Method for synthesizing amino acid compounds with participation of carbon dioxide

Abstract

The invention discloses a synthesis method of amino acid compounds, which is characterized in that under electrochemical reaction conditions, N-methyl-N-phenyl methacrylamide is used as a raw material, and selective synthesis of beta-amino acid and gamma-amino acid compounds is realized in a carbon dioxide atmosphere. Compared with a previously reported preparation method, the method has the advantages of greenness, high efficiency and good selectivity, the substrate application range is wide, the product functional group compatibility is good, raw materials are easy to obtain, operation is easy and convenient, and potential synthesis application prospects are achieved.

Description

Technical Field

[0001] The invention discloses a method for synthesizing amino acid compounds. Under electrochemical conditions, N-methyl-N-phenylmethyl acrylamide compounds are used as raw materials, and reacted in a carbon dioxide atmosphere for 3.5 hours under certain temperature conditions to prepare corresponding amino acid compounds. Compared with the reported preparation methods, the invention has the advantages of being green, efficient, having good selectivity, having a wide range of substrate applications, having good compatibility of product functional groups, being easy to obtain raw materials, and being simple to operate. Background Art

[0002] Amino acids are the origin of life, the basic unit of protein, and a class of organic compounds with amino and carboxyl groups in their molecules. As an important component of living organisms, amino acids are extremely important substances for the nutrition, survival and development of living organisms, and play an important role in the regulation of material metabolism and information transmission in living organisms. Compared with α-amino acids, β-amino acids are less common in nature, but this type of compound has received more and more attention in recent years. β-amino acids are the synthetic precursors of many antibiotics with β-lactam structures, and some β-amino acids themselves have important biological activities. γ-amino acids are very valuable compounds that are widely present in drugs and exhibit a variety of biological activities as agonists and antagonists of neurotransmitter receptors in the central nervous system of mammals.

[0003] Carbon dioxide is an ideal C1 synthon in synthetic chemistry. Using CO2 to participate in organic reactions can synthesize a variety of high value-added products, turning waste into treasure, which is of great significance. Through reasonable design, CO2 can react with many cheap and readily available industrial raw materials to obtain carboxylic acid compounds with diverse structures in a one-step method. Organic synthesizers have invested a lot of energy in using CO2 to synthesize amino acids (T.Ju, Q.Fu, JHYe, Z.Zhang, LLLiao, SSYan, XYTian, ​​SPLuo, J.Li, DGYu, Angew.Chem.Int.Ed., 2018, 57, 13897-13901; X.Fan, X.Gong, MYMa, R.Wang, PJWalsh, Nat.Commun., 2018, 9, 4936; B.Zhang, Y.Yi, ZQWu, C.Chen, CJXi, 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.). However, these synthetic methods are limited in the substrate range or require the addition of precious metal catalysts. We envision that the electrochemical organic synthesis method of acrylamide and carbon dioxide (CO2) through the functionalization of olefins to obtain carboxylic acids will become an ideal way to obtain γ-amino acids or β-amino acids.

[0004] The present invention provides a highly efficient, environmentally friendly and easily scalable method for synthesizing β or γ amino acids by electrochemical carboxylation of acrylamide compounds. The method can obtain different amino acids simply by adjusting the electroreaction conditions. The reaction conditions are mild and the reaction device is simple. The synthesized amino acids can be used as a new building block for the synthesis of 2-methylaspartic acid and as precursor molecules for peptide synthesis (KA Brun, H. Heimgartner, Helv. Chim. Acta, 2005, 88, 2951-2959.). Summary of the invention

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

[0006] In order to achieve the above object, the technical solution of the present invention is as follows:

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

[0008]

[0009] 1. Substituted acrylamide 3 as raw material, the 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 Methyl or hydrogen.

[0013] Where R 4 It 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, the best is tetrabutylammonium chloride or tetraethylammonium perchlorate.

[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 of the reaction is one of graphite carbon, nickel and platinum; among them, the best material is graphite carbon.

[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, and the best reaction temperature is -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: It uses electrochemical methods, without the need to use toxic and harmful reagents and solvents, and without the involvement of precious metals;

[0023] 3) Easy to scale up: The reaction device is simple and easy to realize 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 easily available and inexpensive;

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

[0027] In short, this method utilizes "electrons" as a cleaning agent, does not require the addition of any additional oxidants or reductants, has mild conditions, is energy-saving and environmentally friendly, uses cheap and readily available raw materials, is simple to operate, safe and reliable, can be easily scaled up, and has a high product yield. DETAILED DESCRIPTION

[0028] The following raw materials used in the examples can be prepared according to the reference methods (X.Mu, T.Wu, H.-Y.Wang, Y.-L.Guo, GSLiu, 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, YFZheng, BZXu, JPLiao, FXBu, SCWang, J.-G.Hu, AWLei, ACS Catal., 2020, 10, 6676-6681.)

