Preparation method of (8-bromoindolizine-3-yl) (3, 4, 5-trifluorophenyl) ketone

Abstract

The invention discloses a preparation method of (8-bromoindolizine-3-yl) (3, 4, 5-trifluorophenyl) ketone, and belongs to the technical field of medical intermediates. The method comprises the following steps: synthesizing an intermediate 1 from 2-bromo-1-(3, 4, 5-trifluorophenyl) ethanone and 3-acetamidopyridine, generating an intermediate 2 from the intermediate 1 and maleic anhydride under the action of alkali and an oxidant, and then generating (8-bromoindolizine-3-yl) (3, 4, 5-trifluorophenyl) ketone under the action of copper bromide and t-BuONO. According to the method, 3-acetaminopyridine and 2-bromo-1-(3, 4, 5-trifluorophenyl) ethanone are adopted as raw materials, an intermediate 1 is generated, and then cyclization is performed to generate indolizine. And the cyclization is positioned between pyridine nitrogen and the amino group due to the hydrogen-bond interaction, so that the reaction design is reasonable, and an effective path is provided for the preparation of the product.

Description

Technical Field

[0001] The invention relates to a preparation method of (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone, belonging to the technical field of pharmaceutical intermediates. Background Art

[0002] (8-Bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone (CAS No.: 2641795-78-8) is an important organic synthesis intermediate. As an indolizine compound, it has a wide range of uses, mainly in the following aspects: Pharmaceutical field: It can be used as a key intermediate for the synthesis of important physiologically active alkaloids. Pesticide field: Indolizine compounds can be used as herbicides and have unique physiological activity. Dye industry: Indolizine compounds can be converted into push-pull dyes and have important applications in the dye industry. Many downstream products derived from it can be used as synthetic raw materials for dyes and are used to produce a variety of new functional dyes. Other fields: Indolizine compounds are also widely used in materials science. Due to their outstanding photophysical properties, they are often used in the research of special molecular platforms.

[0003] There are few reports on the synthesis of (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone, and there is only one route:

[0004]

[0005] Patents [WO2024175998A; WO2022232320A; WO222232318A; WO202185653A] report that 3,4,5-trifluoroacetophenone is used as the raw material, which is brominated and then reacted with 3-bromo-2-methylpyridine to generate pyridine bromide, and then a cyclization reaction is carried out to generate (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone.

[0006] In view of the shortcomings of the above routes, it is necessary to conduct in-depth research on the synthesis route of (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone and develop 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 (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone. 2-bromo-1-(3,4,5-trifluorophenyl)ethanone and 3-acetylaminopyridine are used to synthesize intermediate 1, which is reacted with maleic anhydride under the action of a base and an oxidant to generate intermediate 2, and then (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone is generated under the action of copper bromide and t-BuONO.

[0008] The preparation method of (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone of 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-bromo-1-(3,4,5-trifluorophenyl)ethanone and 3-acetylaminopyridine in acetonitrile and react under reflux conditions to generate intermediate 1;

[0012] B. Mixing intermediate 1, maleic anhydride, a base and an oxidant in acetonitrile, reacting under reflux conditions, and then alkaline hydrolysis to generate intermediate 2;

[0013] C. The intermediate 2, copper bromide and t-BuONO are mixed in acetonitrile and reacted at room temperature to generate (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone.

[0014] Preferably, in step A of the above technical solution, the molar ratio of 2-bromo-1-(3,4,5-trifluorophenyl)ethanone to 2-acetylaminopyridine is 1:1-1.2.

[0015] Preferably, in step B of the above technical solution, the base is potassium tert-butoxide.

[0016] Preferably, in step B of the above technical solution, the oxidant is tetrapyridine cobalt dichromate (TPCD).

[0017] Preferably, in step B of the above technical solution, the molar ratio of the intermediate 1, maleic anhydride, base and oxidant is 1:2-2.1:1-1.1:1.5-2.

[0018] Preferably, in step C of the above technical solution, the molar ratio of the intermediate 2, copper bromide and t-BuONO is 1:1.2-1.6:1-1.2

[0019] Beneficial effects of the present invention

[0020] A. The present invention uses 3-acetylaminopyridine and 2-bromo-1-(3,4,5-trifluorophenyl)ethanone as raw materials to generate intermediate 1, and then cyclizes to generate indolizine. Due to the hydrogen bonding effect, the amino group at the meta position of pyridine positions the cyclization between the pyridine nitrogen and the amino group. The reaction design is reasonable and the process is feasible. A new route is provided for the synthesis of such compounds.

[0021] B. The amino group of the present invention is converted into bromine by a one-step reaction of copper bromide and t-BuONO. The process is simple and feasible, and waste acid produced by other diazotization reactions is avoided. At the same time, the use of copper bromide for bromination reaction greatly reduces the generation of dibromine by-products. Specific embodiments

[0022] Example 1

[0023]

[0024] Under nitrogen protection, 25.3 g (0.1 mol) of 2-bromo-1-(3,4,5-trifluorophenyl)ethanone and 15 g (0.11 mol) of 3-acetylaminopyridine were mixed in 200 mL of acetonitrile, reacted under reflux for 20 hours, cooled to room temperature, concentrated, and the crude product was slurried with toluene to generate 33.1 g of intermediate 1 with a yield of 85% and a HPLC purity of 99.3%. 1 HNMR(400MHz, DMSO-d6):9.91(s,1H),9.75(d,1H),9.10(d,1H),8.95(m,1H),8.15-8.1(m,2H),8.06-8.01(m,1H),6.43(s,2H),2.1(s,3H).

