Preparation method of 3-bromopyridine-2-ethanone

Abstract

The invention discloses a preparation method of 3-bromopyridine-2-ethanone, and belongs to the technical field of medical intermediates. The method comprises the following steps: generating an intermediate 2-iodine-3-bromopyridine from 2, 3-dibromopyridine and sodium iodide under the action of trimethylhalosilane and cuprous iodide; and then carrying out a reaction with acetylimidazole by adopting Grignard reagent exchange to obtain the 3-bromopyridine-2-ethanone. In the first step, trimethyl halogenated silane is added for catalysis, so that the positioning effect is enhanced, the iodine exchange reaction yield is increased, and the generation of meta-position by-products is reduced. In the second step, iodine at the ortho-position of pyridine is adopted for Grignard reagent exchange and then reacts with acetylimidazole, so that side reactions are reduced, and an effective new path is provided for preparation of 3-bromopyridine-2-ethanone.

Description

Technical Field

[0001] The invention relates to a preparation method of 3-bromopyridine-2-ethanone, belonging to the technical field of pharmaceutical intermediates. Background Art

[0002] 3-Bromopyridine-2-ethanone (CAS No.: 111043-09-5) is an important organic synthesis intermediate with wide applications in pharmaceutical research and development, fine chemicals, catalytic chemicals, and other fields. Due to its specific 2-acetylpyridine chemical structure and properties, it is an important structural unit for the synthesis of Chalcones compounds. In addition, 3-Bromopyridine-2-ethanone can also be used in pesticides and feed raw materials, which further demonstrates its potential uses and broad application prospects in multiple fields.

[0003] There are few reports on the synthesis of 3-bromopyridine-2-ethanone, mainly the following two routes:

[0004] A. Patents and literature [WO2015173393A; WO202467857A; Organic and Biomolecular Chemistry, 2015, 13, 9418] reported that 3-bromo-2-cyanopyridine was reacted with a methyl Grignard reagent to generate 3-bromopyridine-2-ethanone.

[0005] B. Patent [WO201287782A] reports that 3-bromopyridine-2-carboxaldehyde is used as a raw material and reacts with a methyl Grignard reagent to generate 1-(3-bromopyridin-2-yl)ethanol, which is then oxidized to generate 3-bromopyridine-2-ethanone.

[0006] In view of the shortcomings of the above routes, it is necessary to conduct in-depth research on the synthesis route of 3-bromopyridine-2-ethanone and provide a better process route with cheaper and more readily available raw materials to meet the growing market demand. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 3-bromopyridine-2-ethanone. The method provided by the present invention is to react 2,3-dibromopyridine with sodium iodide under the action of trimethylsilane halide and cuprous iodide to generate an intermediate 2-iodo-3-bromopyridine; the intermediate is then exchanged with acetylimidazole using a Grignard reagent to obtain 3-bromopyridine-2-ethanone.

[0008] The preparation method of 3-bromopyridine-2-ethanone described in the present invention is achieved by the following technical scheme, and the reaction equation is expressed as follows:

[0009]

[0010] The steps include:

[0011] A. Mix 2,3-dibromopyridine, sodium iodide, trimethylsilane halide and cuprous iodide in an organic solvent and react under elevated temperature to generate an intermediate 2-iodo-3-bromopyridine;

[0012] B. Mix 2-iodo-3-bromopyridine, Grignard reagent and acetylimidazole in tetrahydrofuran and react at low temperature to generate 3-bromopyridine-2-ethanone;

[0013] Preferably, in step A of the above technical solution, the trimethylhalosilane is selected from trimethylchlorosilane, trimethylbromosilane or trimethyliodosilane, and the most preferred condition is trimethyliodosilane.

[0014] Preferably, in step A of the above technical solution, the solvent is dioxane or dimethyl sulfoxide.

[0015] Preferably, in step A of the above technical solution, the temperature rising condition is 90-100°C.

[0016] Preferably, in step A of the above technical solution, the molar ratio of 2,3-dibromopyridine, sodium iodide, trimethylsilane halide and cuprous iodide is 1:1-1.5:1-1.2:0.05-0.1.

[0017] Preferably, in step B of the above technical solution, the Grignard reagent is selected from isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride, isopropylmagnesium bromide or isopropylmagnesium bromide-lithium bromide.

[0018] Preferably, in step B of the above technical solution, the molar ratio of 2-iodo-3-bromopyridine, Grignard reagent and acetylimidazole is 1:1-1.3:1-1.3.

[0019] Preferably, in step B of the above technical solution, the low-temperature reaction is at -15°C to 0°C.

[0020] Beneficial effects of the present invention

[0021] A. In the first step of the present invention, benzene 2,3-dibromopyridine and sodium iodide are used to carry out Finkelstein (halogen exchange) reaction, and trimethylhalosilane is added as a catalyst to improve the positioning effect, thereby improving the yield of the iodine exchange reaction and reducing the generation of meta-position by-products; the addition of cuprous iodide improves the reaction efficiency.