[0029] The following examples are helpful to further understand the present invention, but the contents of the present invention are not limited thereto.

[0030] Example 1

[0031]

[0032] In a 10 mL reaction tube, N-methyl-N-phenylmethyl acrylamide 4 (35.0 mg, 0.2 mmol) and tetrabutylammonium chloride (56 mg, 0.2 mmol) were added in sequence, and a magnetic stirrer was used. The reaction tube was equipped with graphite carbon as a cathode (length 20 mm × width 10 mm × thickness 2 mm) and a magnesium sheet as an 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 relative surface of the anode and cathode placed in the reaction solution was 100 mm. 2, apply current between the cathode and the anode in the reaction system. After the reaction tube is sealed, it is evacuated and filled with carbon dioxide (evacuation-filling alternately) 3 times, and 3mL N,N-dimethylformamide is added as solvent. The reaction tube is kept at room temperature 25°C and a constant current of 8mA for 3.5h. After the reaction is completed, hydrochloric acid solution (2N, 2mL) is added, extracted with ethyl acetate, the organic layer is back-extracted with saturated brine, dried with anhydrous Na2SO4, filtered, and the volatile components are removed under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography (eluent is petroleum ether (60-90°C) / ethyl acetate / acetic acid, v / v / v=8:1:1‰ to 2:1:1‰ linear gradient change), to obtain the target product 5 as a white solid (31.1mg, yield 70%).

[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 (KA Brun, H. Heimgartner, Helv. Chim. Acta, 2005, 88, 2951-2959).

[0036]

[0037] Example 2

[0038] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5, except that the reaction is carried out without power supply. The reaction is stopped, and the target product 5 is not obtained after post-treatment, indicating that the reaction cannot be carried out without power supply.

[0039] Example 3

[0040] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5, except that the reaction solvent is acetonitrile. The reaction is stopped and the target product 5 (18.6 mg, yield 42%) is obtained by post-treatment. This indicates that acetonitrile as a solvent is not conducive to the reaction.

[0041] Example 4

[0042] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing 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 post-treatment. This indicates that lowering the reaction temperature is not conducive to the reaction.

[0043] Example 5

[0044] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5. The difference from Example 1 is that tetrabutylammonium perchlorate (the same amount of substance as tetrabutylammonium chloride, replacing tetrabutylammonium chloride) is added as electrolyte in the reaction. The reaction is stopped and the target product 5 (19.5 mg, yield 44%) is obtained after post-treatment. This indicates that tetrabutylammonium perchlorate is not conducive to the reaction.

[0045] Example 6

[0046]

[0047] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5, except that the raw material added to the reaction system is N-methyl-N-(p-methylbenzyl)methyl acrylamide 6 (37.9 mg, 0.2 mmol). The reaction is stopped and the target product 7 (31.6 mg, yield 67%) is obtained by post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0048] Example 7

[0049]

[0050] In a 10 mL reaction tube, N-methyl-N-phenylmethyl acrylamide 8 (35.0 mg, 0.2 mmol) and tetrabutylammonium chloride (56 mg, 0.2 mmol) were added in sequence, and a magnetic stirrer was used. The reaction tube was equipped with graphite carbon as a cathode (length 20 mm × width 10 mm × thickness 2 mm) and a magnesium sheet as an 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 relative surface of the anode and cathode placed in the reaction solution was 100 mm. 2, apply current between the cathode and the anode in the reaction system. After the reaction tube is sealed, it is evacuated and filled with carbon dioxide (evacuation-filling alternately) 3 times, and 3 mL of N, N-dimethylformamide is added as solvent. The reaction tube is kept at room temperature 25°C and a constant current of 8 mA for 3.5 hours. After the reaction is completed, hydrochloric acid solution (2N, 2 mL) is added, extracted with ethyl acetate, the organic layer is back-extracted with saturated brine, dried with anhydrous Na2SO4, filtered, and the volatile components are removed under reduced pressure to obtain a crude product, ether / methanol (v / v=1 / 1, 2 mL) is added, trimethylsilylated diazomethane (2 mol / L n-hexane solution, 0.5 mL) is added at 0°C and stirred for 30 minutes, and the volatile components are removed under reduced pressure, and then separated by silica gel column chromatography (eluent is petroleum ether (60-90°C) / ethyl acetate, v / v=10 / 1 to 5 / 1 linear gradient change) to obtain a colorless oily target product 9 (29.5 mg, yield 59%). 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 in Example 7 for preparing product 9, except that N-methyl-N-(o-methylbenzyl)methyl acrylamide 10 (37.9 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 11 (32.2 mg, 65% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0054] Example 9

