A β-aminoamide compound and its preparation method and application
The preparation of β-aminoamide compounds through electrolytic reaction solves the economic and selectivity problems of the synthesis method in the existing technology, and realizes the efficient synthesis of diversified β-aminoamide compounds, which are suitable for the preparation of drugs for treating heart disease.
Patent Information
- Application Number
- CN202410386152.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-01
- Publication Date
- 2025-09-30
- Estimated Expiration
- 2044-04-01
AI Technical Summary
In the existing technology, the synthesis method of β-aminoamide compounds has poor atom economy and step economy, resulting in limited compound diversity and synthesis speed. In addition, the selectivity of azobenzene and ethyl acrylate during the reduction process is difficult to control, and over-reduction is prone to occur.
Azobenzene compounds and ene ester compounds are electrolytically reacted in an electrolyte and a solvent, and formic acid or acetic acid is used as an additive to achieve a reduction cyclization and ring-opening reaction of the azobenzene compounds to synthesize β-aminoamide compounds, avoiding the use of metal catalysts and simplifying post-processing operations.
The high atom-economic synthesis of β-aminoamide compounds has been achieved, with wide substrate applicability, good diastereoselectivity, suitability for industrial production, and the ability to synthesize different types of compounds for use in drugs for the treatment of heart disease.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and in particular to a beta-aminoamide compound and a preparation method and application thereof. Background Art
[0002] β-Aminoamide compounds are an important class of chemical intermediates, widely used in pharmaceuticals, pesticides, and organic ligands. Many drug molecules contain amide and amine structures, so β-aminoamide compounds have a broad application prospect in organic synthesis. With the growing popularity of green and sustainable economic development concepts, the development of green, efficient, and easy-to-use methods for the construction of nitrogen-oxygen heterocyclic compounds has become a major area of research interest.
[0003] Over the past decade, azobenzene and ethyl acrylate have been widely used in organic synthesis, particularly in reductive coupling to construct diverse bioactive molecules. Experimental studies have shown that azobenzene compounds possess unique chemical and physical properties. The N=N bond in their molecular structure forms a strongly conjugated structure with the benzene ring, making them suitable not only for use in dyes but also for bond cleavage under reducing conditions, making them suitable for a variety of reductive coupling reactions. Consequently, azobenzene compounds have been used to construct molecular fragments with biological and pharmaceutical activities, holding significant applications in diverse fields such as organic synthesis, catalytic chemistry, biology, and materials science. However, the selectivity of azobenzene and ethyl acrylate during the reduction process is difficult to control, prone to overreduction, often resulting in complex reaction conditions and poor substrate compatibility. Currently, the synthesis of β-aminoamides typically requires the preparation of related amides or amines, resulting in poor atom and step economies. This significantly limits the diversity, richness, and speed of synthesis of β-aminoamides.
[0004] Therefore, it is of great significance to develop an atom-economical and step-economical method for synthesizing β-aminoamide compounds and synthesize different types of β-aminoamide compounds. Summary of the Invention
[0005] The purpose of the present invention is to provide a β-aminoamide compound and a preparation method and application thereof.
[0006] The technical solution adopted by the present invention is:
[0007] A β-aminoamide compound, the structural formula of which is as follows:
[0008] Where R 1 is one of hydrogen, methyl, methyl substituted with one or more halogen atoms, ethyl, methoxy, and halogen, R 2is one of hydrogen, methyl, ethyl, methoxy, and halogen, R 3 is one of hydrogen, methyl, phenyl, and benzyl, R 4 It is one of hydrogen, methyl, methoxy, halogen and 4-methoxyphenyl.
[0009] Preferably, the R 1 and R 2 All are hydrogen.
[0010] A method for preparing the above-mentioned β-aminoamide compound comprises the following steps:
[0011] Azobenzene compounds, olefin ester compounds, additives and electrolytes are dispersed in a solvent. The structural formula of the azobenzene compound is: The structural formula of ene ester compounds is Then, electricity is supplied to carry out electrolysis reaction to obtain β-aminoamide compounds.
[0012] Preferably, the molar ratio of the azobenzene compound to the enester compound is 1:2-5.
[0013] Preferably, the azobenzene compound is azobenzene.
[0014] Preferably, the olefin ester compound is one of ethyl acrylate, ethyl α-phenyl acrylate, ethyl α-methacrylate, and methyl 4-methoxycinnamate.
