Preparation method of N-(2-phenoxy phenyl) acetamide derivative
Through the lack of synthesis process in the fields of photoelectric materials and fluorescent probes, N was successfully prepared by etherification and dehydration and condensation reaction of phenol derivatives with ortho-iodominophenylene, combined with copper powder and N-phenylpyridinamide catalytic system. -(2-phenoxyphenyl)acetamide derivatives solve the problem of missing synthesis process in the prior art and achieve efficient and environmentally friendly product preparation.
Patent Information
- Application Number
- CN202411041599.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-07-31
- Publication Date
- 2024-12-20
AI Technical Summary
The lack of the synthesis process of N-(2-phenoxyphenyl)acetamide derivatives in the prior art limits its application in the fields of photoelectric materials, fluorescent probes, etc.
The 2-aminodiphenyl ether derivative was constructed by etherification strategy of halogenated alkyl and alcohol, and reacted under the action of copper, alkali and cesium carbonate, followed by The target product N-(2-phenoxyphenyl)acetamide derivative was formed with the help of an amidation catalyst. The method includes two steps: first, etherification reaction at 50-150°C, then dehydration and condensation reaction at 0-40°C, using copper powder and N-phenylpyridinamide as the catalytic system, optimize the reaction conditions Improve yield and purity.
Achieve efficient preparation of N-(2-phenoxyphenyl)acetamide derivatives, with yields reaching 98.13% and above, simplifying the process flow, reducing operational complexity and energy consumption, and reducing selected reaction conditions The production of harmful by-products meets environmental protection requirements.
Smart Images
Figure FT_1 
Figure SMS_11 
Figure QLYQS_1
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of luminescent material synthesis, and in particular relates to a method for preparing an N-(2-phenoxyphenyl)acetamide derivative. Background Art
[0002] As a new type of molecule, N-(2-phenoxyphenyl)acetamide derivatives contain amino groups (-NH2) in their molecules, which are reactive functional groups that can be used to synthesize more complex organic compounds or added as functional groups to polymer materials. It can also be introduced into existing polymer chains as a side chain or end group modifier to adjust its surface properties, adhesion properties, electrical properties, etc. N-(2-phenoxyphenyl)acetamide derivatives show fluorescence, which may be used in optoelectronic materials (organic light-emitting diodes OLED, solar cells), fluorescent probes (biomarkers, environmental monitoring) and other fields. The prior art does not disclose its synthesis process. Summary of the invention
[0003] This patent uses phenol derivatives and o-iodoaminobenzene as starting materials, and adopts the etherification strategy of halogenated alkyl and alcohol to construct the structure of 2-aminodiphenyl ether derivatives, and then Dehydration condensation occurs to form the target product N-(2-phenoxyphenyl)acetamide derivative. The synthetic route is as follows: .
[0004] The reaction process is: In solvent A, under the action of copper, alkali and cesium carbonate, compound 1 and compound 2 react at 50-150° C. to obtain compound 3, and the molar ratio of compound 1, compound 2, copper, alkali and cesium carbonate is 0.5-3.0:1:0.5-1.2:0.7-1.5:0.05-0.2.
[0005] In solvent B, under the catalysis of the amidation catalyst, compound 3 and The reaction was carried out at 0-40°C to obtain N-(2-phenoxyphenyl)acetamide derivatives, compound 3, The molar ratio of the amidation catalyst is 1:1.0-2.0:0.6-1.2.
[0006] Under the reaction conditions of this patent, the hydrocarbon group on compound 1 does not react with the amino group on compound 2 (as a person skilled in the art would readily appreciate).
[0007] Among them, R2 is selected from hydrogen, R1 is selected from hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, aryl with 6-8 carbon atoms, heteroalkyl with 5-30 carbon atoms, etc.; R3 is selected from alkylamino with 1-4 carbon atoms, etc.; X is selected from bromine, iodine, chlorine, etc., preferably iodine.
[0008] Wherein, for R1: alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc., alkoxy is selected from methoxy, ethoxy, propoxy, etc., aryl is selected from phenyl, tolyl, xylyl, etc., heteroalkyl is selected from pyridyl, furyl, indolyl, etc.; R1 is preferably meta. R3 is selected from methaneamino.
[0009] Specifically, compound 3 is selected from: , , ; Correspondingly, compound 4 is selected from: , , .
