Method for synthesizing amino acid compounds with participation of carbon dioxide

Abstract

The application discloses a synthesis method of amino acid compounds, which realizes selective synthesis of beta-amino acid and gamma-amino acid compounds under an electrochemical reaction condition by using N-methyl-N-phenyl methacrylamide as a raw material in a carbon dioxide atmosphere. Compared with a previously reported preparation method, the application has the advantages of greenness, high efficiency and good selectivity, a wide applicable range of substrates, good functional group compatibility of products, easy acquisition of raw materials and simple operation, and has a potential synthesis application prospect.

Description

Technical Field

[0001] The present invention discloses a method for synthesizing amino acid compounds. Under electrochemical conditions, N-methyl-N-phenylmethacrylamide compounds are used as raw materials, and the corresponding amino acid compounds are prepared by reacting in a carbon dioxide atmosphere at a specific temperature for 3.5 hours. Compared with previously reported preparation methods, the present invention has the advantages of being environmentally friendly, efficient, highly selective, having a wide range of substrate applicability, good compatibility of product functional groups, readily available raw materials, and simple operation. Background Art

[0002] Amino acids are the origins of life, the building blocks of proteins, and a class of organic compounds containing amino and carboxyl groups. As essential components of living organisms, amino acids are crucial for nutrition, survival, and development, playing a crucial role in regulating metabolism and transmitting information within the body. While β-amino acids are less abundant in nature than α-amino acids, this class of compounds has garnered increasing attention in recent years. β-amino acids are the synthetic precursors for many antibiotics with β-lactam structures, and some β-amino acids possess significant biological activity themselves. γ-amino acids are highly valuable compounds, widely found in pharmaceuticals and exhibiting diverse biological activities as agonists and antagonists of neurotransmitter receptors in the mammalian central nervous system.

[0003] Carbon dioxide is an ideal C1 building block in synthetic chemistry. It can be used to synthesize a variety of high-value-added products by participating in organic reactions, turning waste into treasure, which is of great significance. Through rational design, CO2 can react with a variety of cheap and readily available industrial raw materials to obtain a variety of carboxylic acid compounds through one-step method. Organic synthesis workers have invested a lot of effort in the synthesis of amino acids using CO2(T. Ju, Q. Fu, J. H. Ye, Z. Zhang, L. L. Liao, S. S. Yan, X. Y. Tian, S. P. Luo, J. Li, D. G. Yu, Angew. Chem. Int. Ed., 2018, 57, 13897-13901; X. Fan, X. Gong, M. Y. Ma, R. Wang, P. J. Walsh, Nat. Commun., 2018, 9, 4936; B. Zhang, Y. Yi, Z. Q. Wu, C. Chen, C. J. Xi, Green Chem., 2020, 22, 5961-5965; C. Zhou, M. Li, J. Sun, J. Cheng, S. Sun, Org. Lett., 2021, 23, 2895-2899; K. Zhang, X. F. Liu, W. Z. Zhang, W. M. Ren, X. B. Lu, Org. Lett., 2022, 19, 3565-3569.). But these synthesis methods are limited by the range of substrates or the need to add noble metal catalysts. We envisage that the electrochemical organic synthesis method by acrylamide and carbon dioxide (CO2) through the functionalization of olefins to obtain carboxylic acid will be an ideal way to obtain γ-amino acid or β-amino acid.

[0004] The present application provides a method for synthesizing β or γ amino acid by electrochemical carboxylation of acrylamide compounds. This method can obtain different amino acids by adjusting the electrochemical reaction conditions. The reaction conditions are mild and the reaction device is simple. The synthesized amino acid can be used as a new building block for the synthesis of 2-methyl aspartic acid, and as a precursor molecule for peptide synthesis (K. A. Brun, H. Heimgartner, Helv. Chim. Acta, 2005, 88, 2951-2959.). SUMMARY

[0005] The present application aims to provide a method for simply and conveniently preparing amino acid compounds by electrochemical method, which has the advantages of energy saving, environmental protection, easy availability of raw materials, mild and safe reaction conditions, wide adaptability, etc.

