2-phenylbenz-2-dimethylamine-1- (4-morpholinobenzyl) butanone

Abstract

The application discloses a synthesis method of 2-phenyl benz-2-dimethylamine-1-(4-morpholine benzyl phenyl) butanone and belongs to the field of photoinitiator preparation. The method specifically comprises the following steps: (1) reacting chlorobenzene with morpholine to prepare N-phenyl morpholine; (2) performing a Friedel-Crafts reaction on N-phenyl morpholine and 2-amino butyric acid to prepare compound I; (3) performing an aminomethylation reaction on compound I, formic acid and formaldehyde to prepare compound II; and (4) reacting compound II with chlorobenzyl to obtain 2-phenyl benz-2-dimethylamine-1-(4-morpholine benzyl phenyl) butanone. By implementing the application, the process route can be simplified, the use of fluorobenzene, bromine and the like can be avoided, and the yield can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of photoinitiators, in particular to a synthesis method of 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl phenyl) butanone. BACKGROUND

[0002] The initiator 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl phenyl) butanone (369) is a high-efficiency photoinitiator with high photosensitive range and good UV absorption, small migration and low odor, and is particularly suitable for rapid curing of dark systems.

[0003] The existing method generally uses fluorobenzene as a starting material, and the specific reaction route is as follows, but the synthesis method uses fluorobenzene in the synthesis process, and the price of fluorobenzene is high, so that the overall production cost is high, and in the last step of the reaction with morpholine, the waste water produced contains fluoride ions, and the treatment cost is high.

[0004]

[0005] In order to solve the above problems, an existing technology (CN108358871A) proposes a synthesis route using chlorobenzene as a starting reactant (as follows), but the reaction uses bromine, which is highly toxic and highly corrosive to equipment, and has high requirements for reaction equipment. In addition, the reaction route of the prior art is long, and the overall yield is low.

[0006]

[0007] Another existing technology (CN116332877A) also uses chlorobenzene as a starting reactant, and the specific reaction route is as follows, which avoids the use of chlorobenzene and bromine, and the reaction conditions are mild, but the technical route is long, and the overall yield is low, at 60% to 70%.

[0008] SUMMARY

[0009] The technical problem to be solved by the present application is to provide a synthesis method of 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl phenyl) butanone, which has low raw material cost, high yield, simple process route, low equipment requirement and easy large-scale production.

[0010] In order to solve the technical problems of the present application, the present application provides a synthesis method of 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl phenyl) butanone, which comprises the following steps:

[0011] (1) reacting chlorobenzene with morpholine to obtain N-phenyl morpholine;

[0012] (2) N-phenylmorpholine and 2-amino butyric acid are subjected to a Friedel-Crafts reaction to obtain compound I;

[0013]

[0014] (3) Compound I is subjected to an aminomethylation reaction with formic acid and formaldehyde to obtain compound II;

[0015]

[0016] (4) Compound II is reacted with chlorobenzene to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl) butanone.

[0017] As an improvement of the above technical solution, in step (1), chlorobenzene and morpholine are dissolved in a first solvent, an acid-binding agent and a first catalyst are added, and the reaction is carried out at 60-90°C for 8-16h. After the reaction is completed, the first solvent is separated to obtain N-phenylmorpholine; and / or

[0018] In step (2), N-phenylmorpholine and 2-amino butyric acid are dissolved in a second solvent, and a second catalyst is added, and the reaction is carried out at -20-0°C for 4-6h. The second solvent is separated to obtain compound I; and / or

[0019] In step (3), compound I is mixed with formic acid and a formaldehyde aqueous solution with a concentration of 20-60wt%, and the reaction is carried out at 80-100°C for 3-5h to obtain compound II; and / or

[0020] In step (4), compound II is mixed with chlorobenzene at 40-60°C for 2-5h, and then mixed with a lye at 40-60°C for 1-3h to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl) butanone.

[0021] As an improvement of the above technical solution, in step (1), chlorobenzene and morpholine are dissolved in a first solvent, an acid-binding agent and a first catalyst are added, and the reaction is carried out at 60-90°C for 8-16h. After the reaction is completed, the first solvent is separated to obtain N-phenylmorpholine; and / or

[0022] In step (2), 2-amino butyric acid and a second catalyst are mixed uniformly at -20-0°C, and are added dropwise to the intermediate system at -20-0°C. After the dropwise addition is completed, the reaction is carried out at -20-0°C for 4-6h. The reaction is quenched with water with a weight of 2-5 times that of chlorobenzene, the second solvent is separated, and compound I is obtained; and / or

[0023] In step (3), compound I is mixed with formic acid, and a 20-60 wt% formaldehyde aqueous solution is added dropwise at 10-30℃, after the dropwise addition is completed, the reaction is refluxed at 80-100℃ for 3-5h, the reaction is quenched with water in an amount of 1-5 times the weight of compound I, and extracted with the first extracting agent, the organic phase obtained by extraction is separated from the first extracting agent, and compound II is obtained; and / or

[0024] In step (4), compound II is mixed with water in an amount of 2-5 times the weight of compound II, chlorobenzene is added dropwise at 15-30℃, after the dropwise addition is completed, the reaction is carried out at 40-60℃ for 2-5h, and then a lye is added dropwise, the reaction is carried out at 40-60℃ for 1-3h, the temperature is lowered to 15-30℃, a second extracting agent is added for extraction, and the organic phase obtained by extraction is recovered from the second extracting agent, to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl) butanone.