[0010] More specifically, compound 2 is selected from 2-iodoaniline, compound 1 is selected from 3-methoxyphenol, compound 3 is selected from 2-(3-methoxyphenoxy)aniline, and compound 4 is selected from 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide. The preparation method of the N-(2-phenoxyphenyl)acetamide derivative provided by the present invention comprises: (1) In solvent A, 2-iodoaniline and 3-methoxyphenol react at 50-150° C. under the action of copper, alkali and cesium carbonate to obtain 2-(3-methoxyphenoxy)aniline, wherein the molar ratio of 3-methoxyphenol, 2-iodoaniline, copper, alkali and cesium carbonate is 0.5-3.0:1:0.5-1.2:0.7-1.5:0.05-0.2.
[0011] (2) In solvent B, under the catalysis of an amidation catalyst, 2-(3-methoxyphenoxy)aniline and glycine react at 0-40° C. to obtain 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide; the molar ratio of 2-(3-methoxyphenoxy)aniline, glycine and amidation catalyst is 1:1.0-2.0:0.6-1.2.
[0012] Wherein, solvent A is selected from acetonitrile.
[0013] Wherein, solvent B is selected from tetrahydrofuran, pyridine, dioxane, methanol, ethanol, n-heptane, ethyl acetate, dichloromethane, ether, etc., and solvent B is preferably tetrahydrofuran.
[0014] Wherein, the base is selected from triethylamine, pyridine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, N-phenylpyridinecarboxamide, etc. Preferably, the base is selected from triethylamine, sodium tert-butoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, N-phenylpyridinecarboxamide. Most preferably, the base is selected from N-phenylpyridinecarboxamide.
[0015] Wherein, the amidation catalyst is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, etc. Preferably, the amidation catalyst is selected from triethylamine, cesium carbonate, 4-dimethylaminopyridine, 1-hydroxybenzotriazole. Most preferably, the amidation catalyst is selected from 1-hydroxybenzotriazole.
[0016] Preferably, the preparation method of the N-(2-phenoxyphenyl)acetamide derivative provided by the present invention comprises: (1) In acetonitrile, 2-iodoaniline, 3-methoxyphenol, cesium carbonate, N-phenylpyridinecarboxamide and copper powder are reacted at 80-90° C. for 12-36 hours. After the reaction is completed, solid-liquid separation is performed, the liquid phase is extracted by cyclohexane, and the organic phase is rotary evaporated to obtain a crude product; the crude product is dissolved in 1-2 times the mass of tetrahydrofuran, and then 2.5-3.5 times the mass of ethanol is added to precipitate crystals, and solid-liquid separation is performed to obtain 2-(3-methoxyphenoxy)aniline.
[0017] (2) In tetrahydrofuran, 2-(3-methoxyphenoxy)aniline, glycine and N,N'-carbonyldiimidazole are reacted at 0-25°C for 6-15h. After the reaction is completed, the crude product is dried by rotation to obtain a crude product. The crude product is dissolved in 1-2 times the mass of tetrahydrofuran, and then 2.5-3.5 times the mass of toluene is added. After crystals are precipitated, solid-liquid separation is performed to obtain 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide.
[0018] In the first step of this method, a catalytic system consisting of copper powder, N-phenylpyridine carboxamide and cesium carbonate was used. It showed excellent catalytic activity and selectivity in the etherification reaction of the first step, and could efficiently complete the reaction within 20-24 hours under mild conditions of 80-90°C, with sufficient raw material conversion and a yield of up to 98.13%. In the purification stage, a method combining cyclohexane extraction and solvent crystallization was adopted. The effective ingredients were first extracted with cyclohexane, and then the crude product was dissolved with tetrahydrofuran and ethanol was gradually added dropwise to induce crystallization. This process improved the purity and yield of the final product and ensured the high-quality output of the target compound.
[0019] In the first step, if cesium carbonate is not added, the reaction will take more than 40 hours to be basically completed; if copper is not added or other metals (such as iron, silver, etc.) are used, the etherification reaction will not proceed; if other solvents are used, the reaction will not proceed or the yield will be low (the yield is basically less than 90%).