[0006] In order to achieve the above purpose, the technical scheme of the present application is as follows:

[0007] Under electrochemical conditions and in a carbon dioxide atmosphere, acrylamide 3 is electrochemically carboxylated with carbon dioxide to synthesize β-amino acid 1 or γ-amino acid 2. After the reaction, the product is separated and characterized by conventional separation and purification methods to obtain the corresponding product.

[0008]

[0009] 1. Substituted acrylamide 3 as raw material, its substituent is:

[0010] where R 1 It is one of substituted phenyl (the substituents are methyl, methoxy, phenyl, phenoxy, tert-butyl, dimethyl, fluorine, chlorine, bromine, trifluoromethyl, ester, etc.), naphthyl, and tetrahydroquinolinyl.

[0011] where R 2 It is methyl, ethyl, isopropyl, cyclohexyl, benzyl.

[0012] where R 3 is methyl or hydrogen.

[0013] where R 4 is hydrogen or methyl.

[0014] 2. The reaction solvent is one of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; among them, acetonitrile or N,N-dimethylformamide is the best.

[0015] 3. The reaction electrolyte is one of tetrabutylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium perchlorate, tetraethylammonium perchlorate, and tetrabutylammonium tetrafluoroborate; among them, tetrabutylammonium chloride or tetraethylammonium perchlorate is the best.

[0016] 4. The reaction anode material is one of magnesium, nickel, and aluminum; among them, magnesium is the best material.

[0017] 5. The cathode material is one of graphite carbon, nickel, and platinum; among them, graphite carbon is the best material.

[0018] 6. The electrochemical constant reaction current is 6-10. Among them, the optimal reaction current is 6 or 8 mA.

[0019] 7. The reaction temperature is -20-35°C, with the optimal reaction temperature being -10 or 25°C.

[0020] The present invention has the following advantages:

[0021] 1) High efficiency: The synthesis method has short reaction time and high yield;

[0022] 2) Environmental protection: Using electrochemical methods, no toxic or harmful reagents and solvents are required, and no precious metals are required;

[0023] 3) Easy to scale up: The reaction device is simple and easy to achieve industrial production;

[0024] 4) Mild conditions: The reaction conditions are mild, without the need for harsh conditions such as high temperature and high pressure;

[0025] 5) Raw materials are readily available: the raw materials used are readily available and inexpensive;

[0026] 6) Easy to operate: easy to operate and easy to realize laboratory and industrial production.

[0027] In summary, this method utilizes "electrons" as a cleaning reagent, does not require the addition of any additional oxidants or reducing agents, has mild conditions, is energy-saving and environmentally friendly, uses cheap and readily available raw materials, is simple to operate, safe and reliable, is easy to scale up, and has a high product yield. DETAILED DESCRIPTION

[0028] The following raw materials used in the examples can be prepared according to the methods in the literature (X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. S. Liu, J. Am. Chem. Soc., 2012, 134, 878-881; Z. Fang, W. Liu, N. Al-Maharik, R. Cao, Y. Huang, Y. Yuan, Q. Zhang, D. Li, J. Org. Chem., 2023, 88, 15428-15436; Y. Yuan, Y. F. Zheng, B. Z. Xu, J. P. Liao, F. X. Bu, S. C. Wang, J.-G. Hu, A. W. Lei, ACS Catal., 2020, 10, 6676-6681.)

[0029] The following examples are provided to help further understand the present invention, but the present invention is not limited thereto.

