Method for connecting dibromide to aniline compound

Abstract

The invention provides a method for connecting dibromo on an aniline compound, which comprises the following steps: dissolving a compound as shown in a formula I in a solvent, adding calcium carbonate, and reacting with benzyltrimethylammonium tribromide to obtain a compound as shown in a formula II; wherein R is alkyl, trifluoromethoxy, phenyl, carbonyl, nitryl, sulfonic acid group or formic acid alkyl ester group; the method provided by the invention does not need high-temperature heating, is only carried out at normal temperature, is non-toxic and harmless, can quickly prepare the dibromo-substituted aniline compound through one-step reaction by using calcium carbonate and a specific bromination reagent, is simple in process operation, low in cost and simple and convenient in post-treatment, and has a relatively high application value; # imgabs0 #

Description

Technical Field

[0001] The invention relates to the field of organic chemistry, and in particular to a method for connecting dibromine to an aniline compound. Background Art

[0002] Halogen compound pharmaceutical intermediates play an important role in drug development and synthesis. Through the special properties of halogen atoms, the hydrophilicity, lipophilicity, electron density, etc. of molecules can be adjusted, affecting the biological activity and metabolic pathways of drugs. In addition, halogen atoms are often used as markers or drug delivery carriers in drug molecules. In general, halogen compound pharmaceutical intermediates have important application value in the pharmaceutical field and are of great significance for the development of new drugs and clinical treatment. With the development of the pharmaceutical field, the research and development of such compounds will continue to receive attention.

[0003] In existing studies, two bromine atoms are connected to the compound and hydrobromic acid can be used for the reaction. However, this reaction requires heating and has many disadvantages, such as the volatility of hydrobromic acid at high temperatures, which is toxic to the human body, high cost and troublesome post-processing.

[0004] Therefore, how to develop a method to connect two bromine atoms to a compound through a conventional reaction is of great value for the preparation of actual compounds. Summary of the invention

[0005] The technical problem to be solved by the present invention is that the existing method of connecting two bromine atoms is not environmentally friendly and requires high-temperature heating.

[0006] In order to solve the above technical problems, in the first aspect, the present invention provides a method for connecting dibromine to an aniline compound, the method comprising: dissolving the compound represented by formula I in a solvent, adding calcium carbonate, and reacting with benzyltrimethylammonium tribromide to obtain the compound represented by formula II;

[0007]

[0008] Wherein, R is an alkyl group, a trifluoromethoxy group, a phenyl group, a carbonyl group, a nitro group, a sulfonic acid group or an alkyl formate group.

[0009] In the present invention, the alkyl group may be a linear or branched alkyl group such as methyl, ethyl, isopropyl, n-butyl, isobutyl, or the like.

[0010] The compound shown in formula I can be the following structure:

[0011]

[0012] wait.

[0013] The preparation method provided by the invention is non-toxic and harmless, can react in one step by using calcium carbonate and a specific bromination reagent, and can quickly prepare dibromo-substituted aniline compounds, has simple process operation, low cost, simple post-processing, and high application value.

[0014] Preferably, the molar ratio of the compound represented by formula I, benzyltrimethylammonium tribromide and calcium carbonate is 1:(2.1-3):(6-8), for example, it can be 1:2.2:7, 1:2.5:8 or 1:3:6, etc.

[0015] Preferably, the solvent is a mixed solvent of methanol and dichloromethane.

[0016] Preferably, the volume amount of the solvent is 8 to 12 times the mass amount of the compound represented by Formula I. For example, for 1 g of the compound represented by Formula I, the volume amount of the solvent is 10 mL.

[0017] Preferably, the reaction temperature is 10-40°C.

[0018] Preferably, the reaction time is 2 to 5 hours, for example, 2 hours, 3 hours, 4 hours or 5 hours.

