Synthetic method of compound 3, 8-dibromophenanthroline and compound

Abstract

The invention provides a synthetic method of a compound 3, 8-dibromo phenanthroline and the compound, and the synthetic method comprises the following steps: firstly converting a compound 1, 10-phenanthroline into a compound 3, 8-bis (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl)-1, 10-o-phenanthroline, and then converting the compound 3, 8-bis (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl)-1, 10-o-phenanthroline into the compound 3, 8-dibromo phenanthroline. The characteristic that boron ester can be easily brominated is utilized, a new synthesis route is designed, a boron-containing intermediate is obtained through catalysis, then copper bromide is utilized for bromination to obtain a target product, the reaction yield is ideal, aftertreatment is simple, the dosage of a metal catalyst is very small, other raw materials are low in price, the cost and danger are remarkably reduced, and the method is suitable for industrial production. And the method is suitable for manufacturability amplification.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis, and specifically relates to compound 3,8-dibromophenanthroline and compounds. Background Art

[0002] The compound 3,8-dibromophenanthroline is mainly used in the fields of organic synthesis and pharmaceutical synthesis. In the field of organic synthesis, 3,8-dibromophenanthroline can be used as an organic synthesis intermediate and participate in a variety of chemical reactions. For example, it can react with bromine to produce 3,8-dibromo-1,10-phenanthroline, and further oxidation can give 3,8-dibromo-1,10-phenanthroline-5,6-dione. In addition, 3,8-dibromophenanthroline can also be used in the design, synthesis and application of porous materials, especially in the synthesis of organic porous materials. The Sonogashira reaction can be used to synthesize the porous aromatic framework (Phen-PAF) functionalized with o-phenanthroline. This material performs well in removing organic dyes from wastewater and catalyzing organic reactions. In the field of pharmaceutical synthesis, 3,8-dibromophenanthroline also has important applications. It can be used to prepare a variety of drug intermediates, such as 6,11-dibromo-1,4,8,9-tetraazatriphenylene and 6,11-bis(phenoxazine) and other compounds. These compounds have broad application prospects in the field of medicine. Therefore, it is of certain significance to study the synthesis method of 3,8-dibromophenanthroline.

[0003] In the prior art, the compound 3,8-dibromophenanthroline is mainly synthesized by direct bromination of 1,10-phenanthroline. Although the steps are short, the disadvantages of this method are very obvious. Most of the bromine sources for bromination are liquid bromine, and a higher reaction temperature is required. Liquid bromine is highly volatile and has strong toxicity and corrosiveness. The pungent odor is stronger when heated, which is very dangerous. At the same time, monohalogen by-products are easily generated, which are difficult to purify. The conversion rates of other bromine sources such as N-bromosuccinimide (NBS) and dibromohydantoin are also relatively low. Summary of the invention

[0004] In view of the above problems existing in the prior art, the present application provides a method for synthesizing 3,8-dibromophenanthroline, which has the advantages of low cost, mild reaction conditions, ideal yield and potential for process scale-up.

[0005] In the first aspect, the present application provides a method for synthesizing a compound 3,8-dibromophenanthroline, wherein compound 1 (1,10-phenanthroline) is first converted into compound 2 (3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,10-o-phenanthroline), and compound 2 is then converted into compound 3 (3,8-dibromophenanthroline). The specific synthetic route is as follows:

[0006]

[0007] As a preferred embodiment of the present application, the synthesis steps of compound 3 (3,8-dibromophenanthroline) are as follows:

[0008] Under the protection of inert gas, [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester and methoxy(cyclooctadiene)iridium dimer are added to organic solvent I, stirred for 20-40 minutes, and then diboric acid pinacol ester is added, stirred for 20-40 minutes, compound 1 is dissolved in organic solvent I, and added dropwise to the above mixed solution. After the addition is completed, it is heated to reflux and reacted for 10-40 hours. After the reaction is completed, the reaction solution is subjected to the first post-treatment to obtain compound 2;

[0009] Compound 2 is added to organic solvent II and organic solvent III, and copper bromide is added, and the mixture is heated to reflux and reacted for 10-40 hours. After the reaction is completed, the reaction solution is treated for the second time to obtain compound 3, namely 3,8-dibromophenanthroline.

