阅读说明：本技术 一种n-(2-吗啉乙基)取代苯甲酰胺类化合物的光催化合成方法 (Photocatalytic synthesis method of N- (2-morpholinoethyl) substituted benzamide compound ) 是由 尹双凤 邓兰青 陈浪 周永波 于 2021-09-07 设计创作，主要内容包括：一种N-(2-吗啉乙基)取代苯甲酰胺类化合物的光催化合成方法,其特征在于：以式(I)结构的苄醇或式(II)结构的苯甲醛类化合物、N-(2-氨基乙基)吗啉为原料,在含氧气氛、有机溶剂、碱、过渡金属氧化物/C-(3)N-(4)复合光催化剂存在的条件下,经光催化反应制得具有式(III)结构的N-(2-吗啉乙基)取代苯甲酰胺类化合物。本发明以苄醇或苯甲醛类化合物为原料,避免了使用酰氯、氢溴酸,绿色经济制备N-(2-吗啉乙基)取代苯甲酰胺化合物。(A photocatalysis synthesis method of N- (2-morpholine ethyl) substituted benzamide compounds is characterized in that: taking benzyl alcohol with a structure shown in formula (I) or benzaldehyde compound with a structure shown in formula (II) and N- (2-aminoethyl) morpholine as raw materials, and performing reaction in oxygen-containing atmosphere, organic solvent, alkali and transition metal oxide/C 3 N 4 In the presence of the composite photocatalyst, the N- (2-morpholinoethyl) substituted benzamide compound with the structure of the formula (III) is prepared through a photocatalytic reaction. The invention takes benzyl alcohol or benzaldehyde compounds as raw materials, avoids using acyl chloride and hydrobromic acid, and prepares the N- (2-morpholine ethyl) substituted benzamide compound in a green and economic way.)

1. Photocatalysis synthesis of N- (2-morpholinoethyl) substituted benzamide compoundThe method is characterized in that: taking benzyl alcohol with a structure shown in formula (I) or benzaldehyde compound with a structure shown in formula (II) and N- (2-aminoethyl) morpholine as raw materials, and performing reaction in oxygen-containing atmosphere, organic solvent, alkali and transition metal oxide/C₃N₄In the presence of a composite photocatalyst, an N- (2-morpholinoethyl) substituted benzamide compound with a structure shown in a formula (III) is prepared through a photocatalytic reaction;

wherein R is H, alkyl or halogen; the alkyl and the halogen are mono-substituted or multi-substituted in the same or different ways.

2. The photocatalytic synthesis method of N- (2-morpholinoethyl) substituted benzamides compound according to claim 1, wherein: the alkyl group is C₁～C₅Alkyl groups of (a); halogen is F, Cl, Br or I.

3. The photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound according to claim 1 or 2, characterized in that: the molar ratio of the benzyl alcohol or benzaldehyde compound to the N- (2-aminoethyl) morpholine compound is 1: 1 to 1.5.

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

5. The photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound according to claim 1 or 2, characterized in that: the organic solvent is one or more of toluene, trifluorotoluene, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene and dichloromethane.

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

7. The photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound according to claim 1 or 2, characterized in that: the molar ratio of the benzyl alcohol or benzaldehyde compound to the alkali is 1:0.1 to 3.

8. The photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound according to claim 1 or 2, characterized in that: the transition metal oxide/C₃N₄The transition metal in the composite photocatalyst is one or more of silver, ruthenium, cobalt, copper, iron, gold, platinum, palladium, praseodymium, germanium, nickel and manganese.

9. The photocatalytic synthesis method of N- (2-morpholinoethyl) substituted benzamides compound according to claim 8, wherein: the transition metal oxide/C₃N₄In the composite photocatalyst, transition metal and C₃N₄The mass ratio of (A) to (B) is 0.01-0.5: 1.

10. the photocatalytic synthesis method of N- (2-morpholinoethyl) substituted benzamides compound according to claim 8, wherein: the transition metal oxide/C₃N₄The amount of the composite photocatalyst is 0.1-5 wt% of benzyl alcohol or benzaldehyde compound.

