Preparation method of 1-(3,4-diaminophenyl)ethyl ketone

Abstract

This invention discloses a method for preparing 1-(3,4-diaminophenyl)ethyl ketone. The method includes the following steps: reducing 4-ethynyl-3-nitroaniline with iron powder to obtain 1-(3,4-diaminophenyl)ethyl ketone, as shown in the reaction formula below. The preparation method of this invention does not require the use of concentrated nitric acid or concentrated sulfuric acid as nitrating agents, resulting in less environmental pollution. Furthermore, the reduction of the nitro group and the hydration of the ethynyl group to synthesize the acetyl group are completed in a one-pot process, making the preparation method simple and eliminating the need for complex purification of intermediate products, thus making it highly suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and more specifically, relates to a method for preparing 1-(3,4-diaminophenyl)ethyl ketone. Background Technology

[0002] Chinese Patent Publication No. CN113527261 A discloses piperazine derivatives, their preparation methods, and uses, which can be used as inhibitors of coagulation factor XIa (FXIa). Specifically, this prior art discloses the following compounds:

[0003] .

[0004] 1-(3,4-diaminophenyl)acetone is an important intermediate for this coagulation factor XIa (FXIa) inhibitor.

[0005] For 1-(3,4-diaminophenyl)ethyl ketone, international publication WO2013 / 114332A1 reports the preparation using the following method. .

[0006] This method uses fuming nitric acid and concentrated sulfuric acid for nitration, but the synthesis process has drawbacks such as operational hazards and the generation of a large amount of waste acid.

[0007] In addition, existing technology, 3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation, By: Venter, Jana; et al, Bioorganic & Medicinal Chemistry Letters (2019), 29(13), discloses the preparation of 1-(3,4-diaminophenyl)ethyl ketone by the following method:

[0008] .

[0009] This method requires the use of expensive palladium as a catalyst, and the raw materials themselves are not easy to obtain.

[0010] Therefore, there is a need for a low-cost, environmentally friendly synthesis process for 1-(3,4-diaminophenyl)ethyl ketone that is suitable for large-scale production. Summary of the Invention

[0011] To address the shortcomings of existing techniques in the preparation of 1-(3,4-diaminophenyl)ethyl ketone, the present invention aims to provide a method for preparing 1-(3,4-diaminophenyl)ethyl ketone. This method utilizes inexpensive o-nitroaniline as a starting material, employs mild reagents and reaction conditions, is simple to operate, low in cost, and is suitable for industrial-scale production. To achieve the objectives of this invention, the following technical solution is adopted:

[0012] A method for preparing 1-(3,4-diaminophenyl)ethyl ketone, comprising the following steps:

[0013] The reduction of 4-ethynyl-3-nitroaniline with iron powder yields 1-(3,4-diaminophenyl)ethyl ketone, as shown in the following reaction formula:

[0014] .

[0015] In some preferred embodiments of the present invention, the solvent used in the reduction reaction is selected from a mixture of an organic solvent and water. In some preferred embodiments of the present invention, the organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, or combinations thereof. In some preferred embodiments of the present invention, the volume ratio of the organic solvent to water in the mixture is 1 to 4:1, for example, 2:1, 3:1, or 4:1. In some more preferred embodiments of the present invention, the solvent used in the reduction reaction is a mixture of methanol and water.

[0016] In some preferred embodiments of the present invention, the pH value of the reaction system is 3 to 5.

[0017] In some preferred embodiments of the present invention, the molar ratio of 4-ethynyl-3-nitroaniline to iron powder is 1:3 to 6. In some more preferred embodiments of the present invention, the molar ratio of 4-ethynyl-3-nitroaniline to iron powder is 1:4 to 5.

[0018] In some preferred embodiments of the present invention, the temperature of the reduction reaction is 50-80°C. In some more preferred embodiments of the present invention, the temperature of the reduction reaction is 60-75°C.

[0019] In some preferred embodiments of the present invention, the preparation method of 4-ethynyl-3-nitroaniline includes the following steps:

[0020] 4-(trimethylsilylacetynyl)-3-nitroaniline reacts in the presence of a base to produce 4-acetynyl-3-nitroaniline, as shown in the following reaction formula:

[0021] .

[0022] In some preferred embodiments of the present invention, the alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or a combination thereof.