[0025] Example 2

[0026]

[0027] Under nitrogen protection, intermediate 1 (19.5g, 0.05mol), maleic anhydride 10.1 (0.103mol), potassium tert-butoxide 5.9g (0.053mol) and TPCD48.8g (0.08mol) were mixed in 500mL acetonitrile, reacted under reflux for 3 hours, cooled to room temperature, slowly added 150mL 25% NaOH solution, and then heated to 50°C for 6 hours. Add 200mL dichloromethane to extract twice under cooling, combine the organic layers, concentrate, and purify the crude product by column chromatography, eluent ethyl acetate / petroleum ether (v / v=1 / 10-20), to generate intermediate 2, 11.6g, yield 80%, HPLC purity 99.1%. 1 HNMR(400MHz, DMSO-d6):9.75(d,1H),7.81-7.70(m,3H),7.55(d,1H),7.1(d,1H),6.37(d,1H),5.80(s,2H).

[0028] Comparative Example 2

[0029] Under nitrogen protection, intermediate 1 (19.5g, 0.05mol), maleic anhydride 10.1 (0.103mol), potassium carbonate 24g (0.175mol) and TPCD48.8g (0.08mol) were mixed in 500mL acetonitrile, reacted under reflux conditions for 8 hours, cooled to room temperature, slowly added 150mL 25% NaOH, heated to 50°C and reacted for 6 hours. After cooling, 200mL dichloromethane was added and extracted twice, the organic layers were combined, and the crude product obtained by concentration was purified by column chromatography, the eluent was ethyl acetate / petroleum ether (v / v=1 / 10-20), and 9.8g of intermediate 2 was generated, with a yield of 68% and a HPLC purity of 98.8%.

[0030] Example 3

[0031]

[0032] Under nitrogen protection, intermediate 2 (14.5 g, 0.05 mol), copper bromide 16.8 g (0.075 mol) and t-BuONO5.7 g (0.055 mol) were mixed in 200 mL of acetonitrile and reacted at room temperature for 5 hours. Then, saturated sodium carbonate aqueous solution was added to adjust the pH to 8-9, and 200 mL of dichloromethane was added to extract twice. The organic layers were combined and concentrated. The crude product was purified by column chromatography with an eluent of ethyl acetate / petroleum ether (v / v=1 / 10-30) to generate 14.5 g (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone with a yield of 82% and a HPLC purity of 99%. 1 HNMR(400MHz, DMSO-d6):9.77(d,1H),7.78-7.66(m,3H),7.53(d,1H),7.11(t,1H),6.77(d,1H).

[0033] Comparative Example 3

[0034]

[0035] Under nitrogen protection, intermediate 2 (14.5 g, 0.05 mol) and t-BuONO 5.7 g (0.055 mol) were mixed in 200 mL acetonitrile, reacted for 3 hours at room temperature, NBS 13.3 g (0.075 mol) was added, and the reaction was continued for 5 hours, followed by adding saturated sodium carbonate aqueous solution to adjust the pH to 8-9, adding 200 mL dichloromethane to extract twice, combining the organic layers, concentrating, and the crude product was purified by column chromatography, with the eluent being ethyl acetate / petroleum ether (v / v=1 / 10-30), to generate 10.3 g (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone, with a yield of 58% and a HPLC purity of 98.5%. (NMR external standard quantification of the mother liquor, dibromo byproduct content 26%)

[0036] 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 (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone, characterized in that: The steps include: A. Mix 2-bromo-1-(3,4,5-trifluorophenyl)ethanone and 3-acetylaminopyridine in acetonitrile and react under reflux conditions to generate intermediate 1; B. Mixing intermediate 1, maleic anhydride, a base and an oxidant in acetonitrile, reacting under reflux conditions, and then alkaline hydrolysis to generate intermediate 2; C. The intermediate 2, copper bromide and t-BuONO are mixed in acetonitrile and reacted at room temperature to generate (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone.

2. The method for preparing (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone according to claim 1, characterized in that: In step A, the molar ratio of 2-bromo-1-(3,4,5-trifluorophenyl)ethanone to 2-acetylaminopyridine is 1:1-1.

2.

3. The method for preparing (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone according to claim 1, characterized in that: In step B, the base is potassium tert-butoxide.

4. The method for preparing (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone according to claim 1, characterized in that: In step B, the oxidant is tetrapyridine cobalt dichromate (TPCD).

5. The method for preparing (8-bromoindolizine-3-yl) (3,4,5-trifluorophenyl) ketone according to claim 1, characterized in that: In step B, the molar ratio of the intermediate 1, maleic anhydride, base and oxidant is 1:2-2.1:1-1.1:1.5-2.

6. The method for preparing (8-bromoindolizine-3-yl)(3,4,5-trifluorophenyl)methanone according to claim 1, characterized in that: In step C, the molar ratio of the intermediate 2, copper bromide and t-BuONO is 1:1.2-1.6:1-1.2.

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