Technical Field

The invention relates to a photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound, belonging to the technical field of organic drug synthesis.

Background

The N- (2-morpholinoethyl) substituted benzamide compound plays an important role in the field of drug development. The antidepressant Moclobemide (Mocloemide) is a 4-chloro-N- [2- (4-morpholinyl) ethyl ] benzamide which is marketed under the chemical name, is a reversible selective monoamine oxidase inhibitor, and is a reversible A-type MAOI with good selectivity and strong effect. CN 101759667A discloses a synthesis method of moclobemide by using ethanolamine as a raw material, reacting with hydrobromic acid, and then reacting with p-chlorobenzoyl chloride and morpholine. CN108658852A discloses a pharmaceutical intermediate ethanolamine and 5-chloro-2-pyridinecarboxylic acid as starting materials, and the 5-chloro-N- [2- (4-morpholinyl) ethyl ] picolinamide is obtained through the intermediate 2-bromoethylamine hydrobromide and 5-chloro-2-pyridinecarboxylic acid chloride. The traditional synthesis of N- (2-morpholinoethyl) benzamide adopts ethanolamine as a raw material, uses strong acid hydrobromic acid and acyl chloride, has high requirements on reaction and equipment, and releases HCl in the reaction process of the acyl chloride, which is extremely unfavorable for the environment. From the atomic economy, the method has the defects of more wastes, complex post-treatment process, poor atomic economy and no contribution to large-scale production in the using process.

Disclosure of Invention

Aiming at the technical problems in the prior art, the invention aims to provide a photocatalytic synthesis method of an N- (2-morpholinoethyl) substituted benzamide compound, which takes benzyl alcohol or benzaldehyde compounds as raw materials, avoids using acyl chloride and hydrobromic acid, and prepares the N- (2-morpholinoethyl) substituted benzamide compound in a green and economic way.

In order to achieve the technical purpose, the invention adopts the following technical scheme:

a photocatalytic synthesis method of N- (2-morpholinoethyl) substituted benzamide compounds uses benzyl alcohol with a structure of formula (I) or benzaldehyde compounds with a structure of formula (II) and N- (2-aminoethyl) morpholine as raw materials, and comprises the steps of oxidizing atmosphere, organic solvent, alkali, transition metal oxide/C₃N₄In the presence of a composite photocatalyst, an N- (2-morpholinoethyl) substituted benzamide compound with a structure shown in a formula (III) is prepared through a photocatalytic reaction;

wherein R is H, alkyl or halogen; the alkyl and the halogen are mono-substituted or multi-substituted in the same or different ways.

Preferably, the alkyl group is C₁～C₅Alkyl groups of (a); halogen is F, Cl, Br or I.

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

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

Preferably, the organic solvent is one or more of toluene, benzotrifluoride, xylene, benzene, cyclohexane, n-hexane, acetonitrile, mesitylene and dichloromethane; further preferably one or more of n-hexane, cyclohexane, toluene and benzene.

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

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

Preferably, the transition metal oxide/C₃N₄The transition metal in the composite photocatalyst is one or more of silver, ruthenium, cobalt, copper, iron, gold, platinum, palladium, praseodymium, germanium, nickel and manganese.

Preferably, the transition metal oxide/C₃N₄In the composite photocatalyst, transition metal and C₃N₄The mass ratio of (A) to (B) is 0.01-0.5: 1.

preferably, the transition metal oxide/C₃N₄The amount of the composite photocatalyst is 0.1-5 wt% of benzyl alcohol or benzaldehyde compound.

In the present invention, the transition metal oxide/C₃N₄The composite photocatalyst can be prepared by the conventional method, such as C₃N₄Dispersing in water, adding soluble transition metal salt, mixing, drying, and roasting.

Preferably, the conditions of the photocatalytic reaction are as follows: and reacting for 1-10 h under the light source of a 3-100W LED lamp or xenon lamp.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention adopts benzyl alcohol or benzaldehyde as raw materials, the raw materials are easy to obtain, acyl chloride and hydrobromic acid are avoided, the raw materials are greener and more economical, the reaction conditions are mild, the reaction steps are reduced, and the operation is simple and convenient.