[0023] In some preferred embodiments of the present invention, the amount of alkali used is 0.05 to 0.1 equivalents (based on 4-(trimethylsilylethynyl)3-nitroaniline).

[0024] In some preferred embodiments of the present invention, the reaction temperature is 0~15°C.

[0025] In some preferred embodiments of the present invention, the solvent used in the reaction is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or combinations thereof. In some preferred embodiments of the present invention, the solvent used in the reaction is selected from methanol and / or ethanol.

[0026] In some preferred embodiments of the present invention, the preparation method of 4-(trimethylsilylethynyl)-3-nitroaniline includes the following steps:

[0027] (1) o-Nitroaniline reacts with a halogenating agent to produce 4-bromo-3-nitroaniline or 4-iodo-3-nitroaniline; and

[0028] (2) 4-Bromo-3-nitroaniline or 4-iodo-3-nitroaniline is coupled with trimethylsilylacetylene to generate 4-(trimethylsilylacetyl)3-nitroaniline, as shown in the following reaction formula:

[0029] .

[0030] In some preferred embodiments of the present invention, in step (1), the halogenated reagent is selected from N-bromosuccinimide or N-iodosuccinimide.

[0031] In some preferred embodiments of the present invention, the molar ratio of o-nitroaniline to N-bromosuccinimide or N-iodosuccinimide is 1:1 to 2, more preferably 1:1.1 to 1.5.

[0032] In some preferred embodiments of the present invention, the halogenation reaction temperature is 10~30°C. In some more preferred embodiments of the present invention, the halogenation reaction temperature is 15~25°C.

[0033] In some preferred embodiments of the present invention, the solvent for the halogenation reaction is selected from acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or combinations thereof.

[0034] In some preferred embodiments of the present invention, in step (2), the coupling reaction is carried out in the presence of a catalyst, cuprous iodide and a base.

[0035] In some preferred embodiments of the present invention, in step (2), the solvent for the coupling reaction is selected from acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or a combination thereof.

[0036] In some preferred embodiments of the present invention, in step (2), the coupling reaction temperature of 4-bromo-3-nitroaniline with trimethylsilylacetylene is 50~80°C.

[0037] In some preferred embodiments of the present invention, in step (2), the coupling reaction temperature of 4-iodo-3-nitroaniline and trimethylsilylacetylene is 10~40°C.

[0038] In some preferred embodiments of the present invention, the catalyst is selected from palladium on carbon, tetraphenylphosphine palladium, palladium dichloride, or combinations thereof.

[0039] In some preferred embodiments of the present invention, the alkali is selected from triethylamine, potassium carbonate, cesium carbonate, or combinations thereof.

[0040] In some preferred embodiments of the present invention, the preparation method of 1-(3,4-diaminophenyl)ethyl ketone includes the following steps:

[0041] (1) o-Nitroaniline reacts with a halogenating agent to produce 4-bromo-3-nitroaniline or 4-iodo-3-nitroaniline;

[0042] (2) 4-Bromo-3-nitroaniline or 4-iodo-3-nitroaniline is coupled with trimethylsilylacetylene to generate 4-(trimethylsilylacetyl)3-nitroaniline:

[0043] (3) 4-(trimethylsilylacetyl)3-nitroaniline reacts in the presence of a base to produce 4-acetyl-3-nitroaniline.

[0044] (4) 4-ethynyl-3-nitroaniline was reduced with iron powder to obtain 1-(3,4-diaminophenyl)ethyl ketone, as shown in the following reaction formula:

[0045] .

[0046] In some preferred embodiments of the present invention, the halogenated reagent in step (1) is selected from N-bromosuccinimide or N-iodosuccinimide, and / or

[0047] In some preferred embodiments of the present invention, the alkali mentioned in step (3) is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or combinations thereof, and / or

[0048] In some preferred embodiments of the present invention, in step (4), the pH value of the reduction reaction system is 3 to 5, and the solvent used in the reduction reaction is selected from a mixture of organic solvent and water. Preferably, the organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, methanol, or a combination thereof.

[0049] The total yield of the four-step reaction of the preparation method of 1-(3,4-diaminophenyl)ethyl ketone of the present invention is 50.4-55.7%. The intermediate product does not require purification or can be used for the next step of the reaction by simple recrystallization purification, which is particularly suitable for large-scale industrial production. Attached Figure Description

[0050] Figure 1 This is the GC spectrum of 2-nitro-4-bromoaniline.

