A method for synthesizing photoinduced N-arylbenzamide compounds
Through electrophilic amination reaction catalyzed by visible light and metal iron salt under mild conditions, the problems of low atomic economy and environmental pollution in the traditional amide compound synthesis methods were successfully solved, and efficient, green and economical amide compound synthesis was achieved.
Patent Information
- Application Number
- CN202210222840.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-03-09
- Publication Date
- 2025-06-20
- Estimated Expiration
- 2042-03-09
AI Technical Summary
The synthesis method of traditional amide compounds has problems of low atomic economy and environmental pollution, which is difficult to meet the requirements of green chemistry.
The electrophilic amination reaction promoted by visible light was used and the use of cheap metal iron salts as catalysts to convert the aryl boric acid compound into N-arylamide compounds under mild conditions.
The synthesis of highly efficient, green and economical amide compounds is achieved, avoiding the generation of large amounts of organic waste in traditional methods, and improving the atomic economy of the reaction.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing a novel photoinduced N-arylbenzamide compound. Background Art
[0002] Amide compounds are widely present in natural products, drug molecules, material molecules, etc. Amide compounds play an indispensable role in life functions. For example, the construction of important biological molecules such as polypeptides and proteins all originates from the synthesis of amides. And in the process of drug research and development, the construction of the amide skeleton usually plays an important role in all reactions. In 2018, the ACS GCI Pharmaceutical Roundtable redefined the goal of developing a general method for catalytic / sustainable (direct) amide or peptide formation, reflecting the important position of sustainable amidation.
[0003] Traditional methods for synthesizing amides often activate carboxylic acids by using condensation reagents and further react with amine compounds to obtain amides. However, a large amount of organic waste is generated during the reaction process, which is difficult to handle, reducing the atom economy of the reaction and not meeting the requirements of the development of green chemistry. In contrast, the present invention uses a cheap metal iron salt as a catalyst under the action of visible light, and realizes the efficient synthesis of amide compounds through an electrophilic amination reaction of cheap and easily available arylboronic acid compounds under mild conditions.
[0004] In summary, this article describes a method for directly synthesizing high-value-added N-aryl amide compounds by starting from simple and easily available raw materials and innovatively applying visible light to iron-catalyzed organic reactions. Summary of the Invention
[0005] The purpose of the present invention is to provide a method for synthesizing N-aryl amide derivatives.
[0006]
[0007] Reaction Equation 1: Synthesis of Substituted Amide Derivatives
[0008] The specific operation steps are as follows (Reaction Equation 1):
[0009] Under N2 protection, N-methoxybenzamide compound 1, boronic acid derivative 2, additive, and solvent are sequentially added to a photoreaction tube, and the reaction is carried out at 40 °C under visible light irradiation for 18 hours; after the reaction is completed, N-arylbenzamide derivative 3 is separated.
[0010] The molar dosage ratio of N-methoxybenzamide 1 to boronic acid derivative 2 is 2:1.
[0011] The iron catalysts used can be ferrous acetate, ferrous trifluoromethanesulfonate, ferrous dichloride, and ferric chloride. Ferrous dichloride is preferably used as the catalyst for the reaction, and the dosage is 0.10 - 0.50 molar equivalents.
[0012] The additive is one of the molecular sieve powders. The dosage of the additive is 0.10 - 0.50 molar equivalents of the dosage of the boric acid derivative. Preferably the molecular sieve powder, with a dosage of 0.10 - 0.20 molar equivalents.
[0013] The light wavelength used is in the visible light wavelength range of 380 - 480 nm, and blue light with a wavelength of 450 - 450 nm is preferably used for illumination.
[0014] The solvent is one or more of dichloromethane, 1,2 - dichloroethane, chlorobenzene, tetrahydrofuran, and acetone. Dichloromethane is preferred; the dosage of the solvent is 0.2 - 2.0 mL of the solvent per millimole of phenylboronic acid derivative 2, and 0.5 mL is preferably used.
[0015] Starting from simple and easily storable raw materials, the present invention has a high yield and a series of N - arylbenzamide derivatives are obtained under relatively mild conditions.
[0016] The present invention has the following advantages:
[0017] Firstly, the reaction raw material N - methoxybenzamide is simple and easy to store, and the boric acid compound is a commercial product, which is cheap and easily available, and the reaction conditions are mild and simple. Secondly, by using visible light to promote the reaction, the use of a large amount of condensing agents, strong acids, and strong bases is avoided, making the reaction more environmentally friendly. Finally, the obtained product N - arylbenzamide derivatives have high added value and can be used as intermediates for synthesizing various natural products, drugs, and structural units of organic functional materials, etc.