[0022] B. In the second step of the present invention, pyridine ortho-iodine is used for Grignard reagent exchange, followed by reaction with acetylimidazole, which reduces the generation of side reactions and improves the yield. A route reference is provided for the synthesis of such compounds. Specific embodiments

[0023] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art may easily think of changes or substitutions within the technical scope disclosed by the present invention, and these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

[0024] Example 1

[0025]

[0026] Under nitrogen protection, 11.8 g (0.05 mol) of 2,3-dibromopyridine, 10.5 g (0.07 mol) of sodium iodide, 11 g (0.055 mol) of trimethylsilyl iodide and 0.57 g (3 mmol) of cuprous iodide were mixed in 120 mL of dioxane, heated to 90-100 ° C, reacted for 12 hours, cooled to room temperature, added with 100 mL of sodium hydroxide (1M) aqueous solution, and then extracted twice with 120 mL of dichloromethane, combined the organic layers, concentrated, and distilled under reduced pressure to obtain 12.1 g of intermediate 2-iodo-3-bromopyridine, with a yield of 85%, HPLC99.0%. 1 HNMR(400MHz, CDCl3):8.32(d,1H),7.82(d,1H),7.17(d,1H).

[0027] Comparative Example 1

[0028]

[0029] Under nitrogen protection, 11.8 g (0.05 mol) of 2,3-dibromopyridine, 10.5 g (0.07 mol) of sodium iodide, 8.4 g (0.055 mol) of trimethylsilyl bromide and 0.57 g (3 mmol) of cuprous iodide were mixed in 120 mL of dioxane, heated to 100-105 ° C for 19 hours, cooled to room temperature, added with 100 mL of sodium hydroxide (1M) aqueous solution, and then extracted twice with 120 mL of dichloromethane, the organic layers were combined, concentrated, and distilled under reduced pressure to obtain 10.5 g of the intermediate 2-iodo-3-bromopyridine with a yield of 74% and HPLC98.8%.

[0030] Example 2

[0031]

[0032] Under nitrogen protection, 14.2 g (0.05 mol) of 2-iodo-3-bromopyridine was added to 60 mL of THF, cooled to -15 °C, and 27.5 mL of isopropylmagnesium chloride (2M) THF solution was slowly added, maintaining the system temperature below 0 °C. After the addition was completed, stirring was continued for 1 hour. Then, 6.6 g (0.06 mol) of acetylimidazole was slowly added under the condition of continuing to maintain the system temperature below 0 °C. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 1 hour. After the reaction was completed, the reaction system was cooled to 0 °C, 60 mL of hydrochloric acid (2M) was slowly added and stirred for half an hour, and then sodium hydroxide (2M) aqueous solution was added to adjust the pH to 6-7. The layers were separated, and the aqueous layer was extracted twice with 100 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 10) to obtain 9.3 g of 3-bromopyridine-2-ethanone with a yield of 93% and an HPLC yield of 99.1%. 1 HNMR(400MHz, CDCl3):8.56(d,1H),7.97(d,1H),7.27(d,1H),2.66(s,3H).

[0033] Comparative Example 2

[0034] Under nitrogen protection, 14.2 g (0.05 mol) of 2-iodo-3-bromopyridine was added to 60 mL of THF, cooled to -15 °C, and 27.5 mL of ethylmagnesium chloride (2 M) THF solution was slowly added, maintaining the system temperature below 0 °C. After the addition was completed, stirring was continued for 1 hour. Then, 6.6 g (0.06 mol) of acetylimidazole was slowly added under the condition of continuing to maintain the system temperature below 0 °C. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 1 hour. After the reaction was completed, the reaction system was cooled to 0 °C, 60 mL of hydrochloric acid (2 M) was slowly added and stirred for half an hour, and then sodium hydroxide (2 M) aqueous solution was added to adjust the pH to 6-7. The layers were separated, and the aqueous layer was extracted twice with 100 mL of dichloromethane. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / n-hexane (v / v=1 / 10) to obtain 8.5 g of 3-bromopyridine-2-ethanone with a yield of 85% and an HPLC yield of 99.0%.

[0035] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 3-bromopyridine-2-ethanone, characterized in that: The steps include: A. Mix 2,3-dibromopyridine, sodium iodide, trimethylhalosilane and cuprous iodide in an organic solvent and react under elevated temperature to generate an intermediate 2-iodo-3-bromopyridine; B. Mix 2-iodo-3-bromopyridine, Grignard reagent and acetylimidazole in tetrahydrofuran and react at low temperature to generate 3-bromopyridine-2-ethanone.

2. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step A, the trimethylhalosilane is selected from trimethylchlorosilane, trimethylbromosilane or trimethyliodosilane.

3. The method for preparing 3-bromopyridine-2-ethanone according to claim 2, characterized in that: In step A, the trimethylhalosilane is selected from trimethyliodosilane.

4. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step A, the organic solvent is dioxane or dimethyl sulfoxide; and the temperature is raised to 90-100°C.

5. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step A, the molar ratio of 2,3-dibromopyridine, sodium iodide, trimethylhalosilane and cuprous iodide is 1:1-1.5:1-1.2:0.05-0.

1.

6. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step B, the Grignard reagent is selected from isopropylmagnesium chloride, isopropylmagnesium chloride-lithium chloride, isopropylmagnesium bromide or isopropylmagnesium bromide-lithium bromide.

7. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step B, the molar ratio of 2-iodo-3-bromopyridine, Grignard reagent and acetylimidazole is 1:1-1.3:1-1.

3.

8. The method for preparing 3-bromopyridine-2-ethanone according to claim 1, characterized in that: In step B, the low temperature reaction is between -15°C and 0°C.

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