Preparation method of 7-ethyl quinoline-8-amine
Through nitration, coupling and hydrogenation reaction methods, the problems of pollution, poisoning and high cost in the traditional 7-ethylquinoline-8-amine synthesis method are solved, and industrial production with high yield, safety and environmental protection are achieved.
Patent Information
- Application Number
- CN202510003405.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-02
- Publication Date
- 2025-04-25
AI Technical Summary
The traditional synthesis methods of existing 7-ethylquinoline-8-amine have risks of pollution and poisoning, and are difficult to purify and have low yields, resulting in high cost and unenvironmental protection.
7-ethylquinoline-8-amine was prepared by using 7-chloroquinoline as the starting material and through nitration reaction, coupling reaction and hydrogenation reduction reaction. The process of this method is short, there are few types of reagents, easy to operate, mild reaction conditions and easy to control, and the product is easy to purify.
The yield and safety of 7-ethylquinoline-8-amine are improved, the process flow is simplified, the production cost is reduced, and environmentally friendly industrial production is achieved.
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Figure CN119874615A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a method for preparing 7-ethylquinoline-8-amine. Background Art
[0002] Quinoline compounds have good drug activity and are widely used in drug synthesis in the pharmaceutical industry. The chelate ring in the quinoline structure has high stability and can form complexes with a variety of metal cations. This coordination effect makes quinoline play an important role in the pharmaceutical process. For example, quinoline can coordinate with metal ions to form complexes, improving the meshing and bioavailability of drugs.
[0003] Secondly, quinoline has excellent optical properties and is therefore widely used in the field of optoelectronics. Quinoline molecules can absorb ultraviolet and visible light and play an important role in photoelectric conversion in electronic devices. Quinoline can be used to prepare organic optoelectronic devices such as organic light-emitting diodes (OLEDs) and organic solar cells (OPVs). In these devices, quinoline can help conduction and injection of electrons, improving device performance. In addition, quinoline can also be used as a fluorescent probe for the detection of biomolecules and drugs, and has a catalytic effect on the photochemical activity of photosensitive compounds.
[0004] In addition, quinoline is also widely used in the field of chemical analysis. Due to the special properties of quinoline structure, it can react with many cations to form stable complexes. Therefore, quinoline can be used in the development of cation analysis methods, such as complexometric titration and spectrophotometry. Quinoline can also be used as an indicator to determine the pH of the solution based on the change in color. It is often used in acid-base titration, such as forming a red complex with iron ions to quantitatively determine the acidity.
[0005] In summary, quinoline has a wide range of applications. It plays an important role in drug manufacturing, optoelectronic devices, chemical analysis, fluorescent probes, etc. Its special structure and diverse coordination reaction properties make it one of the important organic compounds in scientific research and industrial applications. With the continuous development of science and technology, the role and application of quinoline will continue to expand and deepen.
[0006] In the prior art, the traditional synthesis method of 7-ethylquinoline-8-amine is as follows:
[0007]
[0008] This method uses 3-ethylaniline to undergo a ring closure, which uses highly toxic arsenic, and then nitrates and finally reduces it to obtain the product. This method causes pollution and poisoning risks in the first step, and the separation and purification are difficult, and the yield is low, which leads to high costs and is not environmentally friendly. The latter two steps are basically the same. Therefore, it is of great significance to develop a preparation method for 7-ethylquinoline-8-amine to improve the yield and safety and facilitate purification. Summary of the invention
[0009] In view of the deficiencies of the prior art, the present invention provides a method for preparing 7-ethylquinolin-8-amine. The preparation method of the present invention has a short process route, a small number of reagents involved in the reaction, convenient operation, mild and controllable reaction conditions, and easy purification of the product, which provides more possibilities for new drug research and development.
[0010] The technical solution of the present invention is as follows:
[0011] A preparation method of 7-ethylquinoline-8-amine, wherein the preparation method is carried out according to the following process:
[0012]
[0013] The specific steps include:
[0014] (1) Compound 2 is prepared by nitration reaction using compound 1 as the starting material;
[0015] (2) Compound 2 is subjected to coupling reaction with vinylboronic acid pinacol ester to obtain compound 3;
[0016] (3) Compound 3 is subjected to a hydrogenation reduction reaction to obtain compound 4, namely the 7-ethylquinolin-8-amine.