[0018] Such as Betrixaban [1](Reference: [1.] Garland, S.G., DeRemer, C.E., Smith, S.M., Gums, J.G., Betrixaban: A New Oral Factor Xa Inhibitor for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients. Annals of Pharmacotherapy 2018, 52(6), 554-561.) can be used as a highly selective oral direct factor Xa inhibitor. The following process proposed by the present invention can further shorten the traditional synthesis route, improve the efficiency of drug synthesis, and has broad application prospects.
[0019] As follows:
[0020]
[0021] Reaction Equation 2: Intermediate TM1 of the drug Betrixaban in the present invention
[0022] Under N2 protection, SM1 (0.40 mmol), SM2 (0.20 mmol), FeCl2 (0.02 mmol), molecular sieve (0.02 mmol), and dichloromethane (0.5 mL) were successively added to a photoreaction tube and reacted at 40 °C under 450 nm light for 18 hours; after the reaction, compound TM1 was obtained by column chromatography separation with a yield of 35%. Specific Embodiments
[0023] To better understand the present invention, it is illustrated by the following examples. The reaction raw materials and results of Examples 1-16 are shown in Table 1.
[0024] Table 1 Reaction Results of Different Substituted Substrates
[0025]
[0026]
[0027]
[0028]
[0029] Example 1
[0030] Under N2 protection, N-methoxybenzamide compound 1a (0.40 mmol), phenylboronic acid 2a (0.20 mmol), FeCl2 (0.02 mmol), molecular sieve (0.02 mmol), and dichloromethane (0.5 mL) were successively added to a photoreaction tube and reacted at 40 °C under 450 nm light irradiation for 18 hours; after the reaction, N-phenylbenzamide compound 3aa was obtained by column chromatography separation with a yield of 95%, and the structure was identified by nuclear magnetic resonance (1H NMR and 13C NMR).
[0031] The detection data are as follows:
[0032] 3aa: White solid, 37.6 mg, 95% yield, R f = 0.3 (petroleum ether / ethyl acetate: 8 / 1). 1 1H NMR (700 MHz, CDCl3) δ 7.88 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H). 13 13C NMR (175 MHz, CDCl3) δ 165.88, 138.05, 135.14, 131.98, 129.24, 128.93, 127.15, 124.71, 120.33. mp 161 - 163 °C.
[0033] Example 2:
[0034] The operation process and conditions were the same as those in Example 1, and the product 3ba was obtained with a yield of 72%, and the structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR).
[0035] The detection data are as follows:
[0036] 3ba: white solid, 39.5 mg, 72% yield, R f = 0.2 (petroleum ether / ethyl acetate: 8 / 1). 1 1H NMR (400 MHz, acetone-d6) δ 9.52 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H).13 13C NMR (100 MHz, acetone-d6) δ 166.60, 140.21, 140.02, 133.78, 131.88, 129.70, 129.59, 128.41, 124.75, 120.49, 119.98. mp 120 - 121 °C.
[0037] Example 3:
[0038] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ca, and the yield is 65%. The structure of the compound was identified by NMR (proton and carbon spectra).
[0039] The test data are as follows:
[0040] 3ca: white solid, 51.7 mg, 65% yield, R f = 0.2 (petroleum ether / ethyl acetate: 8 / 1). 1 1H NMR (700 MHz, acetone-d6) δ 9.80 (s, 1H), 8.31 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H). 13 13C NMR (175 MHz, acetone-d6) δ 164.91, 139.93, 137.23, 132.22, 131.06 (q, J = 32.2 Hz), 130.41, 129.54, 128.82 (q, J = 3.7), 125.08 (q, J = 3.8 Hz), 125.02 (q, J = 270.1 Hz), 124.93, 121.19. 19 19F NMR (376 MHz, acetone-d6) δ -63.10. mp 199 - 200 °C.
[0041] Example 4:
[0042] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3da, and the yield is 55%. The structure of the compound was identified by NMR (proton and carbon spectra).