[0030] Example 1

[0031]

[0032] In a 10 mL reaction tube, N-methyl-N-phenylmethylacrylamide 4 (35.0 mg, 0.2 mmol) and tetrabutylammonium chloride (56 mg, 0.2 mmol) were added in sequence and stirred with a magnetic stirrer. The reaction tube was equipped with graphite carbon as the cathode (length 20 mm × width 10 mm × thickness 2 mm) and a magnesium sheet as the anode (length 20 mm × width 10 mm × thickness 1 mm). The anode and cathode were set opposite to each other with a distance of 10 mm, and the area of ​​the anode and cathode relative to each other in the reaction solution was 100 mm. 2A current was applied between the cathode and anode of the reaction system. The reaction tube was sealed and evacuated with carbon dioxide (alternating evacuation and refilling) three times. 3 mL of N,N-dimethylformamide was added as the solvent. The reaction tube was maintained at room temperature (25°C) and a constant current of 8 mA for 3.5 hours. After completion of the reaction, hydrochloric acid solution (2N, 2 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried over anhydrous Na2SO4, filtered, and volatile components removed under reduced pressure to obtain the crude product. This was then separated by silica gel column chromatography (eluent: petroleum ether (60-90°C) / ethyl acetate / acetic acid, v / v / v linear gradient = 8:1:1‰ to 2:1:1‰) to afford the desired product 5 (31.1 mg, 70% yield) as a white solid.

[0033] 1 H NMR (600MHz, DMSO) δ12.03(s,1H),7.47(t,J=7.7Hz,2H),7.39(d,J=7.7Hz,2H),7.36(d,J=7.3Hz,1H),3.13( s,3H),2.70-2.74(m,1H),2.56(dd,J=16.7,9.2Hz,1H),2.16(dd,J=16.7,5.3Hz,1H),0.85(d,J=6.9Hz,3H). 13 C NMR(151MHz,DMSO)δ174.33,173.11,143.79,129.61,127.61,127.55,37.81,37.01,32.23,17.34.HRMS(ESI-MS)m / z:[M+H + ]calculate for C12H16NO3222.1125; Found 222.1126.

[0034] Application Example 1

[0035] The product 5 obtained in Example 1 can react with ZL-valine to synthesize a polypeptide (KABrun, H. Heimgartner, Helv. Chim. Acta, 2005, 88, 2951-2959).

[0036]

[0037] Example 2

[0038] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that the reaction was carried out without power. The reaction was stopped, and no target product 5 was obtained after post-processing, indicating that the reaction could not proceed without power.

[0039] Example 3

[0040] The reaction procedure and operation (process and conditions) were the same as those of Example 1 for the preparation of product 5, except that the reaction solvent was acetonitrile. The reaction was stopped and the target product 5 (18.6 mg, yield 42%) was obtained after work-up. It was indicated that acetonitrile was not suitable for the reaction.

[0041] Example 4

[0042] The reaction procedure and operation (process and conditions) were the same as those of Example 1 for the preparation of product 5, except that the reaction temperature was -10 °C. The reaction was stopped and the target product 5 (8.0 mg, yield 18%) was obtained after work-up. It was indicated that the reaction temperature was not suitable for the reaction.

[0043] Example 5

[0044] The reaction procedure and operation (process and conditions) were the same as those of Example 1 for the preparation of product 5, except that tetrabutylammonium perchlorate (same amount of substance as tetrabutylammonium chloride, instead of tetrabutylammonium chloride) was added as an electrolyte in the reaction. The reaction was stopped and the target product 5 (19.5 mg, yield 44%) was obtained after work-up. It was indicated that tetrabutylammonium perchlorate was not suitable for the reaction.

[0045] Example 6

[0046]

[0047] The reaction procedure and operation (process and conditions) were the same as those of Example 1 for the preparation of product 5, except that N-methyl-N-(p-methylphenyl)methyl acrylamide 6 (37.9 mg, 0.2 mmol) was added in the reaction system. The reaction was stopped and the target product 7 (31.6 mg, yield 67%) was obtained as a colorless liquid after work-up. The target product was confirmed by 1H NMR, 13C NMR and high resolution mass spectrometry.

