Process for the synthesis of the compound 3,8-dibromo-phenanthroline and the compound

Abstract

The application provides a synthesis method and a compound of a compound 3,8-dibromophenanthroline, and the synthesis method comprises the following steps: compound 1,10-phenanthroline is firstly converted into compound 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborinane-2-yl)-1,10-phenanthroline, and then the compound 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborinane-2-yl)-1,10-phenanthroline is converted into the compound 3,8-dibromophenanthroline. The application utilizes the characteristics that boron ester can be easily brominated, designs a new synthesis route of the application, obtains a target product by catalysis to obtain a boron-containing intermediate and then bromination by using copper bromide, the reaction yield is ideal, post-treatment is simple, the amount of metal catalyst is small, the prices of the rest of raw materials are low, cost and danger are significantly reduced, and the method is suitable for process amplification.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis technology, specifically relating to compound 3,8-dibromophenanthroline and related compounds. Background Technology

[0002] Compound 3,8-dibromophenanthroline is primarily used in organic and pharmaceutical synthesis. In organic synthesis, it serves as an intermediate, participating in various chemical reactions. For example, it reacts with bromine to generate 3,8-dibromo-1,10-phenanthroline, which, upon further oxidation, yields 3,8-dibromo-1,10-phenanthroline-5,6-dione. Furthermore, 3,8-dibromophenanthroline is used in the design, synthesis, and application of porous materials, particularly in the synthesis of organic porous materials. The Sonogashira reaction can synthesize o-phenanthroline-functionalized porous aromatic frameworks (Phen-PAF), which exhibit excellent performance in removing organic dyes from wastewater and catalyzing organic reactions. In pharmaceutical synthesis, 3,8-dibromophenanthroline also has significant applications. It can be used to prepare various pharmaceutical intermediates, such as 6,11-dibromo-1,4,8,9-tetraazabenzanthroline and 6,11-bis(phenoxazine), which have broad application prospects in the pharmaceutical field. Therefore, studying the synthesis method of 3,8-dibromophenanthroline is of certain significance.

[0003] In existing technologies, the main method for synthesizing 3,8-dibromophenanthroline is through direct bromination of 1,10-phenanthroline. Although the steps are relatively short, this method has significant drawbacks. The bromine source for bromination is mostly liquid bromine, which requires a high reaction temperature. Liquid bromine is highly volatile, has strong toxicity and corrosiveness, and its pungent odor is even stronger when heated, posing a high risk. It also easily generates monohalogen byproducts, which are difficult to purify. Other bromine sources, such as N-bromosuccinimide (NBS) and dibromohydantoin, also have relatively low conversion rates. Summary of the Invention

[0004] To address the aforementioned problems in the existing technology, this 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 one aspect, this application provides a method for synthesizing 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-dioxaborane-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 this application, the synthesis steps of compound 3 (3,8-dibromophenanthroline) are as follows:

[0008] Under inert gas protection, [2,2'-bipyridine]-4,4'-dicarboxylic acid dibutyl ester and methoxy(cyclooctadiene) iridium dimer were added to organic solvent I and stirred for 20-40 minutes. Then, pinacol diboronate was added and stirred for 20-40 minutes. Compound 1 was dissolved in organic solvent I and added dropwise to the above mixture. After the addition was complete, the mixture was heated to reflux and reacted for 10-40 hours. After the reaction was completed, the reaction solution underwent a first post-treatment to obtain compound 2.

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

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

[0011] The second post-processing includes: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is evaporated to dryness, ammonia water is added and stirred for 10-50 minutes, filtered, the filter cake is dissolved in organic solvent V, the obtained organic phase is washed, dried, and evaporated to dryness to obtain crude product, and the crude product is purified to obtain compound 3.

[0012] In a preferred embodiment of this 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, diethyl 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] In a preferred embodiment of this application, the inert gas is selected from one or more of nitrogen and argon.

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

[0019] In a preferred embodiment of this application, the molar ratio of compound 1 to dibutyl [2,2'-bipyridine]-4,4'-dicarboxylate is 1.0:0.01-0.05; the molar ratio of compound 1 to methoxy(cyclooctadiene)iridium dimer is 1.0:0.01-0.05; and the molar ratio of compound 1 to pinacol diboronate is 1.0:1.0-3.0.

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

[0021] Secondly, this application also provides a compound synthesized by the synthetic method described in any one of the first aspects.

[0022] This application provides a method for synthesizing compound 3,8-dibromophenanthroline and the compound itself, comprising: first converting compound 1,10-phenanthroline into compound 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,10-o-phenanthroline, and then into compound 3,8-dibromophenanthroline. This application utilizes the characteristic that boron esters can be readily brominated to design a novel synthetic route. A boron-containing intermediate is obtained via catalysis, followed by bromination with copper bromide to obtain the target product. The reaction yield is ideal, the post-processing is simple, the amount of metal catalyst used is small, and the remaining raw materials are inexpensive, significantly reducing cost and risk, making it suitable for scale-up. Attached Figure Description

[0023] The accompanying drawings, which are provided to further illustrate this application and form part of this application, illustrate exemplary embodiments of this application and are used to explain this application, but do not constitute an undue limitation of this application.