[0025] As an improvement of the above technical solution, the first solvent is selected from one or more of DMF, DMSO, NMP, and DMA; the weight ratio of the first solvent to the chlorobenzene is 2-5:1; and / or

[0026] The first catalyst is selected from one or more of copper salt catalyst, nickel salt catalyst, and palladium salt catalyst; the weight ratio of the first catalyst to the chlorobenzene is 0.3-1:100; and / or

[0027] The acid-binding agent is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, and sodium hydroxide; the molar ratio of the acid-binding agent to the chlorobenzene is 1.2-2:1; and / or

[0028] The molar ratio of the morpholine to the chlorobenzene is 2-5:1-1.2.

[0029] As an improvement of the above technical solution, the second solvent is selected from one or more of dichloromethane, dichloroethane, and n-heptane; the weight ratio of the second solvent to the chlorobenzene is 3-6:1; and / or

[0030] The second catalyst is selected from one or more of aluminum chloride, zinc chloride, and iron chloride; the molar ratio of the second catalyst to the chlorobenzene is 1-2:1; and / or

[0031] The molar ratio of the 2-amino butyric acid to the chlorobenzene is 1-2:1.

[0032] As an improvement of the above technical solution, the molar ratio of compound I to formic acid is 1:1.5-4; and / or

[0033] The molar ratio of compound I to formaldehyde is 1:2-5.

[0034] As an improvement of the above technical solution, the molar ratio of the compound II to chlorobenzene is 1:1-3; and / or

[0035] The alkali liquor is selected from one or more of NaOH solution, KOH solution, Na2CO3 solution, and K2CO3 solution, and the concentration thereof is 10-60 wt%; the molar ratio of alkali to compound II in the alkali liquor is 1.5-3:1.

[0036] As an improvement of the above technical solution, the first solvent is selected from DMF; the weight ratio of the first solvent to chlorobenzene is 2.5-3.3:1; and / or

[0037] The first catalyst is selected from copper salt catalysts, and the copper salt is cuprous chloride, cupric acetate, cupric chloride, cupric bromide, cuprous bromide, cuprous iodide, or quinoline copper; the weight ratio of the first catalyst to the mass of chlorobenzene is 0.4-0.6:100; and / or

[0038] The acid-binding agent is selected from sodium carbonate; the molar ratio of the acid-binding agent to chlorobenzene is 1.3-1.8:1; and / or

[0039] The molar ratio of morpholine to chlorobenzene is 1.9-3:1; and / or

[0040] The second solvent is selected from dichloroethane; the weight ratio of the second solvent to chlorobenzene is 4.5-5.5:1; and / or

[0041] The second catalyst is selected from aluminum chloride; the molar ratio of the second catalyst to chlorobenzene is 1.1-1.5:1; and / or

[0042] The molar ratio of 2-aminobutyric acid to chlorobenzene is 1.05-1.5:1.

[0043] As an improvement of the above technical solution, the molar ratio of the compound I to formic acid is 1:1.8-2.5; and / or

[0044] The molar ratio of the compound I to formaldehyde is 1:2-2.5; and / or

[0045] The first extractant is selected from dichloromethane or dichloroethane, and the weight ratio of the first extractant to the compound I is 3-5:1; and / or

[0046] The molar ratio of the compound II to chlorobenzene is 1:1-1.5; and / or

[0047] The alkali liquor is selected from NaOH solution, and the concentration thereof is 35-44 wt%; the molar ratio of alkali to compound II in the alkali liquor is 2-2.4:1;

[0048] The second extractant is selected from dichloromethane or dichloroethane, and the weight ratio of the second extractant to the compound II is 3 to 5:1.

[0049] As an improvement to the above technical solution, it also includes a purification step;

[0050] The purification step comprises dissolving the product of step (4) in a third solvent at 60-80° C., then crystallizing at 0-25° C. for 1-3 hours, and separating the solid from the liquid;

[0051] Wherein, the third solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, butanone, and methyl isobutyl ketone.

[0052] The implementation of the present invention has the following beneficial effects:

[0053] The present invention provides a method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone. Chlorobenzene and morpholine are used as starting materials to synthesize N-phenylmorpholine, which is then reacted with 2-aminobutyric acid to synthesize compound I through a Friedel-Crafts reaction. Compound I then undergoes an aminomethylation reaction with formic acid and formaldehyde to synthesize compound II. Finally, compound II is reacted with benzyl chloride and a base to obtain the product. The present invention has a simple process route and a high yield (>70%). Fluorobenzene and bromine are not used, the equipment requirements are relatively low, and the method is convenient for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The present invention is a flow chart of a method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone in accordance with an embodiment of the present invention. DETAILED DESCRIPTION

[0055] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with specific implementation methods.

