Photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds

Abstract

A photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds, characterized in that: using benzyl alcohol with the structure of formula (I) or benzaldehyde compounds with the structure of formula (II) and N-(2-aminoethyl)morpholine as raw materials, in the presence of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, through a photocatalytic reaction to obtain N-(2-morpholinoethyl) substituted benzamide compounds with the structure of formula (III). The present invention uses benzyl alcohol or benzaldehyde compounds as raw materials, avoiding the use of acyl chloride and hydrobromic acid, and preparing N-(2-morpholinoethyl) substituted benzamide compounds in a green and economical way.

Description

Technical Field

[0001] The present invention relates to a photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds, belonging to the technical field of organic pharmaceutical synthesis. Background Art

[0002] N-(2-Morpholinoethyl) substituted benzamide compounds play an important role in the field of drug research and development. Among them, the marketed antidepressant drug moclobemide has the chemical name 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide, which is a reversible selective monoamine oxidase inhibitor and a selective and potent reversible type A MAOI. CN101759667 A discloses a synthesis method of moclobemide, which uses ethanolamine as a raw material, reacts with hydrobromic acid, and then reacts with p-chlorobenzoyl chloride and morpholine. CN108658852A discloses a method using ethanolamine and 5-chloro-2-pyridinecarboxylic acid as starting materials for pharmaceutical intermediates, and through intermediates 2-bromoethylamine hydrobromide and 5-chloro-2-pyridinecarbonyl chloride, to obtain the product 5-chloro-N-[2-(4-morpholinyl)ethyl]picolinamide. Traditional synthesis of N-(2-morpholinoethyl) benzamide uses ethanolamine as a raw material, and strong acids such as hydrobromic acid and acyl chloride are used. These two substances have high requirements for the reaction and high requirements for equipment. Acyl chloride will release HCl during the reaction, which is extremely unfavorable to the environment. In terms of atom economy, such methods have many wastes, complex post-treatment processes, poor atom economy, and are not conducive to large-scale production. Summary of the Invention

[0003] Aiming at the above technical problems existing in the prior art, the purpose of the present invention is to provide a photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds, using benzyl alcohol or benzaldehyde compounds with the structure of formula (I) as raw materials, avoiding the use of acyl chloride and hydrobromic acid, and preparing N-(2-morpholinoethyl) substituted benzamide compounds in a green and economical way.

[0004] In order to achieve the above technical purpose, the present invention adopts the following technical solutions:

[0005] A photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds, using benzyl alcohol with the structure of formula (I) or benzaldehyde compounds with the structure of formula (II) and N-(2-aminoethyl)morpholine as raw materials, in the presence of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, and obtaining N-(2-morpholinoethyl) substituted benzamide compounds with the structure of formula (III) through a photocatalytic reaction;

[0006]

[0007] Wherein R is H, alkyl or halogen; the alkyl or halogen is monosubstituted or the same or different polysubstituted.

[0008] Preferably, the alkyl group is a C1-C5 alkyl group; the halogen is F, Cl, Br or I.

[0009] Preferably, the molar ratio of the benzyl alcohol or benzaldehyde compound to the N-(2-aminoethyl)morpholine compound is 1:1 to 1.5.

[0010] Preferably, the oxygen-containing atmosphere is air and / or oxygen.

[0011] Preferably, the organic solvent is one or more of toluene, trifluorotoluene, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene and dichloromethane; more preferably, it is one or more of n-hexane, cyclohexane, toluene and benzene.

[0012] Preferably, the base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium hydroxide, barium hydroxide, cesium carbonate and potassium carbonate; more preferably, it is one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium hydride and potassium hydride.

[0013] Preferably, the molar ratio of the benzyl alcohol or benzaldehyde compound to the base is 1:0.1-3.

[0014] Preferably, the transition metal in the transition metal oxide / C3N4 composite photocatalyst is one or more of silver, ruthenium, cobalt, copper, iron, gold, platinum, palladium, praseodymium, germanium, nickel and manganese.