[0010] As a preferred embodiment of the present application, the first post-treatment comprises: after the reaction is completed, cooling the reaction solution to room temperature, adding organic solvent IV, filtering, and spinning the filtrate to dryness to obtain a crude product, and purifying the crude product to obtain compound 2;

[0011] The second post-treatment includes: after the reaction is completed, cooling the reaction solution to room temperature, filtering, rotating the filtrate to dryness, adding ammonia water and stirring for 10-50 minutes, filtering, dissolving the filter cake with organic solvent V, washing the obtained organic phase, drying, rotating to dryness to obtain a crude product, and purifying the crude product to obtain compound 3.

[0012] As a preferred embodiment of the present application, the organic solvent I is selected from one or more of n-heptane, tetrahydrofuran, toluene, and 1,4-dioxane;

[0013] The organic solvent II is selected from one or more of methyl tert-butyl ether, ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane;

[0014] The organic solvent III is selected from one or more of ethanol, methanol, and tert-butanol;

[0015] The organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane;

[0016] The organic solvent V is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

[0017] As a preferred embodiment of the present application, the inert gas is selected from one or more of nitrogen and argon.

[0018] As a preferred embodiment of the present application, the mass volume ratio of the compound 1 to the organic solvent I, the organic solvent II and the organic solvent III is 1:5-40 g / mL.

[0019] As a preferred embodiment of the present application, the molar ratio of the compound 1 to [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester is 1.0:0.01-0.05; the molar ratio of the compound 1 to methoxy(cyclooctadiene)iridium dimer is 1.0:0.01-0.05; the molar ratio of the compound 1 to bipyridine-4,4'-dicarboxylic acid dibutyl ester is 1.0:1.0-3.0.

[0020] As a preferred embodiment of the present application, the purification methods of the first post-treatment and the second post-treatment are selected from one or more of beating, recrystallization, column chromatography, or distillation.

[0021] In a second aspect, the present application also provides a compound synthesized by any synthesis method described in the first aspect.

[0022] The present application provides a synthesis method and compound of 3,8-dibromophenanthroline, including: the compound 1,10-phenanthroline is first converted into the compound 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,10-o-phenanthroline, and then converted into the compound 3,8-dibromophenanthroline. The present application utilizes the characteristic that boron ester can be easily brominated, designs a new synthesis route of the present application, obtains a boron-containing intermediate by catalysis, and then obtains the target product by bromination with copper bromide, has an ideal reaction yield, is simple to post-process, uses a small amount of metal catalyst, and the remaining raw materials are inexpensive, and the cost and risk are significantly reduced, which is suitable for process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The drawings described herein are used to provide further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute improper limitations on the present application.

[0024] Figure 1 This is the H NMR spectrum of compound 3 prepared in this application; DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to better understand the scheme of the present application, the technical scheme in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only embodiments of a part of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of this application. In the following embodiments, unless otherwise stated, the specific conditions of the test method are generally implemented according to conventional conditions or conditions recommended by the manufacturer; raw materials and reagents are obtained commercially or prepared using public information.

[0026] The following example synthesizes 3,8-dibromophenanthroline. The raw material compound 1 (1,10-phenanthroline) is first converted into the intermediate compound 2 (3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,10-phenanthroline), and the compound 2 is then converted into the target compound 3 (3,8-dibromophenanthroline). The synthesis route is as follows:

[0027]

[0028] The technical solution of the present invention is further explained below by way of embodiments.

[0029] In this example, the compound 3,8-dibromophenanthroline was synthesized by the following steps:

[0030] Under nitrogen protection, [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester (7.91 g, 22.20 mmol, 0.02 eq) and methoxy(cyclooctadiene)iridium dimer (7.36 g, 11.10 mmol, 0.01 eq) were added to n-heptane (2.0 L), stirred for 30 minutes, and then diboric acid pinacol ester (563.65 g, 2.22 mol, 2.00 eq) was added and stirred for 30 minutes. Compound 1, i.e. 1,10-phenanthroline (200.00 g, 1.11 mol, 1.00 eq) was dissolved in n-heptane (2.0 L) and added dropwise to the above mixture. After the addition was completed, it was heated to reflux and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (2.0 L) was added, and the mixture was filtered through diatomaceous earth. The filtrate was spin-dried to obtain a crude product, which was purified by beating to obtain compound 2, namely 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,10-phenanthroline (weight 453.20 g, purity 98%, yield 93%).