[0015] Preferably, the additive is at least one of formic acid and acetic acid.
[0016] More preferably, the additive is formic acid.
[0017] Preferably, the electrolyte is at least one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium perchlorate.
[0018] Preferably, the solvent is at least one of acetonitrile, toluene, 1,4-dioxane, methanol, and ethanol.
[0019] Preferably, the electrolysis reaction is carried out at a temperature of 20° C. to 30° C. and a current of 10 mA to 30 mA, and the electrolysis reaction time is 2 h to 6 h.
[0020] Preferably, the electrolysis reaction is carried out in an air atmosphere.
[0021] Preferably, after the electrolysis reaction is completed, the product is purified by column chromatography.
[0022] Preferably, the eluent used for column chromatography purification consists of petroleum ether and ethyl acetate in a volume ratio of 1 to 5:1.
[0023] A use of the above-mentioned β-aminoamide compound in the preparation of a medicine for treating heart disease.
[0024] The beneficial effects of the present invention are as follows: the β-aminoamide compounds of the present invention can be used to prepare drugs for treating heart disease, and the preparation method thereof has the advantages of cheap and readily available raw materials, wide substrate applicability, high atom economy, high diastereoselectivity, etc., and has broad prospects for industrial application.
[0025] Specifically:
[0026] 1) The β-aminoamide compounds of the present invention can be used as raw materials for preparing drugs for treating heart disease, and have very broad application prospects;
[0027] 2) The present invention realizes the reductive cyclization and ring-opening reaction of azobenzene compounds and ene ester compounds through an electrolytic reaction. In this reaction, electricity acts as a reducing agent to reduce the azobenzene compound, and formic acid and / or acetic acid act as additives to promote the reductive coupling process. The β-aminoamide compound can be synthesized in a single step without the use of an additional metal catalyst. The post-processing operation is simple, the reaction conditions are mild, and it is suitable for scale-up industrial production.
[0028] 3) The preparation method of the β-aminoamide compounds of the present invention has the advantages of cheap and readily available raw materials, wide substrate applicability, high atom economy, and high diastereoselectivity. In addition, different types of β-aminoamide compounds can be synthesized by adjusting the structures of azobenzene compounds and enester compounds. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 The β-aminoamide compound prepared in Example 1 1 H NMR spectrum.
[0030] Figure 2 The β-aminoamide compound prepared in Example 1 13 C NMR spectrum.
[0031] Figure 3 The β-aminoamide compound prepared in Example 2 1 H NMR spectrum.
[0032] Figure 4 The β-aminoamide compound prepared in Example 2 13 C NMR spectrum.
[0033] Figure 5 The β-aminoamide compound prepared in Example 3 1 H NMR spectrum.
[0034] Figure 6 The β-aminoamide compound prepared in Example 3 13 C NMR spectrum.
[0035] Figure 7 The β-aminoamide compound prepared in Example 4 1 H NMR spectrum.
[0036] Figure 8 The β-aminoamide compound prepared in Example 4 13 C NMR spectrum. DETAILED DESCRIPTION
[0037] The present invention will be further explained and illustrated below with reference to specific embodiments.
[0038] Example 1:
[0039] A β-aminoamide compound, the preparation method of which is as follows:
[0040] Under air atmosphere, 0.2 mmol of azobenzene, 0.4 mmol of ethyl acrylate, 0.4 mmol of formic acid and 0.25 mmol of tetrabutylammonium tetrafluoroborate were stirred and dispersed in 5 mL of acetonitrile. The mixture was then electrolyzed at room temperature and a current of 20 mA for 2.5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification consisted of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a β-aminoamide compound (yellow solid, melting point 87°C to 89°C, yield 83%).
[0041] The nuclear magnetic resonance hydrogen spectrum of the β-aminoamide compound prepared in this example ( 1 H NMR) Figure 1 As shown, the C NMR spectrum ( 13 C NMR) Figure 2 shown.
[0042] The decomposition data of hydrogen NMR spectrum and carbon NMR spectrum are as follows:
[0043] 1 H NMR (400MHz, Chloroform-d): δ7.90(s,1H),7.46(d,J=7.6Hz,2H),7.28(t,J=7.9Hz,2H),7.21-7.17(m,2H),7.09(t, J=7.6Hz,1H),6.76(t,J=7.3Hz,1H),6.65(d,J=8.0Hz,2H),3.96(s,1H),3.50(t,J=6.0Hz,2H),2.61(t,J=6.0Hz,2H).