[0051] Figure 2 This is the GC spectrum of 2-nitro-4-iodoaniline.

[0052] Figure 3 This is the GC spectrum of 4-(trimethylsilylethynyl)3-nitroaniline.

[0053] Figure 4 This is the GC spectrum of 4-ethynyl-3-nitroaniline.

[0054] Figure 5 This is the NMR spectrum of 2-nitro-4-bromoaniline.

[0055] Figure 6 This is the NMR spectrum of 2-nitro-4-iodoaniline.

[0056] Figure 7 This is the NMR spectrum of (trimethylsilylethynyl)3-nitroaniline.

[0057] Figure 8 This is the NMR spectrum of 4-ethynyl-3-nitroaniline.

[0058] Figure 9 This is the NMR spectrum of 1-(3,4-diaminophenyl)ethyl ketone. Detailed Implementation

[0059] Through extensive and in-depth research, the inventors of this application discovered that by using inexpensive o-nitroaniline as a starting material, halogenation followed by catalytic coupling to form an alkynyl group, and for the first time utilizing iron powder to reduce the nitro group and hydrate the meta-ethynyl group to generate an acetyl group in one step, the synthesis of 1-(3,4-diaminophenyl)ethyl ketone was completed with high efficiency and low risk.

[0060] In this article, "room temperature" or "normal temperature" refers to a temperature of 4-40℃, preferably 25±5℃.

[0061] Preparation method of 1-(3,4-diaminophenyl)ethyl ketone

[0062] In the description of this invention, the preparation method of 1-(3,4-diaminophenyl)ethyl ketone includes the following steps:

[0063] (1) o-Nitroaniline reacts with a halogenating agent to produce 4-bromo-3-nitroaniline or 4-iodo-3-nitroaniline;

[0064] (2) 4-Bromo-3-nitroaniline or 4-iodo-3-nitroaniline is coupled with trimethylsilylacetylene to generate 4-(trimethylsilylacetyl)3-nitroaniline:

[0065] (3) 4-(trimethylsilylacetyl)3-nitroaniline reacts in the presence of a base to produce 4-acetyl-3-nitroaniline.

[0066] (4) 4-ethynyl-3-nitroaniline was reduced with iron powder to obtain 1-(3,4-diaminophenyl)ethyl ketone, as shown in the following reaction formula:

[0067] .

[0068] In step (1), the halogenating reagent includes, but is not limited to, N-bromosuccinimide and N-iodosuccinimide. The amount of halogenating reagent used can be conventional in the art; for example, the molar ratio of o-nitroaniline to N-bromosuccinimide or N-iodosuccinimide is 1:1~2, more preferably 1:1.1~1.5. The halogenation reaction temperature is 10~30℃, more preferably 15~25℃. The solvent for the halogenation reaction includes, but is not limited to, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, and tetrahydrofuran. The amount of solvent used is conventional in the art, preferably the minimum amount required to completely dissolve the reactants. This step can be monitored by TLC to ensure complete reaction of the reactants. After the reaction is complete, the reaction solution is treated by conventional methods, for example, by adding water, separating the phases, extracting the aqueous phase with an organic solvent, combining the organic phases, drying, filtering, and concentrating the organic phase to obtain the target product. In one specific embodiment of the present invention, the target product crude 4-bromo-3-nitroaniline can be purified by recrystallization from anhydrous ethyl acetate:petroleum ether = 1:3. In another specific embodiment of the present invention, the target product crude 4-iodo-3-nitroaniline can be purified by recrystallization from anhydrous ethyl acetate:petroleum ether = 1:5.