[0017] Furthermore, in step (1), the specific process of the nitration reaction is:
[0018] First, add a concentrated strong acid solution to the reaction bottle, cool it to -5 to -10°C under nitrogen protection, add compound 1, and then heat it to room temperature to react for 1 to 3 hours; after the reaction is completed, cool it to 0 to 5°C, filter out the precipitated solid, wash it with water and dry it to obtain compound 2.
[0019] Furthermore, the concentrated strong acid solution is prepared by mixing concentrated nitric acid and concentrated sulfuric acid; the concentration of the concentrated nitric acid is ≥63%; the concentration of the concentrated sulfuric acid is 98%; and the volume ratio of the concentrated nitric acid to the concentrated sulfuric acid is 1:0.5-2.
[0020] Furthermore, the concentration of the compound 1 in the concentrated strong acid solution is 1 mol / L.
[0021] Furthermore, in step (2), the specific process of the coupling reaction is:
[0022] Compound 2 and a base are dissolved in solvent I, and vinylboronic acid pinacol ester and a palladium catalyst are added under nitrogen protection. After heating for reaction, the mixture is washed with water, extracted, dried and purified to obtain compound 3.
[0023] Furthermore, the base is potassium phosphate; the amount of the base is 2-3 equivalents of compound 2; the solvent I is a mixture of 1,4-dioxane and water, and the volume ratio of 1,4-dioxane to water is 4:1; the concentration of compound 2 in solvent I is 0.08 g / mL.
[0024] Furthermore, the amount of vinylboronic acid pinacol ester is 2 equivalents of compound 2; the palladium catalyst is Xphos-Pd-G2; the amount of the palladium catalyst is 10%-20% of the mass of compound 2; the reaction temperature is 100° C. and the reaction time is 8 hours.
[0025] Furthermore, in step (3), the specific process of the hydrogenation reduction reaction is:
[0026] Compound 3 is dissolved in solvent II, a catalyst is added, and the mixture is reacted under a hydrogen atmosphere. After the reaction is completed, the mixture is filtered and concentrated to obtain the 7-ethylquinolin-8-amine.
[0027] Furthermore, the solvent II is selected from at least one of methanol and ethanol; the concentration of the compound 3 in the solvent II is 0.1-0.2 g / mL; the catalyst is palladium carbon; and the amount of the catalyst is 10-20% of the mass of the compound 3.
[0028] Furthermore, the reaction temperature is room temperature and the reaction time is 3-8 hours.
[0029] The beneficial technical effects of the present invention are:
[0030] The present invention uses 7-chloroquinoline as a reaction starting material, and obtains the target compound 7-ethylquinoline-8-amine through nitration reaction, coupling reaction, and reduction hydrogenation reaction. The method of the present invention has a short process route, a small number of participating reaction reagents, and is easy to operate. Compared with the traditional synthesis method of 7-ethylquinoline-8-amine, the product of the present invention is easy to purify, has a high yield, and the reaction conditions are safe, mild, and easy to control, and is easy to realize industrialization. BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Figure 1 It is a schematic diagram of the reaction flow of the present invention.
[0032] Figure 2 This is the H NMR spectrum of 7-chloro-8-nitroquinoline prepared in Example 1 of the present invention.
[0033] Figure 3This is the H NMR spectrum of 8-nitro-7-vinylquinoline prepared in Example 1 of the present invention.
[0034] Figure 4 This is the H NMR spectrum of 7-ethylquinoline-8-amine prepared in Example 1 of the present invention. DETAILED DESCRIPTION
[0035] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.
[0036] Example 1
[0037] A method for preparing ethylquinoline-8-amine comprises the following steps:
[0038] (1) Preparation of 7-chloro-8-nitroquinoline
[0039] Carefully mix concentrated nitric acid (40 mL, 63%) and concentrated sulfuric acid (80 mL, 98%) at -10°C, then add 7-chloroquinoline (Compound 1) (20 g, 0.12 mol) at the same temperature. After complete addition, warm the mixture to room temperature and stir for 3 h. Pour the reaction mixture into ice water to precipitate a white solid, which is filtered and the filter cake is washed with water to obtain a white solid 7-chloro-8-nitroquinoline (Compound 2), 22 g, with a yield of 86%. The H NMR spectrum of 7-chloro-8-nitroquinoline is as follows: Figure 2 shown.
[0040] 1 H NMR (400MHz, DMSO-d6): δ9.06(d,J=2.8Hz,1H),8.63(dd,J=8.4,1.2Hz,1H),8.32(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,1H),7.78(dd,J=8.4,4.0Hz,1H).