[0056] The present invention provides a method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone, which comprises the following steps:

[0057] S1: Chlorobenzene reacts with morpholine to produce N-phenylmorpholine;

[0058] The chemical reactions that occur in this step are as follows:

[0059]

[0060] In one embodiment, chlorobenzene and morpholine are dissolved in a first solvent, and an acid binding agent and a first catalyst are added, and the mixture is refluxed at 60 to 90° C. for 8 to 16 hours. After the reaction is completed, the first solvent is separated to obtain N-phenylmorpholine.

[0061] wherein the molar ratio of morpholine to chlorobenzene is 2-5:1-1.2, for example 2:1.2, 2.3:1, 3.5:1.1, 4.7:1.2, 4.3:1.05 or 4:1.1, but not limited thereto. Preferably, the molar ratio of morpholine to chlorobenzene is 1.9-3:1, more preferably 1.9-2.5:1.

[0062] wherein the first solvent is selected from one or more of DMF, DMSO, NMP, DMA, but not limited thereto; preferably, the first solvent is selected from DMF and / or DMA, more preferably, the first solvent is DMF.

[0063] The weight ratio of the first solvent to chlorobenzene is 2-5:1, for example 2.5:1, 2.9:1, 3.3:1, 3.5:1 or 3.8:1, but not limited thereto. Preferably, the weight ratio of the first solvent to chlorobenzene is 2.5-3.3:1, more preferably 2.8-3.2:1.

[0064] wherein the base is one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium hydroxide, but not limited thereto. Preferably, the base is selected from sodium carbonate or potassium carbonate, more preferably, the base is potassium carbonate.

[0065] The molar ratio of the base to chlorobenzene is 1.2-2:1; for example 1.3:1, 1.5:1, 1.7:1 or 1.9:1, but not limited thereto. Preferably, the molar ratio of the base to chlorobenzene is 1.3-1.8:1, more preferably 1.4-1.6:1.

[0066] wherein the first catalyst is selected from one or more of copper salt catalyst, nickel salt catalyst, palladium salt catalyst; for example, the copper salt in the copper salt catalyst is cuprous chloride, copper acetate, copper chloride, copper bromide, cuprous bromide, cuprous iodide or quinoline copper, but not limited thereto. The nickel salt catalyst can be nickel acetate or activated carbon supported metallic nickel, and the palladium salt in the palladium salt catalyst is palladium acetate or tetrakis(triphenylphosphine)palladium, but not limited thereto. Preferably, the first catalyst is selected from copper salt catalyst. More preferably, the first catalyst is selected from cuprous chloride catalyst.

[0067] The weight ratio of the first catalyst to chlorobenzene is 0.3-1:100, for example 0.4:100, 0.6:100, 0.7:100 or 0.8:100, but not limited thereto. Preferably, the weight ratio of the first catalyst to chlorobenzene is 0.4-0.6:100, more preferably 0.4-0.55:100.

[0068] Specifically, after the reaction is completed, the product can be extracted by a polar solvent, and then dried to remove the first solvent, thereby obtaining N-phenylmorpholine, but not limited thereto.

[0069] Preferably, in one embodiment, water and the second solvent are added in sequence after the reaction is completed, and the organic phase is extracted to separate the reaction product (N-phenylmorpholine) from the first solvent. Specifically, the amount of water added is 3 to 6 times the weight of chlorobenzene, and exemplary amounts include 3.3 times, 3.7 times, 4.4 times, 4.7 times, 5.2 times, or 5.8 times, but are not limited thereto. Preferably, the amount of water added is 4 to 6 times the weight of chlorobenzene, and more preferably 4.5 to 5.5 times. The amount of the second solvent added is 3 to 6 times the weight of chlorobenzene, and exemplary amounts include 3.4 times, 3.8 times, 4.2 times, 4.5 times, 5.3 times, or 5.6 times, but are not limited thereto. Preferably, the amount of the second solvent added is 4 to 5.5 times the weight of chlorobenzene, and more preferably 4.5 to 5.2 times.

[0070] The organic phase obtained by extraction with the second solvent can be used in subsequent reactions after the second solvent is separated, or can be directly used in subsequent reactions with the second solvent (intermediate system). More preferably, step S1 includes: dissolving chlorobenzene and morpholine with the first solvent, adding an acid-binding agent and a first catalyst, refluxing at 60 to 90°C for 8 to 16 hours, cooling to 15 to 30°C after the reaction is completed, adding water in an amount of 3 to 6 times the weight of chlorobenzene, and extracting with the second solvent, and the obtained organic phase is used as the intermediate system.

[0071] S2: N-phenylmorpholine and 2-aminobutyric acid are subjected to a Friedel-Crafts reaction to prepare compound I;

[0072] The chemical reaction occurring in this step is as follows:

[0073]

[0074] In one embodiment, step S2 includes: dissolving N-phenylmorpholine and 2-aminobutyric acid with the second solvent, and adding a second catalyst, and reacting at -20°C to 0°C for 4 to 6 hours, and separating the second solvent to obtain compound I.