[0043] The test data are as follows:
[0044] 3da: white solid, 23.2 mg, 55% yield, R f R = 0.3 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (400 MHz, acetone-d6) δ 9.44 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 7.9 Hz, 2H), 7.37 - 7.29 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H), 2.40 (s, 3H). 13 C NMR (100 MHz, acetone-d6) δ 166.17, 142.67, 140.45, 133.47, 129.82, 129.44, 128.35, 124.39, 120.96, 21.37. mp 145 - 146 °C.
[0045] Example 5:
[0046] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ea, with a yield of 52%. The structure of the compound was identified by NMR (1H NMR and 13C NMR).
[0047] Example 6:
[0048] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3fa, with a yield of 76%. The structure of the compound was identified by NMR (1H NMR and 13C NMR).
[0049] Example 7:
[0050] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ga, with a yield of 82%. The structure of the compound was identified by NMR (1H NMR and 13C NMR).
[0051] Example 8:
[0052] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ha, with a yield of 38%. The structure of the compound was identified by NMR (1H NMR and 13C NMR).
[0053] Example 9:
[0054] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ab, with a yield of 70%. The structure of the compound was identified by NMR (1H NMR and 13C NMR).
[0055] The detection data is as follows:
[0056] 3ab: white solid, 32.0 mg, 70% yield, R f = 0.2 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (400 MHz, acetone-d6) δ 9.05 (s, 1H), 8.21 - 8.15 (m, 1H), 8.05 (d, J = 7.2 Hz, 2H), 7.66 - 7.47 (m, 4H), 7.39 (t, J = 7.4 Hz, 1H), 7.22 (t, J = 7.1 Hz, 1H). 13 C NMR (100 MHz, acetone-d6) δ 165.96, 136.07, 135.44, 132.78, 130.14, 129.52, 128.33, 128.24, 126.79, 126.71, 125.51. mp: 102 - 103 °C.
[0057] Example 10:
[0058] The operation process and conditions are the same as those in Example 1, except for Raw material 1 and / or Raw material 2 (see Table 1 for details). The product is 3ac, with a yield of 90%. The structure of the compound was identified by NMR (proton NMR and carbon NMR).
[0059] The detection data is as follows:
[0060] 3ac: white solid, 41.5 mg, 90% yield, R f = 0.3 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.75 (s, 1H), 7.54 - 7.45 (m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.27 - 7.19 (m, 1H), 7.09 (d, J = 8.7 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 166.28, 139.20, 134.69, 134.54, 132.11, 130.05, 128.81, 127.20, 124.67, 120.64, 118.55. mp: 125 - 126 °C.
[0061] Example 11:
[0062] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ad with a yield of 78%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0063] The detection data are as follows:
[0064] 3ad: white solid, 43.1 mg, 78% yield, R f = 0.3 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (400 MHz, CDCl3) δ 7.92 (t, J = 1.9 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.81 (s, 1H), 7.59 - 7.54 (m, 1H), 7.52 - 7.47 (m, 1H), 7.30 - 7.20 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 165.79, 139.32, 134.68, 132.68, 130.52, 129.04, 127.70, 127.15, 123.21, 122.85, 118.72. mp: 135 - 136 °C.
[0065] Example 12:
[0066] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ae with a yield of 65%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0067] The detection data are as follows:
[0068] 3ae: white solid, 29.4 mg, 65% yield, R f = 0.2 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (400 MHz, acetone - d6) δ 10.04 (s, 1H), 9.80 (s, 1H), 8.45 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 7.6 Hz, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 6.7 Hz, 2H), 7.52 (t, J = 7.3 Hz, 2H). The 13 C NMR spectra of this compound display two setof signals for carbons.13 C NMR (175 MHz, acetone-d6) δ 192.84, 192.74, 166.62, 141.12, 138.21, 138.20, 135.79, 132.56, 130.32, 129.30, 128.36, 126.58, 125.87, 121.17. mp: 116 - 117 °C.
[0069] Example 13:
[0070] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3af with a yield of 95%. The structure of the compound was identified by NMR (proton and carbon spectra).
[0071] The detection data are as follows:
[0072] 3af: white solid, 61.3 mg, 95% yield, R f = 0.2 (petroleum ether / ethyl acetate: 8 / 1). 1 H NMR (700 MHz, acetone-d6) δ 9.58 (s, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.87 (dd, J = 8.9, 5.0 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H). 13 C NMR (175 MHz, acetone-d6) δ 166.24, 159.82 (d, J = 239.3 Hz), 136.63, 136.12, 132.36, 129.27, 128.29, 122.84 (d, J = 7.7 Hz), 115.91 (d, J = 22.3 Hz). 19 F NMR (376 MHz, acetone-d6) δ -120.52. mp 193 - 195 °C.