[0041] (2) Preparation of 8-nitro-7-vinylquinoline
[0042] 7-Chloro-8-nitroquinoline (Compound 2) (10 g, 0.048 mol) and K3PO4 (20.4 g, 0.096 mol) were dissolved in a mixture of 1,4-dioxane (100 mL) and H2O (25 mL). Vinylboronic acid pinacol ester (14.8 g, 0.096 mol) and XPhos Pd G2 (1 g, 1.27 mmol) were added in a N2 atmosphere and stirred at 100°C for 8 h. The mixture was extracted with EA (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE / EA=5 / 1 to 3 / 1) to obtain 8-nitro-7-vinylquinoline (Compound 3) as a white solid, 5.4 g, with a yield of 56%. The H NMR spectrum of 8-nitro-7-vinylquinoline is as follows: Figure 3 shown.
[0043] 1 H NMR (400MHz, CDCl3): δ8.98 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8. 8Hz,1H),7.50(dd,J=8.0,4.0Hz,1H),6.88–6.81(m,1H),6.06(d,J=17.6Hz,1H),5.67(d,J=10.8Hz,1H).
[0044] (3) Preparation of 7-ethylquinolin-8-amine
[0045] Pd / C (0.54 g, mass percentage of Pd is 10 wt%) was added to a solution of 8-nitro-7-vinylquinoline (compound 3) (5.4 g, 0.027 mol) in MeOH (54 mL). The mixture was hydrogenated under H2 atmosphere and stirred at room temperature overnight. After filtering the mixture on diatomaceous earth, the solvent was removed under reduced pressure to obtain 7-ethylquinoline-8-amine (compound 4) as a red oily yellow solid, 4.2 g, yield 90%. The H NMR spectrum of 7-ethylquinoline-8-amine is as follows Figure 4 shown.
[0046] 1 H NMR (400MHz, CDCl3) δ8.75 (dd, J=4.4, 1.6Hz, 1H), 8.05 (dd, J=8.0, 1.6Hz, 1H), 7.34–7.30 (m, 2H),7.16(d,J=8.4Hz,1H),4.96(s,2H),2.73(dd,J=14.8,7.2Hz,2H),1.33(t,J=7.6Hz,3H).
[0047] Example 2
[0048] A method for preparing ethylquinoline-8-amine comprises the following steps:
[0049] (1) Preparation of 7-chloro-8-nitroquinoline
[0050] Carefully mix concentrated nitric acid (60 mL, 63%) and concentrated sulfuric acid (60 mL, 98%) at -10°C, then add 7-chloroquinoline (Compound 1) (20 g, 0.12 mol) at the same temperature. After complete addition, warm the mixture to room temperature and stir for 2 h. Pour the reaction mixture into ice water to precipitate a white solid, which is filtered and the filter cake is washed with water to obtain 7-chloro-8-nitroquinoline (Compound 2) as a white solid, 23 g, with a yield of 90%. 1 H NMR (400MHz, DMSO-d6): δ9.06(d,J=2.8Hz,1H),8.63(dd,J=8.4,1.2Hz,1H),8.32(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,1H),7.78(dd,J=8.4,4.0Hz,1H).
[0051] (2) Preparation of 8-nitro-7-vinylquinoline
[0052] 7-Chloro-8-nitroquinoline (Compound 2) (10 g, 0.048 mol) and K3PO4 (25.4 g, 0.12 mol) were dissolved in a mixture of 1,4-dioxane (100 mL) and H2O (25 mL). Vinylboronic acid pinacol ester (14.8 g, 0.096 mol) and XPhos Pd G2 (1.5 g, 1.91 mmol) were added in a N2 atmosphere and stirred at 100°C for 8 h. The mixture was extracted with EA (3 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain 8-nitro-7-vinylquinoline (Compound 3) as a white solid, 6 g, with a yield of 62%.
[0053] 1 H NMR (400MHz, CDCl3): δ8.98 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8. 8Hz,1H),7.50(dd,J=8.0,4.0Hz,1H),6.88–6.81(m,1H),6.06(d,J=17.6Hz,1H),5.67(d,J=10.8Hz,1H).
