A method for bromination of 9,10-dihydroacridine derivatives

Abstract

The application relates to a bromination method of a 9,10-dihydroacridine derivative, and belongs to the technical field of organic synthesis. The bromination method of the 9,10-dihydroacridine derivative comprises the following steps: after compound II is dissolved in a solvent, hydrobromic acid, sodium nitrite and a Lewis acid are added, and then an oxidizing gas is introduced to carry out reaction, and the reaction is completed. In the application, hydrobromic acid is used as a bromine source, a catalytic amount of sodium nitrite and a Lewis acid are used in a solvent, air or oxygen is used as an oxidant to form a bromination system, the reaction system is simple, the by-product is water, the environment is friendly, the atomic economy is high, the use of bromine which has a higher operation safety requirement is avoided, the cost is low, the operation is simple, the substrate application range is wide, the operation is simple and easy, and industrial production is easy.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a bromination method for a 9,10-dihydroacridine derivative. Background Technology

[0002] The rigid structure and excellent optical properties of acridine itself (Journal of Instrumental Analysis, 2005, 24, 39-41) have attracted widespread attention for its applications in photoresists, immunodiagnostics, organic optoelectronic devices, and fluorescence sensors. Acridine derivatives, bromides, are widely used in optoelectronic materials (J. Mater. Chem. C, 2022, 10, 7925-7934) and are often used to synthesize other acridine compounds with optical applications (CN108218850, 2018; EP2703388, 2014).

[0003] Regarding the bromination methods of acridine derivatives, two routes have been reported. The first route patent (JP2016166221, 2016; WO2020205765, 2020) discloses a method for brominating the acridine ring with N-bromosuccinimide (NBS) as the brominating agent. This method is also the most commonly used bromination method at present, but it is relatively expensive and generates a large amount of byproduct succinimide (KR101529161, 2015), which is not easy to remove, has poor atom economy, and high production costs.

[0004]

[0005] The second patent (US20180166636, 2018) discloses the preparation of 2,7-dibromo-9,9-dimethylacridine by bromination of 9,9-dimethylacridine with bromine as the brominating agent. However, bromine has a strong irritant and corrosive effect on the skin and mucous membranes, and is prone to causing allergic dermatitis. Long-term inhalation, in addition to mucous membrane irritation symptoms, is also accompanied by neurasthenia syndrome. The operation requires high safety and generates a large amount of hydrobromic acid as a byproduct.

[0006]

[0007] In summary, existing bromination methods have the following problems: ① Raw materials are expensive, resulting in high production costs; ② Brominating reagents pose significant safety risks and are not easily industrialized; ③ Organic byproducts are generated, leading to poor atom economy. Summary of the Invention

[0008] The purpose of this invention is to provide a bromination method for 9,10-dihydroacridine derivatives to solve the technical problems of expensive raw materials, numerous byproducts, and high risks associated with bromination reagents in existing bromination methods for 9,10-dihydroacridine derivatives.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for brominating a 9,10-dihydroacridine derivative, characterized by comprising the following steps:

[0011] Compound I was reacted with a bromination system consisting of hydrobromic acid, sodium nitrite, and Lewis acid in a solvent by passing an oxidizing gas through it to prepare compound II.

[0012]

[0013] R 1 R 2 Independently selected from hydrogen, alkyl, aryl, or substituted aryl groups;

[0014] R 3 Independently selected from hydrogen, alkyl, aryl, substituted aryl, 1-naphthyl, 2-naphthyl.

[0015] Furthermore, the R 1 R 2 and R 3 The alkyl group is a C1-C2 alkyl group.

[0016] Furthermore, the R 1 R 2 and R 3 The substituted aryl group has the characteristics of formula (1).

[0017]

[0018] R 4 Independently selected from hydrogen, C1-C8 alkyl, alkoxy, triazine, or substituted triazine.

[0019] Furthermore, the R 3 and R 4 The substituted triazine group has the characteristics of formula (2).

[0020]

[0021] R 5 R 6 Independently selected from phenyl or

[0022] Furthermore, the mass fraction of the hydrobromic acid is 20-49%.

[0023] Furthermore, the Lewis acid is selected from one or more of boron trifluoride ether, p-toluenesulfonic acid, triphenylphosphine, ferric oxide, and ferric bromide.