[0069] In step (2), the coupling reaction is preferably carried out under a nitrogen atmosphere in the presence of a catalyst, cuprous iodide, and a base. The solvent for the coupling reaction includes, but is not limited to, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran. The catalyst includes, but is not limited to, palladium on carbon, tetratriphenylphosphine palladium, and palladium dichloride. The amount of catalyst used is the conventional amount for this type of reaction. The base includes, but is not limited to, triethylamine, potassium carbonate, and cesium carbonate; the amount of base used is the conventional amount for this type of reaction, and liquid triethylamine can also be used directly as a solvent. For example, catalytic coupling is carried out by adding 0.1 g of triphenylphosphine palladium to a triethylamine solution containing 0.1 mol of 4-bromo-3-nitroaniline or 4-iodo-3-nitroaniline. The role of cuprous iodide in the coupling reaction is to catalyze the formation of C-C bonds, including diaryl compounds, arylyne compounds, arylene compounds, enyne compounds, 1,3-diene compounds, and 1,n-diyne compounds. The amount of cuprous iodide used is the standard amount for this type of reaction; for example, 0.1 mol of 4-bromo-3-nitroaniline or 4-iodo-3-nitroaniline can be added with 1 g of cuprous iodide. Trimethylsilylacetylene is added dropwise during the reaction, with the temperature controlled to not exceed 50°C. After the addition is complete, the coupling reaction temperature between 4-bromo-3-nitroaniline and trimethylsilylacetylene is 50–80°C, and the coupling reaction temperature between 4-iodo-3-nitroaniline and trimethylsilylacetylene is 10–40°C, until the reactants disappear. Post-reaction processing includes: direct filtration of the reaction solution, addition of an organic solvent to the filtrate, sequential washing of the organic phase with water, drying, and concentration to obtain crude (trimethylsilylacetyl)-3-nitroaniline. The crude product is then stirred and slurried with petroleum ether to obtain a high-purity product.

[0070] Step (3) The base used for desilication includes, but is not limited to, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. The amount of base used is the conventional amount used for this type of reaction, for example, adding 1.7 g of potassium carbonate to a solution containing 0.25 mol of 4-ethynyl-3-nitroaniline. The reaction temperature is 0~15℃. The solvent used in the reaction includes, but is not limited to, methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile. Post-reaction processing includes: after TLC tracking shows that the starting material has disappeared, adding ethyl acetate and water to the reaction solution, separating the liquids, and washing, drying, filtering, and concentrating the organic phase sequentially to obtain 4-ethynyl-3-nitroaniline. The crude product is then slurried with petroleum ether to obtain a high-purity product.

[0071] In step (4), the nitro reduction of 4-ethynyl-3-nitroaniline and the hydration of ethynyl to form acetyl groups are both completed in this step. The solvent used is a mixture of organic solvent and water, and the organic solvent includes, but is not limited to, methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, and acetone. The pH of the reduction reaction system is 3-5. The molar ratio of 4-ethynyl-3-nitroaniline to iron powder is 1:3-6, more preferably 1:4-5. The reduction reaction temperature is 50-80℃. After the TLC tracking shows that the raw material has disappeared, the reaction is stopped. The treatment of the reaction solution includes adding ethyl acetate to the reaction solution, separating the liquid, and sequentially filtering, drying, and concentrating the organic phase to obtain (3,4-diaminophenyl)ethyl ketone. The crude product is recrystallized from methanol to obtain a high-purity product.

[0072] The beneficial effects of this invention are as follows:

[0073] 1. This invention uses inexpensive o-nitroaniline as a starting material and does not use concentrated nitric acid or concentrated sulfuric acid as nitrating agents, thus minimizing environmental pollution;

[0074] 2. In the preparation method of the present invention, iron powder is used as a reducing agent to reduce nitro and hydrate acetyl group to synthesize acetyl group in a one-pot process. The preparation method is simple and the intermediate product does not require complicated purification methods, which is very suitable for industrial production.

[0075] 3. Iron powder is selected for catalytic reduction because the raw material is cheap and the post-processing is relatively simple.

[0076] The present invention will now be described in detail with reference to specific embodiments. These embodiments are illustrative and do not limit the scope of protection of the present invention in any way. Experimental methods in the following embodiments, unless otherwise specified, are generally performed according to the conditions recommended by the manufacturer. Unless otherwise stated, the raw materials and reagents used in the following embodiments are commercially available or can be prepared by known methods.

[0077] Example 1

[0078] Synthesis of 4-bromo-3-nitroaniline

[0079] To a 1000 mL three-necked flask, o-nitroaniline (69 g, 0.5 mol) was added sequentially, followed by 500 mL of ethyl acetate. NBS (97.9 g, 0.55 mol) was added in portions, maintaining the internal temperature at 15-25 °C. TLC was monitored until the starting material disappeared. The reaction mixture was poured into 1 L of cold water, and the layers were separated. The aqueous phase was extracted with 100 mL of ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain crude 4-bromo-3-nitroaniline. The crude product was recrystallized from anhydrous ethyl acetate:petroleum ether = 1:3 to obtain 115 g of purified 4-bromo-3-nitroaniline, with a yield of 94%.