[0054] (3) Preparation of 7-ethylquinolin-8-amine
[0055] Pd / C (0.81 g, mass percentage of Pd is 10 wt%) was added to a solution of 8-nitro-7-vinylquinoline (compound 3) (5.4 g, 0.027 mol) in MeOH (36 mL). The mixture was hydrogenated under H2 atmosphere and stirred at room temperature for 4 h. After filtering the mixture on diatomaceous earth, the solvent was removed under reduced pressure to obtain red oily 7-ethylquinoline-8-amine (compound 4), yellow solid, 4.1 g, yield 88%.
[0056] 1 H NMR (400MHz, CDCl3) δ8.75 (dd, J=4.4, 1.6Hz, 1H), 8.05 (dd, J=8.0, 1.6Hz, 1H), 7.34–7.30 (m, 2H),7.16(d,J=8.4Hz,1H),4.96(s,2H),2.73(dd,J=14.8,7.2Hz,2H),1.33(t,J=7.6Hz,3H).
[0057] Example 3
[0058] A method for preparing ethylquinoline-8-amine comprises the following steps:
[0059] (1) Preparation of 7-chloro-8-nitroquinoline
[0060] Carefully mix concentrated nitric acid (80 mL, 63%) and concentrated sulfuric acid (40 mL, 98%) at -10°C, then add 7-chloroquinoline (Compound 1) (20 g, 0.12 mol) at the same temperature. After complete addition, warm the mixture to room temperature and stir for 1 h. Pour the reaction mixture into ice water to precipitate a white solid, which is filtered and the filter cake is washed with water to obtain 7-chloro-8-nitroquinoline (Compound 2) as a white solid, 24 g, with a yield of 94%.
[0061] 1 H NMR (400MHz, DMSO-d6): δ9.06(d,J=2.8Hz,1H),8.63(dd,J=8.4,1.2Hz,1H),8.32(d,J=8.8Hz,1H),7.94(d,J=8.8Hz,1H),7.78(dd,J=8.4,4.0Hz,1H).
[0062] (2) Preparation of 8-nitro-7-vinylquinoline
[0063] 7-Chloro-8-nitroquinoline (Compound 2) (10 g, 0.048 mol) and K3PO4 (30.5 g, 0.14 mol) were dissolved in a mixture of 1,4-dioxane (100 mL) and H2O (25 mL). Vinylboronic acid pinacol ester (14.8 g, 0.096 mol) and XPhos Pd G2 (2 g, 2.54 mmol) were added in a N2 atmosphere and stirred at 100°C for 8 h. The mixture was extracted with EA (3 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain 8-nitro-7-vinylquinoline (Compound 3) as a white solid, 6.7 g, with a yield of 70%.
[0064] 1 H NMR (400MHz, CDCl3): δ8.98 (d, J = 3.2 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8. 8Hz,1H),7.50(dd,J=8.0,4.0Hz,1H),6.88–6.81(m,1H),6.06(d,J=17.6Hz,1H),5.67(d,J=10.8Hz,1H).
[0065] (3) Preparation of 7-ethylquinolin-8-amine
[0066] Pd / C (1.08 g, mass percentage of Pd is 10 wt%) was added to a solution of 8-nitro-7-vinylquinoline (compound 3) (5.4 g, 0.027 mol) in MeOH (27 mL). The mixture was hydrogenated under H2 atmosphere and stirred at room temperature for 1 h. After filtering the mixture on diatomaceous earth, the solvent was removed under reduced pressure to obtain 7-ethylquinoline-8-amine (compound 4) as a red oily yellow solid, 4.2 g, with a yield of 90%.
[0067] 1 H NMR (400MHz, CDCl3) δ8.75 (dd, J=4.4, 1.6Hz, 1H), 8.05 (dd, J=8.0, 1.6Hz, 1H), 7.34–7.30 (m, 2H),7.16(d,J=8.4Hz,1H),4.96(s,2H),2.73(dd,J=14.8,7.2Hz,2H),1.33(t,J=7.6Hz,3H).
[0068] Comparative Example 1
[0069] A method for preparing ethylquinoline-8-amine is carried out according to the following process:
[0070]
[0071] The steps include:
[0072] (1) 3-Ethylaniline 1 (10 g, 82.5 mmol), glycerol (11.4 g, 123.75 mmol), arsenic pentoxide (28.5 g, 123.75 mmol) and concentrated sulfuric acid (20 mL) were dissolved in N-methylpyrrolidone (200 mL), protected by nitrogen, heated to 130°C for overnight reaction, cooled to room temperature, filtered, the filtrate was washed with water, and extracted with EA (3×100 mL). The organic phases were combined, dried and spin-dried, and purified by column chromatography (PE / EA=5 / 1 to 3 / 1) to obtain 7-ethylquinoline (compound 2) as a yellow solid, 2.3 g, with a yield of 17.7%.