[0020] In the second step of the method, 2-(3-methoxyphenoxy)aniline is connected to glycine by a condensation reaction catalyzed by N,N'-carbonyldiimidazole. The entire second step reaction can achieve an ideal conversion rate in only 6-15 hours (usually 12 hours) at a low temperature of 0-25°C, achieving a high yield of 92.12%.
[0021] During the reaction and purification process, the selected solvents such as acetonitrile, tetrahydrofuran and cyclohexane can be recycled and reused. Due to the optimization of the reaction conditions, catalyst use and purification process of the method, the overall synthesis process is more economical and efficient, the material consumption and energy cost are reduced, and it has a high practical value for industrial production. The final product is verified by mass spectrometry characterization means, and the structure is confirmed to be correct, proving that the present invention has indeed successfully synthesized 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide, which ensures the accuracy of the synthesis result.
[0022] This patent has the following advantages: 1) Select mild conditions such as etherification reaction and dehydration condensation to reduce the generation of harmful by-products and meet environmental protection requirements.
[0023] 2) The target compound can be prepared through only two steps of direct conversion, which simplifies the process flow and reduces operation complexity and energy consumption.
[0024] 3) The selected reaction conditions are conducive to the efficient formation of the target product, and are expected to achieve high yield (total yield greater than 90%, which is very high in organic synthesis) and excellent stereoselectivity. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 It is the mass spectrum of 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide prepared by the present invention. DETAILED DESCRIPTION
[0026] In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is described in further detail below.
[0027] Example 1 Example 1 provides a method for preparing 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide, which is carried out according to the following steps:
[0028] Step 1: At room temperature, compound 1 (0.1 mol) was placed in a 50 mL round-bottom flask, and acetonitrile (40 mL) and compound 2 (0.1 mol), cesium carbonate (0.01 mol), N-phenylpyridine carboxamide (0.1 mol), copper powder (0.1 mol) were added, and the mixture was stirred at 80-90 ° C for 20-24 hours; after TLC monitoring of the complete consumption of the raw materials, the mixture was filtered and the residue was removed. About 40 ml of cyclohexane was added to the reaction solution for extraction, and the extract phase was taken and rotary evaporated to obtain a crude product. The crude product was dissolved in tetrahydrofuran (1.5 times the mass of the crude product), and ethanol (3 times the mass of the crude product) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour, and crystals were precipitated to obtain a fine product. The product was filtered and dried to obtain 21.10 g of an intermediate with a yield of 98.13% and a purity of 99.5%.
[0029] Step 2: Add 2-(3-methoxyphenoxy)aniline obtained in step 1, glycine (0.1 mol) and N,N'-carbonyldiimidazole (0.1 mol) to tetrahydrofuran, and react at 0-25°C for 12 hours; after the raw materials are completely consumed as monitored by TLC, spin dry, dissolve the crude product in tetrahydrofuran (1.5 times the mass of the crude product), slowly add toluene (3 times the mass of the crude product), stir at room temperature for 1 hour, precipitate crystals to obtain fine products, filter and dry to obtain 24.59 g of the final product, with a yield of 92.12% and a purity of 99.2%.
[0030] Comparative Example 1 Step 2 is the same as that of Example 1, wherein step 1 is as follows: at room temperature, compound 1 (0.1 mol) is placed in a 50 mL round-bottom flask, acetonitrile (40 mL) and compound 2 (0.1 mol), N-phenylpyridinecarboxamide (0.1 mol), copper powder (0.1 mol) are added, and the mixture is stirred at 80-90° C. for 20-24 hours; after the raw material is completely consumed as monitored by TLC, the mixture is filtered off with suction, the residue is removed, about 40 ml of cyclohexane is added to the reaction mixture for extraction, the aqueous phase is discarded, and the crude product is obtained by rotary evaporation. The crude product is dissolved in tetrahydrofuran (1.5 times the mass of the crude product), ethanol (3 times the mass of the crude product) is slowly added dropwise, and the mixture is stirred at room temperature for 1 hour. Crystals are precipitated to obtain a fine product, which is filtered off with suction and dried to obtain 17.51 g of an intermediate with a yield of 78.03% and a purity of 96.13%.
[0031] From comparative example 1, it can be seen that the reaction will be much slower if cesium carbonate is not added. The present invention can significantly increase the reaction speed by adding only a small amount of cesium carbonate.