[0015] Preferably, in the transition metal oxide / C3N4 composite photocatalyst, the mass ratio of transition metal to C3N4 is 0.01 to 0.5:1.

[0016] Preferably, the amount of the transition metal oxide / C3N4 composite photocatalyst is 0.1 to 5 wt % of the benzyl alcohol or benzaldehyde compound.

[0017] It should be noted that the transition metal oxide / C3N4 composite photocatalyst in the present invention can be prepared by existing conventional methods, for example, first dispersing C3N4 in water, then adding a soluble transition metal salt and mixing thoroughly, and then drying and calcining to obtain the result.

[0018] Preferably, the conditions for the photocatalytic reaction are: reacting for 1 to 10 hours under a 3 to 100 W LED lamp or xenon lamp light source.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The present invention uses benzyl alcohol or benzaldehyde as raw materials, which are more readily available. Moreover, the use of acyl chloride and hydrobromic acid is avoided, making it more environmentally friendly and economical in terms of raw materials. In addition, the reaction conditions are mild, reducing the reaction steps and making the operation simple.

[0021] (2) The purification of the product in the present invention is convenient. After the reaction is completed, the product can be obtained only by filtering to remove the catalyst, drying, and then washing with water, avoiding the use of a chromatography column or a large amount of organic solvents for separation.

[0022] (3) The reaction of the present invention is carried out in an oxygen-containing atmosphere, having mild oxidation performance, avoiding the use of peroxides, and being more conducive to the recycling of the catalyst. Moreover, the transition metal oxide / C3N4 composite photocatalyst can be separated from the reaction system only by simple filtration, effectively solving the problem that it is difficult to separate the homogeneous catalyst from the reaction solution. The loss of catalytic activity is not significant, reducing the production cost and meeting the requirements of green chemistry.

[0023] (4) Under visible light irradiation, the photocatalyst of the present invention forms electron-hole pairs, which can effectively avoid high-temperature thermal reactions and make the selectivity of the product higher. Description of the Drawings

[0024] Figure 1 1H NMR spectrum of 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide in Example 1;

[0025] Figure 2 1H NMR spectrum of N-[2-(4-morpholinyl)ethyl]benzamide in Example 2;

[0026] Figure 3 Mass spectrum of N-[2-(4-morpholinyl)ethyl]benzamide in Example 3. Detailed Embodiments

[0027] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art fall within the protection scope of the present invention. Unless otherwise defined, all the professional terms used hereinafter have the same meaning as commonly understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the protection scope of the present invention.

[0028] In the embodiments, all parts and percentages refer to mass unless otherwise specified.

[0029]

[0030] ​The specific preparation process of the transition metal oxide / C3N4 composite photocatalyst in the present invention is as follows:

[0031] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid being 1:40 - 100:1.5 - 5, dissolve melamine in water, then add concentrated phosphoric acid, crystallize at 120 - 200 °C, filter, and dry to obtain solid I;

[0032] (2) Calcinate solid I at 400 - 550 °C in an N2 atmosphere for 2 - 8 h to obtain C3N4;

[0033] (3) Add C3N4 to water, add soluble transition metal salt, control the mass ratio of C3N4 to transition metal to be 1:0.01 - 0.5, and the mass ratio of water to C3N4 to be 10 - 200:1, and vacuum dry at 30 - 80 °C to obtain solid II;

[0034] (4) Calcinate solid II at 200 - 550 °C for 0.5 - 6 h to obtain the transition metal oxide / C3N4 composite photocatalyst.

