the groups represented by R 1 and R 2 in the starting alkynylamide molecule correspond one by one to the groups represented by R 1 and R 2 in the product α-amido ketone compound molecule. Table 1 2. The method according to claim 1, characterized in that The additive added in step (1) is water.

3. The method according to claim 1, characterized in that, In step (1), the reaction solvent is selected from any one of trifluoroethanol, hexafluoroisopropanol, tert-butanol, and water.

4. The method according to claim 3, wherein The solvent is trifluoroethanol.

5. The method according to claim 1, wherein In step (1), the reaction temperature is any temperature in the range of 40 to 120 °C.

6. The method according to claim 5, characterized in that, The temperature is 90 °C.

7. An α-amido ketone compound obtained by the preparation method according to any one of claims 1 to 6.

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