[0075] The molar ratio of 2-aminobutyric acid to the chlorobenzene is 1 to 2:1, and exemplary ratios include 1.2:1, 1.4:1, 1.6:1, or 1.8:1, but are not limited thereto. Preferably, the molar ratio is 1.05 to 1.5:1, and more preferably 1.05 to 1.2:1.

[0076] The second solvent is selected from one or more of dichloromethane, dichloroethane, and n-heptane, but is not limited thereto. Preferably, the second solvent is selected from dichloromethane or dichloroethane, and more preferably dichloroethane.

[0077] The weight ratio of the second solvent to chlorobenzene is 3-6:1, and examples include 3.4:1, 3.8:1, 4.2:1, 4.5:1, 4.7:1, 5.2:1, or 5.5:1, but the present application is not limited thereto. Preferably, the weight ratio is 4-5.5:1, and more preferably, the weight ratio is 4.5-5.2:1.

[0078] The second catalyst is selected from one or more of aluminum chloride, zinc chloride, and iron chloride, but the present application is not limited thereto. Preferably, aluminum chloride is used.

[0079] The molar ratio of the second catalyst to chlorobenzene is 1-2:1, and examples include 1.2:1, 1.4:1, 1.6:1, or 1.8:1, but the present application is not limited thereto. Preferably, the molar ratio is 1.1-1.5:1, and more preferably, the molar ratio is 1.1-1.3:1.

[0080] Specifically, in this step, the N-phenylmorpholine and 2-aminobutyric acid can be dissolved in the second solvent, or the intermediate system obtained in step S1 can be directly used for the reaction. Preferably, the 2-aminobutyric acid is added to the intermediate system obtained in step S1 for the reaction. More preferably, the intermediate system obtained in step S1 is added dropwise to the 2-aminobutyric acid, which can improve the conversion efficiency of the reaction. The present application does not have a special limitation on the dropping speed.

[0081] Specifically, after the reaction is completed, water can be directly added, and the second solvent can be removed by concentration or distillation after separation, thereby obtaining compound I. In one embodiment, step S2 includes: uniformly mixing the 2-aminobutyric acid and the second catalyst at -20°C-0°C, and adding the mixture dropwise to the intermediate system at -20°C-0°C. After the dropping is completed, the mixture is reacted at -20°C-0°C for 4-6 h. The reaction is quenched by adding water in an amount of 2-5 times the weight of chlorobenzene. The second solvent is separated, thereby obtaining compound I.

[0082] S3: Compound I is subjected to a carboxymethylation reaction with formic acid and formaldehyde to obtain compound II;

[0083] The chemical reaction occurring in this step is as follows:

[0084]

[0085] Specifically, in one embodiment, step S3 includes: mixing compound I with formic acid and a formaldehyde aqueous solution with a concentration of 20-60 wt%, and refluxing the mixture at 80-100°C for 3-5 h, thereby obtaining compound II.

[0086] The molar ratio of compound I to formic acid is 1:1.5-4, and examples include 1:1.9, 1:2.3, 1:2.7, 1:3.2, 1:3.6, or 1:3.9, but the present application is not limited thereto. Preferably, the molar ratio is 1:1.8-2.5, and more preferably, the molar ratio is 1:1.9-2.2.

[0087] The molar ratio of compound I to formaldehyde is 1:2-5, for example 1:2.2, 1:2.8, 1:3.4, 1:3.6, 1:4.3 or 1:4.8, but is not limited thereto. Preferably, the molar ratio is 1:2-2.5, and more preferably 1:2-2.3.

[0088] The formaldehyde is provided in the form of an aqueous formaldehyde solution, which can be added dropwise, but is not limited thereto. The present application does not have a special limitation on the dropwise addition rate of the aqueous formaldehyde solution.

[0089] The concentration of the aqueous formaldehyde solution is for example 25wt%, 28wt%, 35wt%, 40wt%, 47wt%, 50wt% or 55wt%, but is not limited thereto. Preferably, the concentration is 25wt%-50wt%, and more preferably 30wt%-45wt%.

[0090] Specifically, after the reaction is completed, the organic phase can be separated by standing and separation, or can be extracted by the first extracting agent. Preferably, in one embodiment, step S3 comprises mixing compound I with formic acid, adding dropwise an aqueous formaldehyde solution with a concentration of 20-60wt% at 10-30°C, refluxing the reaction at 80-100°C for 3-5h after the dropwise addition is completed, quenching the reaction with water in an amount of 1-5 times the weight of the compound I, and extracting with the first extracting agent, and separating the organic phase obtained by extraction from the first extracting agent to obtain compound II.

[0091] The weight ratio of the water used for quenching the reaction to the compound I is 1-5:1, for example 1.3:1, 1.7:1, 2.4:1, 2.7:1, 3.5:1, 4:1 or 4.8:1, but is not limited thereto. Preferably, the weight ratio is 1-3:1, and more preferably 1.5-2.5:1.

[0092] The first extracting agent is dichloromethane or dichloroethane, but is not limited thereto. Preferably, the first extracting agent is dichloromethane.

[0093] The weight ratio of the first extracting agent to the compound I is 3-5:1, for example 3.4:1, 3.8:1, 4.2:1, 4.5:1 or 4.9:1, but is not limited thereto. Preferably, the weight ratio is 3-4:1.