[0035] Example 1

[0036] The preparation process of the Ag2O / C3N4 photocatalyst is as follows:

[0037] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid being 1:80:2, dissolve melamine in water, add concentrated phosphoric acid, crystallize at 190 °C, filter, and dry to obtain solid I;

[0038] (2) Calcinate solid I at 520 °C in an N2 atmosphere for 5 h to obtain C3N4;

[0039] (3) Add C3N4 to water, add AgNO3, control the mass ratio of C3N4 to Ag to be 1:0.05, and the mass ratio of water to C3N4 to be 20:1, and vacuum dry at 60 °C to obtain solid II;

[0040] (4) Calcinate solid II at 300 °C for 2 h to obtain the Ag2O / C3N4 photocatalyst.

[0041] 1.4402 g of 4-chlorobenzyl alcohol (with a content of 99%) was added to a 100 mL reaction flask, 25 mL of toluene was added as a solvent, then 0.4 g of sodium hydride (with a content of 60%) was added, 1.2889 g of N-(2-aminoethyl)morpholine (with a content of 99%) was added, and then 20 mg of Ag2O / C3N4 was added. The reaction was carried out for 8 hours under normal temperature and 30 W LED light irradiation conditions to obtain a mixed solution, which was filtered, rotary evaporated, and washed with water to obtain a white solid. Through analysis and detection, the content of 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide was 93.4%, and the yield of 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide based on 4-chlorobenzyl alcohol was 85.7%.

[0042] The white solid was characterized, and its 1H NMR spectrum was as Figure 1 shown: δ 2.50 was the solvent peak, δ 1.31 (t, J = 6 Hz, 6H), δ 3.14 - 3.20 (m, 4H), δ 3.49 (m, 2H), 6.19 (s, 1H), 6.68 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H). Its chemical shift and the number of hydrogens were consistent with the hydrogens on 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide.

[0043] Comparative Example 1

[0044] 1.4402 g of 4-chlorobenzyl alcohol (with a content of 99%) was added to a 100 mL reaction flask, 25 mL of toluene was added as a solvent, then 0.4 g of sodium hydride (with a content of 60%) was added, 1.2889 g of N-(2-aminoethyl)morpholine (with a content of 99%) was added, and then 0.5206 g of MnO2 (with a content of 99%) and 9.7363 g of tert-butyl hydroperoxide (with a content of 70%) were added. The reaction was carried out for 10 hours under normal temperature and 30 W LED light irradiation conditions. Through analysis and detection, the target product 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide of 4-chlorobenzyl alcohol was not obtained.

[0045] Example 2

[0046] The preparation process of the Ru2O3 / C3N4 photocatalyst was as follows:

[0047] (1) According to the mass ratio of melamine: water: concentrated phosphoric acid of 1:70:3, melamine was dissolved in water, concentrated phosphoric acid was added, and crystallization was carried out at 170 °C, followed by filtration and drying to obtain solid I;

[0048] (2) Solid I was calcined at 550 °C in an N2 atmosphere for 4.5 h to obtain C3N4;

[0049] (3) Add the C3N4 catalyst to water, add RuCl3, control the mass ratio of C3N4 to Ru to be 1:0.1, and the mass ratio of water to C3N4 to be 40:1, and vacuum dry at 50 °C to obtain solid II;

[0050] (4) Calcinate solid II at 500 °C for 3.5 h to obtain the Ru2O3 / C3N4 photocatalyst.

[0051] Add 1.0923 g of benzyl alcohol (content 99%) to a 100 mL reaction flask, add 50 mL of n-hexane as a solvent, add 1.1445 g of potassium tert-butoxide (content 98%), add 1.2889 g of N-(2-aminoethyl)morpholine (content 99%), and then add 20 mg of Ru2O3 / C3N4. React for 3 hours under normal temperature and xenon lamp illumination conditions to obtain a light gray mixed solution. After filtration, rotary evaporation, and washing with water, a white solid is obtained for detection. The content of N-[2-(4-morpholinyl)ethyl]benzamide in benzyl alcohol is 93.4%, and the yield of N-[2-(4-morpholinyl)ethyl]benzamide based on benzyl alcohol is 82.5%. The 1H NMR spectrum of the white solid is as Figure 2 shown:

[0052] δ 2.50 is the solvent peak, δ 2.41~2.44 (m, 4H), δ 2.45~2.50 (m, 2H), δ 3.36 (t, J = 6 Hz, 2H), δ 3.56 (t, J = 4 Hz, 4H), δ 7.44 (t, J = 6 Hz, 2H), δ 7.50 (t, J = 6 Hz, 1H), 7.82 (d, J = 4 Hz, 2H), 8.39 (t, 1H). Its chemical shift and the number of hydrogens are consistent with those of the hydrogens of N-[2-(4-morpholinyl)ethyl]benzamide.