[0048] Example 7

[0049]

[0050] In a 10 mL reaction tube, N-methyl-N-phenylmethyl acrylamide 8 (35.0 mg, 0.2 mmol), tetrabutylammonium chloride (56 mg, 0.2 mmol), a stirring magnet and a reaction tube equipped with graphite carbon as a cathode (20 mm long x 10 mm wide x 2 mm thick) and magnesium sheet as an anode (20 mm long x 10 mm wide x 1 mm thick) were sequentially added. The anode and the cathode were oppositely arranged with a distance of 10 mm, and the area of the oppositely arranged surfaces of the anode and the cathode in the reaction liquid was 100 mm2. The reaction was carried out at room temperature for 24 h. The reaction was stopped and the target product 5 (19.5 mg, yield 44%) was obtained after work-up. 2A current was applied between the cathode and anode of the reaction system. The reaction tube was sealed and evacuated with carbon dioxide (alternating evacuation and refilling) three times. 3 mL of N,N-dimethylformamide was added as the solvent. The reaction tube was maintained at room temperature (25°C) and a constant current of 8 mA for 3.5 hours. After completion of the reaction, hydrochloric acid solution (2N, 2 mL) was added and extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried over anhydrous Na2SO4, filtered, and volatile components removed under reduced pressure to obtain the crude product. Ether / methanol (v / v = 1 / 1, 2 mL) was added, and trimethylsilylated diazomethane (2 mol / L in n-hexane, 0.5 mL) was added with stirring at 0°C. The mixture was stirred for 30 minutes. The volatile components were removed under reduced pressure, and then the product was separated by silica gel column chromatography (eluent: petroleum ether (60-90°C) / ethyl acetate, v / v = 10 / 1 to 5 / 1 linear gradient) to obtain the desired product 9 as a colorless oil (29.5 mg, 59% yield). The target product was confirmed by hydrogen nuclear magnetic resonance spectroscopy, carbon nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry.

[0051] Example 8

[0052]

[0053] The reaction steps and operations (process and conditions) were the same as those for preparing product 9 in Example 7, except that N-methyl-N-(o-methylphenyl)methacrylamide 10 (37.9 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 11 as a colorless oil (32.2 mg, 65% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0054] Example 9

[0055]

[0056] The reaction steps and operations (process and conditions) were the same as those for preparing product 9 in Example 7, except that N-methyl-N-(p-methoxyphenyl)methacrylamide 12 (41.1 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 13 as a colorless oil (34.1 mg, 64% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0057] Example 10

[0058]

[0059] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-phenoxyphenyl)methacrylamide 14 (53.5 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 15 as a colorless oil (45.3 mg, 72% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0060] Example 11

[0061]

[0062] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-phenoxyphenyl)methacrylamide 16 (50.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 17 as a white solid (43.5 mg, 73% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0063] Example 12

[0064]

[0065] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-tert-butylphenyl)methacrylamide 18 (46.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 19 as a white solid (37.9 mg, 68% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0066] Example 13

[0067]

[0068] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(3,5-dimethylphenyl)methyl acrylamide 20 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 21 as a white solid (45.0 mg, 90% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0069] Example 14

[0070]

[0071] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-fluorophenyl)methacrylamide 22 (38.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 23 as a white solid (25.0 mg, 52% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0072] Example 15

[0073]

[0074] The reaction steps and operations (process and conditions) were the same as those for preparing product 9 in Example 7, except that N-methyl-N-(p-bromophenyl)methacrylamide 24 (50.8 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 25 as a colorless oil (40.5 mg, 64% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0075] Example 16

[0076]

[0077] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-trifluoromethylphenyl)methacrylamide 26 (48.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 27 as a white solid (37.3 mg, 65% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0078] Example 17

[0079]

[0080] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-(p-methylformylphenyl)methacrylamide 28 (46.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 39 as a colorless oil (17.6 mg, 32% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0081] Example 18

[0082]

[0083] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-methyl-N-naphthylmethacrylamide 30 (45.1 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 31 as a colorless oil (40.9 mg, 75% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0084] Example 19

[0085]

[0086] The reaction steps and operations (process and conditions) were the same as those used in Example 7 to prepare product 9, except that 1-(3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2-propen-1-one 32 (40.1 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 33 as a colorless oil (27.7 mg, 53% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0087] Example 20

[0088]

[0089] The reaction steps and operations (process and conditions) were the same as those for preparing product 9 in Example 7, except that N-ethyl-N-phenylmethylacrylamide 34 (37.9 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 35 as a colorless oil (37.0 mg, 74% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0090] Example 21

