阅读说明：本技术 合成邻氨基苯乙酮的方法 (Method for synthesizing o-aminoacetophenone ) 是由 习林刚 叶伟平 费安杰 周章涛 谢阳银 于 2020-04-21 设计创作，主要内容包括：本发明公开了一种合成医药中间体邻氨基苯乙酮的方法,以邻乙基硝基苯为起始原料,经过氧化乙基、还原硝基2步反应,得到该化合物。采用本发明合成方法合成邻氨基苯乙酮,采用新颖的氧化剂和还原剂,收率56％左右,具有工艺安全性高、物料廉价、易于生产放大等特点。(The invention discloses a method for synthesizing a medical intermediate o-aminoacetophenone, which takes o-ethyl nitrobenzene as a starting material to obtain the compound through 2 steps of reactions of oxidizing ethyl and reducing nitro. The synthesis method of o-aminoacetophenone adopts novel oxidant and reducer, has the yield of about 56%, and has the characteristics of high process safety, cheap materials, easy production and amplification and the like.)

1. The method for synthesizing o-aminoacetophenone is characterized in that o-ethylaminonitrobenzene is used as a starting material, and the o-aminoacetophenone is obtained by 2-step reaction of oxidizing ethyl by a strong oxidant and reducing nitro by a reducing agent, wherein the reaction formula is as follows:

。

2. the method for synthesizing o-aminoacetophenone according to claim 1, characterized in that the oxidation of ethyl group with strong oxidant comprises at least one of potassium chlorate, sodium bromate and sodium chlorite to obtain the intermediate ketone.

3. The method according to claim 1 or 2, characterized in that the strong oxidizing agent is sodium bromate.

4. The method of claim 1 or 2, wherein the reducing agent is a low-valent sulfur reducing agent comprising at least one of sodium thiosulfate, sodium hydrosulfite, sodium sulfide, sodium polysulfide.

5. The method of claim 4, wherein the reducing agent is sodium polysulfide.

6. The method according to claim 1 or 2, wherein in the step of oxidizing the ethyl group with the strong oxidizing agent, the solvent used comprises at least one of acetonitrile, water, and an ionic liquid;

preferably, the solvent is water;

preferably, the solvent is water: acetonitrile = 1: 1 (mass ratio).

7. The method according to claim 1 or 2, wherein sulfuric acid is further added in the step of oxidizing the ethyl group with a strong oxidizing agent.

8. The method according to claim 1 or 2, wherein in the step of oxidizing the ethyl group with the strong oxidant, the reaction temperature is controlled to be 80-90 ℃ and the reaction time is 12-20 hours;

the reaction time is preferably 16 hours;

preferably, in the step of oxidizing the ethyl group by using the strong oxidant, after the reaction is finished, cooling to room temperature, adjusting the pH =7-8, then quenching by using a sodium thiosulfate solution until the color of the starch potassium iodide paper is not changed, separating the liquid, and directly using the organic phase for the next reaction.

9. The method of claim 8, wherein the reducing the nitro group with the reducing agent comprises: adding sodium polysulfide (Na) into the organic phase₂S_x) Reacting with water at 75-85 ℃ for 10-15 hours, and sampling and controlling; after the reaction is finished, cooling to room temperature, extracting twice by using toluene, merging organic phases, and concentrating and drying under reduced pressure to obtain a crude product of o-aminoacetophenone; distillation collection 105-^oC/5 mbar to obtain pure product.

10. The method of claim 9, wherein the reaction time is controlled at 12 hours.

Technical Field

The invention belongs to the field of organic chemical synthesis, and particularly relates to a novel synthesis method of o-aminoacetophenone.

Background

O-aminoacetophenone is a key intermediate of the diabetes drug ligliptae, and is also an intermediate of a plurality of important heat-insulating materials (the structure is shown as follows), and the annual demand is in the tens of tons.

The current synthetic route for this intermediate is shown below.

The route is simple, but a series of problems exist in the specific oxidation and reduction methods.

As reported in documents such as Chinese patent application publication No. CN101774925A, the oxidation step uses oxygen and metal catalysts containing copper, cobalt, etc., and the reaction is carried out at a high temperature of 160 ℃ of 120-.

Such as Organic Letters,7(21), 4549-4552; et al report that the oxidation step uses t-butanol peroxide as an oxidant and a transition metal as a catalyst. The tert-butyl alcohol peroxide has poor safety and easy explosion, and is difficult to industrialize.

As reported in chinese patent application publication No. CN103113349A, the reducing step mainly uses a reducing agent such as iron powder, zinc powder, and tin powder, and the reducing is performed under acidic conditions. The methods are simple and easy to operate, but because nitro reduction needs to consume at least 3 equivalent of reducing agent, the reducing agent has large molecular weight, a large amount of heavy metal solid waste residue is generated, the post-treatment in the process is difficult, and the environmental pollution is also great.

As reported in Chinese patent application publication No. CN104693211A, hydrogenation or transfer hydrogenation can be carried out using a catalyst such as palladium, Raney nickel, rhodium, etc. These methods are atom economical, but palladium and rhodium are expensive and it is difficult to produce this product very inexpensively; and the Raney nickel is dangerous, can be spontaneously combusted when meeting air, and has great process safety risk.