[0053] Comparative Example 2

[0054] Add 1.0923 g of benzyl alcohol (content 99%) to a 100 mL reaction flask, add 50 mL of n-hexane as a solvent, add 1.1445 g of potassium tert-butoxide (content 98%), add 1.2889 g of N-(2-aminoethyl)morpholine (content 99%), and then add 0.10 g of RuCl3. React for 3 hours under normal temperature and xenon lamp illumination conditions. After analysis and detection, the target product N-[2-(4-morpholinyl)ethyl]benzamide of benzyl alcohol is not obtained.

[0055] Example 3

[0056] The preparation process of the CuO / C3N4 photocatalyst is as follows:

[0057] (1) Dissolve melamine in water according to the mass ratio of melamine: water: concentrated phosphoric acid of 1:70:3, add concentrated phosphoric acid, crystallize at 170 °C, filter, and dry to obtain solid I;

[0058] (2) Calcinate solid I at 550 °C in an N₂ atmosphere for 4.5 h to obtain C₃N₄;

[0059] (3) Add C₃N₄ to water, add CuCl₂, control the mass ratio of C₃N₄ to Cu to be 1:0.15, and the mass ratio of water to C₃N₄ to be 40:1, and vacuum dry at 50 °C to obtain solid II;

[0060] (4) Calcinate solid II at 500 °C for 3.5 h to obtain the CuO / C₃N₄ photocatalyst.

[0061] Add 1.0923 g of benzaldehyde (with a content of 99%) to a 100 mL reaction flask, add 50 mL of cyclohexane as a solvent, 0.9796 g of sodium tert-butoxide (with a content of 98%), add 1.2889 g of N-(2-aminoethyl)morpholine (with a content of 99%), and then add 20 mg of CuO / C₃N₄. React under normal temperature and 15 W LED light illumination conditions for 6 hours to obtain a light gray mixed solution. After filtration, rotary evaporation, and washing with water, a white solid is obtained for detection. The content of N-[2-(4-morpholinyl)ethyl]benzamide in benzyl alcohol is 91.7%, and the yield of N-[2-(4-morpholinyl)ethyl]benzamide based on benzyl alcohol is 84.5%. The mass spectrum of the white solid is as Figure 3 shown:

[0062] The mass spectrum of the white solid is as Figure 3 shown. The peak with a mass-to-charge ratio of 235.1458 in the spectrum is the [M + 1] ion peak. The theoretical molecular weight [M + H] of N-[2-(4-morpholinyl)ethyl]benzamide is 235.1441, confirming that the product is N-[2-(4-morpholinyl)ethyl]benzamide.

[0063] Comparative Example 3

[0064] Add 1.0829 g of benzaldehyde (with a content of 99%) to a 100 mL reaction flask, add 50 mL of cyclohexane as a solvent, add 0.9796 g of sodium tert-butoxide (with a content of 98%), add 1.2889 g of N-(2-aminoethyl)morpholine (with a content of 99%), and then add 0.10 g of CuCl₂. React under normal temperature and 15 W LED light illumination conditions for 8 hours. After analysis and detection, the target product N-[2-(4-morpholinyl)ethyl]benzamide of benzyl alcohol is not obtained.