[0055]

[0056] The reaction steps and operations (process and conditions) were the same as those in Example 7 for preparing product 9, except that N-methyl-N-(p-methoxyphenyl)methyl acrylamide 12 (41.1 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 13 (34.1 mg, 64% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0057] Example 10

[0058]

[0059] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-(p-phenoxybenzene)methyl acrylamide 14 (53.5 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 15 (45.3 mg, 72% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0060] Embodiment 11

[0061]

[0062] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-(p-phenoxybenzene) methacrylamide 16 (50.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 17 (43.5 mg, yield 73%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0063] Example 12

[0064]

[0065] The reaction steps and operations (process and conditions) are the same as those of Example 1 for preparing product 5, except that N-methyl-N-(p-tert-butylbenzene) methacrylamide 18 (46.3 mg, 0.2 mmol) is added to the reaction system. The reaction is stopped and the target product 19 (37.9 mg, yield 68%) is obtained by post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0066] Example 13

[0067]

[0068] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-(3,5-dimethylbenzyl)methyl acrylamide 20 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 21 (45.0 mg, yield 90%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0069] Embodiment 14

[0070]

[0071] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-(p-fluorophenyl)methyl acrylamide 22 (38.6 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 23 (25.0 mg, yield 52%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0072] Embodiment 15

[0073]

[0074] The reaction steps and operations (process and conditions) were the same as those in Example 7 for preparing product 9, except that N-methyl-N-(p-bromobenzene)methyl acrylamide 24 (50.8 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 25 (40.5 mg, 64% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0075] Example 16

[0076]

[0077] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-(p-trifluoromethylbenzene)methyl acrylamide 26 (48.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 27 (37.3 mg, yield 65%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0078] Embodiment 17

[0079]

[0080] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5, except that N-methyl-N-(p-methylformylbenzene)methylacrylamide 28 (46.7 mg, 0.2 mmol) is added to the reaction system. The reaction is stopped and the target product 39 (17.6 mg, 32% yield) is obtained as a colorless oil after post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0081] Embodiment 18

[0082]

[0083] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-methyl-N-naphthylmethyl acrylamide 30 (45.1 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 31 (40.9 mg, yield 75%) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0084] Embodiment 19

[0085]

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

[0087] Embodiment 20

[0088]

[0089] The reaction steps and operations (process and conditions) were the same as those in Example 7 for preparing product 9, except that N-ethyl-N-phenylmethyl acrylamide 34 (37.9 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 35 (37.0 mg, yield 74%) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic spectrum and high-resolution mass spectrum.

[0090] Embodiment 21

[0091]

[0092] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-isopropyl-N-phenylmethyl acrylamide 36 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 37 (35.3 mg, yield 71%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0093] Embodiment 22

[0094]

[0095] The reaction steps and operations (process and conditions) are the same as those in Example 1 for preparing product 5, except that N-cyclohexyl-N-phenylmethyl acrylamide 38 (48.7 mg, 0.2 mmol) is added to the reaction system. The reaction is stopped and the target product 39 (40.9 mg, yield 71%) is obtained by post-treatment as a white solid. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0096] Embodiment 23

[0097]

[0098] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-benzyl-N-phenylmethyl acrylamide 40 (50.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 41 (56.7 mg, yield 95%) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0099] Embodiment 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-methylmethylacrylamide 42 (40.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 43 (24.5 mg, 49% yield) was obtained after post-treatment as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0102] Embodiment 25

[0103]

[0104] The reaction steps and operations (process and conditions) were the same as those in Example 1 for preparing product 5, except that N-(p-methoxybenzoyl)-N-methylmethylacrylamide 44 (46.7 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 45 (26.3 mg, 47% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0105] Embodiment 26

[0106]

[0107] 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-isopropylmethacrylamide 46 (46.3 mg, 0.2 mmol) was added to the reaction system. The reaction was stopped and the target product 47 (25.5 mg, 46% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0108] Embodiment 27