[0032] Comparative Example 2 Step 2 is the same as that of Example 1, wherein step 1 is as follows: at room temperature, compound 1 (0.1 mol) is placed in a 50 mL round-bottom flask, acetonitrile (40 mL) and compound 2 (0.1 mol), potassium carbonate (0.01 mol), N-phenylpyridinecarboxamide (0.1 mol), and copper powder (0.1 mol) are added, and the mixture is stirred at 80-90° C. for 20-24 hours; after TLC monitoring of the complete consumption of the raw materials, the mixture is filtered off with suction, the residue is removed, about 40 ml of cyclohexane is added to the reaction mixture for extraction, the aqueous phase is discarded, and the crude product is obtained by rotary evaporation. The crude product is dissolved in tetrahydrofuran (1.5 times the mass of the crude product), and ethanol (3 times the mass of the crude product) is slowly added dropwise, and the mixture is stirred at room temperature for 1 hour. Crystals are precipitated to obtain fine products, which are filtered off with suction and dried to obtain 17.51 g of the intermediate with a yield of 78.03% and a purity of 96.14%.
[0033] From Comparative Example 2, it can be seen that the catalytic effect is not improved compared with Comparative Example 1 when cesium carbonate is replaced by potassium carbonate.
[0034] Comparative Example 3 Step 2 is the same as that of Example 1, wherein step 1 is as follows: at room temperature, compound 1 (0.1 mol) is placed in a 50 mL round-bottom flask, acetonitrile (40 mL) and compound 2 (0.1 mol), cesium carbonate (0.01 mol), N-phenylpyridinecarboxamide (0.1 mol), and silver powder (0.1 mol) are added, stirred at 80-90° C. for 20-24 hours, and monitored by TLC. The etherification reaction did not proceed.
[0035] From comparative example 3, it can be seen that copper has selective catalytic properties for the system of this patent.
[0036] Comparative Example 4 Step 2 is the same as that of Example 1, wherein step 1 is as follows: at room temperature, compound 1 (0.1 mol) is placed in a 50 mL round-bottom flask, acetonitrile (40 mL) and compound 2 (0.1 mol), cesium carbonate (0.11 mol), and copper powder (0.1 mol) are added, and the mixture is stirred at 80-90° C. for 20-24 hours; after the raw material is completely consumed as monitored by TLC, the mixture is filtered off with suction, the residue is removed, about 40 ml of cyclohexane is added to the reaction mixture for extraction, the aqueous phase is discarded, and the crude product is obtained by rotary evaporation. The crude product is dissolved in tetrahydrofuran (1.5 times the mass of the crude product), and ethanol (3 times the mass of the crude product) is slowly added dropwise, and the mixture is stirred at room temperature for 1 hour. Crystals are precipitated to obtain fine products, which are filtered off with suction and dried to obtain 19.95 g of the intermediate with a yield of 92.31% and a purity of 99.03%.
[0037] From Comparative Example 4, it can be seen that the etherification yield is higher when a specific base is used (cesium carbonate itself is also a base).
[0038] Comparative Example 5 Step 2 is the same as that of Example 1, wherein Step 1 is as follows: at room temperature, compound 1 (0.1 mol) is placed in a 50 mL round-bottom flask, tetrahydrofuran (40 mL) and compound 2 (0.1 mol), cesium carbonate (0.01 mol), N-phenylpyridinecarboxamide (0.1 mol), copper powder (0.1 mol) are added, and stirred at 80-90° C. for 20-24 hours; TLC monitoring shows that the reaction has not proceeded.
[0039] From comparative example 5, it can be seen that a specific solvent is required for the reaction of this patent to proceed.
[0040] Example 2-3 The reaction raw materials, reaction products, total yield and purity of Example 2-3 are shown in Table 1: Table 1 .
[0041] Wherein, the reaction conditions are consistent with those in Example 1.
[0042] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims
1. A method for preparing an N-(2-phenoxyphenyl)acetamide derivative, characterized in that: The reaction is as follows: In solvent A, under the action of copper, alkali and cesium carbonate, compound 1 and compound 2 react at 50-150° C. to obtain compound 3, wherein the molar ratio of compound 1, compound 2, copper, alkali and cesium carbonate is 0.5-3.0:1:0.5-1.2:0.7-1.5:0.05-0.2; In solvent B, under the catalysis of the amidation catalyst, compound 3 and The reaction was carried out at 0-40°C to obtain N-(2-phenoxyphenyl)acetamide derivatives, compound 3, The molar ratio of amidation catalyst is 1:1.0-2.0:0.6-1.2; Among them, R2 is selected from hydrogen, R1 is selected from hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-3 carbon atoms, aryl with 6-8 carbon atoms, heteroalkyl with 5-30 carbon atoms; R3 is selected from alkylamino with 1-4 carbon atoms; X is selected from bromine, iodine and chlorine.