[0065] Example 4

[0066] The preparation process of the Mn3O4 / C3N4 photocatalyst is as follows:

[0067] (1) Dissolve melamine in water according to the mass ratio of melamine: water: concentrated phosphoric acid of 1:80:2, add concentrated phosphoric acid, crystallize at 190 °C, filter, and dry to obtain solid I;

[0068] (2) Calcinate solid I at 520 °C in an N2 atmosphere for 5 h to obtain C3N4;

[0069] (3) Add C3N4 to water, add manganese acetate, control the mass ratio of C3N4 to manganese to be 1:0.1, and the mass ratio of water to C3N4 to be 20:1, and vacuum dry at 60 °C to obtain solid II;

[0070] (4) Calcinate solid II at 300 °C for 2 h to obtain the Mn3O4 / C3N4 photocatalyst.

[0071] Add 1.4402 g of 4-chlorobenzyl alcohol (content 99%) to a 100 mL reaction flask, add 25 mL of benzene as a solvent, then add 0.67 g of potassium hydride (content 60%), add 1.2889 g of N-(2-aminoethyl)morpholine (content 99%), and then add 50 mg of Mn3O4 / C3N4. React under normal temperature and 30 W LED light illumination conditions for 9 hours to obtain a mixed solution, which is filtered, rotary evaporated, and washed with water to obtain a white solid. After analysis and testing, the content of 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide is 94.8%, and the yield of 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide based on 4-chlorobenzyl alcohol is 83.5%.

[0072] Comparative Example 4

[0073] Add 1.4402 g of 4-chlorobenzyl alcohol (content 99%) to a 100 mL reaction flask, add 25 mL of benzene as a solvent, then add 0.67 g of potassium hydride (content 60%), add 1.2889 g of N-(2-aminoethyl)morpholine (content 99%), and then add 0.50 g of MnO2 (content 99%). React under normal temperature and 15 W LED light illumination conditions for 9 hours. After analysis and testing, the target product 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide of 4-chlorobenzyl alcohol was not obtained.

Claims

1. A photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds, characterized in that: Using a benzaldehyde compound with the structure of formula (II) and N-(2-aminoethyl)morpholine as raw materials, in the presence of an oxygen-containing atmosphere, an organic solvent, a base, and a transition metal oxide / C3N4 composite photocatalyst, an N-(2-morpholinoethyl)substituted benzamide compound with the structure of formula (III) is prepared through a photocatalytic reaction; wherein R is H, an alkyl group or a halogen; the alkyl group and the halogen are mono-substituted or the same or different multi-substituted; the alkyl group is a C1-C5 alkyl group; the halogen is F, Cl, Br or I; the organic solvent is one or more of toluene, benzotrifluoride, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene and dichloromethane; the transition metal in the transition metal oxide / C3N4 composite photocatalyst is copper.

2. The photocatalytic synthesis method of the N-(2-morpholinoethyl) substituted benzamide compounds according to claim 1, characterized in that: The molar ratio of the benzaldehyde compound to the N-(2-aminoethyl)morpholine compound is 1:1 to 1.

5.

3. The photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds according to claim 1, characterized in that: The oxygen-containing atmosphere is air and / or oxygen.

4. The photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds according to claim 1, characterized in that: The base is one or more of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium hydroxide, barium hydroxide, cesium carbonate and potassium carbonate.

5. The photocatalytic synthesis method of N-(2-morpholinoethyl) substituted benzamide compounds according to claim 1, characterized in that: The molar ratio of the benzaldehyde compound to the base is 1:0.1 to 3.

6. The photocatalytic synthesis method of the N-(2-morpholinoethyl) substituted benzamide compounds according to claim 1, characterized in that: In the transition metal oxide / C3N4 composite photocatalyst, the mass ratio of the transition metal to C3N4 is 0.01 to 0.5:

1.

7. The photocatalytic synthesis method of the N-(2-morpholinoethyl) substituted benzamide compound according to claim 1, characterized in that: The amount of the transition metal oxide / C3N4 composite photocatalyst is 0.1 to 5 wt% of the benzaldehyde compound.

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