[0109]

[0110] In a 10 mL reaction tube, N-methyl-N-phenylmethyl acrylamide 4 (17.6 mg, 0.1 mmol) and tetraethylammonium perchlorate (46 mg, 0.2 mmol) were added in sequence, and a magnetic stirrer was used. The reaction tube was equipped with graphite carbon as a cathode (20 mm long × 10 mm wide × 2 mm thick) and a magnesium sheet as an 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 relative surface of the anode and cathode placed in the reaction solution was 100 mm. 2 , apply current between the cathode and anode in the reaction system. After the reaction tube is sealed, it is evacuated and filled with carbon dioxide (evacuation-filling alternately) 3 times, and 3 mL of acetonitrile is added as solvent. The reaction tube is kept at -10°C and a constant current of 6 mA for 3.5 hours. After the reaction is completed, hydrochloric acid solution (2N, 2 mL) is added, extracted with ethyl acetate, the organic layer is back-extracted with saturated brine, dried with anhydrous Na2SO4, filtered, and the volatile components are removed under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography (eluent is petroleum ether (60-90°C) / ethyl acetate / acetic acid, v / v / v=6:1:1‰ to 2:1:1‰ gradient change), to obtain a white solid target product 48 (25.5 mg, yield 70%). The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic spectrum 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] Embodiment 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-methylbenzyl)methyl acrylamide 6 (19.0 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 49 (19.1 mg, yield 81%) as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0115] Embodiment 29

[0116]

[0117] The reaction steps and operations (process and conditions) are the same as those in Example 27 for preparing product 48, except that N-methyl-N-(m-methylbenzyl)methyl acrylamide 8 (19.0 mg, 0.1 mmol) is added to the reaction system. The reaction is stopped and the target product 50 (15.3 mg, 65% yield) is obtained by post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0118] Embodiment 30

[0119]

[0120] 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-methoxyphenyl)methyl acrylamide 12 (20.6 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and the target product 51 (17.4 mg, yield 69%) was obtained by post-treatment as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0121] Embodiment 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-phenoxybenzene)methyl acrylamide 14 (26.8 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and the target product 52 (22.0 mg, 70% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0124] Embodiment 32

[0125]

[0126] 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-phenoxybenzene)methacrylamide 16 (25.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and the target product 53 (23.2 mg, yield 78%) was obtained by post-treatment as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0127] Embodiment 33

[0128]

[0129] 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-tert-butylbenzene)methyl acrylamide 18 (23.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 54 (24.2 mg, yield 87%) as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0130] Embodiment 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-dimethylbenzyl)methyl acrylamide 20 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 55 (13.5 mg, yield 54%) as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0133] Embodiment 35

[0134]

[0135] 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-fluorophenyl)methyl acrylamide 22 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 56 (14.1 mg, yield 59%) as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0136] Embodiment 36

[0137]

[0138] The reaction steps and operations (process and conditions) are the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-chlorobenzene)methyl acrylamide 57 (21.0 mg, 0.1 mmol) is added to the reaction system. The reaction is stopped and the target product 58 (15.3 mg, yield 60%) is obtained by post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0139] Embodiment 37

[0140]

[0141] 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-bromobenzene)methyl acrylamide 24 (25.5 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 59 (17.4 mg, yield 58%) as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0142] Embodiment 38

[0143]

[0144] The reaction steps and operations (process and conditions) are the same as those in Example 27 for preparing product 48, except that N-methyl-N-(p-trifluoromethylbenzene)methyl acrylamide 26 (24.4 mg, 0.1 mmol) is added to the reaction system. The reaction is stopped and the target product 60 (11.6 mg, 40% yield) is obtained by post-treatment. The target product is confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0145] Embodiment 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-methylformylbenzene)methylacrylamide 28 (23.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 61 (13.7 mg, yield 49%) as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0148] Embodiment 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-naphthylmethyl acrylamide 30 (22.6 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and the target product 62 (14.1 mg, 52% yield) was obtained by post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0151] Embodiment 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-propene-1-one 32 (20.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and the target product 63 (18.1 mg, 73% yield) was obtained by post-treatment as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0154] Embodiment 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-phenylmethyl acrylamide 36 (20.4 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 64 (22.0 mg, yield 88%) as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0157] Embodiment 43

[0158]

[0159] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, 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 the target product 65 (15.7 mg, 54% yield) was obtained by post-treatment. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0160] Embodiment 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-phenylmethyl acrylamide 40 (25.2 mg, 0.1 mmol) was added to the reaction system. The reaction was stopped and post-treated to obtain the target product 66 (21.7 mg, yield 73%) as a white solid. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0163] Embodiment 45

[0164]

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

[0166] Embodiment 46

[0167]

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

[0169] Embodiment 47

[0170]

[0171] The reaction steps and operations (process and conditions) were the same as those of Example 27 for preparing product 48, except that 2,3-diphenyl-N-(methacryloyl)indole 71 (33.8 mg, 0.1 mmol) was added to the reaction system, and the constant current was 4 mA. The reaction was stopped, and the target product 72 (28.4 mg, yield 74%) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0172] Embodiment 48

[0173]

[0174] The reaction steps and operations (process and conditions) were the same as those of Example 27 for preparing product 48, except that 2,3-diphenyl-5-methyl-N-(methacryloyl)indole 73 (35.2 mg, 0.1 mmol) was added to the reaction system, and the constant current was 4 mA. The reaction was stopped, and the target product 74 (17.9 mg, 45% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0175] Embodiment 49

[0176]

[0177] The reaction steps and operations (process and conditions) were the same as those of Example 27 for preparing product 48, 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 the constant current was 4 mA. The reaction was stopped, and the target product 76 (20.6 mg, 50% yield) was obtained as a colorless oil after post-treatment. The target product was confirmed by H NMR, C NMR and high-resolution mass spectrometry.

[0178] Embodiment 50

[0179]

[0180] The reaction steps and operations (process and conditions) were the same as those of Example 27 for preparing product 48, except that 2,3-diphenyl-5-fluoro-N-(methacryloyl)indole 77 (35.6 mg, 0.1 mmol) was added to the reaction system, and the constant current was 4 mA. The reaction was stopped, and the target product 78 (14.1 mg, yield 35%) was obtained as a colorless oil after post-treatment. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0181] Embodiment 51

[0182]

[0183] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that 2,3-diphenyl-5-chloro-N-(methacryloyl)indole 79 (37.2 mg, 0.1 mmol) was added to the reaction system, and the constant current was 4 mA. The reaction was stopped, and the target product 80 (12.5 mg, 30% yield) was obtained by post-treatment as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

[0184] Embodiment 52

[0185]

[0186] The reaction steps and operations (process and conditions) were the same as those in Example 27 for preparing product 48, except that 2-phenyl-N-(methacryloyl)indole 81 (26.2 mg, 0.1 mmol) was added to the reaction system, and the constant current was 4 mA. The reaction was stopped, and the target product 82 (14.8 mg, yield 48%) was obtained by post-treatment as a white solid. The target product was confirmed by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and high-resolution mass spectrum.

Claims

1. A method for synthesizing an amino acid compound, wherein the amino acid compound is synthesized from acrylamide and carbon dioxide by electrochemical means, wherein: The amino acid compound structural formula 1 or 2 is as follows: Where R 1 It is one or more of phenyl or substituted phenyl, naphthyl, tetrahydroquinolyl, benzoyl, indole or substituted indole. The substituent on the substituted phenyl is one or more of methyl, methoxy, phenyl, phenoxy, tert-butyl, 3,5-dimethyl, fluorine, chlorine, bromine, trifluoromethyl, methyl formate. The substituent on the substituted indole is one or more of methyl, phenyl, fluorine, chlorine. R 2 is one or more of hydrogen, methyl, ethyl, isopropyl, cyclohexyl and benzyl; R 3 is one or both of hydrogen and methyl; R 4 It is one or both of hydrogen and methyl.

2. The synthesis method according to claim 1, characterized in that: The synthesis route is shown in the following reaction formula, using substituted acrylamide 3 as a raw material, reacting with carbon dioxide under electrocatalytic conditions to generate amino acid compounds 1 or 2; The substituent R 1 , R 2 , R 3 and R 4 Respectively with the R described in claim 1 1 , R 2 , R 3 and R 4 same.