2. The method for preparing N-(2-phenoxyphenyl)acetamide derivatives according to claim 1, characterized in that: For R1: the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; the alkoxy group is selected from methoxy, ethoxy, and propoxy; the aryl group is selected from phenyl, tolyl, and xylyl; the heteroalkyl group is selected from pyridyl, furyl, and indolyl; and R3 is selected from methaneamino.
3. The method for preparing the N-(2-phenoxyphenyl)acetamide derivative according to claim 1, characterized in that: Compound 3 is selected from: 、 、 ； Correspondingly, compound 4 is selected from: 、 、 。 4. The method for preparing N-(2-phenoxyphenyl)acetamide derivatives according to claim 1, characterized in that: Compound 2 is selected from 2-iodoaniline, compound 1 is selected from 3-methoxyphenol, compound 3 is selected from 2-(3-methoxyphenoxy)aniline, and compound 4 is selected from 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide.
5. The method for preparing the N-(2-phenoxyphenyl)acetamide derivative according to claim 4, characterized in that: The method comprises: (1) In solvent A, under the action of copper, alkali and cesium carbonate, 2-iodoaniline and 3-methoxyphenol react at 50-150° C. to obtain 2-(3-methoxyphenoxy)aniline, wherein the molar ratio of 3-methoxyphenol, 2-iodoaniline, copper, alkali and cesium carbonate is 0.5-3.0:1:0.5-1.2:0.7-1.5:0.05-0.2; (2) In solvent B, under the catalysis of an amidation catalyst, 2-(3-methoxyphenoxy)aniline and glycine react at 0-40° C. to obtain 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide; the molar ratio of 2-(3-methoxyphenoxy)aniline, glycine and amidation catalyst is 1:1.0-2.0:0.6-1.
2.
6. The method for preparing the N-(2-phenoxyphenyl)acetamide derivative according to claim 1 or 5, characterized in that: The solvent A is selected from acetonitrile.
7. The method for preparing an N-(2-phenoxyphenyl)acetamide derivative according to claim 1 or 5, characterized in that: The solvent B is selected from tetrahydrofuran, pyridine, dioxane, methanol, ethanol, n-heptane, ethyl acetate, dichloromethane, and ether.
8. The method for preparing an N-(2-phenoxyphenyl)acetamide derivative according to claim 1 or 5, characterized in that: The base is selected from triethylamine, pyridine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, sodium bicarbonate, sodium carbonate, cesium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and N-phenylpicolinamide.
9. The method for preparing an N-(2-phenoxyphenyl)acetamide derivative according to claim 1 or 5, characterized in that: The amidation catalyst is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, and 1-hydroxybenzotriazole.
10. The method for preparing an N-(2-phenoxyphenyl)acetamide derivative according to claim 1 or 5, characterized in that: The method comprises: (1) In acetonitrile, 2-iodoaniline, 3-methoxyphenol, cesium carbonate, N-phenylpyridinecarboxamide and copper powder are reacted at 80-90° C. After the reaction is completed, solid-liquid separation is performed, the liquid phase is extracted by cyclohexane, and the organic phase is rotary evaporated to obtain a crude product; the crude product is dissolved in tetrahydrofuran (1-2 times the mass), and then ethanol (2.5-3.5 times the mass of the crude product) is added, and after crystals are precipitated, solid-liquid separation is performed to obtain 2-(3-methoxyphenoxy)aniline; (2) In tetrahydrofuran, 2-(3-methoxyphenoxy)aniline, glycine and N,N'-carbonyldiimidazole are reacted at 0-25°C. After the reaction is completed, the crude product is dried by rotation to obtain a crude product. The crude product is dissolved in 1-2 times the mass of tetrahydrofuran, and then 2.5-3.5 times the mass of toluene is added to precipitate crystals and then solid-liquid separation is performed to obtain 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide.