A preparation method of 1-(3-bromopyridin-2-yl)ethanone

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 1-(3-bromopyridine-2-yl)ethanone, comprising the following steps: (1) synthesizing an intermediate 3-bromopyridine oxide: 3-bromopyridine is subjected to hydrogen peroxide oxidation to obtain an intermediate 3-bromopyridine oxide; (2) synthesizing 1-(3-bromopyridine-2-yl)ethanone: the intermediate 3-bromopyridine oxide and acetic anhydride are subjected to an acylation reaction under the catalysis of aluminum chloride to obtain the final product 1-(3-bromopyridine-2-yl)ethanone. Beneficial effects of the present invention: the method for preparing 1-(3-bromopyridine-2-yl)ethanone of the present invention uses 3-bromopyridine, which has a simple molecular structure and is cheap and easily available, as a raw material, and sequentially performs oxidation and acylation reactions to obtain a target product with high yield and high purity, while avoiding the use of Grignard reagents and difficult-to-recover solvents, thereby reducing material costs, improving production safety, and reducing wastewater discharge.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 1-(3-bromopyridin-2-yl)ethanone. Background Art

[0002] 1-(3-Bromopyridin-2-yl)ethanone is a heterocyclic derivative, an important raw material and intermediate, which can be widely used in the synthesis of medicines and pesticides and has a large market demand.

[0003] The existing preparation method of 1-(3-bromopyridin-2-yl)ethanone usually uses 2-cyano-3-bromopyridine as a raw material, and requires the use of Grignard reagent and tetrahydrofuran. However, the cost of 2-cyano-3-bromopyridine as a raw material is high, and tetrahydrofuran is expensive and difficult to recycle and reuse. At the same time, the Grignard reagent is a hazardous material and has low stability. In addition, patent WO2015173393 discloses a preparation method of 1-(3-bromopyridin-2-yl)ethanone, which uses 2-cyano-3-bromopyridine as a raw material and reacts with methylmagnesium iodide. However, the yield of the preparation method is only 66.8%. Patent WO2024067857 also discloses a preparation method of 1-(3-bromopyridin-2-yl)ethanone, which needs to be purified by column chromatography to obtain the product, which is cumbersome to operate and difficult to use for large-scale industrial production. In summary, the existing preparation methods of 1-(3-bromopyridin-2-yl)ethanone mainly have the problems of high material cost, low production safety, low reaction yield, and difficulty in large-scale industrial production. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing 1-(3-bromopyridin-2-yl)ethanone.

[0005] The present invention relates to a method for preparing 1-(3-bromopyridin-2-yl)ethanone, comprising the following steps:

[0006] (1) Synthesis of intermediate 3-bromopyridine oxide:

[0007] Add acetic acid to the reaction container, then add 3-bromopyridine, start stirring, first increase the temperature, then slowly drop hydrogen peroxide, after the dropwise addition is complete, carry out heat preservation reaction, TLC monitors the reaction, after the reaction is complete, reduce pressure and concentrate the reaction solution, then crystallize and filter, dry the filter cake to obtain the intermediate 3-bromopyridine oxide;

[0008] (2) Synthesis of 1-(3-bromopyridin-2-yl)ethanone:

[0009] The intermediate 3-bromopyridinyl oxide, acetic anhydride and aluminum chloride were added to the reaction container in sequence, stirring was started, and the reaction was carried out under heat preservation. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and then the mixture was extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure to obtain the final product 1-(3-bromopyridin-2-yl)ethanone;

[0010] The synthetic route is as follows:

[0011] .

[0012] Preferably, in step (1), the molar ratio of 3-bromopyridine to hydrogen peroxide is 1:1-3.

[0013] Preferably, in step (1), the mass ratio of 3-bromopyridine to acetic acid is 1:5-10.

[0014] Preferably, in step (1), the temperature is first raised to 50°C to 80°C; and the reaction is carried out at 50°C to 80°C for 3 to 5 hours.

[0015] Preferably, in step (1), methanol is used for crystallization, and the mass ratio of 3-bromopyridine to methanol is 1:0.8-1.5.

[0016] Preferably, in step (2), the molar ratio of the intermediate 3-bromopyridine oxide, acetic anhydride and aluminum chloride is 1:1-3:1-3.