3. The synthesis method according to claim 2, characterized in that: In the electrochemical reaction: the anode material is one or more of magnesium, aluminum, zinc, nickel, iron, and graphite carbon, preferably one or more of magnesium, aluminum, zinc, and nickel, and the best anode material is magnesium; the cathode material is one or more of graphite carbon, nickel, platinum, copper, and graphite felt, preferably one or more of graphite carbon and copper, and the best cathode material is graphite carbon; The reaction solvent is one or more of acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, and the best solvent is one or two of acetonitrile and N,N-dimethylformamide; The reaction electrolyte is one or more of tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, and tetraethylammonium perchlorate, and the best electrolyte is one or more of tetraethylammonium perchlorate and tetrabutylammonium chloride; the electrochemical constant reaction current density is 4-10mA, and the reaction time is 3.5-6 hours; the reaction temperature is 35 to -10 degrees Celsius, and the reaction atmosphere is a carbon dioxide atmosphere; after the reaction is completed, the product is separated and purified to obtain an amino acid compound 1 or 2.

4. The synthesis method according to claim 2, characterized in that: When the N-methyl-N-phenylmethacrylamide compound 3 with different phenyl groups reacts with carbon dioxide to obtain the amino acid compound 1, the best reaction solvent is acetonitrile, the optional temperature range is room temperature to -10 degrees Celsius, preferably: 0 to -10 degrees Celsius, the best reaction temperature is to -5 to -10 degrees Celsius, and the best electrolyte is tetraethylammonium perchlorate; In the amino acid compound structural formula 1, R 1 is one or more of phenyl or substituted phenyl, naphthyl, and the substituent on the substituted phenyl is one or more of methyl, phenyl, phenoxy, and 3,5-dimethyl; R 2 is one or more of methyl, ethyl, isopropyl, cyclohexyl and benzyl; R 3 It is one or both of hydrogen and methyl.

5. The synthesis method according to claim 2, characterized in that: When N-methyl-N-phenylmethacrylamide compounds 3 with different phenyl groups react with carbon dioxide to obtain amino acid compounds 2, the best reaction solvent is N,N-dimethylformamide, the optional temperature range is 35 to -10 degrees Celsius, preferably: room temperature to -10 degrees Celsius, the best reaction temperature is room temperature, and the best electrolyte is tetrabutylammonium chloride; In the amino acid compound structural formula 2, R 1 is one or more of phenyl or substituted phenyl, naphthyl, tetrahydroquinolyl, and benzoyl, and the substituent on the substituted phenyl is one or more of methyl, phenyl, and tert-butyl; R 2 is one or more of hydrogen, methyl, isopropyl, and benzyl; R 3 is one or both of hydrogen and methyl; R 4 It is one or both of hydrogen and methyl.

6. The synthesis method according to claim 5, characterized in that: Preferably, when R 4 When the reaction is hydrogen, the process is as follows: in a reaction tube, N-methyl-N-phenylmethyl acrylamide 4 and tetrabutylammonium chloride are added, the reaction tube is equipped with graphite carbon as a cathode and a magnesium sheet as an anode, and a current is applied between the cathode and the anode; the reaction tube is sealed and then pumped with carbon dioxide, N,N-dimethylformamide is added as a solvent, and the reaction tube is reacted at room temperature for 3.5 hours at a constant current; after the reaction is completed, a hydrochloric acid solution is added, and the reaction is extracted with ethyl acetate, and the organic layer is stripped with saturated brine, dried, filtered, and the volatile components are removed under reduced pressure to obtain a crude product, which is then separated by silica gel column chromatography to obtain the target product; Or preferably, when R 4 When it is methyl, the specific process is as follows: in a reaction tube, N-methyl-N-phenylmethyl acrylamide, tetrabutylammonium chloride, and a stirring magnet are added, the reaction tube is equipped with graphite carbon as a cathode, a magnesium sheet as an anode, and a current is applied between the cathode and the anode; the reaction tube is sealed and filled with carbon dioxide, and N,N-dimethylformamide is added as a solvent; the reaction tube is reacted at room temperature with a constant current for 3.5 hours; after the reaction is completed, a hydrochloric acid solution is added, extracted with ethyl acetate, the organic layer is back-extracted with saturated brine, dried, filtered, and volatile components are removed under reduced pressure to obtain a crude product, ether / methanol is added, and trimethylsilylated diazomethane is added and stirred at 0°C, and volatile components are removed under reduced pressure, and then separated by silica gel column chromatography to obtain the target product.

7. The synthesis method according to any one of claims 2 to 6, 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 , the best is 90-100mm 2 ; Apply current between the cathode and anode in the reaction system.

8. The synthesis method according to any one of claims 2 to 6, characterized in that: The reaction current is 4-10mA, and the best constant reaction current is 6-8mA, such as: 8mA or 6mA.

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