[0091]

[0092] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-isopropyl-N-phenylmethylacrylamide 36 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 37 as a white solid (35.3 mg, 71% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0093] Example 22

[0094]

[0095] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-cyclohexyl-N-phenylmethyl acrylamide 38 (48.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 39 as a white solid (40.9 mg, 71% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0096] Example 23

[0097]

[0098] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-benzyl-N-phenylmethylacrylamide 40 (50.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 41 as a white solid (56.7 mg, 95% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0099] Example 24

[0100]

[0101] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-benzoyl-N-methylmethacrylamide 42 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 43 as a white solid (24.5 mg, 49% yield). The target product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0102] Example 25

[0103]

[0104] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-(p-methoxybenzoyl)-N-methylmethacrylamide 44 (46.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 45 as a colorless oil (26.3 mg, 47% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0105] Example 26

[0106]

[0107] The reaction steps and operations (process and conditions) were the same as those for preparing product 5 in Example 1, except that N-benzoyl-N-isopropylmethacrylamide 46 (46.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 47 as a colorless oil (25.5 mg, 46% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0108] Example 27

[0109]

[0110] In a 10 mL reaction tube, N-methyl-N-phenylmethylacrylamide 4 (17.6 mg, 0.1 mmol) and tetraethylammonium perchlorate (46 mg, 0.2 mmol) were added in sequence and stirred with a magnetic stirrer. The reaction tube was equipped with graphite carbon as the cathode (20 mm long × 10 mm wide × 2 mm thick) and a magnesium sheet as the anode (20 mm long × 10 mm wide × 1 mm thick). The anode and cathode were set opposite to each other with a distance of 10 mm, and the area of ​​the anode and cathode facing each other in the reaction solution was 100 mm. 2 A current was applied between the cathode and anode of the reaction system. The reaction tube was sealed and evacuated with carbon dioxide (alternating evacuation and refilling) three times, and 3 mL of acetonitrile was added as the solvent. The reaction tube was maintained at -10°C and a constant current of 6 mA for 3.5 hours. After the reaction, hydrochloric acid solution (2N, 2 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the volatile components removed under reduced pressure to obtain the crude product. This was then separated by silica gel column chromatography (eluent: petroleum ether (60-90°C) / ethyl acetate / acetic acid, v / v / v gradient = 6:1:1‰ to 2:1:1‰) to obtain the desired product 48 as a white solid (25.5 mg, 70% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0111] 1 H NMR (600MHz, CDCl3) δ7.31-7.32(m,3H),7.22-7.24(m,2H),3.26(s,3H),1.39(s,6H). 13 C NMR(151MHz, CDCl3)δ179.93,171.71,129.41,50.11,40.41,25.21.HRMS(ESI-MS)m / z:[M+H + ]calculate for C12H16NO3 222.1125; Found222.1129.

[0112] Example 28

[0113]

[0114] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-methylphenyl)methacrylamide 6 (19.0 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 49 as a white solid (19.1 mg, 81% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0115] Example 29

[0116]

[0117] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(m-methylphenyl)methacrylamide 8 (19.0 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 50 as a white solid (15.3 mg, 65% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0118] Example 30

[0119]

[0120] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-methoxyphenyl)methacrylamide 12 (20.6 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 51 as a white solid (17.4 mg, 69% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0121] Example 31

[0122]

[0123] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-phenoxyphenyl)methacrylamide 14 (26.8 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 52 as a colorless oil (22.0 mg, 70% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0124] Example 32

[0125]

[0126] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-phenoxyphenyl)methacrylamide 16 (25.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 53 as a white solid (23.2 mg, 78% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0127] Example 33

[0128]

[0129] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-tert-butylphenyl)methacrylamide 18 (23.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 54 as a white solid (24.2 mg, 87% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0130] Example 34

[0131]

[0132] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(3,5-dimethylphenyl)methyl acrylamide 20 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 55 as a white solid (13.5 mg, 54% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0133] Example 35

[0134]

[0135] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-fluorophenyl)methacrylamide 22 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 56 as a white solid (14.1 mg, 59% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0136] Example 36

[0137]

[0138] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-chlorophenyl)methacrylamide 57 (21.0 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 58 as a white solid (15.3 mg, 60% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0139] Example 37

[0140]

[0141] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-methyl-N-(p-bromophenyl)methacrylamide 24 (25.5 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 59 as a white solid (17.4 mg, 58% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0142] Example 38

[0143]

[0144] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-trifluoromethylphenyl)methacrylamide 26 (24.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 60 as a white solid (11.6 mg, 40% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0145] Example 39

[0146]

[0147] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-methylformylphenyl)methacrylamide 28 (23.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 61 as a white solid (13.7 mg, 49% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0148] Example 40

[0149]

[0150] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-methyl-N-naphthylmethacrylamide 30 (22.6 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 62 as a white solid (14.1 mg, 52% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0151] Example 41

[0152]

[0153] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that 1-(3,4-dihydroquinolin-1(2H)-yl)-2-methyl-2-propen-1-one 32 (20.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 63 as a white solid (18.1 mg, 73% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0154] Example 42

[0155]

[0156] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-isopropyl-N-phenylmethylacrylamide 36 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 64 as a white solid (22.0 mg, 88% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0157] Example 43

[0158]

[0159] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-cyclohexyl-N-phenylmethyl acrylamide 38 (24.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 65 as a white solid (15.7 mg, 54% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0160] Example 44

[0161]

[0162] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that N-benzyl-N-phenylmethylacrylamide 40 (25.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped, and post-processing afforded the desired product 66 as a white solid (21.7 mg, 73% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0163] Example 45

[0164]

[0165] The reaction steps and procedures (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-(p-methoxyphenyl)methyl acrylamide 67 (19.2 mg, 0.1 mmol) was added to the reaction system and a constant current of 10 mA was used. The reaction was terminated and post-processed to obtain the desired product 68 as a colorless oil (9.5 mg, 40% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0166] Example 46

[0167]

[0168] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that N-(p-methylphenyl)acrylamide 69 (16.2 mg, 0.1 mmol) was added to the reaction system and a constant current of 10 mA was used. The reaction was terminated and post-processed to obtain the desired product 70 as a white solid (15.5 mg, 75% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0169] Example 47

[0170]

[0171] The reaction steps and procedures (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2,3-diphenyl-N-(methacryloyl)indole 71 (33.8 mg, 0.1 mmol) was added to the reaction system and a constant current of 4 mA was used. The reaction was terminated and post-processed to obtain the desired product 72 as a colorless oil (28.4 mg, 74% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0172] Example 48

[0173]

[0174] The reaction steps and operation (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2,3-diphenyl-5-methyl-N-(methacryloyl)indole 73 (35.2 mg, 0.1 mmol) was added to the reaction system and a constant current of 4 mA was used. The reaction was terminated and post-processed to obtain the desired product 74 as a colorless oil (17.9 mg, 45% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0175] Example 49

[0176]

[0177] The reaction steps and procedures (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2,3-diphenyl-4,6-dimethyl-N-(methacryloyl)indole 75 (36.6 mg, 0.1 mmol) was added to the reaction system and a constant current of 4 mA was used. The reaction was terminated and post-processed to obtain the desired product 76 as a colorless oil (20.6 mg, 50% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0178] Example 50

[0179]

[0180] The reaction steps and procedures (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2,3-diphenyl-5-fluoro-N-(methacryloyl)indole 77 (35.6 mg, 0.1 mmol) was added to the reaction system and a constant current of 4 mA was used. The reaction was terminated and post-processed to obtain the desired product 78 as a colorless oil (14.1 mg, 35% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0181] Example 51

[0182]

[0183] The reaction steps and operation (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2,3-diphenyl-5-chloro-N-(methacryloyl)indole 79 (37.2 mg, 0.1 mmol) was added to the reaction system, and a constant current of 4 mA was used. The reaction was terminated, and post-processing afforded the desired product 80 as a white solid (12.5 mg, 30% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

[0184] Example 52

[0185]

[0186] The reaction steps and operations (process and conditions) were the same as those for preparing product 48 in Example 27, except that 2-phenyl-N-(methacryloyl)indole 81 (26.2 mg, 0.1 mmol) was added to the reaction system and a constant current of 4 mA was used. The reaction was terminated and post-processed to obtain the desired product 82 as a white solid (14.8 mg, 48% yield). The desired product was confirmed by H NMR, C NMR, and high-resolution mass spectrometry.