[0031] Compound 2 (400.00 g, 925.64 mmol, 1.00 eq) was added to tetrahydrofuran (2.0 L) and methanol (2.0 L), and copper bromide (1.28 kg, 5.74 mol, 6.20 eq) was added, heated to reflux, and reacted for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was dried, and ammonia water (1.0 L) was added and stirred for 15 minutes, and then filtered again. The filter cake was dissolved with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and dried to obtain a crude product. The crude product was purified by pulping and dried to obtain compound 3, i.e., 3,8-dibromophenanthroline (weight 306.90 g, purity 98%, yield 96%).

[0032] The H NMR spectrum of the obtained compound 3 (3,8-dibromophenanthroline) is as follows Figure 1 As shown, the characterization data are as follows: 1H NMR (400MHz, dmso) δ9.16 (s, 1H), 8.87 (s, 1H), 8.03 (s, 1H).

[0033] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit it. Although the present application 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 replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for synthesizing a compound 3,8-dibromophenanthroline, characterized in that: Compound 1 (1,10-phenanthroline) is first converted into compound 2 (3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,10-phenanthroline), and compound 2 is then converted into compound 3 (3,8-dibromophenanthroline). The specific synthesis route is as follows:

2. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 1, characterized in that: The synthesis steps of compound 3 (3,8-dibromophenanthroline) are as follows: Under the protection of inert gas, [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester and methoxy(cyclooctadiene)iridium dimer are added to organic solvent I, stirred for 20-40 minutes, and then diboric acid pinacol ester is added, stirred for 20-40 minutes, compound 1 is dissolved in organic solvent I, and added dropwise to the above mixed solution. After the addition is completed, it is heated to reflux and reacted for 10-40 hours. After the reaction is completed, the reaction solution is subjected to the first post-treatment to obtain compound 2; Compound 2 is added to organic solvent II and organic solvent III, and copper bromide is added, and the mixture is heated to reflux and reacted for 10-40 hours. After the reaction is completed, the reaction solution is treated for the second time to obtain compound 3, namely 3,8-dibromophenanthroline.

3. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 2, characterized in that: The first post-treatment comprises: after the reaction is completed, cooling the reaction solution to room temperature, adding organic solvent IV, filtering, and spinning the filtrate to dryness to obtain a crude product, and purifying the crude product to obtain compound 2; The second post-treatment includes: after the reaction is completed, cooling the reaction solution to room temperature, filtering, rotating the filtrate to dryness, adding ammonia water and stirring for 10-50 minutes, filtering, dissolving the filter cake with organic solvent V, washing the obtained organic phase, drying, rotating to dryness to obtain a crude product, and purifying the crude product to obtain compound 3.

4. A method for synthesizing 3,8-dibromophenanthroline as claimed in claim 3, characterized in that: The organic solvent I is selected from one or more of n-heptane, tetrahydrofuran, toluene, and 1,4-dioxane; The organic solvent II is selected from one or more of methyl tert-butyl ether, ethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane; The organic solvent III is selected from one or more of ethanol, methanol, and tert-butanol; The organic solvent IV and the organic solvent V are both selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

5. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 2, characterized in that: The inert gas is selected from one or more of nitrogen and argon.

6. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 2, characterized in that: The mass volume ratio of the compound 1 to the organic solvent I, the organic solvent II and the organic solvent III is 1:5-40 g / mL.

7. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 2, characterized in that: The molar ratio of the compound 1 to [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester is 1.0:0.01-0.05; the molar ratio of the compound 1 to methoxy(cyclooctadiene)iridium dimer is 1.0:0.01-0.05; the molar ratio of the compound 1 to bipyridyl-2-(2,2'-bipyridine)-4,4'-dicarboxylic acid dibutyl ester is 1.0:1.0-3.

0.

8. A method for synthesizing a compound 3,8-dibromophenanthroline as claimed in claim 2, characterized in that: The purification methods of the first post-treatment and the second post-treatment are selected from one or more of beating, recrystallization, column chromatography and distillation.

9. A compound synthesized by the synthesis method according to any one of claims 1 to 8.

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