[0073] Example 14:
[0074] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ag with a yield of 93%. The structure of the compound was identified by NMR (proton and carbon spectra).
[0075] Example 15:
[0076] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ah, and the yield is 82%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0077] Example 16:
[0078] The operation process and conditions are the same as those in Example 1, except for Raw Material 1 and / or Raw Material 2 (see Table 1 for details). The product is 3ai, and the yield is 41%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0079] Example 17:
[0080] The operation process and conditions are the same as those in Example 1. The difference is that the amount of catalyst FeCl2 used in the reaction is 0.50 molar equivalent (relative to boronic acid derivative 2). The product is 3aa, and the yield is 68%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0081] Example 18:
[0082] The operation process and conditions are the same as those in Example 1. The difference is that the wavelength of the light used in the reaction is 380 - 385 nm. The product is 3aa, and the yield is 76%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0083] Example 19:
[0084] The operation process and conditions are the same as those in Example 1. The difference is that the additive molecular sieve is not used in the reaction. The product is 3aa, and the yield is 56%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0085] Example 20:
[0086] The operation process and conditions are the same as those in Example 1. The difference is that acetic acid or triethylamine (0.10 molar equivalent) is used as the additive in the reaction (relative to boronic acid derivative 2), and the target compound 3aa was not obtained.
[0087] Example 21:
[0088] The operation process and conditions are the same as those in Example 1. The difference is that acetone is used as the solvent in the reaction. The product is 3aa, and the yield is 67%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0089] Example 22:
[0090] The operation process and conditions are the same as those in Example 1. The difference is that FeCl3 is used as the catalyst in the reaction. The product is 3aa, and the yield is 75%. The structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR).
[0091] Example 23:
[0092] Under N2 protection, 1 g (0.40 mmol) of N-methoxybenzamide compound, 2a (0.20 mmol) of phenylboronic acid, 0.02 mmol of FeCl2, 0.02 mmol of molecular sieve, and 0.5 mL of dichloromethane were successively added to the reaction tube and reacted at 80 °C for 24 hours; after the reaction was completed, the target compound 3ga was not obtained.
Claims
1. A method for synthesizing a photoinduced N -arylbenzamide compound, characterized in that: ， wherein R 1 is one of the following groups: ， R 2 is one of the following groups: ， The specific operation steps are as follows: Under an inert atmosphere protection, add N -methoxybenzamide compound 1, boric acid derivative 2, iron catalyst, and solvent into a photoreaction tube or photoreactor, with or without an additive, and react at 30 - 50 °C under visible light irradiation for 10 - 24 hours; after the reaction is completed, separate to obtain N -arylbenzamide derivative 3; The iron catalyst used is one or two of ferrous dichloride and ferric trichloride, The solvent is one or two of dichloromethane and acetone; The additive is one or more of 3 Å, 4 Å, and 5 Å molecular sieve powders.
2. The method according to claim 1, characterized in that: N The molar dosage ratio of 1-methoxybenzamide 1 to boric acid derivative 2 is 1-2:
1.
3. The method according to claim 1, characterized in that: N The molar dosage ratio of 1-methoxybenzamide 1 to the boronic acid derivative 2 is 2:
1.
4. The method according to claim 1, characterized in that: The iron catalyst used is ferrous dichloride, and its dosage is 0.10 - 0.50 molar equivalents relative to the raw material boric acid derivative 2.
5. The method according to claim 2, characterized in that: The dosage of the additive is 0.10 - 0.50 molar equivalents of the dosage of the boric acid derivative.
6. The method according to claim 5, characterized in that: The additive is 4 Å molecular sieve powder, and the dosage of the additive is 0.10 - 0.20 molar equivalents of the dosage of the boric acid derivative.
7. The method according to claim 1, characterized in that: The light wavelength used is in the visible light wavelength range of 380 - 480 nm.
8. The method according to claim 7, characterized in that: The light wavelength used is blue light illumination of 450 - 455 nm.
9. The method according to claim 1, characterized in that: The solvent is dichloromethane, and the dosage of the solvent is 0.2 - 2.0 mL of the solvent per millimole of boric acid derivative 2.
10. The method according to claim 1, characterized in that: The dosage of the solvent is 0.5 mL of the solvent per millimole of boric acid derivative 2.