[0094] S4: Compound II is reacted with chlorobenzyl to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl) butanone;

[0095] The chemical reaction occurring in this step is as follows:

[0096]

[0097] Specifically, in one embodiment, step S4 comprises mixing compound II with chlorobenzene, reacting at 40-60°C for 2-5h, then mixing with alkali liquor, reacting at 40-60°C for 1-3h, to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl) butanone.

[0098] wherein the molar ratio of compound II to chlorobenzene is 1:1-3; illustratively 1:1.2, 1:1.5, 1:1.8, 1:2.4, 1:2.6 or 1:2.9, but not limited thereto. Preferably, the molar ratio of compound II to chlorobenzene is 1:1-1.5.

[0099] wherein the alkali liquor is selected from one or more of NaOH solution, KOH solution, Na2CO3 solution, K2CO3 solution, and is preferably NaOH solution or KOH solution. The concentration of alkali in the alkali liquor is 10-60wt%, illustratively 15wt%, 30wt%, 40wt%, 50wt% or 55wt%, but not limited thereto. Preferably, the concentration of alkali in the alkali liquor is 30-50wt%.

[0100] The molar ratio of alkali in the alkali liquor to compound II is 1.5-3:1, illustratively 1.8:1, 2.1:1, 2.4:1 or 2.7:1, but not limited thereto. Preferably, the molar ratio of alkali in the alkali liquor to compound II is 2-2.4:1, but not limited thereto.

[0101] Specifically, after the reaction is completed, water can be added to separate the organic phase to obtain the product, or the product can be extracted by a second extraction agent. Preferably, in one embodiment, step S4 comprises mixing compound II with water in an amount of 2-5 times the weight of compound II, adding chlorobenzene dropwise at 15-30°C, after the dropwise addition is completed, reacting at 40-60°C for 2-5h, then adding alkali liquor dropwise, reacting at 40-60°C for 1-3h, cooling to 15-30°C, adding a second extraction agent to extract, recovering the second extraction agent from the organic phase obtained by extraction, to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl) butanone.

[0102] wherein the second extraction agent is selected from dichloromethane or dichloroethane, but not limited thereto. Preferably, after the second extraction agent is added, water in an amount of 1-3 times the mass of compound II is added to wash the organic phase, then the second extraction agent is recovered by concentration.

[0103] The weight ratio of the second extraction agent to compound II is 3-5:1, illustratively 3.4:1, 3.9:1, 4.3:1, 4.5:1 or 4.8:1, but not limited thereto. Preferably, the weight ratio of the second extraction agent to compound II is 3-4:1, and more preferably 3-3.5:1.

[0104] Preferably, in one embodiment of the present application, the synthesis method further comprises the following steps:

[0105] S5: purifying the crude product obtained in step S4;

[0106] Specifically, the purification can be performed by recrystallization or the like, but is not limited thereto. Preferably, in one embodiment, the product obtained in step S4 is dissolved in a third solvent at 60-80°C, then crystallized at 0-25°C for 1-3 h, and then solid-liquid separation is performed; wherein the third solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, butanone, methyl isobutyl ketone, but is not limited thereto. The amount of the third solvent is 1-6 times the mass of the product, but is not limited thereto.

[0107] The application is further described below with specific examples:

[0108] Example 1

[0109] This embodiment provides a synthesis method of 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl) butanone, specifically comprising:

[0110] In a 500 ml three-necked flask, a thermometer is inserted, 50 g of chlorobenzene is added to the reaction flask, 150 g of DMF, 77.4 g of morpholine, 92 g of potassium carbonate, and 0.25 g of copper salt catalyst (CuCl) are added, and the system is warmed to reflux at 85°C and kept for 10 h. Liquid phase detection shows that the reaction conversion rate is 98%. The reaction is stopped, the system is cooled to room temperature, and then added to 250 g of water. 200 mL of dichloroethane is used for extraction, and the organic phase is dried with anhydrous sodium sulfate.

[0111] 50.4 g of 2-amino butyric acid is added to the reaction flask, a thermometer is inserted, and the temperature is lowered to -5°C to 0°C. 71.1 g of aluminum chloride is added while keeping the temperature below 0°C. After stirring for 1 h, the organic phase obtained in the previous step is added dropwise while keeping the temperature below 0°C. After the dropwise addition is completed, the reaction is kept for 4 h. Liquid phase detection shows that the purity is 97.5%. The temperature is kept below 40°C, and the system is slowly added to 200 g of water. After stirring for 1 h, the liquid is separated, and the solvent is recovered by concentration to obtain 103 g of light brown solid. The crude product yield is 93.3%, and the purity is 98.3%.

[0112] 100 g of the light brown solid obtained in the previous step is added to a 500 ml three-necked flask with a thermometer. After 37 g of formic acid is added, 60.4 g of 40% formaldehyde aqueous solution is added dropwise at room temperature. The system is warmed to 95°C and refluxed for 3 h. Liquid phase detection shows that the purity is 96.8%. The reaction is stopped, the system is cooled to room temperature, and then added to 100 g of water. 350 g of dichloromethane is used for extraction, and the organic phase is washed with 100 g of water. After drying and concentration, the solvent is recovered to obtain 106 g of brown viscous liquid. The system is solidified at room temperature, the purity is 97.6%, and the crude product yield is 95.2%.