(2) The invention has convenient purification of the product, and the product can be obtained only by filtering to remove the catalyst after the reaction is finished, drying and washing with water, thereby avoiding the use of chromatographic columns or the separation of a large amount of organic solvents.

(3) The invention reacts in an oxygen-containing atmosphere, has mild oxidation performance, avoids using peroxide and is more beneficial to the recycling of the catalyst; and transition metal oxide/C₃N₄The composite photocatalyst can be separated from the reaction system only by simple filtration, so that the problem that the homogeneous catalyst and the reaction liquid are difficult to separate is effectively solved, the loss of catalytic activity is not obvious, the production cost is reduced, and the requirement of green chemistry is met;

(4) the photocatalyst of the invention forms electron-hole pairs under the irradiation of visible light, which can effectively avoid high-temperature thermal reaction and make the selectivity of the product higher.

Drawings

FIG. 1 is the NMR spectrum of 4-chloro-N- [2- (4-morpholinyl) ethyl ] benzamide in example 1;

FIG. 2 is the NMR chart of N- [2- (4-morpholinyl) ethyl ] benzamide in example 2;

FIG. 3 is the mass spectrum of N- [2- (4-morpholinyl) ethyl ] benzamide in example 3.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments that can be derived by one of ordinary skill in the art from the embodiments given herein are intended to be within the scope of the present invention. Unless defined otherwise, all terms of art and skill used hereinafter

The meaning is generally understood by a skilled person. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.

All parts and percentages in the examples are by mass unless otherwise specified.

Transition Metal oxide/C in the invention₃N₄The specific preparation process of the composite photocatalyst comprises the following steps:

(1) according to the following formula, melamine: water: dissolving melamine in water at a mass ratio of concentrated phosphoric acid of 1: 40-100: 1.5-5, adding concentrated phosphoric acid, crystallizing at 120-200 ℃, filtering, and drying to obtain a solid I;

(2) the solid I is processed at 400-550 ℃ and N₂Roasting for 2-8 h in the atmosphere to obtain C₃N₄；

(3) C is to be₃N₄Adding into water, adding soluble transition metal salt, and controlling C₃N₄The mass ratio of the transition metal to the transition metal is 1: 0.01 to 0.5 wt% of water and C₃N₄The mass ratio of (A) to (B) is 10-200: 1, drying at 30-80 ℃ in vacuum to obtain a solid II;

(4) roasting the solid II at 200-550 ℃ for 0.5-6 h to obtain transition metal oxide/C₃N₄A composite photocatalyst is provided.

Example 1

Ag₂O/C₃N₄The preparation process of the photocatalyst comprises the following steps:

(1) according to the proportion of melamine: water: dissolving melamine in water at a mass ratio of 1:80:2, adding concentrated phosphoric acid, crystallizing at 190 ℃, filtering, and drying to obtain a solid I;

(2) subjecting the solid I to a reaction at 520 ℃ and N₂Roasting for 5h under atmosphere to obtain C₃N₄；

(3) C is to be₃N₄Adding into water, adding AgNO₃Control of C₃N₄The mass ratio of the Ag to the water is 1:0.05, and the water to the C₃N₄The mass ratio of (1) to (2) is 20:1, and solid II is obtained by vacuum drying at 60 ℃;

(4) mixing the solidII roasting at 300 deg.C for 2h to obtain Ag₂O/C₃N₄A photocatalyst.

1.4402g of p-chlorobenzyl alcohol (99% content) was charged into a 100mL reaction flask, 25mL of toluene was added as a solvent, 0.4g of sodium hydride (60% content) was added, 1.2889g of N- (2-aminoethyl) morpholine (99% content) was added, and 20mg of Ag was added₂O/C₃N₄Reacting for 8 hours under the conditions of normal temperature and 30W LED lamp illumination to obtain a mixed solution, and filtering, spin-drying and washing to obtain a white solid. The 4-chloro-N- [2- (4-morpholinyl) ethyl is detected by analysis]Benzamide content 93.4%, based on p-chlorobenzyl alcohol 4-chloro-N- [2- (4-morpholinyl) ethyl]The yield of benzamide was 85.7%.