[0017] Preferably, in the step (2), the mass ratio of the 3-bromopyridine oxide to dichloromethane is 1:5-20.

[0018] Preferably, in the step (2), the mass ratio of the 3-bromopyridine oxide to water is 1:5-20.

[0019] Preferably, in step (2), the reaction is carried out at a temperature of 80°C to 100°C.

[0020] Preferably, in step (2), the reaction is carried out by heat preservation for 1 to 3 hours.

[0021] Compared with the prior art, the advantages and positive effects of the present invention are:

[0022] (1) The method for preparing 1-(3-bromopyridin-2-yl)ethanone of the present invention uses 3-bromopyridine, which has a simple molecular structure and is cheap and easily available, as a raw material, and sequentially performs oxidation and acylation reactions to obtain a target product with high yield and high purity. At the same time, the use of Grignard reagents and difficult-to-recover solvents is avoided, thereby reducing material costs, improving production safety, and reducing wastewater discharge;

[0023] (2) The preparation method of 1-(3-bromopyridin-2-yl)ethanone of the present invention has mild reaction conditions, so that the reaction process is easier to control, the safety of large-scale production is improved, and the impact of scaling up to industrial production on reaction performance is reduced;

[0024] (3) The method for preparing 1-(3-bromopyridin-2-yl)ethanone of the present invention has a short reaction time and simple post-treatment, thereby reducing time cost and being easy to carry out large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following briefly introduces the drawings required for describing the embodiment.

[0026] Figure 1 The NMR spectrum of the final product obtained in Example 1. DETAILED DESCRIPTION

[0027] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0028] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0029] Example 1

[0030] A method for preparing 1-(3-bromopyridin-2-yl)ethanone comprises the following steps:

[0031] (1) Synthesis of intermediate 3-bromopyridine oxide:

[0032] Add 500g of acetic acid to a 1L reaction bottle, then add 50g of 3-bromopyridine, start stirring, first heat to 60°C, then slowly add 24g of hydrogen peroxide, after the addition is complete, keep warm at 60°C for 4h, monitor the reaction by TLC, after the reaction is complete, concentrate the reaction solution under reduced pressure, add 40g of methanol for crystallization and filter, dry the filter cake to obtain 52g of intermediate 3-bromopyridine oxide, with a yield of 94.4%, a purity of 99.1%, and a melting point of 41.3°C.

[0033] (2) Synthesis of 1-(3-bromopyridin-2-yl)ethanone:

[0034] To a 1L reaction bottle, 52 g of the intermediate 3-bromopyridine oxide, 58.6 g of acetic anhydride and 76.6 g of aluminum trichloride were added in sequence, stirring was started, and the reaction was kept warm at 90°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, 520 g of water was added to quench, and then 520 g of dichloromethane was added for extraction. The dichloromethane layer was concentrated under reduced pressure to obtain 55.6 g of light yellow liquid, which was the final product 1-(3-bromopyridin-2-yl)ethanone, with a yield of 93% and a purity of 99.5%.

[0035] Example 2

[0036] A method for preparing 1-(3-bromopyridin-2-yl)ethanone comprises the following steps:

[0037] (1) Synthesis of intermediate 3-bromopyridine oxide:

[0038] 1.25 kg of acetic acid was added to a 5L reaction bottle, followed by 250 g of 3-bromopyridine. Stirring was started, the temperature was first raised to 50°C, and then 55 g of hydrogen peroxide was slowly added dropwise. After the addition was complete, the reaction was kept warm at 50°C for 5 hours and monitored by TLC. After the reaction was completed, the reaction solution was concentrated under reduced pressure, 370 g of methanol was added for crystallization, and then filtered. The filter cake was dried to obtain 252 g of intermediate 3-bromopyridine oxide with a yield of 91.5%, a purity of 99.2%, and a melting point of 41.9°C.

[0039] (2) Synthesis of 1-(3-bromopyridin-2-yl)ethanone:

[0040] To a 1L reaction bottle, 252g of the intermediate 3-bromopyridine oxide, 220g of acetic anhydride and 267g of aluminum trichloride were added in sequence, stirring was started, and the reaction was kept warm at 100°C for 1h. The reaction was monitored by TLC. After the reaction was completed, 5kg of water was added to quench, and then 5kg of dichloromethane was added for extraction. The dichloromethane layer was concentrated under reduced pressure to obtain 272.6g of light yellow liquid, which was the final product 1-(3-bromopyridin-2-yl)ethanone, with a yield of 94.1% and a purity of 99.4%.