[0113] Into a 500ml reaction flask with a thermometer, 100g of the product from the previous step was added, 200g of water was added, and benzyl chloride 45.8g was added dropwise with stirring at room temperature. The temperature was raised to 50°C and the reaction was allowed to proceed for 2h. A sample was taken and liquid chromatography was used to determine that the conversion of the product from the previous step was greater than 99.5%. Then 72.4g of 40% sodium hydroxide solution was added dropwise, and the reaction was allowed to proceed for another 2h. A sample was taken and liquid chromatography was used to determine that the purity was 95.5%. The temperature was lowered to room temperature, and 300g of dichloromethane was added to extract the product. The organic phase was washed with 100g of water, dried, and concentrated to recover the solvent. This resulted in 128g of a dark brown liquid. The product was solidified at room temperature, and the purity was 96.1% with a yield of 96.5%.

[0114] The 128g of the crude product from the previous step was added to 128g of methanol, and the temperature was raised to 70°C to reflux. The reflux was allowed to proceed for 1h. The temperature was lowered to -5°C, and the mixture was stirred for 0.5h. The mixture was filtered to obtain bright yellow granular crystals. The product was washed twice with 5ml of cold methanol, and the product was dried at 60°C under vacuum to obtain 117g of bright yellow solid granules. The purity was 99.1%, and the crystallization yield was 91.4%. The total crude product yield was 78.34%.

[0115] Example 2

[0116] This example provides a method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzyl) butanone, which specifically includes:

[0117] Into a 500ml three-necked flask with a thermometer, 50g of chlorobenzene was added to the reaction flask, 200g of DMA was added, 87.5g of morpholine was added, 58g of sodium carbonate was added, and 0.25g of copper salt catalyst (copper acetate) was added. The temperature was raised to reflux, and the reaction was allowed to proceed at 80°C for 12h. Liquid chromatography was used to determine that the conversion rate was 98%. The reaction was stopped, and the temperature was lowered to room temperature. The system was added to 250g of water, and 150ml of dichloroethane was added to extract the product. The organic phase was dried with anhydrous sodium sulfate.

[0118] Into the reaction flask, 59g of 2-amino butyric acid was added, a thermometer was inserted, and the temperature was lowered to -10°C to -5°C. The temperature was maintained below -5°C, and 61.2g of aluminum trichloride was added. The mixture was stirred for 1.5h, and then the organic phase from the previous step was added dropwise while maintaining the temperature below -5°C. The mixture was maintained at -5°C for 5h. Liquid chromatography was used to determine that the purity was 98%. The temperature was maintained below 40°C, and the system was slowly added to 250g of water. The mixture was stirred for 1h, and then the mixture was separated. The solvent was recovered by concentration to obtain 101.8g of a light brown solid. The crude product yield was 92.2%, and the purity was 98.5%.

[0119] Into a 500ml three necked flask with temperature controller, 100g of the light brown solid from the previous step was added, 48g of formic acid was added, and 61g of 60% formaldehyde solution was added dropwise at room temperature. The temperature was raised to 90°C and refluxed for 3h. The sample was taken for liquid phase detection, and the purity was 95.4%. The reaction was stopped and the temperature was lowered to room temperature. 300g of water was added to the system, and 400g of dichloroethane was used for extraction. The organic phase was washed with 100g of water, dried, concentrated, and the solvent was recovered to obtain 104.2g of brown viscous liquid. The product was solidified at room temperature, and the purity was 96.3%. The crude product yield was 93.6%.

[0120] Into a 500ml three necked flask with temperature controller, 100g of the light brown solid from the previous step was added, 48g of formic acid was added, and 61g of 60% formaldehyde solution was added dropwise at room temperature. The temperature was raised to 90°C and refluxed for 3h. The sample was taken for liquid phase detection, and the purity was 95.4%. The reaction was stopped and the temperature was lowered to room temperature. 300g of water was added to the system, and 400g of dichloroethane was used for extraction. The organic phase was washed with 100g of water, dried, concentrated, and the solvent was recovered to obtain 104.2g of brown viscous liquid. The product was solidified at room temperature, and the purity was 96.3%. The crude product yield was 93.6%.

[0121] Into a 500ml three necked flask with temperature controller, 100g of the light brown solid from the previous step was added, 48g of formic acid was added, and 61g of 60% formaldehyde solution was added dropwise at room temperature. The temperature was raised to 90°C and refluxed for 3h. The sample was taken for liquid phase detection, and the purity was 95.4%. The reaction was stopped and the temperature was lowered to room temperature. 300g of water was added to the system, and 400g of dichloroethane was used for extraction. The organic phase was washed with 100g of water, dried, concentrated, and the solvent was recovered to obtain 104.2g of brown viscous liquid. The product was solidified at room temperature, and the purity was 96.3%. The crude product yield was 93.6%.