[0080] Example 2

[0081] Synthesis of 4-bromo-3-nitroaniline

[0082] To a 2000 mL three-necked flask, o-nitroaniline (82.8 g, 0.6 mol) was added sequentially, followed by 800 mL of tetrahydrofuran. NBS (117.5 g, 0.66 mol) was added in portions, maintaining the internal temperature at 15-25 °C. TLC was monitored until the starting material disappeared. The reaction mixture was poured into 1.5 L of cold water, and the layers were separated. The aqueous phase was extracted with 300 mL of ethyl acetate three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain crude 4-bromo-3-nitroaniline. The crude product was recrystallized from anhydrous ethyl acetate:petroleum ether = 1:3 to obtain 121.7 g of purified 4-bromo-3-nitroaniline, with a yield of 93.5%.

[0083] Example 3

[0084] Synthesis of 4-(trimethylsilylethynyl)-3-nitroaniline

[0085] 4-Bromo-3-nitroaniline (65.1 g, 0.3 mol) was added sequentially to a 1000 mL three-necked flask, followed by 300 mL of tetrahydrofuran, 100 mL of triethylamine, 2 g of cuprous iodide, and 0.3 g of tetra(triphenylphosphine)palladium. Under nitrogen protection, the mixture was heated to 50-60 °C, and trimethylsilylacetylene (32.34 g, 0.33 mol) was added dropwise. After the addition was complete, the mixture was kept at 60-70 °C with stirring until the reactants disappeared. The reaction mixture was cooled to room temperature, and the solid was removed by vacuum filtration. The filter cake was washed sequentially with 500 mL of ethyl acetate. The combined filtrates were washed with water, and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 4-(trimethylsilylacetyl)-3-nitroaniline. The crude product was then stirred and slurried with petroleum ether to obtain 59.7 g of purified product, with a yield of 85%.

[0086] Example 4

[0087] Synthesis of 4-iodo-3-nitroaniline

[0088] To a 1000 mL three-necked flask, o-nitroaniline (69 g, 0.5 mol) was added sequentially, followed by 500 mL of ethyl acetate. NIS (123.75 g, 0.55 mol) was added in portions, maintaining the internal temperature of the reaction solution at 15-25 °C. TLC was used to monitor the reaction until the starting material disappeared. The reaction solution was then poured into 1 L of cold water, and the layers separated. The aqueous phase was extracted with 100 mL of ethyl acetate three times. The organic phases were combined and washed sequentially with saturated sodium sulfite aqueous solution, saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to obtain crude 4-iodo-3-nitroaniline. The crude product was recrystallized from anhydrous ethyl acetate:petroleum ether = 1:5 to obtain 121.4 g of purified 4-iodo-3-nitroaniline, with a yield of 92%.

[0089] Example 5

[0090] Synthesis of 4-(trimethylsilylethynyl)-3-nitroaniline

[0091] 4-Iodo-3-nitroaniline (79.2 g, 0.3 mol) was added sequentially to a 1000 mL three-necked flask, followed by 300 mL of N,N-dimethylformamide, 100 mL of triethylamine, 2 g of cuprous iodide, and 0.3 g of tetrakis(triphenylphosphine)palladium. Under nitrogen protection, trimethylsilylacetylene (32.34 g, 0.33 mol) was added dropwise at room temperature, controlling the temperature not to exceed 50 °C. After the addition was complete, the mixture was stirred naturally until the reactants disappeared. The reaction solution was cooled to room temperature, and the solids were removed by vacuum filtration. The filter cake was washed with 500 mL of ethyl acetate, and the eluents and filtrates were combined and washed with water. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then stirred and slurried with petroleum ether to obtain a refined product of 64.6 g, with a yield of 92%.