[0024] Furthermore, the reaction temperature is 10–50°C, and the reaction time is 0.5–2 h.

[0025] Furthermore, the molar ratio of the compound of formula I, hydrobromic acid, sodium nitrite, and Lewis acid is 1:1.5-10:0.2-0.6:0.001-0.05.

[0026] Furthermore, the solvent is a mixed solvent of 1,4-dioxane and acetonitrile, and the mass ratio of the mixed solvent of 1,4-dioxane to acetonitrile is 0-45:55-100; the amount of compound of formula I added per gram of solvent is 0.067-0.34g.

[0027] Furthermore, the oxidizing gas is oxygen or air, the flow rate of the oxidizing gas is 4-20 mL / min, and the introduction time is 0.5-2 h.

[0028] The beneficial effects of this invention are:

[0029] The present invention uses hydrobromic acid as the bromine source, and combines it with a catalytic amount of sodium nitrite and Lewis acid in a solvent, using air or oxygen as the oxidant to form a bromination system. The reaction system is simple, the byproduct is water, it is environmentally friendly, has high atom economy, avoids the use of bromine which has high requirements for operational safety, and is low in cost, simple to operate, has a wide range of applicable substrates, and is easy to operate and industrialize.

[0030] The addition of Lewis acid in this invention can promote the polarization and heterolytic cleavage of Br2 generated during the reaction, thereby promoting the full bromination of the raw materials and increasing the yield of the bromination reaction. Attached Figure Description

[0031] Figure 1 The 1H NMR spectrum of 2,7-dibromo-10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine is shown in Example 1. Detailed Implementation

[0032] The present invention will be further described below with reference to the embodiments and accompanying drawings.

[0033] Example 1

[0034] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0035]

[0036] Add 5.2 g of 10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine to the reaction flask, then add 52 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 10:90); 12.21 g of a 20% (w / w) aqueous solution of hydrogen bromide; and finally add 0.138 g of sodium nitrite. 0.013 g of triphenylphosphine was introduced into the atmosphere with air at a flow rate of 15 mL / min for 1.5 h, reacted at 10 °C for 1.5 h, quenched with water, washed with ethyl acetate, and filtered to obtain 6.41 g of 2,7-dibromo-10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine with a purity of 99.2% and a yield of 94.4%. The 1H NMR spectrum of 2,7-dibromo-10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine prepared in Example 1 is shown below. Figure 1 As shown, from Figure 1 It can be seen that, 1 H NMR (400MHz, DMSO-d6), δ 9.02 (d, 2H), 8.78 (d, 4H), 7.72-7.78 (m, 2H), 7.63-7.72 (m, 8H), 7.17 (dd, 2H), 6.21 (d, 2H), 1.66 (s, 6H).

[0037] Example 2

[0038] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0039]

[0040] 3.0 g of 9,10-dimethyl-9-(p-tolyl)-9,10-dihydroacridine was added to a reaction flask, followed by 45 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 10:90), and 12.16 g of a 20% (w / w) aqueous solution of hydrogen bromide. Finally, 0.138 g of sodium nitrite and 0.056 g of boron trifluoride ether were added. Air was bubbled through the mixture at a flow rate of 18 mL / min for 1.5 h, and the reaction was carried out at 20 °C for 1.5 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 4.31 g of 2,7-dibromo-9,10-dimethyl-9-(p-tolyl)-9,10-dihydroacridine with a purity of 99.3% and a yield of 94.1%. 1H NMR (400MHz, CDCl3), δ7.30 (m, 2H), 7.06 (d, 2H), 7.01-7.03 (m, 4H), 6.79 (d, 2H), 3.33 (s, 3H), 2.34 (s, 3H), 1.77 (s, 3H).

[0041] Example 3

[0042] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0043]

[0044] 3.35 g of 9,9-dimethyl-10-(naphth-1-yl)-9,10-dihydroacridine was added to a reaction flask, followed by 20 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 30:70), and 2.47 g of a 49% hydrobromic acid aqueous solution. Finally, 0.413 g of sodium nitrite and 0.034 g of p-toluenesulfonic acid were added. Oxygen was bubbled through the mixture at a flow rate of 4 mL / min for 0.5 h, and the reaction was carried out at 50 °C for 0.5 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 4.79 g of 2,7-dibromo-9,9-dimethyl-10-(naphth-1-yl)-9,10-dihydroacridine with a purity of 99.1% and a yield of 97.2%. 1 H NMR (400MHz, CDCl3), δ 8.08-7.97 (m, 2H), 7.65 (m, 1H), 7.57-7.5 (m, 4H), 7.45-7.36 (m, 2H), 6.93 (dd, 2H), 5.9 (d, 2H), 1.8 (s, 3H), 1.67 (s, 3H).

[0045] Example 4

[0046] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0047]

[0048] 3.98 g of 9,9-dimethyl-10-(4-octylphenyl)-9,10-dihydroacridine was added to a reaction flask, followed by 35 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 45:55), and 12.15 g of a 20% hydrogen bromide aqueous solution. Finally, 0.14 g of sodium nitrite and 0.0016 g of ferric oxide were added. Air was bubbled through the mixture at a flow rate of 20 mL / min for 0.5 h, and the reaction was carried out at 10 °C for 1 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 5.21 g of 2,7-dibromo-9,9-dimethyl-10-(4-octylphenyl)-9,10-dihydroacridine with a purity of 99.7% and a yield of 93.7%. 1 H NMR (400MHz, CDCl3), δ7.49-7.41(m, 4H), 7.15(d, 2H), 7.04(m, 2H), 6.15(d, 2H), 2 .74-2.69(m, 2H), 1.72-1.66(m, 2H), 1.63(s, 6H), 1.4-1.28(m, 10H), 0.89(t, 3H).

[0049] Example 5

[0050] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0051]

[0052] Add 5.5 g of 10-(4-(4,6-di-o-toluene-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine to the reaction flask, then add 82.5 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 10:90), and 16.67 g of a 49% hydrogen bromide aqueous solution. Finally, add 0.27 g of sodium nitrite. 8 g of boron trifluoride diethyl ether and 0.072 g of 2,7-dibromo-10-(4-(4,6-di-o-toluene-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine were reacted with air at a flow rate of 15 mL / min for 1 h at 10 °C for 1 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 6.78 g of 2,7-dibromo-10-(4-(4,6-di-o-toluene-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine with a purity of 99.1% and a yield of 95.6%. 1 HNMR (400MHz, CDCl3), δ8.94 (d, 2H), 8.26-8.32 (m, 2H), 7.53-7.41 (m, 6H), 7.37 (t, 4H), 7.05 (dd, 2H), 6.21 (d, 2H), 2.85 (s, 6H), 1.66 (s, 6H).

[0053] Example 6

[0054] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0055]

[0056] 3.2 g of 10-(4-methoxyphenyl)-9,9-dimethyl-9,10-dihydroacridine was added to a reaction flask, followed by 32 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 20:80), and 28.73 g of a 20% hydrogen bromide aqueous solution. Finally, 0.28 g of sodium nitrite and 0.057 g of boron trifluoride ether were added. Oxygen was bubbled through the mixture at a flow rate of 4 mL / min for 0.5 h, and the reaction was carried out at 30 °C for 0.5 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 4.54 g of 2,7-dibromo-10-(4-methoxyphenyl)-9,9-dimethyl-9,10-dihydroacridine with a purity of 99.6% and a yield of 94.6%. 1 HNMR (400MHz, CDCl3), δ7.51 (d, 2H), 7.22-7.11 (m, 4H), 7.05 (m, 2H), 6.19 (d, 2H), 3.9 (s, 3H), 1.6 (s, 6H).

[0057] Example 7

[0058] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0059]

[0060] 2.4 g of 10-ethyl-9,9-dimethyl-9,10-dihydroacridine was added to a reaction flask, followed by 7 g of acetonitrile, 13.64 g of a 30% (w / w) aqueous solution of hydrogen bromide, and finally 0.21 g of sodium nitrite and 0.006 g of ferric tribromide. Oxygen was bubbled through the mixture at a flow rate of 8 mL / min for 1 h, and the reaction was carried out at 40 °C for 1 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 3.75 g of 2,7-dibromo-10-ethyl-9,9-dimethyl-9-10-dihydroacridine with a purity of 99.1% and a yield of 93.9%. 1 H NMR (400MHz, CDCl3), δ7.46 (d, 2H), 7.30 (dd, 2H), 6.84 (d, 2H), 3.98 (q, 2H), 1.48 (s, 6H), 1.38 (t, 3H).