[0122] Example 3

[0123] Into a 50L kettle, 5kg of chlorobenzene was added, 15kg of DMF, 7.74kg of morpholine, 9.2kg of potassium carbonate, and 25g of copper salt were added. The temperature was raised to reflux, and the reaction was maintained for 13h. The liquid phase detection showed that the reaction conversion rate was 98.3%. The reaction was stopped and the temperature was lowered to room temperature. The system was added to 25kg of water, and 20L of dichloroethane was used for extraction. The organic phase was dried with anhydrous sodium sulfate.

[0124] Into a 500ml three necked flask with temperature controller, 100g of the light brown solid from the previous step was added, 48g of formic acid was added, and 61g of 60% formaldehyde solution was added dropwise at room temperature. The temperature was raised to 90°C and refluxed for 3h. The sample was taken for liquid phase detection, and the purity was 95.4%. The reaction was stopped and the temperature was lowered to room temperature. 300g of water was added to the system, and 400g of dichloroethane was used for extraction. The organic phase was washed with 100g of water, dried, concentrated, and the solvent was recovered to obtain 104.2g of brown viscous liquid. The product was solidified at room temperature, and the purity was 96.3%. The crude product yield was 93.6%.

[0125] Add 10 kg of the light brown solid from the previous step into a 50 L kettle, add 3.7 kg of formic acid, then add 6.04 kg of 40% formaldehyde aqueous solution dropwise at room temperature, and then raise the temperature to 90°C to reflux, reflux for 3 h, take a sample for liquid phase detection, the purity is 97.5%, stop the reaction, cool to room temperature, add 10 kg of water into the system, extract with 35 kg of dichloromethane, wash the organic phase with 10 kg of water, dry and concentrate to recover the solvent, to obtain 10.66 kg of brown viscous liquid, solidify at room temperature, the purity is 98.4%, the crude product yield is 95.8%.

[0126] Add 10 kg of the product from the previous step into a 50 L kettle, add 20 kg of water, and then add 4.58 kg of chlorobenzene dropwise at room temperature under stirring, raise the temperature to 50°C to react for 3 h, take a sample for liquid phase detection, the conversion rate is more than 99.5%, add 7.24 kg of 40% sodium hydroxide solution dropwise, continue to react for 2 h, take a sample for liquid phase detection, the purity is 96.4%, cool to room temperature, extract with 35 kg of dichloromethane, wash the organic phase with 10 kg of water, dry and concentrate to recover the solvent, to obtain 12.6 kg of dark brown liquid, solidify at room temperature, the purity is 96.7%, the crude product yield is 95%.

[0127] Add 12.6 kg of the crude product into 12.7 kg of methanol, raise the temperature to reflux, reflux for 1 h, cool to -5°C, stir for 1 h, and then filter to obtain bright yellow granular crystals, wash twice with 200 mL of cold methanol, dry at 60°C under vacuum to obtain 11.4 kg of bright yellow solid particles, the purity is 99.2%, the crystallization yield is 90.5%, and the total crude product yield is 76.1%.

[0128] The above describes the preferred embodiments of the application, and it should be noted that those skilled in the art can make several improvements and refinements without departing from the principles of the application, and these improvements and refinements are also considered to be within the protection scope of the application.

Claims

1. A method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone, characterized in that: The following steps are involved: (1) Chlorobenzene reacts with morpholine to produce N-phenylmorpholine; (2) N-phenylmorpholine and 2-aminobutyric acid were reacted by Friedel-Crafts reaction to obtain compound I; (3) Compound I undergoes aminomethylation reaction with formic acid and formaldehyde to obtain compound II; (4) Compound II reacts with benzyl chloride to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone.

2. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone as claimed in claim 1, wherein: In step (1), chlorobenzene and morpholine are dissolved in a first solvent, and an acid binding agent and a first catalyst are added, and the mixture is refluxed at 60 to 90° C. for 8 to 16 hours. After the reaction is completed, the first solvent is separated to obtain N-phenylmorpholine; and / or In step (2), N-phenylmorpholine and 2-aminobutyric acid are dissolved in a second solvent, and a second catalyst is added, and the mixture is reacted at -20°C to 0°C for 4 to 6 hours, and the second solvent is separated to obtain compound I; and / or In step (3), compound I is mixed with formic acid and a 20-60 wt% formaldehyde aqueous solution, and the mixture is refluxed at 80-100° C. for 3-5 h to obtain compound II; and / or In step (4), compound II is mixed with benzyl chloride, reacted at 40-60° C. for 2-5 h, and then mixed with alkali solution, reacted at 40-60° C. for 1-3 h to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone.