[0041] Example 3

[0042] A method for preparing 1-(3-bromopyridin-2-yl)ethanone comprises the following steps:

[0043] (1) Synthesis of intermediate 3-bromopyridine oxide:

[0044] Add 40 kg of acetic acid to a 100 L reaction bottle, then add 5 kg of 3-bromopyridine, start stirring, first heat to 55 ° C, then slowly add 3 kg of hydrogen peroxide, after the addition is complete, keep warm at 55 ° C for 3 hours, monitor the reaction by TLC, after the reaction is completed, concentrate the reaction solution under reduced pressure, add 5 kg of methanol for crystallization and filter, dry the filter cake to obtain 5.2 kg of intermediate 3-bromopyridine oxide, with a yield of 94.6%, a purity of 99.3%, and a melting point of 41.5 ° C.

[0045] (2) Synthesis of 1-(3-bromopyridin-2-yl)ethanone:

[0046] To a 1L reaction bottle, 5.2kg of the intermediate 3-bromopyridine oxide, 8.9kg of acetic anhydride and 11.6kg of aluminum trichloride were added in sequence, stirring was started, and the reaction was kept warm at 90°C for 3h. The reaction was monitored by TLC. After the reaction was completed, 26kg of water was added to quench, and then 26kg of dichloromethane was added for extraction. The dichloromethane layer was concentrated under reduced pressure to obtain 5.6kg of light yellow liquid, which was the final product 1-(3-bromopyridin-2-yl)ethanone, with a yield of 93.6% and a purity of 99.2%.

[0047] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing 1-(3-bromopyridin-2-yl)ethanone, characterized in that: The following steps are involved: (1) Synthesis of intermediate 3-bromopyridine oxide: Add acetic acid to the reaction container, then add 3-bromopyridine, start stirring, first increase the temperature, then slowly drop hydrogen peroxide, after the dropwise addition is complete, carry out heat preservation reaction, TLC monitors the reaction, after the reaction is complete, reduce pressure and concentrate the reaction solution, then crystallize and filter, dry the filter cake to obtain the intermediate 3-bromopyridine oxide; (2) Synthesis of 1-(3-bromopyridin-2-yl)ethanone: The intermediate 3-bromopyridinyl oxide, acetic anhydride and aluminum chloride were added to the reaction container in sequence, stirring was started, and the reaction was carried out under heat preservation. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, and then the mixture was extracted with dichloromethane. The dichloromethane layer was concentrated under reduced pressure to obtain the final product 1-(3-bromopyridin-2-yl)ethanone; The synthetic route is as follows: ； In the step (1), the molar ratio of 3-bromopyridine to hydrogen peroxide is 1:1 to 3; In the step (1), the mass ratio of 3-bromopyridine to acetic acid is 1:5-10; In the step (2), the molar ratio of the intermediate 3-bromopyridine oxide, acetic anhydride and aluminum chloride is 1:1-3:1-3; In the step (2), the reaction is carried out at a temperature of 80°C to 100°C.

2. The method for preparing 1-(3-bromopyridin-2-yl)ethanone according to claim 1, characterized in that: In the step (1), the temperature is first raised to 50°C to 80°C; and the reaction is carried out at 50°C to 80°C for 3 to 5 hours.

3. The method for preparing 1-(3-bromopyridin-2-yl)ethanone according to claim 1, characterized in that: In the step (1), methanol is used for crystallization, and the mass ratio of 3-bromopyridine to methanol is 1:0.8-1.

5.

4. The method for preparing 1-(3-bromopyridin-2-yl)ethanone according to claim 1, characterized in that: In the step (2), the mass ratio of the 3-bromopyridine oxide to dichloromethane is 1:5-20.

5. The method for preparing 1-(3-bromopyridin-2-yl)ethanone according to claim 1, characterized in that: In the step (2), the mass ratio of the 3-bromopyridine oxide to water is 1:5-20.

6. The method for preparing 1-(3-bromopyridin-2-yl)ethanone according to claim 1, characterized in that: In the step (2), the reaction is kept warm for 1 to 3 hours.

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