[0061] Example 8

[0062] The bromination method of the 9,10-dihydroacridine derivative in this embodiment includes the following steps:

[0063]

[0064] 3.4 g of 9,9-diphenyl-9,10-dihydroacridine was added to a reaction flask, followed by 40.8 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 10:90), and 18.86 g of a 35% hydrogen bromide aqueous solution. Finally, 0.35 g of sodium nitrite and 0.017 g of p-toluenesulfonic acid were added. Air was bubbled through the mixture at a flow rate of 12 mL / min for 2 h, and the reaction was carried out at 25 °C for 2 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 4.73 g of 2,7-dibromo-9,9-diphenyl-9,10-dihydroacridine with a purity of 99.5% and a yield of 94.4%. 1 HNMR (300MHz, Acetone-d6), δ8.63 (s, 1H), 7.35-7.27 (m, 8H), 6.96-6.92 (m, 8H), 6.86 (d, 2H).

[0065] Comparative Example 1

[0066] 5.2 g of 10-(4-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-9,9-dimethyl-9,10-dihydroacridine was added to a reaction flask, followed by 52 g of a mixed solvent of 1,4-dioxane and acetonitrile (mass ratio of 1,4-dioxane to acetonitrile: 10:90), and 12.21 g of a 20% hydrogen bromide aqueous solution. Finally, 0.138 g of sodium nitrite was added. Air was bubbled through the mixture at a flow rate of 15 mL / min for 1.5 h, and the reaction was carried out at 10 °C for 1.5 h. After quenching with water, the mixture was washed with ethyl acetate and filtered to obtain 2.16 g of solid, with a yield of 31.8%.

Claims

1. A method for brominating a 9,10-dihydroacridine derivative, characterized in that, Includes the following steps: Compound I is prepared by reacting it with a bromination system consisting of hydrobromic acid, sodium nitrite, and Lewis acid in a solvent under an oxidizing gas; wherein the Lewis acid is selected from one or more of boron trifluoride diethyl ether, p-toluenesulfonic acid, triphenylphosphine, ferric oxide, and ferric bromide; and wherein the oxidizing gas is oxygen or air. ； R 1 R 2 Independently selected from hydrogen, alkyl, or substituted aryl groups; R 3 Independently selected from hydrogen, alkyl, substituted aryl, 1-naphthyl, 2-naphthyl; R 1 R 2 and R 3 The alkyl group is a C1-C2 alkyl group; The R 1 R 2 and R 3 The substituted aryl group has the characteristics of formula (1), Equation (1); R 4 Independently selected from hydrogen, C1-C8 alkyl, triazine, or substituted triazine; The substituted triazine group has the characteristics of formula (2), Equation (2), R 5 R 6 Independently selected from phenyl or .

2. The bromination method for 9,10-dihydroacridine derivatives according to claim 1, characterized in that, The mass fraction of the hydrobromic acid is 20-49%.

3. The bromination method for 9,10-dihydroacridine derivatives according to claim 1, characterized in that, The reaction temperature is 10–50 °C, and the reaction time is 0.5–2 h.

4. The bromination method for 9,10-dihydroacridine derivatives according to claim 1, characterized in that, The molar ratio of the compound of formula I, hydrobromic acid, sodium nitrite, and Lewis acid is 1:1.5-10:0.2-0.6:0.001-0.

05.

5. The bromination method for the 9,10-dihydroacridine derivative according to claim 1, characterized in that, The solvent is a mixture of 1,4-dioxane and acetonitrile, and the mass ratio of the 1,4-dioxane to acetonitrile mixture is 0-45:55-100; the amount of compound of formula I added per gram of solvent is 0.067-0.34 g.

6. The bromination method for the 9,10-dihydroacridine derivative according to claim 1, characterized in that, The flow rate of the oxidizing gas is 4–20 mL / min, and the introduction time is 0.5–2 h.

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