3. The synthetic method of 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to claim 1, characterized in that, In step (1), chlorobenzene and morpholine are dissolved in a first solvent, and an acid binding agent and a first catalyst are added, and the reaction is refluxed at 60-90° C. for 8-16 hours. After the reaction is completed, the temperature is lowered to 15-30° C., water 3-6 times the weight of chlorobenzene is added, and the second solvent is used for extraction, and the resulting organic phase is used as an intermediate system; In step (2), 2-aminobutyric acid and the second catalyst are mixed uniformly at -20°C to 0°C, and added dropwise to the intermediate system at -20°C to 0°C. After the addition is complete, the mixture is reacted at -20°C to 0°C for 4 to 6 hours, the reaction is quenched with water 2 to 5 times the weight of the chlorobenzene, and the second solvent is separated to obtain compound I; and / or In step (3), compound I is mixed with formic acid, and a 20-60 wt% formaldehyde aqueous solution is added dropwise at 10-30° C. After the addition is complete, the mixture is refluxed at 80-100° C. for 3-5 hours, the reaction is quenched with water in an amount of 1-5 times the weight of compound I, and the mixture is extracted with a first extractant. The organic phase obtained by extraction is separated from the first extractant to obtain compound II; and / or In step (4), compound II is mixed with water 2 to 5 times its weight, benzyl chloride is added dropwise at 15 to 30° C., and after the addition is complete, the reaction is carried out at 40 to 60° C. for 2 to 5 hours. Alkali solution is then added dropwise, and the reaction is carried out at 40 to 60° C. for 1 to 3 hours. The temperature is lowered to 15 to 30° C., and a second extractant is added for extraction. The organic phase obtained by extraction is recovered by recovering the second extractant to obtain 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone.

4. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to claim 2 or 3, wherein: The first solvent is selected from one or more of DMF, DMSO, NMP, and DMA; the weight ratio of the first solvent to the chlorobenzene is 2 to 5:1; and / or The first catalyst is selected from one or more of a copper salt catalyst, a nickel salt catalyst, and a palladium salt catalyst; the weight ratio of the first catalyst to the chlorobenzene is 0.3 to 1:100; and / or The acid binding agent is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, and sodium hydroxide; the molar ratio of the acid binding agent to the chlorobenzene is 1.2 to 2:1; and / or The molar ratio of the morpholine to the chlorobenzene is 2-5:1-1.

2.

5. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to claim 2 or 3, wherein: The second solvent is selected from one or more of dichloromethane, dichloroethane, and n-heptane; the weight ratio of the second solvent to the chlorobenzene is 3 to 6:1; and / or The second catalyst is selected from one or more of aluminum chloride, zinc chloride, and ferric chloride; the molar ratio of the second catalyst to the chlorobenzene is 1 to 2:1; and / or The molar ratio of the 2-aminobutyric acid to the chlorobenzene is 1 to 2:

1.

6. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to claim 2 or 3, wherein: The molar ratio of the compound I to formic acid is 1:1.5-4; and / or The molar ratio of the compound I to formaldehyde is 1:2-5.

7. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to claim 2 or 3, wherein: The molar ratio of the compound II to benzyl chloride is 1:1 to 3; and / or The alkali solution is selected from one or more of NaOH solution, KOH solution, Na2CO3 solution, and K2CO3 solution, and its concentration is 10-60wt%; the molar ratio of alkali to compound II in the alkali solution is 1.5-3:

1.

8. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone as claimed in claim 3, wherein: The first solvent is DMF; the weight ratio of the first solvent to the chlorobenzene is 2.5-3.3:1; and / or The first catalyst is a copper salt catalyst, wherein the copper salt is cuprous chloride, cupric acetate, cupric chloride, copper bromide, cuprous bromide, cuprous iodide or quinoline copper; the weight ratio of the first catalyst to the chlorobenzene is 0.4-0.6:100; and / or The acid binding agent is sodium carbonate; the molar ratio of the acid binding agent to the chlorobenzene is 1.3 to 1.8:1; and / or The molar ratio of the morpholine to the chlorobenzene is 1.9 to 3:1; and / or The second solvent is dichloroethane; the weight ratio of the second solvent to the chlorobenzene is 4.5-5.5:1; and / or The second catalyst is aluminum chloride; the molar ratio of the second catalyst to the chlorobenzene is 1.1 to 1.5:1; and / or The molar ratio of the 2-aminobutyric acid to the chlorobenzene is 1.05 to 1.5:

1.

9. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone as claimed in claim 3, wherein: The molar ratio of the compound I to formic acid is 1:1.8-2.5; and / or The molar ratio of the compound I to formaldehyde is 1:2 to 2.5; and / or The first extractant is dichloromethane or dichloroethane, and the weight ratio of the first extractant to the compound I is 3 to 5:1; and / or The molar ratio of the compound II to benzyl chloride is 1:1 to 1.5; and / or The alkali solution is a NaOH solution with a concentration of 35-44 wt %; the molar ratio of the alkali to the compound II in the alkali solution is 2-2.4:1; The second extractant is selected from dichloromethane or dichloroethane, and the weight ratio of the second extractant to the compound II is 3 to 5:

1.

10. The method for synthesizing 2-phenylbenzyl-2-dimethylamine-1-(4-morpholinobenzylphenyl)butanone according to any one of claims 1 to 3, characterized in that: Also included are purification steps; The purification step comprises dissolving the product of step (4) in a third solvent at 60-80° C., then crystallizing at 0-25° C. for 1-3 hours, and separating the solid from the liquid; Wherein, the third solvent is selected from one or more of methanol, ethanol, isopropanol, tert-butanol, butanone, and methyl isobutyl ketone.

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