[0092] Example 6

[0093] Synthesis of 4-ethynyl-3-nitroaniline

[0094] 4-(trimethylsilylethynyl)-3-nitroaniline (58.5 g, 0.25 mol) was added sequentially to a 1000 mL three-necked flask, followed by 300 mL of methanol. The mixture was cooled to below 10 °C with ice water, and 1.7 g of potassium carbonate was added. The mixture was stirred and the reaction was monitored by TLC until the starting material disappeared. Then, 300 mL of ethyl acetate and 300 mL of water were added to the reaction mixture. The mixture was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then slurried with petroleum ether, stirred, and filtered to obtain 36.5 g of a brown solid, with a yield of 90%.

[0095] Example 7

[0096] Synthesis of 4-ethynyl-3-nitroaniline

[0097] 4-(trimethylsilylethynyl)-3-nitroaniline (46.8 g, 0.2 mol) was added to a 500 mL three-necked flask, followed by 300 mL of tetrahydrofuran. The mixture was stirred to dissolve, cooled to below 10 °C with ice water, and then 0.8 g of sodium hydroxide was added. The reaction was stirred, and TLC was used to monitor the reaction until the starting material disappeared. The reaction solution was then transferred to a system of 250 mL of water and 250 mL of ethyl acetate and stirred. The mixture was allowed to stand and separate into layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then slurried with petroleum ether, stirred, and filtered to obtain 28.5 g of a brown solid, with a yield of 88%.

[0098] Example 8

[0099] Synthesis of 1-(3,4-diaminophenyl)ethyl ketone

[0100] Reduced iron powder (44.8 g, 0.8 mol) was added sequentially to a 1000 mL three-necked flask, followed by 300 mL of methanol and 100 mL of water. Then, 5 mL of hydrochloric acid (35% by mass) was added dropwise for activation. Next, 32.4 g (0.2 mol) of 4-ethynyl-3-nitroaniline was added. The mixture was stirred at room temperature for 30 minutes, then slowly heated to reflux. The reaction was stopped by TLC when the starting intermediate disappeared. The reaction solution was cooled to room temperature, and 300 mL of ethyl acetate was added. The mixture was separated into liquid and liquid phases, filtered through a diatomaceous earth liner, and the filter cake was washed sequentially with 200 mL of ethyl acetate. The combined filtrates were washed with water, dried over anhydrous sodium sulfate solution, filtered, and concentrated to obtain a crude product. The crude product was crystallized from methanol to obtain 21.5 g of a brown solid, with a yield of 71.6%.

[0101] Example 9

[0102] Synthesis of 1-(3,4-diaminophenyl)ethyl ketone

[0103] Reduced iron powder (33.6 g, 0.6 mol) was added sequentially to a 1000 mL three-necked flask, followed by 250 mL of ethanol and 80 mL of water. Then, 4 mL of hydrochloric acid (30% by mass) was added dropwise for activation. Next, 24.3 g (0.15 mol) of 4-ethynyl-3-nitroaniline was added. The mixture was stirred at room temperature for 30 minutes, then slowly heated to reflux. The reaction was stopped by TLC when the starting intermediate disappeared. The reaction solution was cooled to room temperature, and 300 mL of ethyl acetate was added. The mixture was separated into liquid and liquid phases, filtered through a diatomaceous earth liner, and the filter cake was washed with 200 mL of ethyl acetate. The combined filtrates were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was crystallized from methanol to obtain 15.8 g of a brown solid, with a yield of 70.5%.

[0104] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Various variations can be made to the above embodiments of the present invention. That is, all simple and equivalent changes and modifications made based on the claims and description of this invention fall within the protection scope of the claims. All aspects not described in detail in this invention are conventional technical content.

Claims

A method for preparing 1,1-(3,4-diaminophenyl)ethyl ketone, characterized in that, The preparation method includes the following steps: (1) 4-ethynyl-2-nitroaniline was reduced with iron powder to obtain 1-(3,4-diaminophenyl)ethyl ketone, as shown in the following reaction formula: ， The solvent used in the reduction reaction is a mixture of an organic solvent and water. The pH value of the reduction reaction system is 3-5. (2) The reaction was stopped when the raw material intermediate disappeared, as tracked by TLC. The organic solvent is selected from methanol, ethanol, or a combination thereof, and the volume ratio of organic solvent to water in the mixture of organic solvent and water is 3~4:

1. The molar ratio of 4-ethynyl-2-nitroaniline to iron powder is 1:4~5, and The reduction reaction temperature is 60~75℃.