[0044] 13 C NMR (101MHz, CDCl3): δ170.1,147.4,137.6,129.4,128.9,124.4,120.0,118.2,113.5,40.1,36.5.
[0045] The high-resolution mass spectrometry data of the β-aminoamide compound prepared in this example are as follows:
[0046] HRMS(ESI):Calcd.for C 15 H 16 N2O[M+H] + :241.1263;found:241.1335.
[0047] Based on the H NMR spectrum data, C NMR spectrum data and high-resolution mass spectrometry data, the structural formula of the β-aminoamide compound prepared in this example is as follows:
[0048]
[0049] Example 2:
[0050] A β-aminoamide compound, the preparation method of which is as follows:
[0051] Under air atmosphere, 0.2 mmol of azobenzene, 0.8 mmol of α-phenyl ethyl acrylate, 0.4 mmol of formic acid and 0.25 mmol of tetrabutylammonium tetrafluoroborate were stirred and dispersed in 5 mL of acetonitrile. The mixture was then electrolyzed at room temperature and a current of 15 mA for 4 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification consisted of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a β-aminoamide compound (yellow solid, melting point 152°C to 154°C, yield 42%).
[0052] The nuclear magnetic resonance hydrogen spectrum of the β-aminoamide compound prepared in this example ( 1 H NMR) Figure 3 As shown, the C NMR spectrum ( 13 C NMR) Figure 4 shown.
[0053] The decomposition data of hydrogen NMR spectrum and carbon NMR spectrum are as follows:
[0054] 1H NMR (400MHz, Chloroform-d): δ7.42-7.34(m,7H),7.29-7.25(m,2H),7.19(t,J=7.8Hz,3H),7.08(t,J=7. 4Hz, 1H), 6.74 (t, J = 7.3Hz, 1H), 6.64 (d, J = 7.9Hz, 2H), 4.17 (s, 1H), 3.99-3.88 (m, 2H), 3.54-3.50 (m, 1H).
[0055] 13 C NMR (126MHz, CDCl3): δ170.5,147.2,137.5,137.3,129.4,129.3,128.9,128.1,128.0,124.5,119.8,117.9,113.2,52.6,46.8.
[0056] The high-resolution mass spectrometry data of the β-aminoamide compound prepared in this example are as follows:
[0057] HRMS(ESI):Calcd.for C 21 H 20 N2O[M+H] + :317.1576;found:317.1648.
[0058] Based on the H NMR spectrum data, C NMR spectrum data and high-resolution mass spectrometry data, the structural formula of the β-aminoamide compound prepared in this example is as follows:
[0059]
[0060] Example 3:
[0061] A β-aminoamide compound, the preparation method of which is as follows:
[0062] Under air atmosphere, 0.2 mmol of azobenzene, 0.8 mmol of α-ethyl methacrylate, 0.4 mmol of formic acid and 0.25 mmol of tetrabutylammonium tetrafluoroborate were stirred and dispersed in 5 mL of acetonitrile, and then electrolyzed at room temperature and a current of 15 mA for 4 h. The reaction was filtered and the filtrate was concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification consisted of petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain a β-aminoamide compound (white solid, melting point 109°C to 112°C, yield 76%).
[0063] The H NMR spectrum of the β-aminoamide compound prepared in this example ( 1 H NMR) Figure 5 As shown, the C NMR spectrum ( 13 C NMR) Figure 6 shown.
[0064] The decomposition data of hydrogen NMR spectrum and carbon NMR spectrum are as follows:
[0065] 1 H NMR (400MHz, Chloroform-d): δ7.75(s,1H),7.45(d,J=7.0Hz,2H),7.28(t,J=8.0Hz,2H),7.18(d,J=7.3Hz,2H),7.08(t,J=7.4Hz,1H),6 .74(t,J=7.0Hz,1H),6.63(d,J=7.6Hz,2H),4.05(s,1H),3.44-3.39(m,1H),3.31-3.26(m,1H),2.76-2.68(m,1H),1.26(d,J=7.0Hz,3H).
[0066] 13 C NMR (101MHz, CDCl3): δ173.6,147.4,137.7,129.3,128.8,124.2,120.0,117.9,113.2,47.4,41.0,15.4.