[0019] The implementation of the present invention has the following beneficial effects:

[0020] The method provided by the invention does not require high-temperature heating and can be carried out at room temperature only, is non-toxic and harmless, can react in one step by using calcium carbonate and a specific bromination reagent, can quickly prepare dibromo-substituted aniline compounds, has simple process operation, low cost, simple post-processing, and has high application value. DETAILED DESCRIPTION

[0021] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0022] Example 1

[0023] This embodiment provides a method for connecting dibromoaniline compounds

[0024]

[0025] Add calcium carbonate (212.07g, 2118.747mmol) to a 2L reaction bottle, add methanol (500mL), and start stirring. Add ethyl p-aminobenzoate (50g, 302.678mmol). Cool down to 2℃. Add benzyltrimethylammonium tribromide (260.34g, 665.892mmol) in batches, and control the temperature within 10℃. After the addition, add dichloromethane (500.00mL). Naturally warm to room temperature and react for 3 hours. Check the reaction of the raw materials by tapping the plate, filter the reaction solution, rinse the filter cake until there is no product, and spin dry the filtrate to obtain 350g of crude product. Purify by column, flush the column with pure ethyl acetate, and obtain about 100g of crude product. Rinse the crude product to reduce the weight. The product was flushed out by column purification twice, with a volume ratio of petroleum ether: ethyl acetate of 10:1, and the volume ratio of petroleum ether: ethyl acetate of 5:1, and the solvent was spin-dried to obtain 81 g of the product as an off-white solid. Yield: 82%, purity: 99%.

[0026] H NMR spectrum: 1 HNMR (400MHz, CDCl 3 ): δ8.07(s,2H),4.98(s,2H),4.32(q,J=7.1Hz,2H),1.37(q,J=7.0Hz,3H).

[0027] Example 2

[0028] This embodiment provides a method for connecting dibromoaniline compounds

[0029]

[0030] Add calcium carbonate (197.63g, 1976.28mmol) to a 2L reaction bottle, add methanol (500mL), and start stirring. Add p-trifluoromethoxyaniline (50g, 282.33mmol). Cool to 2°C. Add benzyltrimethylammonium tribromide (242.2g, 621.12mmol) in batches, and control the temperature within 10°C. After addition, add dichloromethane (500.00mL). Naturally warm to room temperature and react for 3 hours. Check the plate to see that the raw materials have reacted, filter the reaction solution, rinse the filter cake until there is no product, and spin dry the filtrate to obtain 385g of crude product. Purify by column, flush the column with pure ethyl acetate to obtain about 110g of crude product, and reduce the weight of the crude product by rough. Purify by column twice, the volume ratio of petroleum ether: ethyl acetate is 10:1 to flush out the product, the volume ratio of petroleum ether: ethyl acetate is 5:1 to flush, and the solvent is spin-dried to obtain 78g of product, which is an off-white solid. Yield: 82.5%, purity: 99%.

[0031] H NMR spectrum: 1 HNMR (400MHz, CDCl 3):8.34(s,1H),5.29(s,1H).

[0032] Example 3

[0033] This embodiment provides a method for connecting dibromoaniline compounds

[0034]

[0035] Add calcium carbonate (253.44g, 2534.4mmol) to a 2L reaction bottle, add methanol (500mL), and start stirring. Add p-nitroaniline (50g, 362.06mmol). Cool down to 2℃. Add benzyltrimethylammonium tribromide (310.6g, 796.52mmol) in batches, and control the temperature within 10℃. After addition, add dichloromethane (500.00mL). Naturally warm to room temperature and react for 3 hours. Check the plate to see that the raw materials have reacted, filter the reaction solution, rinse the filter cake until there is no product, and spin dry the filtrate to obtain 390g of crude product. Purify by column, flush the column with pure ethyl acetate to obtain about 119g of crude product, and reduce the weight of the crude product by rough. Purify by column twice, the volume ratio of petroleum ether: ethyl acetate is 10:1 to flush out the product, the volume ratio of petroleum ether: ethyl acetate is 5:1 to flush, and the solvent is spin-dried to obtain 90g of product, which is an off-white solid. Yield: 84.11%, purity: 99%.