2. The preparation method according to claim 1, characterized in that, 4-Ethynyl-2-nitroaniline is prepared by the following method, which includes the following steps: 4-(trimethylsilylacetyl)-2-nitroaniline reacts in the presence of a base to produce 4-acetyl-2-nitroaniline, as shown in the following reaction formula: 。 3. The preparation method according to claim 2, characterized in that, The alkali is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or combinations thereof, and / or The reaction temperature is 0~15℃, and / or The solvent used in the reaction is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or a combination thereof.

4. The preparation method according to claim 3, characterized in that, The solvent used in the reaction is selected from methanol and / or ethanol.

5. The preparation method according to claim 2, characterized in that, 4-(trimethylsilylethynyl)-2-nitroaniline is prepared by the following method, which includes the following steps: (1) o-Nitroaniline reacts with a halogenating agent to produce 4-bromo-2-nitroaniline or 4-iodo-2-nitroaniline; and (2) 4-Bromo-2-nitroaniline or 4-iodo-2-nitroaniline is coupled with trimethylsilylacetylene to generate 4-(trimethylsilylacetyl)-2-nitroaniline, as shown in the following reaction formula: 。 6. The preparation method according to claim 5, characterized in that, In step (1), the halogenated reagent is selected from N-bromosuccinimide or N-iodosuccinimide, and / or The halogenation reaction temperature is 10~30℃, and / or The solvent for the halogenation reaction is selected from acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, tetrahydrofuran, or combinations thereof.

7. The preparation method according to claim 6, characterized in that, The molar ratio of o-nitroaniline to N-bromosuccinimide or N-iodosuccinimide is 1:1 to 3.

8. The preparation method according to claim 6, characterized in that, In step (1), The molar ratio of o-nitroaniline to N-bromosuccinimide or N-iodosuccinimide is 1:1~2, and / or The halogenation reaction temperature is 15~25℃.

9. The preparation method according to claim 5, characterized in that, In step (2), the coupling reaction is carried out in the presence of a catalyst, cuprous iodide, and a base, and / or The solvent for the coupling reaction is selected from acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or combinations thereof, and / or The coupling reaction of 4-bromo-2-nitroaniline with trimethylsilylacetylene occurs at temperatures of 50–80 °C.

10. The preparation method according to claim 5, characterized in that, In step (2), the coupling reaction of 4-iodo-2-nitroaniline with trimethylsilylacetylene is carried out at a temperature of 10~40℃.

11. The preparation method according to claim 9, characterized in that, The catalyst is selected from palladium on carbon, tetraphenylphosphine palladium, palladium dichloride, or combinations thereof, and / or The base is selected from triethylamine, potassium carbonate, cesium carbonate, or combinations thereof. A method for preparing 12.1-(3,4-diaminophenyl)ethyl ketone, characterized in that, The preparation method includes the following steps: (1) o-Nitroaniline reacts with a halogenating agent to produce 4-bromo-2-nitroaniline or 4-iodo-2-nitroaniline; (2) 4-Bromo-2-nitroaniline or 4-iodo-2-nitroaniline is coupled with trimethylsilylacetylene to generate 4-(trimethylsilylacetyl)-2-nitroaniline; (3) 4-(trimethylsilylethynyl)-2-nitroaniline reacts in the presence of a base to produce 4-ethynyl-2-nitroaniline; (4) 4-ethynyl-2-nitroaniline was reduced with iron powder to obtain 1-(3,4-diaminophenyl)ethyl ketone; (5) The reaction was stopped when the TLC tracked the disappearance of the raw material intermediate. The reaction formula for the preparation method is as follows: ， In step (4), the solvent used in the reduction reaction is selected from a mixture of an organic solvent and water, wherein the organic solvent is selected from methanol, ethanol, or a combination thereof, and the volume ratio of organic solvent to water in the mixture is 3~4:

1. The pH value of the reduction reaction system is 3-5. The molar ratio of 4-ethynyl-2-nitroaniline to iron powder is 1:4~5, and The reduction reaction temperature is 60~75℃.

13. The preparation method according to claim 12, characterized in that, The halogenating agent mentioned in step (1) is selected from N-bromosuccinimide or N-iodosuccinimide, and / or In step (2), the coupling reaction is carried out in the presence of a catalyst, cuprous iodide, and a base, and / or The alkali mentioned in step (3) is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or a combination thereof.

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