In conclusion, the development of the pharmaceutical industry needs o-aminoacetophenone, a class of medical intermediates, but the current process route has certain improvement space.

Disclosure of Invention

In order to overcome the defects of low process safety, more three wastes in part of processes, high cost in part of processes and the like of the o-aminoacetophenone, the invention develops a novel preparation method of the o-aminoacetophenone. The method comprises the following reaction steps: (1) oxidizing o-ethyl nitrobenzene into o-nitroacetophenone by sodium bromate; (2) the o-nitroacetophenone is reduced to o-aminoacetophenone by sodium polysulfide.

The preparation method has the advantages that: the first step oxidant is high in safety and low in price. The reaction is mild (80 ℃), the process is easy to be amplified, and the method is suitable for industrialization. And no metal reducing agent is adopted in the second step, so that the method basically has no safety risk, the three wastes are less, and the process is easy to amplify. Meanwhile, the reducing agent is low in price.

Preferred embodiments of the invention:

the solvent in the step (1) comprises acetonitrile, water, ionic liquid and the like, and preferably water. The reaction can be carried out more stably and safely due to the high specific heat capacity of water. In addition, water also has cost advantages over other solvents.

The required oxidant can be selected from potassium chlorate, sodium bromate, sodium chlorite, etc., preferably sodium bromate. Sodium bromate has cost advantages over other oxidizing agents.

The reduction method in the step (2) comprises methods such as sodium thiosulfate, sodium hydrosulfite, sodium sulfide, sodium polysulfide and the like, and preferably sodium polysulfide. Sodium polysulfide has cost advantages over other reducing agents.

The invention provides a method for synthesizing o-aminoacetophenone, which takes o-ethyl nitrobenzene as a starting material, and obtains the o-aminoacetophenone by 2-step reaction of oxidizing ethyl by a strong oxidant and reducing nitro by a reducing agent, wherein the reaction formula is as follows:

according to a mode of realisation of the present invention, in said process the oxidation of the ethyl group is carried out using a strong oxidizing agent to obtain an intermediate ketone, wherein said oxidizing agent comprises potassium chlorate, sodium bromate, sodium chlorite.

According to a mode of realisation of the present invention, in said method, said strong oxidizing agent is sodium bromate.

According to a mode of the invention, in the method, the reducing agent is a low-valent sulfur reducing agent comprising at least one of sodium thiosulfate, sodium hydrosulfite, sodium sulfide, sodium polysulfide.

According to a mode of embodiment of the invention, in the method, the reducing agent is sodium polysulfide.

According to a mode of realisation of the present invention, in said method, in said step of oxidizing ethyl groups with a strong oxidizing agent, the solvents used comprise acetonitrile, water, ionic liquids;

according to a mode of realisation of the present invention, in the method, it is preferred that the solvent is water;

according to a mode of realisation of the present invention, in the method, it is preferred that the solvent is water: acetonitrile 1: 1 (mass ratio).

According to a mode of realisation of the present invention, in said process, in said step of oxidizing the ethyl group with a strong oxidizing agent, further sulfuric acid is added.

According to a mode of realisation of the present invention, in the method, it is preferable that the sulfuric acid is concentrated sulfuric acid having a concentration of 98% or more.

According to a mode of realisation of the present invention, in said method, in said step of oxidizing ethyl group with a strong oxidizing agent, the reaction temperature is controlled at 80-90 ℃ for 12-20 hours;

according to a particular embodiment of the invention, the reaction time in the process is preferably 16 hours.

According to a practical mode of the invention, in the method, in the step of oxidizing the ethyl by using the strong oxidant, after the reaction is finished, the temperature is reduced to room temperature, the pH value is adjusted to 7-8, then the reaction is quenched by using a sodium thiosulfate solution until the color of the starch potassium iodide paper is not changed, liquid separation is carried out, and the organic phase is directly used for the next reaction.

According to a mode of the invention, in the method, the reduction of the nitro group with the reducing agent comprises: adding sodium polysulfide (Na) into the organic phase₂S_x) Reacting with water at 75-85 ℃ for 10-15 hours, and sampling and controlling; after the reaction is finished, cooling to room temperature, extracting twice by using toluene, merging organic phases, and concentrating and drying under reduced pressure to obtain a crude product of o-aminoacetophenone; and (5) rectifying and collecting 105 and 110 ℃/5mbar products to obtain a pure product.

According to a practical form of the invention, in the process, the reaction time is controlled at 12 hours.

The synthesis method of the invention is adopted to synthesize ethyl p-aminophenylpropionate, the process adopts a novel process route, the total molar yield is more than 56 percent, and the invention has the characteristics of high yield, cheap materials, mild reaction conditions, less three wastes and the like.

Drawings

FIG. 1 shows the nuclear magnetic characterization results of the intermediate obtained in example 1 of the present invention.

FIG. 2 shows the nuclear magnetic characterization of the product obtained in example 1 of the present invention.

Detailed Description