[0024] Figure 1 The 1H NMR spectrum of compound 3 prepared in this application; Detailed Implementation

[0025] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present application, and not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present application. In the following embodiments, unless otherwise stated, the specific conditions of the test methods are generally implemented according to conventional conditions or conditions recommended by the manufacturer; raw materials and reagents are obtained commercially or prepared using publicly available information.

[0026] The following examples demonstrate the synthesis of 3,8-dibromophenanthroline. The starting compound 1 (1,10-phenanthroline) was first converted to intermediate compound 2 (3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,10-o-phenanthroline), and compound 2 was then converted to the target compound 3 (3,8-dibromophenanthroline). The synthetic route is as follows:

[0027]

[0028] The technical solution of the present invention will be further explained and illustrated below through embodiments.

[0029] In this embodiment, the compound 3,8-dibromophenanthroline was synthesized using 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) and stirred for 30 minutes. Then, pinacol diborate (563.65 g, 2.22 mol, 2.00 eq) was added and stirred for 30 minutes. Compound 1, 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 complete, the mixture 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 a diatomaceous earth filter. The filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by pulping to obtain compound 2, namely 3,8-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1,10-o-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), followed by copper bromide (1.28 kg, 5.74 mol, 6.20 eq). The mixture was heated to reflux and reacted for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated to dryness. Ammonia water (1.0 L) was added, and the mixture was stirred for 15 minutes. The mixture was then filtered again, and the filter cake was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain the crude product. The crude product was purified by pulping and evaporated to dryness to obtain compound 3, namely 3,8-dibromophenanthroline (306.90 g, 98% purity, 96% yield).

[0032] The 1H NMR spectrum of the obtained compound 3 (3,8-dibromophenanthroline) is as follows: Figure 1 The characterization data are as follows: 1H NMR (400MHz, dmso) δ 9.16 (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 this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for the synthesis of the compound 3,8-dibromo-phenanthroline, 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 then compound 2 is converted into compound 3 (3,8-dibromo-phenanthroline), and the specific synthesis route is as follows: The synthesis steps of compound 3 (3,8-dibromo-phenanthroline) are as follows: Under the protection of inert gas, dibutyl [2,2'-bipyridine]-4,4'-dicarboxylate and methoxy (cyclooctadiene) iridium dimer are added into organic solvent I, stirred for 20-40 minutes, then pinacol diborane is added, stirred for 20-40 minutes, compound 1 is dissolved in organic solvent I, and then added dropwise into the above mixture, after the addition is completed, heated to reflux, and reacted for 10-40 hours; after the reaction is completed, the reaction solution is subjected to first post-treatment to obtain compound 2; Compound 2 is added into organic solvent II and organic solvent III, then copper bromide is added, heated to reflux, and reacted for 10-40 hours; after the reaction is completed, the reaction solution is subjected to second post-treatment to obtain compound 3, i.e. 3,8-dibromo-phenanthroline; 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, diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 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.

2. A process for the synthesis of compound 3,8-dibromo phenanthroline as claimed in claim 1, wherein, The first post-treatment includes: after the reaction is completed, the reaction solution is cooled to room temperature, organic solvent IV is added, filtered, and the filtrate is rotary dried to obtain a crude product, and the crude product is purified to obtain compound 2; The second post-treatment includes: after the reaction is completed, the reaction solution is cooled to room temperature, filtered, the filtrate is rotary dried, then ammonia water is added and stirred for 10-50 minutes, filtered, the filter cake is dissolved in organic solvent V, the obtained organic phase is washed, dried, rotary dried to obtain a crude product, and the crude product is purified to obtain compound 3.

3. A process for the synthesis of a compound 3,8-dibromo phenanthroline as claimed in claim 1, wherein, The inert gas is selected from one or more of nitrogen and argon.

4. A process for the synthesis of compound 3,8-dibromo phenanthroline as claimed in claim 1, wherein, The mass / volume ratio g / mL of compound 1, organic solvent I, organic solvent II and organic solvent III is 1:5-40.

5. The process for synthesis of compound 3,8-dibromo phenanthroline as claimed in claim 1, wherein, The molar ratio of compound 1 to dibutyl [2,2'-bipyridine]-4,4'-dicarboxylate is 1.0:0.01-0.05; the molar ratio of compound 1 to methoxy (cyclooctadiene) iridium dimer is 1.0:0.01-0.05; and the molar ratio of compound 1 to pinacol diborane is 1.0:1.0-3.

0.

6. The process for the synthesis of compound 3,8-dibromo-phenanthroline as claimed in claim 1, wherein, The purification mode of the first post-treatment and the second post-treatment is selected from one or more of beating, recrystallization, column chromatography and distillation.

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