[0073] (2) Carefully mix fuming nitric acid (10 mL, 63%) and concentrated sulfuric acid (20 mL, 98%) at -10°C, then add 7-ethylquinoline (Compound 2) (3 g, 19.1 mmol) dropwise at the same temperature. After complete addition, warm the mixture to room temperature and stir for 1 h. Pour the reaction mixture into ice water to precipitate a white solid, which is filtered and the filter cake is washed with water to obtain 7-ethyl-8-nitroquinoline (Compound 3) as a white solid, 3.5 g, with a yield of 91%.
[0074] (3) Pd / C (1 g, 20 wt.%) was added to a solution of 7-ethyl-8-nitroquinoline (Compound 3) (5 g, 24.73 mmol) in MeOH (50 mL). The mixture was hydrogenated under H2 atmosphere and stirred at room temperature for 8 h. After filtering the mixture on diatomaceous earth, the solvent was removed under reduced pressure to obtain 7-ethylquinoline-8-amine (Compound 4) as a red oily yellow solid, 3.93 g, yield 92%.
[0075] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.
Claims
1. A method for preparing 7-ethylquinoline-8-amine, characterized in that: The preparation method is carried out according to the following process: The specific steps include: (1) Compound 2 is prepared by nitration reaction using compound 1 as the starting material; (2) Compound 2 is subjected to coupling reaction with vinylboronic acid pinacol ester to obtain compound 3; (3) Compound 3 is subjected to a hydrogenation reduction reaction to obtain compound 4, namely the 7-ethylquinolin-8-amine.
2. The preparation method according to claim 1, characterized in that: In step (1), the specific process of the nitration reaction is: First, add a concentrated strong acid solution to the reaction bottle, cool it to -5 to -10°C under nitrogen protection, add compound 1, and then heat it to room temperature to react for 1 to 3 hours; after the reaction is completed, cool it to 0 to 5°C, filter out the precipitated solid, wash it with water and dry it to obtain compound 2.
3. The preparation method according to claim 2, characterized in that: The concentrated strong acid solution is prepared by mixing concentrated nitric acid and concentrated sulfuric acid; the concentration of the concentrated nitric acid is ≥63%; the concentration of the concentrated sulfuric acid is 98%; the volume ratio of the concentrated nitric acid to the concentrated sulfuric acid is 1:0.5-2.
4. The preparation method according to claim 2, characterized in that: The concentration of the compound 1 in the concentrated strong acid solution is 1 mol / L.
5. The preparation method according to claim 1, characterized in that: In step (2), the specific process of the coupling reaction is: Compound 2 and a base are dissolved in solvent I, and vinylboronic acid pinacol ester and a palladium catalyst are added under nitrogen protection. After heating for reaction, the mixture is washed with water, extracted, dried and purified to obtain compound 3.
6. The preparation method according to claim 5, characterized in that: The base is potassium phosphate; the amount of the base is 2-3 equivalents of compound 2; the solvent I is a mixture of 1,4-dioxane and water, and the volume ratio of 1,4-dioxane to water is 4:1; the concentration of compound 2 in solvent I is 0.08 g / mL.
7. The preparation method according to claim 5, characterized in that: The amount of the vinylboronic acid pinacol ester used is 2 equivalents of compound 2; the palladium catalyst is Xphos-Pd-G2; the amount of the palladium catalyst used is 10%-20% of the mass of compound 2; the reaction temperature is 100° C. and the reaction time is 8 hours.
8. The preparation method according to claim 1, characterized in that: In step (3), the specific process of the hydrogenation reduction reaction is: Compound 3 is dissolved in solvent II, a catalyst is added, and the mixture is reacted under a hydrogen atmosphere. After the reaction is completed, the mixture is filtered and concentrated to obtain the 7-ethylquinolin-8-amine.
9. The preparation method according to claim 8, characterized in that: The solvent II is selected from at least one of methanol and ethanol; the concentration of the compound 3 in the solvent II is 0.1-0.2 g / mL; the catalyst is palladium carbon; the amount of the catalyst is 10-20% of the mass of the compound 3.
10. The preparation method according to claim 8, characterized in that: The reaction temperature is room temperature and the reaction time is 3-8 hours.