[0036] H NMR spectrum: 1 HNMR (400MHz, CDCl 3 ):8.34(s,1H),5.29(s,1H).

[0037] Example 4

[0038] This embodiment provides a method for connecting dibromoaniline compounds

[0039]

[0040] Add calcium carbonate (258.88g, 2588.76mmol) to a 500ml reaction bottle, add methanol (500mL), and start stirring. Add p-aminoacetophenone (50g, 369.82mmol). Cool down to 2℃. Add benzyltrimethylammonium tribromide (317.27g, 813.61mmol) in batches, and control the temperature within 10℃. After addition, add dichloromethane (500.00mL). Naturally warm to room temperature and react for 3 hours. Check the plate to see that the raw materials have reacted, filter the reaction solution, rinse the filter cake until there is no product, and spin dry the filtrate to obtain 385g of crude product. Purify by column, flush the column with pure ethyl acetate to obtain about 120g of crude product, and reduce the weight of the crude product by rough. Purify by column twice, the volume ratio of petroleum ether: ethyl acetate is 10:1 to flush out the product, the volume ratio of petroleum ether: ethyl acetate is 5:1 to flush, and the solvent is spin-dried to obtain 81g of product as an off-white solid. Yield: 75%, purity: 99%.

[0041] H NMR spectrum: 1 HNMR (300MHz, CDCl 3 ): δ8.01(s,2H),5.06(s,2H),2.50(s,3H).

[0042] Example 5

[0043] This embodiment provides a method for connecting dibromoaniline compounds

[0044]

[0045] Add calcium carbonate (206.86g, 2068.56mmol) to a 500ml reaction bottle, add methanol (500mL), and start stirring. Add 4-aminobiphenyl (50g, 295.5mmol). Cool down to 2℃. Add benzyltrimethylammonium tribromide (253.51g, 650.12mmol) in batches, and control the temperature within 10℃. After addition, add dichloromethane (500.00mL). Naturally warm to room temperature and react for 3 hours. Check the plate to see that the raw materials have reacted, filter the reaction solution, rinse the filter cake until there is no product, and spin dry the filtrate to obtain 340g of crude product. Purify by column, flush the column with pure ethyl acetate to obtain about 104g of crude product, and reduce the weight of the crude product by rough. Purify by column twice, the volume ratio of petroleum ether: ethyl acetate is 10:1 to flush out the product, the volume ratio of petroleum ether: ethyl acetate is 5:1 to flush, and the solvent is spin-dried to obtain 80g of product, which is an off-white solid. Yield: 83.3%, purity: 99%.

[0046] H NMR spectrum: 1 HNMR (400MHz, CDCl 3)δ8.07(s,2H),4.98(s,2H),4.32(q,J=7.1Hz,2H),1.37(q,J=7.0Hz,3H).

[0047] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for connecting a dibromine to an aniline compound, characterized in that: The method comprises: dissolving the compound represented by formula I in a solvent, adding calcium carbonate, and reacting with benzyltrimethylammonium tribromide to obtain the compound represented by formula II; Wherein, R is an alkyl group, a trifluoromethoxy group, a phenyl group, a carbonyl group, a nitro group, a sulfonic acid group or an alkyl formate group.

2. The method according to claim 1, characterized in that: The molar ratio of the compound represented by formula I, benzyltrimethylammonium tribromide and calcium carbonate is 1:(2.1-3):(6-8).

3. The method according to claim 1, characterized in that The solvent is a mixed solvent of methanol and dichloromethane.

4. The method according to claim 1, characterized in that The volume amount of the solvent is 8 to 12 times the mass amount of the compound represented by formula I.

5. The method according to claim 1, characterized in that: The reaction temperature is 10-40°C.

6. The method according to claim 1, characterized in that The reaction time is 2 to 5 hours.

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