Process for the preparation of a bipyridine derivative

Abstract

The application provides a preparation method of a bipyridine derivative, and the preparation method comprises the following steps: reacting a halogenated bipyridine raw material shown in formula II with an amino compound Ra-NH2 or a hydroxyl compound Rb-OH to obtain a bipyridine derivative shown in formula I. In the application, the halogenated bipyridine is used as the raw material, the second reaction raw material, i.e., the amino compound or the hydroxyl compound, is added, and the target product, i.e., the bipyridine derivative, is synthesized by one-pot method. The method is simple in synthesis, high in yield, and suitable for industrial production.

Description

Technical Field

[0001] This application belongs to the field of dye synthesis technology and relates to a method for preparing bipyridine derivatives. Background Technology

[0002] Bipyridine derivatives are an important class of organic compounds with wide-ranging chemical and biological applications. They typically consist of two pyridine rings linked by a shared nitrogen atom, forming the basic structure of bipyridine. These compounds have significant applications in coordination chemistry, medicinal chemistry, materials science, and biochemistry.

[0003] Due to their unique structural properties, bipyridine derivatives have seen rapid development in the dye industry. For example, a typical bipyridine derivative, indigoidine, is a substance with a bipyridine structure formed by the condensation of two glutamine molecules under the action of indigoidine synthase. Indigoidine is a stable and brightly colored natural blue pigment with many excellent properties, and its applications are wide-ranging, including cosmetics, textile printing and dyeing, and the medical industry.

[0004] However, indigo itself can only provide one color. By appropriately modifying the structure of indigo and synthesizing new dyes, not only can a rich variety of colors be produced, but the performance of the dyes can also be improved.

[0005] Invention patent CN120230032 reports a 5,5'-disubstituted amino-3,3'-bipyridine derivative, its preparation method, and its applications. The preparation method starts with ginseng and can yield substituted bipyridine derivatives. However, this method has a low yield and is not sufficient for large-scale preparation. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of this application is to provide a method for preparing bipyridine derivatives.

[0007] To achieve this objective, the present application adopts the following technical solution: On the one hand, this application provides a method for preparing a bipyridine derivative, the method comprising the following steps: The halobipyridine starting material shown in Formula II reacts with an amino compound Ra-NH2 or a hydroxy compound Rb-OH to obtain the bipyridine derivative shown in Formula I, as shown in the following reaction formula: ; Where R is a halogen; R1 and R2 are independently any one of halogen, Ra-NH-, Rb-O-, and R1 and R2 are not simultaneously halogens; Ra and Rb are independently any one of the following substituted or unsubstituted groups: C1~C6 (e.g., C1, C2, C3, C4, C5 or C6, etc.) alkyl, C1~C6 (e.g., C1, C2, C3, C4, C5 or C6, etc.) alkenyl, C1~C6 (e.g., C1, C2, C3, C4, C5 or C6, etc.) ynyl, C3~C6 (e.g., C3, C2, C3, C4, C5 or C6, etc.) alkynyl, C3~C6 (e.g., C3, C2, C3, C4, C5 or C6, etc.) alkyne ... Cycloalkyl (C1, C4, C5, or C6, etc.), C5-C6 aryl, and substituted or unsubstituted heterocyclic groups of the following: furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazolyl, pyridinyl, piperidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, pteridinyl, acridineyl, naphthyl, phenanthreneyl, anthraceneyl, pyreneyl, naphthoquinyl, phenanthrenequinyl, or anthraquinyl; wherein the substituents in the substituted groups are selected from C1-C6 (e.g., C1, C2, C3, C4, C5, or C6, etc.) alkyl (e.g., methyl, ethyl, n-propyl, pentyl, etc.).

[0008] In this application, the halogen is one of F, Cl, Br or I.

[0009] In this application, a one-pot synthesis of the target product, a bipyridine derivative, is achieved by using halobipyridine as a raw material and adding an amino or hydroxyl compound as a second reactant. This method is simple to synthesize, has a high yield, and is suitable for industrial production.

[0010] In some embodiments, the bipyridine derivative is selected from any one of the following compounds: .

[0011] In some embodiments, the reaction is carried out in a polar solvent, which includes one or a combination of at least two of acetone, acetonitrile, ethyl acetate, toluene, chloroform, DMF, or DMSO. In some embodiments, the polar solvent includes one of DMF or DMSO.

[0012] In some embodiments, the reaction is carried out in the presence of an alkaline substance.

[0013] In some embodiments, the alkaline substance includes one or a combination of at least two of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or pyridine.