The white solid is characterized, and the nuclear magnetic resonance hydrogen spectrum of the white solid is shown in figure 1: δ 2.50 is the solvent peak, δ 1.31 (t, J ═ 6Hz,6H), δ 3.14 to 3.20(m,4H), δ 3.49(m,2H),6.19(s,1H),6.68(d, J ═ 8Hz,2H), 7.77(d, J ═ 8Hz,2H) with chemical shifts and number of hydrogens matching those on 4-chloro-N- [2- (4-morpholinyl) ethyl ] benzamide.

Comparative example 1

1.4402g of p-chlorobenzyl alcohol (99% content) was charged into a 100mL reaction flask, 25mL of toluene was added as a solvent, 0.4g of sodium hydride (60% content) was added, 1.2889g of N- (2-aminoethyl) morpholine (99% content) was added, and 0.5206g of MnO was added₂(content: 99%) and 9.7363g of tert-butyl hydroperoxide (content: 70%). And reacting for 10 hours at normal temperature under the illumination condition of 30W LED lamp. Analysis and detection show that the target product, namely the 4-chloro-N- [2- (4-morpholinyl) ethyl of p-chlorobenzyl alcohol is not obtained]A benzamide.

Example 2

Ru₂O₃/C₃N₄The preparation process of the photocatalyst comprises the following steps:

(1) according to the proportion of melamine: water: dissolving melamine in water at a mass ratio of 1:70:3, adding concentrated phosphoric acid, crystallizing at 170 ℃, filtering, and drying to obtain solid I;

(2) subjecting the solid I to a temperature of 550 ℃ and a temperature of N₂Roasting for 4.5h in the atmosphere to obtain C₃N₄；

(3) C is to be₃N₄Adding catalyst into water, adding RuCl₃Control of C₃N₄The mass ratio of the Ru to water is 1:0.1, and the ratio of the C to the water is₃N₄The mass ratio of the solid II to the solid II is 40:1, and the solid II is obtained by vacuum drying at the temperature of 50 ℃;

(4) roasting the solid II at 500 ℃ for 3.5h to obtain Ru₂O₃/C₃N₄A photocatalyst.

1.0923g of benzyl alcohol (99% content) was put into a 100mL reaction flask, 50mL of n-hexane was added as a solvent, 1.1445g of potassium tert-butoxide (98% content) was added, 1.2889g of N- (2-aminoethyl) morpholine (99% content) was added, and 20mg of Ru was added₂O₃/C₃N₄And reacting for 3 hours at normal temperature under the condition of illumination of a xenon lamp to obtain light gray mixed liquor. Filtering, spin-drying, washing with water to obtain white solid, wherein the benzyl alcohol has N- [2- (4-morpholinyl) ethyl group]Benzamide content 93.4%, N- [2- (4-morpholinyl) ethyl based on benzyl alcohol]The yield of benzamide was 82.5%. The nmr spectrum of the white solid is shown in fig. 2:

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

Comparative example 2

1.0923g of benzyl alcohol (content: 99%) was put into a 100mL reaction flask, 50mL of n-hexane was added as a solvent, 1.1445g of potassium tert-butoxide (content: 98%) was added, 1.2889g of N- (2-aminoethyl) morpholine (content: 99%) was added, and 0.10g of RuCl was added₃And reacting for 3 hours at normal temperature under the condition of illumination of a xenon lamp. Analysis and detection show that the target product of benzyl alcohol N- [2- (4-morpholinyl) ethyl]A benzamide.

Example 3

CuO/C₃N₄The preparation process of the photocatalyst comprises the following steps:

(1) according to the proportion of melamine: water: dissolving melamine in water at a mass ratio of 1:70:3, adding concentrated phosphoric acid, crystallizing at 170 ℃, filtering, and drying to obtain solid I;

(2) subjecting the solid I to a temperature of 550 ℃ and a temperature of N₂Roasting for 4.5h in the atmosphere to obtain C₃N₄；

(3) C is to be₃N₄Adding into water, adding CuCl₂Control of C₃N₄The mass ratio of the Cu to the water is 1:0.15, and the mass ratio of the water to the C is₃N₄The mass ratio of the solid II to the solid II is 40:1, and the solid II is obtained by vacuum drying at the temperature of 50 ℃;

(4) roasting the solid II at 500 ℃ for 3.5h to obtain CuO/C₃N₄A photocatalyst.