[0067] The high-resolution mass spectrometry data of the β-aminoamide compound prepared in this example are as follows:
[0068] HRMS(ESI):Calcd.for C 16 H 18 N2O[M+H] + :255.1419;found:255.1492.
[0069] Based on the H NMR spectrum data, C NMR spectrum data and high-resolution mass spectrometry data, the structural formula of the β-aminoamide compound prepared in this example is as follows:
[0070]
[0071] Example 4:
[0072] A β-aminoamide compound, the preparation method of which is as follows:
[0073] Under air atmosphere, 0.2 mmol of azobenzene, 0.8 mmol of methyl 4-methoxycinnamate, 0.4 mmol of formic acid and 0.25 mmol of tetrabutylammonium tetrafluoroborate were stirred and dispersed in 5 mL of acetonitrile, and then electrolyzed at room temperature and a current of 15 mA for 4 h. The reaction was filtered and the filtrate was concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification consisted of petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a β-aminoamide compound (yellow solid, melting point 149°C to 151°C, yield 41%).
[0074] The H NMR spectrum of the β-aminoamide compound prepared in this example ( 1 H NMR) Figure 7 As shown, the C NMR spectrum ( 13 C NMR) Figure 8 shown.
[0075] The decomposition data of hydrogen NMR spectrum and carbon NMR spectrum are as follows:
[0076] 1 H NMR (400MHz, Chloroform-d): δ7.82(s,1H),7.34(d,J=8.0Hz,2H),7.27-7.24(m,4H),7.12-7.06(m,3H),6.83(d, J=8.2Hz,2H),6.69(t,J=7.4Hz,1H),6.60(d,J=7.9Hz,2H),4.82-4.76(m,2H),3.75(s,3H),2.78(d,J=6.1Hz,2H).
[0077] 13 C NMR (126MHz, CDCl3): δ169.0,158.8,146.5,137.3,134.0,129.2,128.9,127.2,124.5,120.2,118.3,114.2,114.2,55.2,55.0,45.5.
[0078] The high-resolution mass spectrometry data of the β-aminoamide compound prepared in this example are as follows:
[0079] HRMS(ESI):Calcd.for C 22 H 22 N2O2[M+H] + :347.1681;found:347.1754.
[0080] Based on the H NMR spectrum data, C NMR spectrum data and high-resolution mass spectrometry data, the structural formula of the β-aminoamide compound prepared in this example is as follows:
[0081]
[0082] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.
Claims
1. A method for preparing a β-aminoamide compound, characterized in that: The following steps are involved: Azobenzene compounds, olefin ester compounds, additives and electrolytes are dispersed in a solvent. The structural formula of the azobenzene compound is: The structural formula of the enester compound is , then pass electricity to carry out electrolysis reaction to obtain β-aminoamide compounds; The structural formula of the β-aminoamide compound is as follows: , where R 1 is one of hydrogen, methyl, methyl substituted with one or more halogen atoms, ethyl, methoxy, and halogen, R 2 is one of hydrogen, methyl, ethyl, methoxy, and halogen, R 3 is one of hydrogen, methyl, phenyl, and benzyl, R 4 It is one of hydrogen, methyl, methoxy, halogen and 4-methoxyphenyl.
2. The preparation method according to claim 1, wherein: The molar ratio of the azobenzene compound to the enester compound is 1:2-5.
3. The preparation method according to claim 1 or 2, characterized in that: The additive is at least one of formic acid and acetic acid.
4. The preparation method according to claim 1 or 2, characterized in that: The electrolyte is at least one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, and tetrabutylammonium perchlorate.
5. The preparation method according to claim 1 or 2, characterized in that: The solvent is at least one of acetonitrile, toluene, 1,4-dioxane, methanol, and ethanol.
6. The preparation method according to claim 1 or 2, characterized in that: The electrolysis reaction is carried out at a temperature of 20° C. to 30° C. and a current of 10 mA to 30 mA, and the electrolysis reaction time is 2 h to 6 h.
7. The preparation method according to claim 1 or 2, characterized in that: After the electrolysis reaction is completed, the product is purified by column chromatography.
8. The preparation method according to claim 7, characterized in that: The eluent used in the column chromatography purification is composed of petroleum ether and ethyl acetate in a volume ratio of 1 to 5:1.