[0014] In some embodiments, the alkaline substance is selected from potassium carbonate or sodium carbonate.

[0015] In some embodiments, the reaction temperature is 30°C to 50°C (e.g., 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 42°C, 44°C, 46°C, or 50°C). When the temperature exceeds this range, the impurities in the reaction increase significantly.

[0016] Compared with the prior art, this application has the following advantages: This application utilizes halobipyridine as a raw material to efficiently synthesize secondary amine derivatives or ether derivatives. The preparation method provided in this application is simple, highly controllable, and suitable for large-scale industrial production. Attached Figure Description

[0017] Figure 1 This is the HPLC chromatogram of compound 1.

[0018] Figure 2 This is the UV absorption spectrum of compound 1.

[0019] Figure 3 This is the HPLC chromatogram of compound 3.

[0020] Figure 4 This is the UV absorption spectrum of compound 3.

[0021] Figure 5 This is a diagram showing the staining effect of compound 3. Detailed Implementation

[0022] The technical solution of this application will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely to help understand this application and should not be regarded as specific limitations on this application.

[0023] In the following embodiments, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0024] The halopyridine raw materials used in the following examples were provided by Nanjing Hegu Life Biotechnology Co., Ltd. (as described in patent application number 2025120575194). Product structure identification: The synthesized product was sent to the Analysis and Testing Center of Nanjing Normal University for testing.

[0025] Example 1 28.5 g of chlorobipyridine starting material was weighed into a 500 mL three-necked round-bottom flask, and 200 g of DMF was added. Then, 1.1 equivalents of cyclohexylamine and 1.3 equivalents of potassium carbonate were added sequentially, and the mixture was reacted at 30 °C for 3 h. The solvent was then removed by suction filtration, and the filter cake was washed with 200 mL of deionized water. The target product, compound 1, was obtained. After drying, the product weighed 26.8 g, with a yield of 77%. LC-MS: 350.7 ([M+H)+ ).

[0026] Example 2 The equivalent amount of cyclohexylamine and potassium carbonate in Example 1 was increased by 2.5 times, the temperature was increased to 50°C, and the reaction was carried out for 8 hours. This yielded 32 g of the target product compound 2, with a yield of 78%. LC-MS: 413.5 ([M+H]) + ).

[0027] Example 3 Replacing cyclohexylamine in Example 1 with N,N-dimethyl-p-phenylenediamine yielded the target product compound 3, with a yield of 79%. LC-MS: 387.8 ([M+H]). + ).

[0028] Example 4 The equivalent amount of N,N-dimethyl-p-phenylenediamine in Example 3 was increased by 2.2 times, the equivalent amount of potassium carbonate was increased by 2.5 times, the temperature was increased to 40°C, and the reaction was carried out for 10 h. This yielded the target product compound 4, with a yield of 76%. LC-MS: 487.5 ([M+H]) + ).

[0029] Example 5 Replacing cyclohexylamine in Example 1 with 3-buten-1-amine yielded the target product compound 5, with a yield of 72%. LC-MS: 322.7 ([M+H]) + ).

[0030] Example 6 Replacing cyclohexylamine in Example 3 with 3-buten-1-amine yielded the target product compound 6, with a yield of 80%. LC-MS: 357.4 ([M+H]) + ).

[0031] Example 7 Replacing cyclohexylamine with phenol in Example 1 and raising the temperature to 30°C yielded the target product compound 7, with a yield of 81%. LC-MS: 345.7 ([M+H]). + ).

[0032] Example 8 Replacing the chlorobipyridine in Example 3 with fluorobipyridine and raising the temperature to 40°C yielded the target product compound 8, with a yield of 77%. LC-MS: 370.1 ([M+H]) + ).

[0033] Example 9 Replacing the chlorobipyridine in Example 3 with bromobipyridine and raising the temperature to 50°C yielded the target product compound 9, with a yield of 79%. LC-MS: 430.0 ([M+H]) + ).

[0034] Example 10 Replacing the chlorobipyridine in Example 3 with iodobipyridine and heating at 30°C yielded the target product compound 10, with a yield of 81.9%. LC-MS: 478.0 ([M+H]) + ).

[0035] Example 11 Replacing cyclohexylamine with anthranilic acid in Example 1 and raising the temperature to 40°C yielded the target product compound 11, with a yield of 82.6%. LC-MS: 388.0 ([M+H]) + ).