1.0923g benzaldehyde (99% content) was charged into a 100mL reaction flask, 50mL cyclohexane was added as solvent, 0.9796g sodium tert-butoxide (98% content) was added, 1.2889g N- (2-aminoethyl) morpholine (99% content) was added, and 20mg CuO/C was added₃N₄And reacting for 6 hours at normal temperature under the condition of 15W LED lamp illumination to obtain light gray mixed liquor. Filtering, spin-drying, washing with water to obtain white solid, wherein the benzyl alcohol has N- [2- (4-morpholinyl) ethyl group]Benzamide content 91.7% N- [2- (4-morpholinyl) ethyl ] on benzyl alcohol]The yield of benzamide was 84.5%. The mass spectrum of the white solid is shown in FIG. 3:

the mass spectrum of the white solid is shown in FIG. 3, and the peak having a mass-to-charge ratio of 235.1458 in the spectrum is an ion peak of [ M +1], the theoretical molecular weight of N- [2- (4-morpholino) ethyl ] benzamide [ M + H ] is 235.1441, and it was confirmed that the product is N- [2- (4-morpholino) ethyl ] benzamide.

Comparative example 3

1.0829g benzaldehyde (99% content) was charged into a 100mL reaction flask, 50mL cyclohexane was added as solvent, 0.9796g sodium tert-butoxide (98% content) was added, 1.2889g N- (2-aminoethyl) morpholine (99% content) was added, and 0.10g CuCl was added₂And reacting for 8 hours at normal temperature under the condition of 15W LED lamp illumination. Analysis and detection show that the target product of benzyl alcohol N- [2- (4-morpholinyl) ethyl]A benzamide.

Example 4

Mn₃O₄/C₃N₄The preparation process of the photocatalyst comprises the following steps:

(1) according to the proportion of melamine: water: dissolving melamine in water at a mass ratio of 1:80:2, adding concentrated phosphoric acid, crystallizing at 190 ℃, filtering, and drying to obtain a solid I;

(2) subjecting the solid I to a reaction at 520 ℃ and N₂Roasting for 5h under atmosphere to obtain C₃N₄；

(3) C is to be₃N₄Adding into water, adding manganese acetate, and controlling C₃N₄The mass ratio of the manganese to the water is 1:0.1, and the mass ratio of the water to the C is₃N₄The mass ratio of (1) to (2) is 20:1, and solid II is obtained by vacuum drying at 60 ℃;

(4) roasting the solid II at 300 ℃ for 2h to obtain Mn₃O₄/C₃N₄A photocatalyst.

1.4402g of p-chlorobenzyl alcohol (99% content) was charged into a 100mL reaction flask, 25mL of benzene was added as a solvent, 0.67g of potassium hydride (60% content) was added, 1.2889g of N- (2-aminoethyl) morpholine (99% content) was added, and 50mg of Mn was added₃O₄/C₃N₄Reacting for 9 hours under the conditions of normal temperature and 30W LED lamp illumination to obtain a mixed solution, and filtering, spin-drying and washing to obtain a white solid. The 4-chloro-N- [2- (4-morpholinyl) ethyl is detected by analysis]Benzamide content of 94.8% based on p-chlorobenzyl alcohol 4-chloro-N- [2- (4-morpholinyl) ethyl]The yield of benzamide was 83.5%.

Comparative example 4

1.4402g of p-chlorobenzyl alcohol (99% content) was charged into a 100mL reaction flask, 25mL of benzene was added as a solvent, 0.67g of potassium hydride (60% content), 1.2889g of N- (2-aminoethyl) morpholine (99% content) was added, and 0.50g of MnO was added₂(content: 99%). And reacting for 9 hours at normal temperature under the condition of 15W LED lamp illumination. Analysis and detection show that the target product, namely the 4-chloro-N- [2- (4-morpholinyl) ethyl of p-chlorobenzyl alcohol is not obtained]A benzamide.