Claims

1. A method for synthesizing an amino acid compound, characterized in that: Using substituted acrylamide 3 as raw material, it reacts with carbon dioxide under electrocatalytic conditions to generate amino acid compounds 1 or 2; the synthetic route is as follows ; where R 1 is phenyl, substituted phenyl, naphthyl, or benzoyl, and the substituent on the substituted phenyl is one or more of methyl, methoxy, phenyl, phenoxy, tert-butyl, fluorine, chlorine, bromine, trifluoromethyl, and methyl formate; R 2 is hydrogen, methyl, ethyl, isopropyl, cyclohexyl, or benzyl; R 3 is hydrogen or methyl; R 4 is hydrogen; the electrocatalytic conditions are: the anode material is magnesium; the cathode material is graphite carbon; The reaction electrolyte is tetraethylammonium perchlorate or tetrabutylammonium chloride; the electrochemical constant reaction current density is 4-10 mA, and the reaction time is 3.5-6 hours.

2. The synthesis method according to claim 1, characterized in that: The reaction solvent is acetonitrile, N , N -dimethylformamide, dimethyl sulfoxide, N -methylpyrrolidone, The reaction temperature is -10°C-35°C, the reaction atmosphere is carbon dioxide, and after the reaction is completed, the product is separated and purified to obtain amino acid compound 1 or 2.

3. The synthesis method according to claim 1, wherein: When amino acid compound 1 is obtained, the reaction solvent is acetonitrile, the temperature range is -10°C to room temperature, and the electrolyte is tetraethylammonium perchlorate; In the amino acid compound 1, R 1 is phenyl, substituted phenyl, or naphthyl, and the substituent on the substituted phenyl is one of methyl, phenyl, and phenoxy; R 2 is methyl, ethyl, isopropyl, cyclohexyl or benzyl; R 3 is hydrogen or methyl.

4. The synthesis method according to claim 1, characterized in that: When obtaining amino acid compound 2, the reaction solvent is N , N -Dimethylformamide, temperature range -10℃-35℃; In the amino acid compound 2, R 1 is phenyl, substituted phenyl, naphthyl, or benzoyl, and the substituent on the substituted phenyl is one or more of methyl, phenyl, and tert-butyl; R 2 is hydrogen, methyl, isopropyl, benzyl; R 3 is hydrogen or methyl; R 4 For hydrogen.

5. The synthesis method according to claim 4, characterized in that: The synthesis process of amino acid compound 2 is as follows: In a reaction tube, add N -methyl- N -phenylmethylacrylamide, tetrabutylammonium chloride, the reaction tube is equipped with graphite carbon as the cathode and magnesium sheet as the anode, and current is applied between the cathode and the anode; the reaction tube is sealed and filled with carbon dioxide, and then added N,N -dimethylformamide was used as solvent, and the reaction tube was reacted at room temperature under constant current for 3.5 hours. After the reaction, hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was back-extracted with saturated brine, dried, filtered, and the volatile components were removed under reduced pressure to obtain a crude product, which was then separated by silica gel column chromatography to obtain the target product.

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The reaction is carried out in a reaction vessel provided with a cathode and an anode. The anode and the cathode are arranged opposite to each other with a distance of 8-12 mm. Part or all of the cathode and the anode are placed in the reaction solution of the reaction system, and the area of ​​the relative surface of the anode and the cathode placed in the reaction solution is 80-100 mm. 2 ; Apply current between the cathode and anode in the reaction system.

7. The synthesis method according to any one of claims 1 to 5, characterized in that: The current of the reaction is 6-8 mA.

Images