[0036] Example 12 Replacing cyclohexylamine with p-aminobenzoic acid in Example 1 and raising the temperature to 50°C yielded the target product compound 12, with a yield of 76.9%. LC-MS: 388.1 ([M+H]) + ).

[0037] Comparative Example 1 Weigh 24.8 g of chlorobipyridine raw material and add it to a 500 mL three-necked round-bottom flask. Add 200 g of DMF, then add 1 equivalent of cyclohexylamine and 1.3 equivalents of potassium carbonate sequentially. React at 100 °C for 12 h. The raw material was found to have deteriorated, and no product was formed.

[0038] Comparative Example 2 28.5 g of chlorobipyridine feedstock was weighed into a 500 mL three-necked round-bottom flask, and 200 g of DMF was added. Then, 1.2 equivalents of cyclohexylamine and 1.3 equivalents of potassium carbonate were added sequentially, and the mixture was reacted at 15 °C for 6 h. The solvent was then removed by suction filtration, and the filter cake was washed with 200 mL of deionized water. The product was dried and weighed to 1.9 g, yielding 5%.

[0039] Comparative Example 3 28.5 g of chlorobipyridine feedstock was weighed into a 500 mL three-necked round-bottom flask, 200 g of DMF was added, and 2 equivalents of cyclohexylamine were added. The mixture was reacted at 50 °C for 12 h without adding alkali. The solvent was removed, and the filter cake was washed with 100 mL of deionized water. The product was dried and weighed to 3.2 g, yielding 9%.

[0040] Figure 1 This is the HPLC chromatogram of compound 1. Figure 2 This is the UV absorption spectrum of compound 1. Figure 3This is the HPLC chromatogram of compound 3. Figure 4 This is the UV absorption spectrum of compound 3. Figure 5 The staining effect of compound 3 (concentration: 10 mg / mL).

[0041] The high-performance liquid chromatograph (HPLC) was an Agilent 1260; the ultraviolet-visible spectrophotometer was a Thermo Fisher SPECTRONIC 200.

[0042] The test results show that the target product has an absorption wavelength of about 590~620nm and a blue color, which is significantly different from other products, indicating the feasibility of the reaction technology.

[0043] The applicant declares that this application illustrates the process method through the above embodiments, but this application is not limited to the above process steps, that is, it does not mean that this application must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to this application, equivalent substitutions of the raw materials used in this application, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of this application.

Claims

1. A method for preparing a bipyridine derivative, characterized in that, The preparation method includes the following steps: The halobipyridine starting material shown in Formula II reacts with an amino compound Ra-NH2 or a hydroxy compound Rb-OH to obtain the bipyridine derivative shown in Formula I, as shown in the following reaction formula: ； Wherein R is a halogen; R1 and R2 are independently any one of halogen, Ra-NH-, Rb-O-, and R1 and R2 are not simultaneously halogens; Ra and Rb are independently any one of the following substituted or unsubstituted groups: C1~C6 alkyl, C1~C6 alkenyl, C1~C6 alkynyl, C3~C6 cycloalkyl, C5~C6 aryl, and substituted or unsubstituted heterocyclic groups of the following: furanyl, thiopheneyl, pyrroleyl, thiazolyl, imidazolyl, pyridinyl, piperidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, pteridinyl, acridineyl, naphthyl, phenanthreneyl, anthraceneyl, pyreneyl, naphthoquinyl, phenanthrenequinyl, or anthraquinyl; the substituents in the substituted groups are selected from C1~C6 alkyl.

2. The preparation method according to claim 1, characterized in that, The bipyridine derivatives are selected from any one of the following compounds: 。 3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the halobipyridine shown in Formula II to the amino compound Ra-NH2 or the hydroxy compound Rb-OH is 1:1-3.

4. The preparation method according to claim 1, characterized in that, The reaction is carried out in a polar solvent, which includes one or a combination of at least two of acetone, acetonitrile, ethyl acetate, toluene, chloroform, DMF, or DMSO.

5. The preparation method according to claim 4, characterized in that, The polar solvent is one or a combination of at least two of acetone, acetonitrile, DMF, or DMSO.

6. The preparation method according to any one of claims 1-4, characterized in that, The reaction is carried out in the presence of an alkaline substance, which includes one or a combination of at least two of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, or pyridine.

7. The preparation method according to claim 6, characterized in that, The alkaline substance is one or a combination of at least two of potassium carbonate, sodium carbonate, and sodium hydroxide.

8. The preparation method according to any one of claims 1-7, characterized in that, The reaction temperature is 30-50℃.

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